ArticleLiterature Review

Specific inflammatory condition in nucleus tractus solitarii of the SHR: Novel insight for neurogenic hypertension?

September 2008
Autonomic Neuroscience 142(1-2):25-31

September 2008
142(1-2):25-31

DOI:10.1016/j.autneu.2008.07.003

Source
PubMed

Authors:

Sabine Gouraud

International Christian University

Human essential hypertension is a complex polygenic trait with underlying genetic components that remain unknown. Since the brainstem structure--the nucleus of the solitary tract (NTS)--is a pivotal region for regulating the set-point of arterial pressure, we proposed a role for it in the development of primary hypertension. Using microarray and real-time RT-PCR, we have recently identified that some pro-inflammatory molecules, such as junctional adhesion molecule-1 (JAM-1; a leukocyte/platelet adhesion molecule), were over expressed in endothelial cells in the NTS of an animal model of human essential hypertension--the spontaneously hypertensive rat (SHR) compared to normotensive Wistar Kyoto rats (WKY). Adenoviral mediated over expression of JAM-1 in NTS of WKY rats produced both hypertension and localized leukocyte adherence to the microvasculature. With a known effect of leukocyte adhesion causing cytokine release, we predicted differences in the level of gene expression of cytokines in the NTS of SHR relative to WKY. Gene expression of monocyte chemoattractant protein-1 (MCP-1) was higher in the NTS of SHR while inter-leukin-6 (IL-6) was lower in the NTS of SHR compared to the WKY. Because both inflammatory molecules are known to affect neural functions, our data suggest that the microvasculature of NTS of the SHR exhibits a specific inflammatory state. We propose a new hypothesis that as a consequence of enhanced expression of leukocyte adhesion molecules within the microvasculature of NTS there is a specific inflammatory response that leads to cardiovascular autonomic dysfunction contributing to neurogenic hypertension.

Pathogenesis of Cognitive Dysfunction in Patients with Obstructive Sleep Apnea: A Hypothesis with Emphasis on the Nucleus Tractus Solitarius

Article

Full-text available

Jan 2012

Mak Daulatzai

OSA is characterized by the quintessential triad of intermittent apnea, hypoxia, and hypoxemia due to pharyngeal collapse. This paper highlights the upstream mechanisms that may trigger cognitive decline in OSA. Three interrelated steps underpin cognitive dysfunction in OSA patients. First, several risk factors upregulate peripheral inflammation; these crucial factors promote neuroinflammation, cerebrovascular endothelial dysfunction, and oxidative stress in OSA. Secondly, the neuroinflammation exerts negative impact globally on the CNS, and thirdly, important foci in the neocortex and brainstem are rendered inflamed and dysfunctional. A strong link is known to exist between neuroinflammation and neurodegeneration. A unique perspective delineated here underscores the importance of dysfunctional brainstem nuclei in etiopathogenesis of cognitive decline in OSA patients. Nucleus tractus solitarius (NTS) is the central integration hub for afferents from upper airway (somatosensory/gustatory), respiratory, gastrointestinal, cardiovascular (baroreceptor and chemoreceptor) and other systems. The NTS has an essential role in sympathetic and parasympathetic systems also; it projects to most key brain regions and modulates numerous physiological functions. Inflamed and dysfunctional NTS and other key brainstem nuclei may play a pivotal role in triggering memory and cognitive dysfunction in OSA. Attenuation of upstream factors and amelioration of the NTS dysfunction remain important challenges.

Excessive Leukotriene B4 in Nucleus Tractus Solitarii Is Prohypertensive in Spontaneously Hypertensive Rats

Article

Nov 2012
Hypertension

Inflammation within the brain stem microvasculature has been associated with chronic cardiovascular diseases. We found that the expression of several enzymes involved in arachidonic acid-leukotriene B4 (LTB4) production was altered in nucleus tractus solitarii (NTS) of spontaneously hypertensive rat (SHR). LTB4 produced from arachidonic acid by 5-lipoxygenase is a potent chemoattractant of leukocytes. Leukotriene B4-12-hydroxydehydrogenase (LTB4-12-HD), which degrades LTB4, was downregulated in SHR rats compared with that in Wistar-Kyoto rats. Quantitative real-time PCR revealed that LTB4-12-HD was reduced by 63% and 58% in the NTS of adult SHR and prehypertensive SHR, respectively, compared with that in age-matched Wistar-Kyoto rats (n=6). 5-lipoxygenase gene expression was upregulated in the NTS of SHR (≈50%; n=6). LTB4 levels were increased in the NTS of the SHR, (17%; n=10, P<0.05). LTB4 receptors BLT1 (but not BLT2) were expressed on astroglia in the NTS but not neurons or vessels. Microinjection of LTB4 into the NTS of Wistar-Kyoto rats increased both leukocyte adherence and arterial pressure for over 4 days (peak: +15 mm Hg; P<0.01). In contrast, blockade of NTS BLT1 receptors lowered blood pressure in the SHR (peak: -13 mm Hg; P<0.05) but not in Wistar-Kyoto rats. Thus, excessive amounts of LTB4 in NTS of SHR, possibly as a result of upregulation of 5-lipoxygenase and downregulation of LTB4-12-HD, can induce inflammation. Because blockade of NTS BLT1 receptors lowered arterial pressure in the SHR, their endogenous activity may contribute to the hypertensive state of this rodent model. Thus, inflammatory reactions in the brain stem are causally associated with neurogenic hypertension.

Neuroinflammation and oxidative stress in rostral ventrolateral medulla contribute to neurogenic hypertension induced by systemic inflammation

Article

Full-text available

Sep 2012
J NEUROINFLAMM

In addition to systemic inflammation, neuroinflammation in the brain, which enhances sympathetic drive, plays a significant role in cardiovascular diseases, including hypertension. Oxidative stress in rostral ventrolateral medulla (RVLM) that augments sympathetic outflow to blood vessels is involved in neural mechanism of hypertension. We investigated whether neuroinflammation and oxidative stress in RVLM contribute to hypertension following chronic systemic inflammation. In normotensive Sprague-Dawley rats, systemic inflammation was induced by infusion of Escherichia coli lipopolysaccharide (LPS) into the peritoneal cavity via an osmotic minipump. Systemic arterial pressure and heart rate were measured under conscious conditions by the non-invasive tail-cuff method. The level of the inflammatory markers in plasma or RVLM was analyzed by ELISA. Protein expression was evaluated by Western blot or immunohistochemistry. Tissue level of superoxide anion (O2·-) in RVLM was determined using the oxidation-sensitive fluorescent probe dihydroethidium. Pharmacological agents were delivered either via infusion into the cisterna magna with an osmotic minipump or microinjection bilaterally into RVLM. Intraperitoneal infusion of LPS (1.2 mg/kg/day) for 14 days promoted sustained hypertension and induced a significant increase in plasma level of C-reactive protein, tumor necrosis factor-α (TNF-α), or interleukin-1β (IL-1β). This LPS-induced systemic inflammation was accompanied by activation of microglia, augmentation of IL-1β, IL-6, or TNF-α protein expression, and O2·- production in RVLM, all of which were blunted by intracisternal infusion of a cycloxygenase-2 (COX-2) inhibitor, NS398; an inhibitor of microglial activation, minocycline; or a cytokine synthesis inhibitor, pentoxifylline. Neuroinflammation in RVLM was also associated with a COX-2-dependent downregulation of endothelial nitric oxide synthase and an upregulation of intercellular adhesion molecule-1. Finally, the LPS-promoted long-term pressor response and the reduction in expression of voltage-gated potassium channel, Kv4.3 in RVLM were antagonized by minocycline, NS398, pentoxifylline, or a superoxide dismutase mimetic, tempol, either infused into cisterna magna or microinjected bilaterally into RVLM. The same treatments, on the other hand, were ineffective against LPS-induced systemic inflammation. These results suggest that systemic inflammation activates microglia in RVLM to induce COX-2-dependent neuroinflammation that leads to an increase in O2·- production. The resultant oxidative stress in RVLM in turn mediates neurogenic hypertension.

Neuroinflammation and sympathetic overactivity: Mechanisms and implications in hypertension

Article

Jan 2018
AUTON NEUROSCI-BASIC

Essential hypertension is a multifactorial disorder with a strong genetic predisposition. Although anti-hypertensive medications have drastically reduced cardiovascular diseases mortality and morbidity rates, a significant percentage of hypertensive individuals currently on anti-hypertensive therapy, remain hypertensive. In spite of the emergence of transgenic animals and sophisticated tools to study the pathophysiology of hypertension, unraveling the causal mechanisms remains a challenge. Research on borderline hypertensive humans and/or prehypertensive rat models revealed an elevation in centrally-mediated sympathetic activity and a heightened neuroinflammatory state. Hyperactive brain renin angiotensin system (RAS), oxidative stress and neuroinflammation in brainstem cardiovascular centers and other brain regions are implicated as key factors in augmenting sympathetic activity in hypertension and other cardiovascular abnormalities. Angiotensin (Ang) II, the main RAS effector peptide, has been shown to trigger significant upsurges in pro-inflammatory cytokines and reactive oxygen species (ROS). Both microglial and astroglial cells, via a host of different mechanisms, contribute to pro-inflammatory states and ROS generation in the brain. Hence, it becomes essential to understand the impact of Ang II and neuroinflammatory mediators on the impairment of cardioregulatory centers in the brain, and to investigate the role of glia in Ang II-mediated sympathoexcitation. Understanding the mechanisms leading to an elevation in neuroinflammatory states, and the possible ways of counteracting it, could aid in devising better therapeutic strategies for the treatment of cardiovascular diseases and hypertension. This review primarily focuses on the molecular aspects of hypertension from a neuroinflammatory standpoint within brainstem cardiovascular centers.

Alerted microglia and the sympathetic nervous system: A novel form of microglia in the development of hypertension

Article

Nov 2015
RESP PHYSIOL NEUROBI

Altered neurotrophic factors expression profiles in the nucleus of the solitary tract of spontaneously hypertensive rats

Article

Oct 2015
ACTA PHYSIOL

Aim: Our previous findings suggest that the nucleus of the solitary tract (NTS), a pivotal region for regulating the set-point of arterial pressure, exhibits abnormal inflammation in pre-hypertensive and spontaneously hypertensive rats (SHRs), with elevated anti-apoptotic and low apoptotic factor levels compared with that of normotensive Wistar-Kyoto (WKY) rats. Whether this chronic condition affects neuronal growth and plasticity in the NTS remains unknown. To unveil the characteristics of the neurodevelopmental environment in the NTS of SHRs, we investigated the expression of neurotrophic factors transcripts in SHRs. Methods: RT(2) Profiler PCR Array targeting rat neurotrophins and their receptors was used to screen for differentially expressed transcripts in the NTS of SHRs compared to that of WKY rats. Protein expression and physiological functions of some of the differentially expressed transcripts were also studied. Results: Gene and protein expressions of glial cell line-derived neurotrophic factor family receptor alpha-3 (Gfrα-3) factor were both upregulated in the NTS of adult SHRs. Gene expressions of corticotropin releasing hormone binding protein (Crhbp), Interleukin-10 receptor alpha (Il10ra), and hypocretin (Hcrt) were downregulated in the NTS of adult SHRs. The Gfrα-3 transcript was increased and the Hcrt transcript was decreased in the NTS of young pre-hypertensive SHRs, suggesting that these profiles are not secondary to hypertension. Moreover, microinjection in the NTS of hypocretin-1 decreased blood pressure in adult SHRs. Conclusion: These results suggest that altered neurotrophic factors transcript profiles may affect the normal development and function of neuronal circuitry that regulates cardiovascular autonomic activity; thereby resulting in manifestations of neurogenic hypertension in SHRs. This article is protected by copyright. All rights reserved.

Neuroimmune Communication in Hypertension and Obesity: A new therapeutic angle?

Article

Full-text available

Feb 2013

Hypertension is an epidemic health concern and a major risk factor for the development of cardiovascular disease. Although there are available treatment strategies for hypertension, numerous hypertensive patients do not have their clinical symptoms under control and it is imperative that new avenues to treat or prevent high blood pressure in these patients are developed. It is well established that increases in sympathetic nervous system (SNS) outflow and enhanced renin-angiotensin system (RAS) activity are common features of hypertension and various pathological conditions that predispose individuals to hypertension. More recently, hypertension has also become recognized as an immune condition and accumulating evidence suggests that interactions between the RAS, SNS and immune systems play a role in blood pressure regulation. This review summarizes what is known about the interconnections between the RAS, SNS and immune systems in the neural regulation of blood pressure. Based on the reviewed studies, a model for RAS/neuroimmune interactions during hypertension is proposed and the therapeutic potential of targeting RAS/neuroimmune interactions in hypertensive patients is discussed. Special emphasis is placed on the applicability of the proposed model to obesity-related hypertension.

Peptide and Lipid Modulation of Glutamatergic Afferent Synaptic Transmission in the Solitary Tract Nucleus

Article

Full-text available

Jan 2012

The brainstem nucleus of the solitary tract (NTS) holds the first central neurons in major homeostatic reflex pathways. These homeostatic reflexes regulate and coordinate multiple organ systems from gastrointestinal to cardiopulmonary functions. The core of many of these pathways arise from cranial visceral afferent neurons that enter the brain as the solitary tract (ST) with more than two-thirds arising from the gastrointestinal system. About one quarter of ST afferents have myelinated axons but the majority are classed as unmyelinated C-fibers. All ST afferents release the fast neurotransmitter glutamate with remarkably similar, high-probability release characteristics. Second order NTS neurons receive surprisingly limited primary afferent information with one or two individual inputs converging on single second order NTS neurons. A- and C-fiber afferents never mix at NTS second order neurons. Many transmitters modify the basic glutamatergic excitatory postsynaptic current often by reducing glutamate release or interrupting terminal depolarization. Thus, a distinguishing feature of ST transmission is presynaptic expression of G-protein coupled receptors for peptides common to peripheral or forebrain (e.g., hypothalamus) neuron sources. Presynaptic receptors for angiotensin (AT1), vasopressin (V1a), oxytocin, opioid (MOR), ghrelin (GHSR1), and cholecystokinin differentially control glutamate release on particular subsets of neurons with most other ST afferents unaffected. Lastly, lipid-like signals are transduced by two key ST presynaptic receptors, the transient receptor potential vanilloid type 1 and the cannabinoid receptor that oppositely control glutamate release. Increasing evidence suggests that peripheral nervous signaling mechanisms are repurposed at central terminals to control excitation and are major sites of signal integration of peripheral and central inputs particularly from the hypothalamus.

Neurogenic Hypertension, the Blood–Brain Barrier, and the Potential Role of Targeted Nanotherapeutics

Article

Full-text available

Jan 2023
INT J MOL SCI

Hypertension is a major health concern globally. Elevated blood pressure, initiated and maintained by the brain, is defined as neurogenic hypertension (NH), which accounts for nearly half of all hypertension cases. A significant increase in angiotensin II-mediated sympathetic nervous system activity within the brain is known to be the key driving force behind NH. Blood pressure control in NH has been demonstrated through intracerebrovascular injection of agents that reduce the sympathetic influence on cardiac functions. However, traditional antihypertensive agents lack effective brain permeation, making NH management extremely challenging. Therefore, developing strategies that allow brain-targeted delivery of antihypertensives at the therapeutic level is crucial. Targeting nanotherapeutics have become popular in delivering therapeutics to hard-to-reach regions of the body, including the brain. Despite the frequent use of nanotherapeutics in other pathological conditions such as cancer, their use in hypertension has received very little attention. This review discusses the underlying pathophysiology and current management strategies for NH, as well as the potential role of targeted therapeutics in improving current treatment strategies.

Central α7 and α4β2 nicotinic acetylcholine receptors offset arterial baroreceptor dysfunction in endotoxic rats

Article

Full-text available

Sep 2022
N Schmied Arch Pharmacol

Cardiac autonomic neuropathy is a prominent feature of endotoxemia. Given the defensive role of the cholinergic pathway in inflammation, we assessed the roles of central homomeric α7 and heteromeric α4β2 nAChRs in arterial baroreceptor dysfunction caused by endotoxemia in rats. Endotoxemia was induced by i.v. administration of lipopolysaccharides (LPS, 10 mg/kg), and baroreflex activity was measured by the vasoactive method, which assesses reflex chronotropic responses to increments (phenylephrine, PE) or decrements (sodium nitroprusside, SNP) in blood pressure. Shifts caused by LPS in PE/SNP baroreflex curves and associated decreases in baroreflex sensitivity (BRS) were dose-dependently reversed by nicotine (25–100 μg/kg, i.v.). The nicotine effect disappeared after intracisternal administration of methyllycaconitine (MLA) or dihydro-β-erythroidine (DHβE), selective blockers of α7 and α4β2 receptors, respectively. The advantageous effect of nicotine on BRSPE was replicated in rats treated with PHA-543613 (α7-nAChR agonist) or 5-iodo-A-85380 (5IA, α4β2-nAChRs agonist) in dose-dependent fashions. Conversely, the depressed BRSSNP of endotoxic rats was improved after combined, but not individual, treatments with PHA and 5IA. Central α7 and α4β2 nAChR activation underlies the nicotine counteraction of arterial baroreflex dysfunction induced by endotoxemia. Moreover, the contribution of these receptors depends on the nature of the reflex chronotropic response (bradycardia vs. tachycardia).

CNS and peripheral immunity in cerebral ischemia: partition and interaction

Article

Jan 2021

Stroke elicits excessive immune activation in the injured brain tissue. This well-recognized neural inflammation in the brain is not just an intrinsic organ response but also a result of additional intricate interactions between infiltrating peripheral immune cells and the resident immune cells in the affected areas. Given that there is a finite number of immune cells in the organism at the time of stroke, the partitioned immune systems of the central nervous system (CNS) and periphery must appropriately distribute the limited pool of immune cells between the two domains, mounting a necessary post-stroke inflammatory response by supplying a sufficient number of immune cells into the brain while maintaining peripheral immunity. Stroke pathophysiology has mainly been neurocentric in focus, but understanding the distinct roles of the CNS and peripheral immunity in their concerted action against ischemic insults is crucial. This review will discuss stroke-induced influences of the peripheral immune system on CNS injury/repair and of neural inflammation on peripheral immunity, and how comorbidity influences each.

Treating the Network: Targeted inhibition of two specific microRNAs in the brainstem prevents the development of hypertension

Preprint

Mar 2020

We here test the concept that disease states may result not from a single cause but from small changes in a network that are collectively significant. We recently showed that development of hypertension (HTN) in the spontaneously hypertensive rat (SHR) model of human essential hypertension is accompanied by changes in microRNA expression levels in the brainstem tracking the development of HTN 1,2 . This led to the hypothesis that preventing the change in microRNA levels could prevent the development of HTN. We propose that hypertension emerges from a network that has been pushed out of a normotensive equilibrium into a compensatory, pathological state. We show that small perturbations in the gene regulatory networks in the brainstem by selectively blocking two microRNAs highlighted in our previous results, miR-135a and miR-376a, is sufficient to prevent development of hypertension in the SHR model. This effect appears driven by only modest changes in the expression of rate-limiting genes, many of which are targets of these miRNAs, suggesting that the combination of genes that are targeted in the network is responsible for the effect. The demonstration that hypertension is an emergent property of an underlying regulatory network suggests that a new treatment paradigm altogether is needed. One Sentence Summary A brief summary of the main result of your paper, without excessive jargon.

Glia and central cardiorespiratory pathology

Article

Aug 2018
AUTON NEUROSCI-BASIC

Respiration and blood pressure are primarily controlled by somatic and autonomic motor neurones, respectively. Central cardiorespiratory control is critical in moment-to-moment survival, but it also has a role in the development and maintenance of chronic pathological conditions such as hypertension. The glial cells of the brain are non-neuronal cells with metabolic, immune, and developmental functions. Recent evidence shows that glia play an active role in supporting and regulating the neuronal circuitry which drives the cardiorespiratory system. Here we will review the activities of two key types of glial cell, microglia and astrocytes, in assisting normal central cardiorespiratory control and in pathology.

Antihypertensive Treatment Fails to Control Blood Pressure During Exercise

Article

Jun 2018

Peter B. Raven

Effect of centrally acting angiotensin converting enzyme inhibitor on the exercise‐induced increases in muscle sympathetic nerve activity

Article

Feb 2018

Key points: The arterial baroreflex's operating point pressure is reset upwards and rightwards from rest in direct relation to the increases in dynamic exercise intensity. The intraneural pathways and signalling mechanisms that lead to upwards and rightwards resetting of the operating point pressure, and hence the increases in central sympathetic outflow during exercise, remain to be identified. We tested the hypothesis that the central production of angiotensin II during dynamic exercise mediates the increases in sympathetic outflow and, therefore, the arterial baroreflex operating point pressure resetting during acute and prolonged dynamic exercise. The results identify that perindopril, a centrally acting angiotensin converting enzyme inhibitor, markedly attenuates the central sympathetic outflow during acute and prolonged dynamic exercise. Abstract: We tested the hypothesis that the signalling mechanisms associated with the dynamic exercise intensity related increases in muscle sympathetic nerve activity (MSNA) and arterial baroreflex resetting during exercise are located within the central nervous system. Participants performed three randomly ordered trials of 70° upright back-supported dynamic leg cycling after ingestion of placebo and two different lipid soluble angiotensin converting enzyme inhibitors (ACEi): perindopril (high lipid solubility), captopril (low lipid solubility). Repeated measurements of whole venous blood (n = 8), MSNA (n = 7) and arterial blood pressures (n = 14) were obtained at rest and during an acute (SS1) and prolonged (SS2) bout of steady state dynamic exercise. Arterial baroreflex function curves were modelled at rest and during exercise. Peripheral venous superoxide concentrations measured by electron spin resonance spectroscopy were elevated during exercise and were not altered by ACEi at rest (P ≥ 0.4) or during exercise (P ≥ 0.3). Baseline MSNA and mean arterial pressure were unchanged at rest (P ≥ 0.1; P ≥ 0.8, respectively). However, during both SS1 and SS2, the centrally acting ACEi perindopril attenuated MSNA compared to captopril and the placebo (P < 0.05). Arterial pressures at the operating point and threshold pressures were decreased with perindopril from baseline to SS1 with no further changes in the operating point pressure during SS2 under all three conditions. These data suggest that centrally acting ACEi is significantly more effective at attenuating the increase in the acute and prolonged exercise-induced increases in MSNA.

Anti-Inflammatory Effects of Melatonin in Obesity and Hypertension

Article

Full-text available

May 2018
Curr Hypertens Rep

Purpose of review: Here, we review the known relations between hypertension and obesity to inflammation and postulate the endogenous protective effect of melatonin and its potential as a therapeutic agent. We will describe the multiple effects of melatonin on blood pressure, adiposity, body weight, and focus on mitochondrial-related anti-inflammatory and antioxidant protective effects. Recent findings: Hypertension and obesity are usually associated with systemic and tissular inflammation. The progressive affection of target-organs involves multiple mediators of inflammation, most of them redundant, which make anti-inflammatory strategies ineffective. Melatonin reduces blood pressure, body weight, and inflammation. The mechanisms of action of this ancient molecule of protection involve multiple levels of action, from subcellular to intercellular. Mitochondria is a key inflammatory element in vascular and adipose tissue and a potential pharmacological target. Melatonin protects against mitochondrial dysfunction. Melatonin reduces blood pressure and adipose tissue dysfunction by multiple anti-inflammatory/antioxidant actions and provides potent protection against mitochondria-mediated injury in hypertension and obesity. This inexpensive and multitarget molecule has great therapeutic potential against both epidemic diseases.

Impact of melatonin on central blood pressure regulation

Article

Full-text available

Jan 2016

The dysbalance between the sympathetic and parasympathetic vegetative system and increased free radical burden in the central nervous system (CNS) are the important pathophysiological disorders and therapeutic targets in hypertension. Besides the effects on cardiovascular system, the pineal hormone, melatonin (N-acetyl-5-methoxytryptamine) may exert part of its antihypertensive action just through its interaction with the CNS. Melatonin may be protective in CNS on several different levels: it reduces production of reactive oxygen species, improves endothelial dysfunction, reduces inflammation and shifts the balance between the sympathetic and parasympathetic system in favor of the parasympathetic system. Increased level of serum melatonin observed in some types of hypertension may represent a counterregulatory adaptive mechanism against the sympathetic overstimulation. All these effects of melatonin may include increased production of nitric oxide in their mechanisms of protection. In different experimental models of hypertension upregulation of nitric oxide synthase (NOS) activity and NOS isoform expression in different parts of brain after melatonin treatment have been documented. Thus, it is supposed that the correction of absolute or relative melatonin deficiency by exogenous melatonin administration in conditions of increased blood pressure, may help to attenuate the excessive catecholamine outflow providing a rational background for therapeutic application of melatonin in hypertension treatment.

Targeting the pro-inflammatory factor CCL2 (MCP-1) with Bindarit for influenza A (H7N9) treatment

Article

Full-text available

Mar 2017

Influenza A viruses are important human and animal pathogens. Seasonal influenza viruses cause infections every year, and occasionally zoonotic viruses emerge to cause pandemics with significantly higher morbidity and mortality rates. Three cases of laboratory confirmed human infection with avian influenza A (H7N9) virus were reported in 2013, and there have been several cases reported across South East Asia, and recently in North America. Most patients experience severe respiratory illness, with mortality rates approaching 40%. No vaccine is currently available and the use of antivirals is complicated due to the emergence of drug resistant strains. Thus, there is a need to identify new drugs for therapeutic intervention and disease control. In humans, following H7N9 infection, there is excessive expression of pro-inflammatory factors CCL2, IL-6, IL-8, IFNα, interferon-γ, IP-10, MIG and macrophage inflammatory protein-1β, which has been shown to contribute to fatal disease outcomes in mouse models of infection. In the current study, the potent inhibitor of CCL2 synthesis, Bindarit, was examined as a countermeasure for H7N9-induced inflammation in a mouse model. Bindarit treatment of mice did not have any substantial therapeutic efficacy in H7N9 infection. Consequently, the results suggest that Bindarit may be ill-advised in the treatment of influenza H7N9 infection.

Heterologous Regulation of the Cannabinoid Type 1 Receptor by Angiotensin II in Astrocytes of Spontaneously Hypertensive Rats

Article

Full-text available

Aug 2016

Brainstem and cerebellar astrocytes have critical roles to play in hypertension and attention‐deficit hyperactivity disorder, respectively. Angiotensin (Ang) II , via the astroglial Ang type 1 receptor ( AT 1R), has been demonstrated to elevate pro‐inflammatory mediators in the brainstem and the cerebellum. The activation of astroglial cannabinoid type 1 receptor ( CB 1R), a master regulator of homeostasis, has been shown to neutralize inflammatory states. Factors that drive disease progression are known to alter the expression of CB 1Rs. In this study, we investigated the role of Ang II in regulating CB 1R protein and mRNA expression in astrocytes isolated from the brainstem and the cerebellum of spontaneously hypertensive rats ( SHR s). The results were then compared with their normotensive counterpart, Wistar rats. Not only was the basal expression of CB 1R protein and mRNA significantly lower in SHR brainstem astrocytes, but treatment with Ang II resulted in lowering it further in the initial 12 h. In the case of cerebellum, Ang II up‐regulated the CB 1R protein and mRNA in SHR astrocytes. While the effect of Ang II on CB 1R protein was predominantly mediated via the AT 1R in SHR brainstem; both AT 1R‐ and AT 2R‐mediated Ang II 's effect in the SHR cerebellum. These data are strongly indicative of a potential new mode of cross‐talk between components of the renin angiotensin system and the endocannabinoid system in astrocytes. The consequence of such a cross‐talk could be a potential reduced endocannabinoid tone in brainstem in hypertensive states, but not in the cerebellum under the same conditions. image

Microglia and Monocyte-Derived Macrophages in Stroke

Article

Aug 2016

Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood–brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood–brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

Microglial number is related to the number of tyrosine hydroxylase neurons in SHR and normotensive rats

Article

May 2016

Microglia are ubiquitously distributed throughout the central nervous system (CNS) and play a critical role in the maintenance of neuronal homeostasis. Recent advances have shown that microglia, never resting cells of the CNS, continuously monitor and influence neuronal/ synaptic activity levels, by communicating with neurons with the aid of their dynamic processes. The brainstem contains many catecholaminergic nuclei that are key to many aspects of brain function. This includes C1 neurons of the ventrolateral medulla that are thought to play a critical role in control of the circulation. Despite the role of catecholaminergic brainstem neurons in normal physiology, the presence of microglia that surrounds them is poorly understood. Here, we investigate the spatial distribution and morphology of microglia in catecholaminergic nuclei of the brainstem in 3 strains of rat: Sprague-Dawley (SD), Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Our data reveal that microglia are heterogeneously distributed within and across different strains of rats. Interestingly, intra-strain comparison of tyrosine hydroxylase-immunoreactive (TH-ir) neuronal and microglial number reveals that microglial number varies with the TH-ir neuronal number in the brainstem. Even though microglial spatial distribution varies across brainstem nuclei, microglial morphology (% area covered, number of end processes and branch length) does not differ significantly. This work provides the first evidence that even though microglia, in their surveilling state, do not vary appreciably in their morphology across brainstem areas, they do have a heterogeneous pattern of distribution that may be influenced by their local environment.

The Nucleus of the Solitary Tract: Processing Information from Viscerosensory Afferents

Article

Apr 2011

The nucleus of the solitary tract (NTS) is the first location within the central nervous system for the integration and modulation of cardiovascular afferent as well as other viscerosensory input. The NTS is therefore a pivotal structure for maintaining homeostasis. This chapter examines the fundamental cellular and molecular building blocks of NTS pathways. It discusses NTS neurotransmitters, (glutamate and ϒ-amino-butyric acid, GABA) and the baroreceptor reflex, the mechanisms regulating afferent information transfer to sites beyond the NTS and the mechanisms by which two major modulators, angiotensin II and nitric oxide, transform afferent information related to cardiovascular regulation. Particular consideration is given to emerging views on the nature and role of heterogeneity in afferents and NTS neurons and their projection targets outside the NTS. The chapter also considers the impact of new signaling molecules in the endothelial interface between the bloodstream and brain on neural control of the circulation. © Oxford University Press, Inc. 2011, 1990. All rights reserved.

microRNA Network Changes in the Brainstem Underlie the Development of Hypertension

Article

Jun 2015
PHYSIOL GENOMICS

Hypertension is a major chronic disease whose molecular mechanisms remain poorly understood. We compared neuroanatomical patterns of microRNAs in the brainstem of the Spontaneous Hypertensive Rat (SHR) to the Wistar Kyoto Rat (WKY; control). We assayed 419 well-annotated microRNAs in the nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM), from SHR and WKY rats, during three main stages of hypertension development. Changes in microRNA expression were stage- and region-dependent, with a majority of SHR vs. WKY differential expression occurring at the hypertension onset stage in NTS versus at the prehypertension stage in RVLM. Our analysis identified 24 microRNAs showing time-dependent differential expression in SHR compared to WKY in at least one brain region. We predicted potential gene regulatory targets corresponding to catecholaminergic processes, neuroinflammation and neuromodulation using the miRWALK and RNA22 databases, and we tested those bioinformatics predictions using high-throughput qPCR to evaluate correlations of differential expression between the microRNAs and their predicted gene targets. We found a novel regulatory network motif consisting of microRNAs likely down-regulating a negative regulator of pro-hypertensive processes such as Angiotensin II (Ang II) signaling and leukotriene-based inflammation. Our results provide new evidence on the dynamics of microRNA expression in the development of hypertension and predictions of microRNA-mediated regulatory networks playing a region-dependent role in potentially altering brainstem cardiovascular control circuit function leading to the development of hypertension. Copyright © 2015, Physiological Genomics.

Peripheral and Central Effects of Melatonin on Blood Pressure Regulation

Article

Full-text available

Oct 2014
INT J MOL SCI

The pineal hormone, melatonin (N-acetyl-5-methoxytryptamine), shows potent receptor-dependent and -independent actions, which participate in blood pressure regulation. The antihypertensive effect of melatonin was demonstrated in experimental and clinical hypertension. Receptor-dependent effects are mediated predominantly through MT1 and MT2 G-protein coupled receptors. The pleiotropic receptor-independent effects of melatonin with a possible impact on blood pressure involve the reactive oxygen species (ROS) scavenging nature, activation and over-expression of several antioxidant enzymes or their protection from oxidative damage and the ability to increase the efficiency of the mitochondrial electron transport chain. Besides the interaction with the vascular system, this indolamine may exert part of its antihypertensive action through its interaction with the central nervous system (CNS). The imbalance between the sympathetic and parasympathetic vegetative system is an important pathophysiological disorder and therapeutic target in hypertension. Melatonin is protective in CNS on several different levels: It reduces free radical burden, improves endothelial dysfunction, reduces inflammation and shifts the balance between the sympathetic and parasympathetic system in favor of the parasympathetic system. The increased level of serum melatonin observed in some types of hypertension may be a counter-regulatory adaptive mechanism against the sympathetic overstimulation. Since melatonin acts favorably on different levels of hypertension, including organ protection and with minimal side effects, it could become regularly involved in the struggle against this widespread cardiovascular pathology.

The Nucleus of the Solitary Tract and the coordination of respiratory and sympathetic activities

Article

Full-text available

Jun 2014

It is well known that breathing introduces rhythmical oscillations in the heart rate and arterial pressure levels. Sympathetic oscillations coupled to the respiratory activity have been suggested as an important homeostatic mechanism optimizing tissue perfusion and blood gas uptake/delivery. This respiratory-sympathetic coupling is strengthened in conditions of blood gas challenges (hypoxia and hypercapnia) as a result of the synchronized activation of brainstem respiratory and sympathetic neurons, culminating with the emergence of entrained cardiovascular and respiratory reflex responses. Studies have proposed that the ventrolateral region of the medulla oblongata is a major site of synaptic interaction between respiratory and sympathetic neurons. However, other brainstem regions also play a relevant role in the patterning of respiratory and sympathetic motor outputs. Recent findings suggest that the neurons of the nucleus of the solitary tract (NTS), in the dorsal medulla, are essential for the processing and coordination of respiratory and sympathetic responses to hypoxia. The NTS is the first synaptic station of the cardiorespiratory afferent inputs, including peripheral chemoreceptors, baroreceptors and pulmonary stretch receptors. The synaptic profile of the NTS neurons receiving the excitatory drive from afferent inputs is complex and involves distinct neurotransmitters, including glutamate, ATP and acetylcholine. In the present review we discuss the role of the NTS circuitry in coordinating sympathetic and respiratory reflex responses. We also analyze the neuroplasticity of NTS neurons and their contribution for the development of cardiorespiratory dysfunctions, as observed in neurogenic hypertension, obstructive sleep apnea and metabolic disorders.

Obesity induces neuroinflammation mediated by altered expression of the renin-angiotensin system in mouse forebrain nuclei

Article

Sep 2014

Obesity is a widespread health concern that is associated with an increased prevalence of hypertension and cardiovascular disease. Both obesity and hypertension have independently been associated with increased levels of inflammatory cytokines and immune cells within specific brain regions, as well as increased activity of the renin-angiotensin system (RAS). To test the hypothesis that high-fat diet (HFD) induced obesity leads to an angiotensin-II (Ang-II)-dependent increase in inflammatory cells within specific forebrain regions that are important for cardiovascular regulation, we first assessed microglial activation, astrocyte activation, inflammation and RAS component gene expression within selected metabolic and cardiovascular control centers of the forebrain in adult male C57BL/6 mice given either a HFD or a low-fat diet (LFD) for 8 weeks. Subsequently, we assessed the necessity of the paraventricular nucleus of the hypothalamus (PVN) angiotensin type-1a (AT1a) receptor for these responses by using the Cre/lox system in mice to selectively delete the AT1a receptor from the PVN. These studies reveal that in addition to the arcuate nucleus of the hypothalamus (ARC), the PVN and the subfornical organ (SFO), two brain regions that are known to regulate blood pressure and energy balance, also initiate proinflammatory responses after the consumption of a diet high in fat. They further indicate that some, but not all, of these responses are reversed upon deletion of AT1a specifically within the PVN.

Blood Pressure Regulation XI: Overview and Future Research Directions

Article

Jan 2014
EUR J APPL PHYSIOL

While the importance of regulating arterial blood pressure within a 'normal' range is widely appreciated, the definition of 'normal' and the means by which humans and other species regulate blood pressure under various conditions remain hotly debated. The effects of diverse physiological, pathological and environmental challenges on blood pressure and the mechanisms that attempt to maintain it at an optimal level are reviewed and critically analyzed in a series of articles published in this themed issue of the European Journal of Applied Physiology. We summarize here the major points made in these reviews, with emphasis on unifying concepts of regulatory mechanisms and future directions for research.

The CCL2 Synthesis Inhibitor Bindarit Targets Cells of the Neurovascular Unit, and Suppresses Experimental Autoimmune Encephalomyelitis

Article

Full-text available

Jul 2012
J NEUROINFLAMM

Production of the chemokine CCL2 by cells of the neurovascular unit (NVU) drives critical aspects of neuroinflammation. Suppression of CCL2 therefore holds promise in treating neuroinflammatory disease. Accordingly, we sought to determine if the compound bindarit, which inhibits CCL2 synthesis, could repress the three NVU sources of CCL2 most commonly reported in neuroinflammation - astrocytes, microglia and brain microvascular endothelial cells (BMEC) - as well as modify the clinical course of neuroinflammatory disease. The effect of bindarit on CCL2 expression by cultured murine astrocytes, microglia and BMEC was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Bindarit action on mouse brain and spinal cord in vivo was similarly investigated by qRT-PCR following LPS injection in mice. And to further gauge the potential remedial effects of bindarit on neuroinflammatory disease, its impact on the clinical course of experimental autoimmune encephalomyelitis (EAE) in mice was also explored. Bindarit repressed CCL2 expression by all three cultured cells, and antagonized upregulated expression of CCL2 in both brain and spinal cord in vivo following LPS administration. Bindarit also significantly modified the course and severity of clinical EAE, diminished the incidence and onset of disease, and evidenced signs of disease reversal. Bindarit was effective in suppressing CCL2 expression by cultured NVU cells as well as brain and spinal cord tissue in vivo. It further modulated the course of clinical EAE in both preventative and therapeutic ways. Collectively, these results suggest that bindarit might prove an effective treatment for neuroinflammatory disease.

Anti-inflammatory interventions to mitigate the cardiovascular risk in metabolic syndrome

Chapter

Jan 2024

Dynamic dysregulation of transcriptomic networks in brainstem autonomic nuclei during hypertension development in the female spontaneously hypertensive rat

Article

Dec 2023

Neurogenic hypertension stems from an imbalance in autonomic function that shifts the central cardiovascular control circuits towards a state of dysfunction. Using the female spontaneously hypertensive rat (SHR) and the normotensive Wistar Kyoto (WKY) rat model, we compared the transcriptomic changes in three autonomic nuclei in the brainstem, the nucleus of the solitary tract (NTS), caudal ventrolateral medulla (CVLM), and rostral ventrolateral medulla (RVLM) in a time series at 8, 10, 12, 16, and 24 weeks of age, spanning the pre-hypertensive stage through extended chronic hypertension. RNAseq data was analyzed using an unbiased, dynamic pattern-based approach that uncovered a dominant and several subtle differential gene regulatory signatures. Our results showed a persistent dysregulation across all three autonomic nuclei regardless of the stage of hypertension development, as well as a cascade of transient dysregulation beginning in the RVLM at the pre-hypertensive stage that shifts towards the NTS at the hypertension onset. Genes that were persistently dysregulated were heavily enriched for immunological processes such as antigen processing and presentation, the adaptive immune response, and the complement system. Genes with transient dysregulation were also largely region specific and were annotated for processes that influence neuronal excitability such as synaptic vesicle release, neurotransmitter transport, and an array of neuropeptides and ion channels. Our results demonstrate that neurogenic hypertension is characterized by brainstem region-specific transcriptomic changes that are highly dynamic with significant gene regulatory changes occuring at the hypertension onset as a key time window for dysregulation of homeostatic processes across the autonomic control circuits.

Estradiol-dependent gene expression profile in the amygdala of young ovariectomized spontaneously hypertensive rats

Article

Jan 2022

Estrogen plays a role in cardiovascular functions, emotional health, and energy homeostasis via estrogen receptors expressed in the brain. The comorbid relationship between rising blood pressure, a decline in mood and motivation, and body weight gain after menopause, when estrogen levels drop, suggests that the same brain area(s) contributes to protection from all of these postmenopausal disorders. The amygdala, a major limbic system nucleus known to express high estrogen receptor levels, is involved in the regulation of such physiological and psychological responses. We hypothesized that elevated estrogen levels contribute to premenopausal characteristics by activating specific genes and pathways in the amygdala. We examined the effect of 1-month estradiol treatment on the gene expression profile in the amygdala of ovariectomized young adult female spontaneously hypertensive rats. Estradiol substitution significantly decreased blood pressure, prevented body weight gain, and enhanced the voluntary physical activity of ovariectomized rats. In the amygdala of ovariectomized rats, estradiol treatment downregulated the expression of genes associated with estrogen signaling, cholinergic synapse, dopaminergic synapse, and long-term depression pathways. These findings indicate that the transcriptomic characteristics of the amygdala may be involved in estrogen-dependent regulation of blood pressure, physical activity motivation, and body weight control in young adult female spontaneously hypertensive rats.

Contrasting Roles of Ang II and ACEA in the Regulation of IL10 and IL1β Gene Expression in Primary SHR Astroglial Cultures

Article

Full-text available

May 2021
MOLECULES

Angiotensin (Ang) II is well-known to have potent pro-oxidant and pro-inflammatory effects in the brain. Extensive crosstalk between the primary Ang II receptor, Ang type 1 receptor (AT1R), and the cannabinoid type 1 receptor (CB1R) has been demonstrated by various groups in the last decade. Since activation of glial CB1R has been demonstrated to play a key role in the resolution of inflammatory states, we investigated the role of Ang II (100 nM) and/or ACEA (10 nM), a potent CB1R-specific agonist in the regulation of inflammatory markers in astrocytes from spontaneously hypertensive rats (SHR) and Wistar rats. Astrocytes were cultured from brainstems and cerebellums of SHR and Wistar rats and assayed for IL1β and IL10 gene expression and secreted fraction, in treated and non-treated cells, by employing qPCR and ELISA, respectively. mRNA expression of both IL10 and IL1β were significantly elevated in untreated brainstem and cerebellar astrocytes isolated from SHR when compared to Wistar astrocytes. No changes were observed in the secreted fraction. While ACEA-treatment resulted in a significant increase in IL10 gene expression in Wistar brainstem astrocytes (Log2FC ≥ 1, p < 0.05), its effect in SHR brainstem astrocytes was diminished. Ang II treatment resulted in a strong inhibitory effect on IL10 gene expression in astrocytes from both brain regions of SHR and Wistar rats (Log2FC ≤ −1, p < 0.05), and an increase in IL1β gene expression in brainstem astrocytes from both strains (Log2FC ≥ 1, p < 0.05). Co-treatment of Ang II and ACEA resulted in neutralization of Ang II-mediated effect in Wistar brainstem and cerebellar astrocytes, but not SHR astrocytes. Neither Ang II nor ACEA resulted in any significant changes in IL10 or IL1β secreted proteins. These data suggest that Ang II and ACEA have opposing roles in the regulation of inflammatory gene signature in astrocytes isolated from SHR and Wistar rats. This however does not translate into changes in their secreted fractions.

Androgenic modulation of arterial baroreceptor dysfunction and neuroinflammation in endotoxic male rats

Article

Feb 2021
BRAIN RES

Autonomic neuropathy contributes to cardiovascular derangements induced by endotoxemia. In this communication, we tested the hypothesis that androgenic hormones improve arterial baroreflex dysfunction and predisposing neuroinflammatory response caused by endotoxemia in male rats. Baroreflex curves relating changes in heart rate to increases or decreases in blood pressure evoked by phenylephrine (PE) and sodium nitroprusside (SNP), respectively, were constructed in conscious sham-operated, castrated, and testosterone-replaced castrated rats treated with or without lipopolysaccharide (LPS, 10 mg/kg i.v.). Slopes of baroreflex curves were taken as measures of baroreflex sensitivity (BRS). In sham rats, LPS significantly reduced reflex bradycardia (BRSPE) and tachycardia (BRSSNP) and increased immunohistochemical expression of nuclear factor kappa B (NFκB) in heart and brainstem neurons of nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM). The baroreflex depressant effect of LPS was maintained in castrated rats despite the remarkably attenuated inflammatory response. Testosterone replacement of castrated rats counteracted LPS-evoked BRSPE, but not BRSSNP, depression and increased cardiac, but not neuronal, NFκB expression. We also evaluated whether LPS responses could be affected following pharmacologic inhibition of androgenic biosynthetic pathways. Whereas none of LPS effects were altered in rats pretreated with formestane (aromatase inhibitor) or finasteride (5α-reductase inhibitor), the LPS-evoked BRSPE, but not BRSSNP, depression and cardiac and neuronal inflammation disappeared in rats pretreated with degarelix (gonadotropin-releasing hormone receptor blocker). Overall, despite the seemingly provocative role for the hypothalamic-pituitary-gonadal axis in the neuroinflammatory and baroreflex depressant effects of LPS, testosterone appears to distinctly modulate the two LPS effects.

Gut microbiota and neuroinflammation in pathogenesis of hypertension: A potential role for hydrogen sulfide

Article

Mar 2020

Nervus vagus

Book

Full-text available

Feb 2008

Boris Mravec

Experimentálne a klinické pozorovania, podobne ako aj voľnejšie úvahy a zamyslenia excelentných vedcov naznačujú, že silná vôľa, po- zitívny prístup k chorobe, viera, temperament a iné procesy súvisiace s činnosťou mozgu často zásadným spôsobom ovplyvňujú priebeh cho- rôb periférnych tkanív, ako aj účinnosť terapie. V tomto prípade má označenie „periférne tkaniváÿ zdôrazniť, že ide o choroby týkajúce sa tkanív mimo nervového systému. Ak je takýto predpoklad opodstatnený, alebo aj správny, tak sa vynárajú tri základné otázky: Ktoré mechanizmy umožňujú mozgu ovplyvňovať priebeh chorôb periférnych tkanív a úspešnosť ich liečby ? Sú to mechanizmy aktivovateľné vôľou, alebo pochody prebiehajúce na úrovni podvedomia ? Je možné využiť tieto mechanizmy aktívne pri liečbe chorôb ? V súčasnosti nie je možné na tieto otázky jednoznačne odpovedať. Experimentálne štúdie a klinické pozorovania z posledných desaťročí však poskytujú údaje, ktoré môžu pomôcť aspoň hľadať odpovede na tieto otázky. Pochopenie toho, akú úlohu má nervový systém pri vzniku a progresii chorôb periférnych tkanív môže umožniť tzv. neurobiologický pohľad na etiopatogenézu chorôb periférnych tkanív. Neurobiologický pohľad spočíva v predpoklade, že v procesoch spo- jených so vznikom a priebehom chorôb periférnych tkanív majú vý- znamnú úlohu aj interakcie medzi nervovým, endokrinným a imunitným systémom a bunkami tkanív postihnutých patologickým procesom. In- terakcie medzi nervovým, endokrinným a imunitným systémom prebie- hajú na viacerých úrovniach a vykazujú vysoký stupeň komplexnosti. Výmena signálnych molekúl medzi regulačnými systémami a bunkami tkanív podmieňuje to, že mozog je o prebiehajúcom patologickom pro- cese informovaný a následne môže jeho priebeh ovplyvňovať. Tento fakt je základom neurobiologického pohľadu na etiopatogenézu chorôb peri- férnych tkanív. Neurobiologický pohľad vedie k rozšíreniu spektra chorôb, v etiopa- togenéze ktorých sa predpokladá aj aktívna úloha nervového systému. Pritom často ide o choroby, pri ktorých sa v minulosti účasť nervového systému v ich etiopatogenéze nepredpokladala, alebo sa pokladala za málo významnú (napr. ateroskleróza, diabetes mellitus, nádorové cho- roby, sepsa). Predložený text je pokusom o priblíženie komplexnosti interakcií medzi nervovým, endokrinným a imunitným systémom s cieľom ná- sledne poukázať na význam úlohy nervového systému v etiopatogenéze chorôb periférnych tkanív. Pokusom je aj naša snaha definovať neuro- biológiu chorôb periférnych tkanív ako oblasť, ktorá umožňuje kom- plexný popis procesov súvisiacich s patologickým narušením činnosti periférnych tkanív. V tomto prípade by sme mohli z iného pohľadu chá- pať niektoré procesy, ktorých význam bol doteraz nejasný. Okrem toho predložený text naznačuje využitie neurobiologického pohľadu v diag- nostike a terapii viacerých chorôb periférnych tkanív. Na podklade ne- urobiologického pohľadu je možné pokúsiť sa odpovedať aj na otázky mechanizmov pôsobenia nepriamych terapeutických postupov, posúdiť možnosť liečby závažných chorôb látkami ovplyvňujúcimi synaptický prenos, ako aj naznačiť mechanizmy pôsobenia farmák, ktoré sa v sú- časnosti používajú. Považujeme za potrebné uviesť, že viacero údajov má skôr charakter hypotéz, ktoré vyžadujú exaktnú verifikáciu. Našim zámerom nie je ne- kritické preceňovanie úlohy nervového systému v etiopatogenéze chorôb periférnych tkanív. Na druhej strane je však potrebné brať do úvahy fakt, že etiopatogenéza chorôb je vysoko komplexný dej. Štúdium eti- opatogenetických mechanizmov výhradne na úrovni poškodeného tka- niva, zameranie sa výhradne na štúdium poruchy na úrovni vybraných molekulárnych dráh bez uvažovania o vplyve interakciímedzi nervovým, endokrinným a imunitným systémom a bunkami tkanív, v ktorých pre- bieha patologický proces, môže prinášať riziko „limitovanéhoÿ pohľadu, ktorý neumožňuje komplexne pochopiť sled patologických dejov, ktoré vedú k vzniku a progresii choroby. Podklad pre tvorbu publikácie tvoril výber prác z oblasti neuroimu- nológie, neurofyziológie, neuroanatómie a iných neurovedných a medi- cínskych disciplín, ako aj spoločné práce viacerých pracovníkov a autora tohto textu.

Proinflammatory Cytokines in the Nucleus of the Solitary Tract of Hypertensive Rats Exposed to Chronic Intermittent Hypoxia: New Directions and Translational Perspectives

Chapter

Jan 2018
ADV EXP MED BIOL

Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH), which is considered the main factor for developing hypertension. Sympathetic overflow, oxidative stress and inflammation have been associated with the CIH-induced hypertension. In rats exposed to CIH mimicking OSA, intermittent hypoxia enhanced carotid body (CB) chemosensory discharge, leading to an increase in arterial blood pressure in 3–5 days. In addition, CIH increases the CB levels of proinflammatory cytokines IL-1β, IL-6 and TNF-α in the CB. Proinflammatory molecules have been also involved in neurogenic hypertension acting on brain cardiovascular centers, like the nucleus of the solitary tract (NTS), which is the primary site for afferent CB inputs. Accordingly, we aim to study if proinflammatory cytokines in the NTS may play a role in the hypertension induced by CIH. Male Sprague-Dawley rats 250 g were exposed to CIH (5% O2, 12 times/h, 8 h/day) for 7–28 days. Brains were removed and processed to measure IL-1β, IL-6 and TNF-α in the NTS using qPCR and immunofluorescence. The mRNA levels were significantly augmented in the NTS of rats exposed during 21 days to CIH compared with control animals. In addition, a significant increase of IL-1β, IL-6 and TNF-α immunofluorescence was found in the NTS at day 28 of CIH exposure compared with control rats. Present results suggest that proinflammatory cytokines in the NTS may contribute to the maintenance of hypertension in CIH-exposed animals. © 2018, Springer International Publishing AG, part of Springer Nature.

Molecular basis of brain RAS in cardiovascular and neurological disorders: Uncovering a key role for the astroglial AT1R

Article

May 2018

The central renin angiotensin system (RAS) is one of the most widely investigated cardiovascular systems in the brain. It is implicated in a myriad of cardiovascular diseases. However, studies from the last decade have identified its involvement in several neurological abnormalities. Understanding the molecular functionality of the various RAS components can thus provide considerable insight into the phenotypic differences and mechanistic drivers of not just cardiovascular, but also neurological disorders. Since activation of one of its primary receptors, the angiotensin type-1 receptor (AT1R) results in an augmentation of oxidative stress and inflammatory cytokines, it becomes essential to investigate not just neuronal RAS, but also glial RAS as well. Glial cells are key homeostatic regulators in the brain, and are critical players in the resolution of overt oxidative stress and neuroinflammation. Designing better and effective therapeutic strategies that target the brain RAS, could well hinge on understanding the molecular basis of both neuronal and glial RAS. This review provides a comprehensive overview of the major studies that have investigated the mechanisms and regulation of brain RAS, and it also provides insight into the potential role of glial AT1Rs in the pathophysiology of cardiovascular and neurological disorders.

Trpv4 involvement in the gender differences in blood pressure regulation in spontaneously hypertensive rats

Article

Full-text available

Jan 2018

Arterial pressure (AP) is lower in pre-menopausal women than in men of a similar age. Pre-menopausal women exhibit a lower sympathetic outflow and a greater baroreceptor reflex; however, mechanisms for the gender differences in blood pressure regulation are still not well understood. We hypothesized that different neuronal functions in the cardiovascular centers in the brains of men and women could contribute to the gender difference in cardiovascular homeostasis. Our previous studies on male spontaneously hypertensive rats (SHRs) and their normotensive counterparts, Wistar Kyoto (WKY) rats, revealed that the gene expression profile of the nucleus tractus solitarius (NTS), a pivotal region of the medulla oblongata for regulating the set-point of AP, is strongly associated with the AP level. Thus, we hypothesized that gene expression profiles in the rat NTS are related to gender differences in AP regulation. Since female SHRs clearly exhibit lower AP levels than their male counterparts at a similar age, we investigated whether the NTS of SHRs exhibit gender differences in gene expression by using microarray and RT-qPCR experiments. The transcript for transient receptor potential cation channel subfamily V member 4 (Trpv4) was found to be upregulated in the NTS of SHR females compared with males. The channel was expressed in neurons and microglial cells within the NTS. The TRPV4 agonist 4 alpha-phorbol 12,13-didecanoate (4α-PDD) decreased blood pressure when injected into the NTS of rats. These findings suggest that altered TRPV4 expression might be involved in the gender differences in blood pressure.

Cues Guiding Leukocyte Transendothelial Migration across the Blood-Brain Barrier in Neuroinflammation: Endothelial Heterogeneity, Chemokines, and Extracellular Vesicles

Article

Aug 2015

Debayon Paul

Leukocyte infiltration into the central nervous system (CNS) underlies the pathology in a wide spectrum of neuroinflammatory and neurodegenerative diseases like multiple sclerosis (MS), stroke, meningitis, and neuroAIDS. While the steps that mediate the initial adhesion of activated leukocytes to the endothelial wall has been well-characterized, not much is known about their subsequent transendothelial migration (TEM) across the blood-brain barrier (BBB), a highly restrictive paracellular barrier established by the specialized CNS endothelial cells, thus severely limiting the treatment options. In Multiple Sclerosis (MS) ‘focal’ leukocyte infiltration into the CNS parenchyma early in disease is thought to be critical for the inflammatory response, and eventual neurodegeneration. Therefore, to explore the cues that regulate leukocyte TEM across the BBB in a neuroinflmmatory milieu, in this dissertation, we evaluated the role of three factors- endothelial heterogeneity, chemokine CCL2 from CNS sources, and extracellular vesicles (EVs) from endothelial cells containing a major tight-junction (TJ) protein, Claudin-5 (CLN-5), in CNS leukocyte infiltration, in an animal model of MS called Experimental Autoimmune Encephalomyelitis (EAE). Using a novel high-resolution three-dimensional confocal image analysis approach, existence of a functional heterogeneity in microvascular response was found during neuroinflammation in EAE. Specifically BBB damage and leukocyte extravasation in EAE was restricted to venules only. Furthermore, Chemokine CCL2, which only surges in a neuroinflammatory milieu to detectable levels and released predominantly from endothelium and astrocytes in the CNS, was shown to uniquely guide leukocytes across the 'respective' (endothelial and astrocyte) basement membranes. Interestingly, leukocytes invading the CNS early in EAE were found to be coated with TJ protein CLN-5. Brain microvascular endothelial cells (BMECs) were seen to release extracellular vesicles (EVs) in neuroinflammation that contained CLN-5, and could bind to the adherent leukocytes possibly for conveying the TJ protein cargo. These CLN-5+ leukocytes were found to transmigrate more efficiently across cultured BMECs. The obtained results from these studies have shed significant light on previously uncharacterized cues and mechanisms that guide circulating leukocytes across the BBB in disease, and holds the key for novel therapeutic strategies to treat a myriad of neurologic disorders and vasculopathies that display immune infiltration in the CNS.

Ascending CNS Progression of EAE: Linkage of Events at the Choroid Plexus and Spinal Cord

Article

Sep 2015

Bandana Shrestha

Dysfunction of the blood brain barrier (BBB), the specialized complex of cells situated at the central nervous system (CNS) microvasculature has been associated with numerous neuroinflammatory disorders like multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). BBB known to restrict passage of soluble and cellular elements between the blood and CNS is breached. The mechanism by which auto-reactive T cells cross the normally “impermeable” BBB, invade the initially naive CNS, and cause neuroinflammation, remains unclear. Recent studies suggest an initial route by which these cells first gain entry from circulating blood through the choroid plexus (CP). The permeable fenestrated capillaries of CP allow these sentinal T cells into the cerebrospinal fluid (CSF) across the surrounding tight junction expressing choroidal epithelium also known as the blood-CSF-barrier (BCSFB). Once into the CSF, these cells travel to the subarachnoid space (SAS) that surrounds the CNS parenchyma. Here, T cells are known to encounter their cognate antigen and set off a cytokine storm that propagates inflammation. The effects are first observed within the SAS in the meningeal vessels followed by activation of parenchymal inflammation. However, several critical questions in this scenario remain. First, how do these T cells cross the epithelium of the CP to enter the CSF? Does this involve changes in the tight junctional integrity between adjacent epithelial cells to allow leukocyte diapedesis? Second, once they enter the CSF, do these cells select a segment within the SAS to ignite the inflammatory sequence? Given the ascending inflammation within spinal cord segments in developing EAE (caudal to rostral), regional blood vessels in meninges and parenchyma might display unique vulnerabilities depending upon the segment of the spinal column in which they reside. Third, what links the inflammatory signals in the SAS to neuroinflammation in the parenchyma? Results obtained from this work show evidence towards the hypothesis that the ascending course of EAE is due to initial penetration of sentinal T cells through a structurally compromised CP choroidal epithelium, followed by a spinal segment-dependent relay of inflammatory signals between meningeal and parenchymal vessels.

Role of neurons and glia in the CNS actions of the renin-angiotensin system in cardiovascular control

Article

Jun 2015
AM J PHYSIOL-REG I

Despite tremendous research efforts, hypertension remains an epidemic health concern, leading often to the development of cardiovascular disease. It is well-established that in many instances, the brain plays an important role in the onset and progression of hypertension via activation of the sympathetic nervous system. Further, the activity of the renin angiotensin system (RAS) and of glial-mediated pro-inflammatory processes have independently been linked to this neural control and are, as a consequence, both attractive targets for the development of anti-hypertensive therapeutics. Although it is clear that the predominant effector peptide of the RAS, angiotensin-II, activates its type-1 receptor on neurons to mediate some of its hypertensive actions, additional nuances of this brain RAS control of blood pressure are constantly being uncovered. One of these complexities is that the RAS is now thought to impact cardiovascular control, in part, via facilitating a glial cell-dependent pro-inflammatory milieu within cardiovascular control centers. Another is that the newly-characterized antihypertensive limbs of the RAS are now recognized to, in many cases, antagonize the pro-hypertensive AT1R-mediated effects. That being said, the mechanism by which the RAS, glia and neurons interact to regulate blood pressure is an active area of ongoing research. Here we review the current understanding of these interactions and present a hypothetical model of how these exchanges may ultimately regulate cardiovascular function. Copyright © 2015, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.

Increased anti-apoptotic condition in the nucleus tractus solitarii of spontaneously hypertensive rats

Article

Aug 2009
AUTON NEUROSCI-BASIC

P7.22 Somatic stimulation reveals unique response patterns in different sympathetic nerves in the rat

Article

Aug 2009
AUTON NEUROSCI-BASIC

Gene expression profiles of major chemokines in the nucleus tractus solitarii of the spontaneously hypertensive rat

Article

Aug 2009
AUTON NEUROSCI-BASIC

New insights into central control mechanisms of circulation

Article

Nov 2008
AUTON NEUROSCI-BASIC

Animal Models for the Study of Neurohumeral and Central Neural Control of the Cardiovascular System

Article

Apr 2009

David R. Gross

Studies investigating the integrative central control of the locomotor and cardiovascular system have mostly been conducted in rats. These studies have shown that control of cardiovascular responses is located in neurons in close proximity, if not overlapping or possibly identical to, neurons responsible for respiratory and locomotor control. In rats cardiorespiratory and locomotor centers have been identified in the periaqueductal gray (PAG), posterior hypothalamic area (PHA), nucleus tractus solitarius (NTS), rostral ventrolateral medulla (rVLM), and the cuneiform nucleus (CnF). Of these, the PH has been clearly identified as both a locomotor and cardiovascular center.1 The CnF, with the pedunculopontine nucleus, has been identified as the mesencephalic locomotor center.2,3 The spinal cord and the lateral tegmental field (LTF) have been identified as integration sites for cardiorespiratory and locomotor responses.4 Interestingly, exercise training induced attenuation of dendritic fields of neurons in the exercising rat model.1

SHRSP/Izm and WKY/NCrlCrlj Rats Having a Missense Mutation in Abcg5 Deposited Plant Sterols in the Body, but Did Not Change Their Biliary Secretion and Lymphatic Absorption—Comparison with Jcl:Wistar and WKY/Izm Rats

Article

Apr 2012
BIOSCI BIOTECH BIOCH

We had previously found plant sterols deposited in the bodies of stroke-prone spontaneously hypertensive rats (SHRSP)/Sea and Wistar Kyoto (WKY)/NCrlCrlj rats that had a missense mutation in the Abcg5 cDNA sequence that coded for ATP-binding cassette transporter (ABC) G5. We used SHRSP/Izm, WKY/NCrlCrlj, and WKY/Izm rats in the present study to determine the mechanisms for plant sterol deposition in the body. Jcl:Wistar rats were used as a control strain. A diet containing 0.5% plant sterols fed to the rats resulted in plant sterol deposition in the body of SHRSP/Izm, but not in WKY/Izm or Jcl:Wistar rats. Only a single non-synonymous nucleotide change, G1747T, resulting in a conservative cysteine substitution for glycine at amino acid 583 (Gly583Cys) in Abcg5 cDNA was identified in the SHRSP/Izm and WKY/NCrlCrlj rats. However, this mutation was not found in the WKY/Izm or Jcl:Wistar rats. No significant difference in the biliary secretion or lymphatic absorption of plant sterols was apparent between the rat strains with or without the missense mutation in Abcg5 cDNA. Our observations suggest that plant sterol deposition in rat strains with the missense mutation in Abcg5 cDNA can occur, despite there being no significant change in the biliary secretion or lymphatic absorption of plant sterols.

Long-term blood pressure control: Is there a set-point in the brain?

Article

Feb 2012
J PHYSIOL SCI

Mean arterial pressure fluctuates depending on physical or psychological activity, but should be stable at rest at around 100 mmHg throughout an entire life in human. The causes of hypertension and the blood pressure regulation mechanisms have been discussed for a long time, and many aspects have recently become more clear. Circulatory shock or short-term hypotension can be treated based on what is now known, but chronic hypertension is still difficult to treat thoroughly. The exact mechanisms for long-term blood pressure regulation have yet not been elucidated. Neuro–humoral interaction has been suggested as one of the mechanisms. Then, from the 1990s, paracrine hormones like nitric oxide or endothelins have been extensively researched in order to develop endothelial local control mechanisms for blood pressure, which have some relationships to long-term control. Although these new ideas and mechanisms are newly developed, no clear explanation for long-term control has yet been discussed, except for renal abnormality. Recently, a central set-point theory has begun to be discussed. This review will discuss the mechanisms for long-term blood pressure control, based on putative biological missions of circulatory function for life support.

The effects of catalase inhibition into the fourth cerebral ventricle on the Bezold-Jarisch reflex in spontaneously hypertensive rats

Article

Jan 2012

Many studies have investigated the role of oxidative stress on cardiovascular system in the brainstem of spontaneously hypertensive rats (SHR). However, we do not know yet if catalase inhibition influences cardiopulmonary reflex (Bezol-Jarisch reflex). Thus, we aimed to evaluate the effects of central catalase inhibition on cardiopulmonary reflex in SHR. Males Wistar Kyoto (WKY) rats and SHR were implanted with a stainless steel guide cannula into the fourth cerebral ventricle (4th V). The femoral artery and vein were cannulated for mean arterial pressure (MAP) and heart rate (HR) measurement and drug infusion, respectively. The cardiopulmonary reflex was tested with phenylbiguanide (PBG, 8 mu g/kg, bolus, i.v.). Cardiopulmonary reflex was evaluated before and 15 minutes after 3-amino-1,2,4-triazole (ATZ, 0.01 g/ 100 mu L) injection into the 4th V. Vehicle treatment did not change basal MAP and HR and cardiopulmonary reflex responses in SHR and WKY rats. Central ATZ increased hypotensive (p = 0.038) responses without influencing the bradycardic reflex (p = 0.287) in WKY rats. In SHR, ATZ increased hypotension (p = 0.0004) and bradycardic (p = 0.04) responses to i.v. PBG. No changes were observed regarding basal MAP and HR after ATZ injection in SHR and WKY rats. We suggest central catalase inhibition affects cardiopulmonary reflex with more intensity in SHR compared to WKY rats.

Dysfunctional Nucleus Tractus Solitarius: Its Crucial Role in Promoting Neuropathogentic Cascade of Alzheimer’s Dementia—A Novel Hypothesis

Article

Jan 2012
NEUROCHEM RES

Mak Daulatzai

The pathophysiological mechanism(s) underlying Alzheimer's disease (AD) still remain unclear, and no disease-modifying or prophylactic therapies are currently available. Unraveling the fundamental neuropathogenesis of AD is an important challenge. Several studies on AD have suggested lesions in a number of CNS areas including the basal forebrain, hippocampus, entorhinal cortex, amygdale/insula, and the locus coeruleus. However, plausible unifying studies on the upstream factors that involve these heterogeneous regions and herald the onset of AD pathogenesis are not available. The current article presents a novel nucleus tractus solitarius (NTS) vector hypothesis that underpins several disparate biological mechanisms and neural circuits, and identifies relevant hallmarks of major presumptive causative factor(s) linked to the NTS, in older/aging individuals. Aging, obesity, infection, sleep apnea, smoking, neuropsychological states, and hypothermia-all activate inflammatory cytokines and oxidative stress. The synergistic impact of systemic proinflammatory mediators activates microglia and promotes neuroinflammation. Acutely, the innate immune response is protective defending against pathogens/toxins; however, when chronic, it causes neuroinflammation and neuronal dysfunction, particularly in brainstem and neocortex. The NTS in the brainstem is an essential multiple signaling hub, and an extremely important central integration site of baroreceptor, chemoreceptor, and a multitude of sensory afferents from gustatory, gastrointestinal, cardiac, pulmonary, and upper airway systems. Owing to persistent neuroinflammation, the dysfunctional NTS exerts deleterious impact on nucleus ambiguus, dorsal motor nucleus of vagus, hypoglossal, parabrachial, locus coeruleus and many key nuclei in the brainstem, and the hippocampus, entorhinal cortex, prefrontal cortex, amygdala, insula, and basal forebrain in the neocortex. The neuronal and synaptic dysfunction emanating from the inflamed NTS may affect its interconnected pathways impacting almost the entire CNS--which is already primed by neuroinflammation, thus promoting cognitive and neuropsychiatric symptoms. The upstream factors discussed here may underpin the neuropathopgenesis of AD. AD pathology is multifactorial; the current perspective underscores the value of attenuating disparate upstream factors--in conjunction with anticholinesterase, anti-inflammatory, immunosuppressive, and anti-oxidant pharmacotherapy. Amelioration of the NTS pathology may be of central importance in countering the neuropathological cascade of AD. The NTS, therefore, may be a potential target of novel therapeutic strategies.

Endothelial cell responses to hypoxia: Initiation of a cascade of cellular interactions

Article

Full-text available

Jul 2000
Biochim Biophys Acta

The origin of several vascular pathologies involves sudden or recurrent oxygen deficiency. In this review, we examine what the biochemical and molecular responses of the endothelial cells to the lack of oxygen are and how these responses may account for the features observed in pathological situations, mainly by modifications of cell–cell interactions. Two major responses of the endothelial cells have been observed depending on the degree and duration of the oxygen deficiency. Firstly, acute hypoxia rapidly activates the endothelial cells to release inflammatory mediators and growth factors. These inflammatory mediators are able to recruit and promote the adherence of neutrophils to the endothelium where they become activated. The synthesis of platelet-activating factor plays a key role in this adherence process. Secondly, longer periods of hypoxia increase the expression of specific genes such as those encoding some cytokines as well as for the growth factors platelet-derived growth factor and vascular endothelial growth factor. The transcriptional induction of these genes is mediated through the activation of several transcription factors, the most important one being hypoxia inducible factor-1. The link between our knowledge of the signalling cascade of the cellular and molecular events initiated by hypoxia and their involvement in several vascular pathological situations, varicose veins, tumor angiogenesis and pulmonary hypertension is discussed briefly.

Trends in the Prevalence, Awareness, Treatment, and Control of Hypertension in the Adult US Population : Data From the Health Examination Surveys, 1960 to 1991

Article

Full-text available

Aug 1995

The objective of this study was to describe secular trends in the distribution of blood pressure and prevalence of hypertension in US adults and changes in rates of awareness, treatment, and control of hypertension. The study design comprised nationally representative cross-sectional surveys with both an in-person interview and a medical examination that included blood pressure measurement. Between 6530 and 13,645 adults, aged 18 through 74 years, were examined in each of four separate national surveys during 1960-1962, 1971-1974, 1976-1980, and 1988-1991. Protocols for blood pressure measurement varied significantly across the surveys and are presented in detail. Between the first (1971-1974) and second (1976-1980) National Health and Nutrition Examination Surveys (NHANES I and NHANES II, respectively), age-adjusted prevalence of hypertension at > or = 160/95 mm Hg remained stable at approximately 20%. In NHANES III (1988-1991), it was 14.2%. Age-adjusted prevalence at > or = 140/90 mm Hg peaked at 36.3% in NHANES I and declined to 20.4% in NHANES III. Age-specific prevalence rates have decreased for every age-sex-race subgroup except for black men aged 50 and older. Age-adjusted mean systolic pressures declined progressively from 131 mm Hg at the NHANES I examination to 119 mm Hg at the NHANES III examination. The mean systolic and diastolic pressures of every sex-race subgroup declined between NHANES II and III (3 to 6 mm Hg systolic, 6 to 9 mm Hg diastolic). During the interval between NHANES II and III, the threshold for defining hypertension was changed from 160/95 to 140/90 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of platelet activation by a stimulatory antibody: Cross-linking of a novel platelet receptor for monoclonal antibody F11 with the FcγRII receptor

Article

Full-text available

Sep 1995

The mechanisms by which a stimulatory monoclonal antibody (mAb), called mAb F11, induces granular secretion and aggregation in human platelets have been characterized. Fab fragments of mAb F11, as well as an mAb directed against the platelet Fc gamma RII receptor (mAb IV.3) were found to inhibit mAb F11-induced platelet secretion and aggregation, indicating that the mAb F11 IgG molecule interacts with the Fc gamma RII receptor through its Fc domain and with its own antigen through its Fab domain. The mAb F11 recognized two platelet proteins of 32 and 35 kDa on the platelet membrane surface, as identified by Western blot analysis. We purified both proteins from human platelet membranes using DEAE-Sepharose chromatography followed by mAb F11 affinity chromatography. When added to platelet-rich plasma, the purified proteins dose-dependently inhibited mAb F11-induced platelet aggregation. The purified protein preparation also competitively inhibited the binding of 125I-labelled mAb F11 to intact platelets. The N-terminal 26 amino acid sequences of both the 32 and 35 kDa proteins were identical and contained a single unblocked serine in the N-terminal position. When digested with N-glycanase, the 32 and 35 kDa proteins were converted into a single approximately 29 kDa protein, indicating that these two proteins are derived from the same core protein but differ in their degree of glycosylation. Internal amino acid sequence analysis of the F11 antigen provided information concerning 68 amino acids and suggested two consensus phosphorylation sites for protein kinase C (PKC). The phosphorylation by PKC of the isolated F11 antigen was observed following stimulation by phorbol 12-myristate 13-acetate. Databank analysis of the N-terminal and internal amino acid sequences of the F11 antigen indicated that the N-terminal sequence exhibited the highest degree of similarity to the variable region of the alpha-chain of human T-cell receptors (TCR). In contrast, the F11 internal sequences did not exhibit any similarity to the TCR. Our results demonstrate that the F11 antigen is a novel platelet membrane surface glycoprotein which becomes cross-linked with the Fc gamma RII receptor when platelets are activated by the stimulatory mAb F11. These mechanisms may be relevant to the production of immune thrombocytopenia by platelet-activating antibodies.

Developmental Requirement of gp130 Signaling in Neuronal Survival and Astrocyte Differentiation

Article

Full-text available

Aug 1999

gp130 is a signal-transducing receptor component used in common by the interleukin-6 (IL-6) family of hematopoietic and neurotrophic cytokines, including IL-6, IL-11, leukemia-inhibitory factor, ciliary neurotrophic factor, oncostatin-M, and cardiotrophin-1. We have examined in this study a role of gp130 in the nervous system by analyzing developmental cell death of several neuronal populations and the differentiation of astrocytes in gp130-deficient mice. A significant reduction was observed in the number of sensory neurons in L5 dorsal root ganglia and motoneurons in the facial nucleus, the nucleus ambiguus, and the lumbar spinal cord in gp130 -/- mice on embryonic day 18.5. On the other hand, no significant neuronal loss was detectable on day 14.5, suggesting a physiological role of gp130 in supporting newly generated neurons during the late phase of development when naturally occurring cell death takes place. Moreover, expression of an astrocyte marker, GFAP, was severely reduced in the brain of gp130 -/- mice. Our data demonstrate that gp130 expression is essential for survival of subgroups of differentiated motor and sensory neurons and for the differentiation of major populations of astrocytes in vivo.

Leukocyte Recruitment in the Cerebrospinal Fluid of Mice with Experimental Meningitis Is Inhibited by an Antibody to Junctional Adhesion Molecule (Jam)

Article

Full-text available

Nov 1999
J EXP MED

The mechanisms that govern leukocyte transmigration through the endothelium are not yet fully defined. Junctional adhesion molecule (JAM) is a newly cloned member of the immunoglobulin superfamily which is selectively concentrated at tight junctions of endothelial and epithelial cells. A blocking monoclonal antibody (BV11 mAb) directed to JAM was able to inhibit monocyte transmigration through endothelial cells in in vitro and in vivo chemotaxis assays. In this study, we report that BV11 administration was able to attenuate cytokine-induced meningitis in mice. The intravenous injection of BV11 mAb significantly inhibited leukocyte accumulation in the cerebrospinal fluid and infiltration in the brain parenchyma. Blood-brain barrier permeability was also reduced by the mAb. We conclude that JAM may be a new target in limiting the inflammatory response that accompanies meningitis.

Raised human cartilage glycoprotein-39 plasma levels in patients with rheumatoid arthritis and other inflammatory conditions

Article

Full-text available

Aug 2000

To evaluate plasma human cartilage glycoprotein (HC gp-39) as a possible marker for the presence and/or activity of rheumatoid arthritis (RA) and other inflammatory conditions. HC gp-39 is a secretory product of chondrocytes, synovial cells, macrophages, and neutrophils. HC gp-39, also described as YKL-40, was found to be a marker of joint disease and tissue injury in RA and various other diseases. Levels of HC gp-39 were determined by a sandwich enzyme linked immunosorbent assay (ELISA) in 47 patients with RA, 47 with osteoarthritis (OA), 24 with systemic lupus erythematosus (SLE), 24 with inflammatory bowel disease (IBD), and in 47 healthy controls. A disease activity score was assessed in the patients with RA, SLE, and IBD. The plasma level of HC gp-39 in the RA patient group was significantly higher than in the other patient groups and healthy controls. The level in patients with OA, SLE, and IBD was also significantly higher than the HC gp-39 level found in the healthy control group. HC gp-39 levels in patients with RA correlated positively with the ESR and IgM rheumatoid factor level but not with other variables of disease activity. In the patients with SLE and IBD no correlation was found with the disease activity score. The plasma level of HC gp-39 is increased in inflammatory conditions with and without joint disease (SLE, IBD, OA, and RA). Thus increased levels of HC gp-39 do not only reflect joint disease but also reflect inflammation or tissue degradation in various conditions. Notably, the highest level of HC gp-39 was found in patients with RA. Only in the RA patient group was a correlation between HC gp-39 plasma levels and some laboratory variables of disease activity found.

Monocyte: Astrocyte interactions regulate MCP-1 expression in both cell types

Article

Full-text available

Nov 2000

As astrocytes are a source of monocyte chemoattractant protein-1 (MCP-1) and lie in close apposition to brain microvessels, interactions between astrocytes and infiltrating monocytes might regulate production of this chemokine. To investigate this possibility, a monocyte:astrocyte co-culture model was utilized to assess the respective roles of these two cell types in regulating MCP-1 production. Results indicate that, while neither monocytes nor astrocytes alone produce detectable levels of MCP-1, co-culture of these two cell types results in time-dependent production of this chemokine. Such production requires de novo protein synthesis and is dependent on physical contact between monocytes and astrocytes, involving engagement of the cell-adhesion molecules ICAM-1 and VCAM-1. Additionally, interleukin 1-beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are soluble mediators of this response. These findings imply that monocyte extravasation into the CNS may be critically regulated at the blood-brain barrier by specialized monocyte:astrocyte interactions.

Specific actions of cyanide on membrane potential and voltage-gated ion currents in rostral ventrolateral medulla neurons in rat brainstem slices

Article

Full-text available

Sep 2001
NEUROSCI LETT

The present study examined specific effects of sodium cyanide (CN) on the membrane potential (MP), spontaneous discharge (SD) and voltage-gated ion current of the identified bulbospinal rostral ventrolateral medulla (RVLM) neuron in the rat pup brainstem slice. 125 microM CN rapidly depolarized MP in the RVLM neuron by 11.6 mV as well as enhanced the SD rate by 300%. In contrast, the same dose of CN immediately hyperpolarized unlabeled, non-RVLM neurons by 4.8 mV. 50 microM CN did not significantly affect voltage-gated Ca(++) or A-type K(+) currents. The same concentration of CN, however, rapidly and reversibly suppressed voltage-gated Na(+) currents and sustained outward K(+) currents in the RVLM neuron by 22.5% and 23%, respectively. Tetraethylammonium could mimic the effect of CN on MP, SD and sustained K(+) current in the RVLM neuron. It is concluded that: (1) like that from the adult rat, the rat pup bulbospinal RVLM neuron can be selectively and rapidly excited by CN; (2) the hypoxia-sensitive, sustained outward K(+) channel may play an important role in the acute hypoxia-induced excitation of the RVLM neurons.

Hypoxia Diminishes Toll-Like Receptor 4 Expression Through Reactive Oxygen Species Generated by Mitochondria in Endothelial Cells

Article

Full-text available

Sep 2002

Hypoxia and inflammation often occur simultaneously due to prevention of adequate gas exchange. Understanding the influence of hypoxia on the inflammatory response is important because hypoxia directly regulates expression of many genes, including those regulating inflammation, and plays a role in modulating the resolution of an inflammatory response. LPS is a major mediator of cellular injury and inflammation that induces its effects through Toll-like receptor 4 (TLR4). The aim of this study was to evaluate the effect of hypoxia on TLR4 expression. Hypoxia decreased TLR4 expression on cultured endothelial cells. Furthermore, LPS-induced ICAM-1 up-regulation was decreased by hypoxia. Because reactive oxygen species (ROS) generated from mitochondria are one of the signaling molecules induced by hypoxia, the role of ROS in hypoxia-induced TLR4 down-regulation was evaluated. Our data showed that hypoxia increased ROS generation and that hypoxia-induced TLR4 down-regulation was inhibited by myxothiazol, a mitochondrial site III electron transport inhibitor. Hypoxia also inhibited AP-1 translocation. Since the TLR4 promoter has a binding site for AP-1, hypoxia-induced TLR4 down-regulation may be due to an ROS-mediated decrease in AP-1-binding activity. We conclude that hypoxia decreases TLR4 expression in endothelial cells and that this change is mediated by mitochondrial ROS leading to attenuation of AP-1 transcriptional activity.

Cardiovascular and renal sympathetic activation by blood-borne TNF-alpha in rat: the role of central prostaglandins

Article

Full-text available

May 2003

In pathophysiological conditions, increased blood-borne TNF-alpha induces a broad range of biological effects, including activation of the hypothalamic-pituitary-adrenal axis and sympathetic drive. In urethane-anesthetized adult Sprague-Dawley rats, we examined the mechanisms by which blood-borne TNF-alpha activates neurons in paraventricular nucleus (PVN) of hypothalamus and rostral ventrolateral medulla (RVLM), two critical brain regions regulating sympathetic drive in normal and pathophysiological conditions. TNF-alpha (0.5 microg/kg), administered intravenously or into ipsilateral carotid artery (ICA), activated PVN and RLVM neurons and increased sympathetic nerve activity, arterial pressure, and heart rate. Responses to intravenous TNF-alpha were not affected by vagotomy but were reduced by mid-collicular decerebration. Responses to ICA TNF-alpha were substantially reduced by injection of the cyclooxygenase inhibitor ketorolac (150 microg) into lateral ventricle. Injection of PGE(2) (50 ng) into lateral ventricle or directly into PVN increased PVN or RVLM activity, respectively, and sympathetic drive, with shorter onset latency than blood-borne TNF-alpha. These findings suggest that blood-borne cytokines stimulate cardiovascular and renal sympathetic responses via a prostaglandin-dependent mechanism operating at the hypothalamic level.

Neurogenic essential hypertension revisited: The case for increased clinical and research attention

Article

Full-text available

Nov 2003

Samuel Mann

The management of essential hypertension has increasingly focused on the use of diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, which lower blood pressure (BP) through effects on blood volume and on the renin-angiotensin system. However, in many individuals these agents, whether given alone or in combination, fail to normalize BP. In such cases it is likely that hypertension is at least partly maintained by pathophysiologic mechanisms other than volume and the renin-angiotensin system, and therefore, that pharmacotherapy directed at other mechanisms is needed. One such form of hypertension is the often overlooked entity of neurogenic hypertension. The purpose of this article is to renew attention to this overlooked entity, to provide a very clinically oriented overview of its possible causes and manifestations, and to discuss the potentially important treatment implications of recognizing this form of hypertension. These implications underscore the need for further clinical and research attention concerning neurogenically mediated hypertension.

Ebnet K, Suzuki A, Ohno S, Vestweber DJunctional adhesion molecules (JAMs): more molecules with dual functions? J Cell Sci 117:19-29

Article

Full-text available

Feb 2004

Junctional adhesion molecules (JAMs) are members of an immunoglobulin subfamily expressed by leukocytes and platelets as well as by epithelial and endothelial cells, in which they localize to cell-cell contacts and are specifically enriched at tight junctions. The recent identification of extracellular ligands and intracellular binding proteins for JAMs suggests two functions for JAMs. JAMs associate through their extracellular domains with the leukocyte beta2 integrins LFA-1 and Mac-1 as well as with the beta1 integrin alpha4beta1. All three integrins are involved in the regulation of leukocyte-endothelial cell interactions. Through their cytoplasmic domains, JAMs directly associate with various tight junction-associated proteins including ZO-1, AF-6, MUPP1 and the cell polarity protein PAR-3. PAR-3 is part of a ternary protein complex that contains PAR-3, atypical protein kinase C and PAR-6. This complex is highly conserved through evolution and is involved in the regulation of cell polarity in organisms from Caenorhabditis elegans and Drosophila to vertebrates. These findings point to dual functions for JAMs: they appear to regulate both leukocyte/platelet/endothelial cell interactions in the immune system and tight junction formation in epithelial and endothelial cells during the acquisition of cell polarity.

Gene expression profiles in the nucleus tractus solitarii of the spontaneously hypertensive rat: New hypothesis for a neurogenic mechanism of hypertension

Article

Jan 2006
NEUROSCI RES

Development of a strain spontaneously hypertensive rats

Article

Jan 1963

Gene expression profiles of major chemokines in the nucleus tractus solitarii of the spontaneously hypertensive rat

Article

Aug 2009
AUTON NEUROSCI-BASIC

Interleukin‐6 inhibits neurotransmitter release and the spread of excitation in the rat cerebral cortex

Article

Dec 2001
EUR J NEUROSCI

Cytokines are extracellular mediators that have been reported to affect neurotransmitter release and synaptic plasticity phenomena when applied in vitro. Most of these effects occur rapidly after the application of the cytokines and are presumably mediated through the activation of protein phosphorylation processes. While many cytokines have an inflammatory action, interleukin-6 (IL-6) has been found to have a neuroprotective effect against ischaemia lesions and glutamate excitotoxicity, and to increase neuronal survival in a variety of experimental conditions. In this paper, the functional effects of IL-6 on the spread of excitation visualized by dark-field/infrared videomicroscopy in rat cortical slices and on glutamate release from cortical synaptosomes were analysed and correlated with the activation of the STAT3, mitogen-activated protein kinase ERK (MAPK/ERK) and stress-activated protein kinase/cJun NH2-terminal kinase (SAPK/JNK) pathways. We have found that IL-6 depresses the spread of excitation and evoked glutamate release in the cerebral cortex, and that these effects are accompanied by a stimulation of STAT3 tyrosine phosphorylation, an inhibition of MAPK/ERK activity, a decreased phosphorylation of the presynaptic MAPK/ERK substrate synapsin I and no detectable effects on SAPK/JNK. The effects of IL-6 were effectively counteracted by treatment of the cortical slices with the tyrosine kinase inhibitor lavendustin A. The inhibitory effects of IL-6 on glutamate release and on the spread of excitation in the rat cerebral cortex indicate that the protective effect of IL-6 on neuronal survival could be mediated by a downregulation of neuronal activity, release of excitatory neurotransmitters and MAPK/ERK activity.

IL-6 and APPs: Anti-inflammatory and immunosuppressive mediators

Article

Oct 1997
Immunol Today

Acute inflammation is accompanied by changes in the concentrations of acute phase proteins (APPs), While much is known about the cytokines involved in the initiation of inflammation, less is known about the mediators involved in its resolution. Recent data suggest that interleukin 6 (IL-6) and IL-6-regulated APPs are anti-inflammatory and immuno-suppressive, and may negatively regulate the acute phase response.

Huber JD, Egleton RD, Davis TPMolecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci 24:719-725

Article

Jan 2002
TRENDS NEUROSCI

Disruption of the tight junctions (TJs) of the blood–brain barrier (BBB) is a hallmark of many CNS pathologies, including stroke, HIV encephalitis, Alzheimer's disease, multiple sclerosis and bacterial meningitis. Furthermore, systemic-derived inflammation has recently been shown to cause BBB tight junctional disruption and increased paracellular permeability. The BBB is capable of rapid modulation in response to physiological stimuli at the cytoskeletal level, which enables it to protect the brain parenchyma and maintain a homeostatic environment. By allowing the ‘loosening’ of TJs and an increase in paracellular permeability, the BBB is able to ‘bend without breaking’; thereby, maintaining structural integrity.

Blood pressure and heart rate development in young spontaneously hypertensive rats

Article

Mar 1998
Am J Physiol

The course of hypertension development in young spontaneously hypertensive rats (SHR) was studied by the measurement of changes in systolic blood pressure (BP), body weight, and heart rate (HR) at 2, 3, 4, and 6 wk of age. To achieve this, we compared inbreeding lines of SHR and Wistar-Kyoto rats (WKY) to determine if differences in BP, body weight, or HR were present among inbreeding lines of the same strain or between strains. The effect of these differences on the eventual level of BP was then assessed. We found that BP began to diverge between SHR and WKY at 4 wk of age. Significant differences in systolic BP (24 mmHg) between SHR inbreeding lines at 4 wk of age did not affect the BP at 8 wk (172 vs. 170 mmHg). Pulse pressure was significantly higher in SHR than in WKY at 4 wk of age. HR was elevated in SHR over age-matched WKY at 3 wk of age and positively correlated to the level of BP attained by individual animals at 6 wk (P = 0.037). Moreover, WKY inbreeding lines showing elevated HR developed higher BP (145 vs. 127 mmHg) at 10-12 and 20 wk of age. The prehypertensive tachycardia in SHR was investigated further and found to result from an increased intrinsic HR. Because HR at 3 wk is a genetic trait that can be partitioned into inbreeding lines, and inbreeding lines most expressive of this trait showed the highest eventual BP, we conclude that prehypertensive tachycardia may be an important first step during hypertension development in SHR. Moreover, early elevations in HR are highly predictive (r = 0.41) of hypertension occurrence in the animal population studied.

Gene expression profiles of major cytokines in the nucleus tractus solitarii of the spontaneously hypertensive rat

Article

Sep 2008

Since the nucleus of the solitary tract (NTS) is a pivotal region for regulating the set-point of arterial pressure, we proposed a role for it in the development of neurogenic hypertension. Recent studies have suggested that pro-inflammatory molecules are highly expressed in the NTS of an animal model of human essential hypertension--the spontaneously hypertensive rat (SHR), compared to normotensive Wistar-Kyoto rat (WKY). Based on this evidence, we hypothesized that inflammatory mediators such as cytokines are up-regulated in the hypertensive NTS. In the present study, we have assessed the level of gene expression of some cytokines in the NTS of SHR compared to WKY. In addition, for further confirmation of abnormal inflammatory condition within the NTS of SHR, we identified gene expression levels of an inflammatory marker, glycoprotein-39 (gp39) precursor, which is homologous to chitinase 3-like protein 1, human cartilage-gp39 or YKL40. The NTS was micro-dissected from 15-week-old male SHR and WKY rats. Total RNA was extracted and quantitative RT-PCR was performed. Gene expression of gp39 precursor and monocyte chemoattractant protein-1 were higher in the NTS of SHR while inter-leukin-6 was lower in the NTS of SHR compared to the WKY. In contrast, there were no significant differences in the expression of other cytokines including: inter-leukin-1 beta, tumor necrosis factor-alpha and transforming growth factor beta 1. These data together with our previous published finding of an over expression of junctional adhesion molecule-1 suggest that the NTS of the SHR exhibits a specific inflammatory state.

Arterial baroreceptor reflex control of sympathetic nerve activity in the spontaneously hypertensive rat

Article

Nov 1979

The combined and individual carotid sinus and aortic baroreceptor control of sympathetic nerve activity (SNA) and mean arterial pressure (MAP) were studied by direct measurement in groups of spontaneously hypertensive rats (SHR) and normotensive Kyoto Wistar rats (WKY) of 5 to 40 weeks of age. The SHR showed a significantly greater SNA and resultant MAP increase as a function of age compared to that of the WKY rats. Both SHR and WKY rats showed a significant rise in SNA and MAP with ablation of all four major baroreceptors. The proportionate change of SNA and MAP after ablation was greater in the younger SHR than in the younger WKY groups and the change in these decreased as a function of age in the SHR. The reflex inhibition of SNA via baroreceptor stimulation also decreased as a function of age in the SHR, due to a 43% loss of aortic inhibitory function; no significant loss of carotid sinus function was found in either the SHR or WKY. The decrement in aortic function occurred after the rapid phase of blood pressure development; therefore baroreceptor dysfunction cannot be the cause of the high SNA and MAP observed in young SHR. An upward resetting of central sympathetic centers was evaluated via the baroreceptor deafferentation; and it appears that the hyperactive sympathetic nervous system and resultant hypertension in the SHR is due to central resetting of sympathetic centers rather than baroreceptor dysfunction.

Neurogenic Mechanisms Initiating Essential Hypertension

Article

Jan 1990

Brent Egan

Evidence for increased sympathetic drive, as assessed both by measurements of plasma norepinephrine and by studies of tritiated norepinephrine kinetics, is most frequently obtained in young hypertensive patients. During the initial phases of hypertension, the increased sympathetic drive may persistently elevate arterial pressure through effects on the heart, the blood vessels, and the kidneys. In some patients, signs of a hyperkinetic circulation--including elevated heart rate and, less often, high cardiac output--predominate. In others, elevated vascular resistance, reflecting increased alpha-adrenergic tone, is the principal hemodynamic aberration. Even in patients with high cardiac output, a relative increase of vascular alpha-adrenergic tone accounts for their higher blood pressure. Increased sympathetic drive to the kidneys diminishes the efficiency of pressure diuresis, which is designed to restore normal arterial pressure. Although increased plasma norepinephrine levels are not consistently observed among older hypertensive patients compared with age-matched controls, neurogenic hypertension is not only a temporary event. In fact, tachycardia, which is neutrogenically mediated, doubles the risk of sustained hypertension later in life. The precise sequence of events in the transition from a principally neurogenic hypertension early in life to a predominantly nonneurogenic hypertension later in life is not known, although it likely includes decreased beta-receptor sensitivity with consequently reduced tachycardia and beta-mediated vasodilation. Functional diminution in endothelium-dependent vasodilation may augment sensitivity to vasoconstrictors such as norepinephrine and serotonin. Moreover, structural vascular changes nonspecifically enhance vascular reactivity to all vasoactive compounds and may provide a more permanent basis for altered pressure diuresis. Thus, hypertension initiated predominantly by neurogenic mechanisms could be sustained later without excessive sympathetic drive.

'Steady-state' properties of the baroreceptor-heart rate reflex in essential hypertension in man

Article

Feb 1974

SUMMARY 1. Rises and falls in mean arterial (MAP) and pulse (PP) pressures from the resting value were evoked by intravenous injections of phenylephrine and glyceryl trinitrate, and were related to the reflexly evoked changes in heart period (HP; pulse interval). 2. The steady-state properties of the baroreceptor-heart rate reflex were examined by deriving MAP-HP curves in a group of twenty-three healthy normotensive subjects, and in two groups of sixteen and eight subjects with essential hypertension of different severity. Each group was subdivided into two subgroups according to age: (i) 18–30 years; (ii) 33–57 years. The MAP-HP curves are sigmoid and each is characterized by its median blood pressure (BP50), average gain (Ḡ1) and heart period range (HPR). 3. In a given age group, the curves are ‘reset’ about a higher BP50 with increasing severity of hypertension. There is progressive reduction in HPR (to 80–55% of normotensive HPR) due to lowering of the upper HP plateau, which probably indicates impairment of function of the vagal component of the reflex. In three out of four hypertensive groups, Ḡ is also significantly reduced to between 60 and 30% of Ḡ of normotensive subjects of the same age. 4. The effect of age on the curve parameters is independent of the effects due to hypertension. For a given MAP, Ḡ and HPR are lower in older than in younger subjects.

Sympathetic Activity and Essential Hypertension

Article

Sep 1973
Clin Sci Mol Med Suppl

1. In thirty-one patients with essential hypertension there was a close relationship between resting diastolic blood pressure and basal plasma noradrenaline levels (r = 0.729, P<O.001). 2. After ganglionic blockade there was a highly significant correlation between change in resting blood pressure and change in plasma noradrenaline (r = 0.813, P<0*001). 3. Patients with the highest resting blood pressure had the largest falls in blood pressure and plasma noradrenaline. 4. These results suggest that the level of the blood pressure in essential hypertension is at least in part due to excess of sympathetic activity.

Acute Fulminating Neurogenic Hypertension Produced by Brainstem Lesions in the Rat

Article

Jun 1973

Bilateral electrolytic lesions of the nucleus tractus solitarii in the rat at the level of the obex abolished baroreceptor reflexes and resulted in an immediate, marked elevation in systemic blood pressure without a change in heart rate. In unansthetized rats the hypertension was associated with a marked increase in total peripheral resistance, a reduction in blood flow in the abdominal aorta, and an increase in central venous pressure. The cardiac output was reduced to 62% of control as a consequence of reduced stroke volume, which was reflected, in turn, by increased end diastolic pressure. The hypertension was abolished and the end diastolic pressure lowered by blockade of alpha receptors with phentolamine. The hypertension was not due to changes in blood gases or to release of agents from the kidneys or the adrenal glands; it was very sensitive to anesthetics and was abolished or aborted by midcollicular decerebration. Within hours after lesioning, the rats developed progressive congestive heart failure and died in shock, often in association with pulmonary edema. The authors concluded that the fulminating hypertension evoked by lesions of the nucleus tractus solitarii was due to the increased vasoconstriction caused by the augmented discharge of sympathetic nerves in response to central deafferentation of baroreceptor reflexes; the hypertension was mediated by alpha receptors and depended on the integrity of structures lying above the midbrain.

Renal sympathetic activity in spontaneously hypertensive rats and normotensive controls, as studied by three different methods

Article

Mar 1984

Recordings of sympathetic activity from multifibre preparations of renal nerves have produced conflicting results concerning the presence or absence of an increased sympathetic discharge in spontaneously hypertensive rat (SHR) compared to normotensive Wistar-Kyoto rats (WKY). Therefore, recordings of single fibre activity to the kidney were performed in anesthetized SHR and WKY in comparison with multifibre recordings in conscious, undisturbed rats. A new method of estimating sympathetic discharge by analyzing the variability of "cycle activity" in multifibre nerve recordings was also used. The average nerve activity in a great number of cardiac cycles was then expressed in relation (in per cent) to the nerve activity in a small number of cardiac cycles with the highest and lowest nerve activity in each rat. Single fibre recordings showed a significantly higher sympathetic activity to the kidneys in SHR (3.8 +/- 0.3 Hz) than in WKY (1.7 +/- 0.2 Hz; p less than 0.001). Also average "cycle activity" was significantly higher in conscious SHR (34 +/- 1%) than in WKY (26 +/- 2%, p less than 0.01). This was due to the larger number of cardiac cycles in SHR with high sympathetic activity while WKY showed more of "silent" cardiac cycles which lacked nerve impulses. Further, the recordings of rectified multifibre renal nerve activity also showed an elevated sympathetic activity in conscious SHR rats. The increased renal sympathetic activity appears to reflect the "primary" central nervous "hyperreactivity" characterizing SHR hypertension. It is suggested that the increased renal sympathetic activity may be of particular importance for the development of primary hypertension in SHR and perhaps also in man.

Acute hypertension after the local injection of kainic acid into the nucleus tractus solitarii of rats

Article

Mar 1981

Kainic acid (KA), an analogue of L-glutamate, was microinjected in 0.1 μl of saline into the nucleus tractus solitarii (NTS) of adult rats. In rats anesthetized with halothane or α-chloralose, KA injected unilaterally elicited hypotension, bradycardia, and apnea. The threshold dose was 0.1-0.2 ng (10-13 mol). Doses >0.2 ng blocked responses to subsequent injections for at least 30 minutes. Doses of KA>15 ng reduced the reflex bradycardia elicited by raising the arterial pressure with phenylephrine and produced arterial hypertension in rats anesthetized with α-chloralose or in other rats within 15 minutes of terminating halothane anesthesia. Bilateral injection of KA in doses >15 ng completely blocked baroreflexes and resulted in a dose-dependent elevation of arterial pressure (167 ± 9.4; P < 0.001) both in α-chloralose-anesthetized rats and in awake rats after the termination of halothane anesthesia. The hypertension rapidly led to pulmonary edema and death. Procaine microinjected also elicited fulminating hypertension; vehicle did not. Doses of KA producing hypertension caused no histological or biochemical evidence of neuronal death. The cardiovascular responses to KA were restricted to sites in the intermediate one-third of NTS and could not be elicited by injection into adjacent sites in brainstem. The results indicate that, in low doses, KA injected into NTS stimulates neurons which mediate the baroreflex, whereas, in higher doses, it produces baroreflex blockade and neurogenic hypertension. The results suggest that fulminating hypertension can be produced by nondestructive perturbations of neurochemical transmission in brain. Since the cardiovascular responses of KA are similar to those produced by microinjection into NTS of the amino acid neurotransmitter glutamic acid, the study adds further support to the hypothesis that L-glutamate is the neurotransmitter by baroreceptor afferent nerves.

Cytokines and the nervous system II: Actions and mechanisms of action

Article

Apr 1995
TRENDS NEUROSCI

Cytokines exert diverse actions on the PNS and the CNS and have been implicated in neuronally mediated responses to disease and injury. Certain cytokines participate in the central control of host systemic responses to disease, acting as signals to and within the brain. These molecules are also involved in neuronal degeneration and repair in the PNS and CNS, and have been proposed as mediators of various neuropathologies. The actions, mechanisms of action and potential strategies for modifying cytokines in the nervous system will be considered in this review, which continues the discussion of cytokine expression and recognition published in the February issue of TINS.

Expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) mRNAs in rat brain during postnatal development

Article

Mar 1994
BRAIN RES

Using RT-PCR, the development profile of interleukin-6 (IL-6) and its receptor (IL-6R) mRNAs in rat brain was investigated. Our results indicate that IL-6 and IL-6R mRNAs are coexpressed and are developmentally regulated in a tissue-specific manner. Highest levels of both transcripts were detected in the adult hippocampus. Most pronounced developmental changes of IL-6 message levels were observed in the rat striatum increasing up to 8-fold. By contrast, in all other regions such as neocortex, hippocampus, cerebellum and pons/medulla oblongata only minor changes (2- to 3-fold) in IL-6 expression were seen. In most tissues IL-6 mRNA levels peaked at day 20. Marked induction of the receptor message levels was detected in the striatum, hippocampus and neocortex (8- to 10-fold) whereas no changes were observed in the cerebellum and the pons/medulla oblongata. The expression pattern of both genes in various brain areas during postnatal development strongly supports the concept of IL-6 as a candidate for a new neurotrophic factor.

Evidence for activation of endothelium and monocytes in hypertensive rats

Article

Jul 1996
Am J Physiol

We have proposed that an interaction between perivascular macrophages and endothelium via cytokines could underlie the increased risk of stroke in hypertension. Therefore, the activation of monocytes, the endothelial expression of intercellular adhesion molecule-1 (ICAM-1), and the numbers of monocytes/macrophages in carotid arteries, as well as the cytokine production in carotid tissue, of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto and Sprague-Dawley rats were studied. The total number of blood monocytes (890 +/- 153 cells/mm3, n = 10) and the number of activated (nitro blue tetrazolium-positive) monocytes (220 +/- 51 cells/mm3, n = 10) were significantly greater (P < 0.05) in SHR than in WKY rats (440 +/- 81 and 40 +/- 16 cells/mm3, respectively, n = 10). Patchy endothelial expression of ICAM-1 was found in 77 +/- 9% of carotid sections from stroke-prone SHR (SHR-SP, n = 5) and in 75 +/- 7% of the sections from SHR (n = 7) but in none of the sections from the two normotensive rat strains (n = 7). The number of endothelium-attached monocytes/macrophages per millimeter of internal elastic lamina was significantly greater in SHR-SP than in SHR [5.1 +/- 0.7 (n = 4) and 3.3 +/- 0.3 (n = 6), P < 0.05], whereas no monocytes were found around the endothelium in either of the normotensive rat strains (n = 7 in each group). Incubation of the carotid arteries with lipopolysaccharide (30-300 ng/ml) induced a concentration-dependent expression of mRNAs for interleukin-1 beta and release of tumor necrosis factor-alpha to a significantly greater degree in the SHR than in the Wistar-Kyoto rats. The results demonstrate that hypertension is associated with activation of monocytes and endothelium and an increased endothelial adhesion and subendothelial accumulation of monocytes/macrophages and with an increased vascular capacity to produce cytokines.

Effect of IL-1β on neuronal activities in the dorsal motor nucleus of the vagus in rat brain slices

Article

Feb 1996
BRAIN RES BULL

Effects of recombinant human interleukin-1 beta (IL-1 beta) on the neuronal activities in the rat dorsal motor nucleus of the vagus (DMV) were investigated by extra- and intracellular recordings in slice preparations. Twelve (52%) of 23 spontaneously firing neurons recorded extracellularly, 7 of which were electrophysiologically identified as vagal motoneurons, were inhibited by a bath application of IL-1 beta at a dose of either 5.8 x 10(-8) or 5.8 x 10(-8) M. The duration of the responses ranged widely from about 10 min to more than 2 h. Two (9%) of the 23 neurons were excited, whereas the remaining 9 (39%) were not affected by IL-1 beta. Of 42 DMV neurons recorded intracellularly, 19 (45%) showed a hyperpolarization following an application of 5.8 x 10(-8) M IL-1 beta, which still persisted in a TTX-containing solution. Two (5%) displayed depolarization and 21 (50%) were unaffected. The hyperpolarization in 16 of the 19 neurons (84%) ranged from -5 to -10 mV and lasted for more than 30 min without changing the input resistance. The IL-1 beta-induced hyperpolarization was completely blocked by concurrent perfusion with sodium salicylate. The remaining three neurons showed a short-lasting (5-14 min) hyperpolarization (ranging from -6 to -15 mV) with a decrease in the input resistance. These findings indicate that IL-1 beta mainly inhibits the vagal motoneurons in the DMV, at least partly through prostaglandin synthesis. This provides a mechanism that could account for the central action of IL-1 beta on visceral processes such as the inhibition of gastric acid secretion.

Angiotensin II acts at AT1 receptors in the nucleus of the solitary tract to attenuate the baroreceptor reflex

Article

Dec 1998
Am J Physiol

The object of the current study was to determine if ANG II acts at type 1 (AT1) or type 2 (AT2) receptors in the nucleus of the solitary tract (NTS) to reduce baroreceptor reflex control of renal sympathetic nerve activity (RSNA) and heart rate (HR). Experiments were carried out in urethan-anesthetized Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Reflex changes in RSNA and HR were elicited by intravenous infusion of either phenylephrine or sodium nitroprusside before and after bilateral microinjection of CV-11974 (AT1 receptor antagonist, 10 pmol), PD-123319 (AT2 receptor antagonist, 100 pmol), or artificial cerebrospinal fluid (aCSF, 50 nl) in the NTS. Mean arterial pressure (MAP)-RSNA and MAP-HR data were fit to logistic functions to analyze the baroreceptor reflex. Baroreceptor reflex sensitivities for RSNA and HR were attenuated in SHR compared with those in WKY rats. Bilateral injection of CV-11974, PD-123319, or aCSF in the NTS of either strain had no effect on baseline arterial pressure, HR, or RSNA. However, CV-11974 injected in the NTS increased significantly (P < 0.01) the sensitivities for baroreceptor reflex control of RSNA and HR in SHR and WKY rats. Neither PD-123319 nor aCSF altered baroreceptor reflex control of RSNA and HR in either SHR or WKY rats. These results demonstrate that endogenous ANG II acts at AT1 receptors of the NTS to attenuate the baroreceptor reflex in SHR as well as in WKY rats.

A central role for astrocytes in the inflammatory response to ??-amyloid; chemokines, cytokines and reactive oxygen species are produced

Article

Feb 1999
J NEUROIMMUNOL

Alzheimer's disease (AD) is the commonest form of adult onset dementia and is characterised neuropathologically by the accumulation of plaques containing beta-amyloid (A beta) fibrils, reactive astrocytes, activated microglia, and leukocytes. A beta plays a role in the pathology of AD by directly causing neuronal cytotoxicity and stimulating microglia to secrete cytokines and reactive oxygen species (ROS) which also damage neurons. Here, we demonstrate that A beta activates astrocytes and oligodendrocytes (the most common cell types in the brain) to produce chemokines, in particular MCP-1 and RANTES, which serve as potent in vitro microglial and macrophage chemoattractants. Furthermore, we have shown that A beta activates astrocytes to upregulate pro-inflammatory cytokine expression and enhances the production of ROS. We propose therefore that A beta-mediated astrocyte activation initiates an inflammatory cascade which could be targeted for therapeutic intervention in AD.

Nucleus Tractus Solitarii: Integrating Structures

Article

Oct 1999

Julian F R Paton

Presently, many researchers have adopted a reductionistic approach to physiology. Specifically, this involves studies on acutely isolated or cultured cells. While this is essential for our understanding of important cellular and subcellular mechanisms, it should not be forgotten that physiology is about the function of an integrating body. One view point is that definitive interpretations can only be made by crossing boundaries of physiology from the molecular/ cellular to the systems/behavioural level. An aim of this lecture will stress the importance of a multidisciplinary approach to physiology, that is, 'putting the cell back into the system'. The lecture attempts to demonstrate why this is important for enhancing the functional significance and relevance of physiological data as well as for validating predictions.

The gain of the baroreflex bradycardia is reduced by microinjection of NMDA receptor antagonist into the nucleus tractus solitarii of awake rats

Article

Mar 2000
J Auton Nerv Syst

The baroreflex activation with phenylephrine infusion produces a bradycardic response. In the present study, the role of NMDA receptors in the nucleus tractus solitarii (NTS) in the processing of the parasympathetic component of the baroreflex was evaluated using acid phosphonivaleric (AP-5), a selective NMDA receptor antagonist. Baroreflex activation was performed before and after bilateral microinjection of AP-5 into the intermediate commissural NTS (0.5 mm lateral to the midline). Microinjection of the vehicle (saline, 0.9%) or a dose of 2 nmol/50 nl of AP-5 into the NTS produced no effect on the gain of the baroreflex while a dose of 10 nmol/50 nl of AP-5 produced a significant reduction in the gain of the baroreflex 2 min after microinjection [-1.43+/-0.22 vs. -0. 43+/-0.03 bpm/mmHg, (n=6)], with a return to control levels 10 min after the microinjections. The dose of 10 nmol/50 nl was selective for NMDA receptors considering that the cardiovascular responses to microinjection of AMPA (0.05 pmol/50 nl), a non-NMDA receptor agonist, were not affected by this dose of AP-5 and the responses to microinjection of NMDA (2 nmol/50 nl) were blocked. The data show that the bradycardic response to baroreflex activation was blocked by AP-5 microinjected into the NTS, indicating that the neurotransmission of the parasympathetic component of the baroreflex is mediated by NMDA receptors in the NTS.

Interleukin-6 inhibits neurotransmitter release and the spread of excitation in the rat cerebral cortex

Article

May 2000

Adenoviral vector demonstrates that angiotensin II-induced depression of the cardiac baroreflex is mediated by endothelial nitric oxide synthase in the nucleus tractus solitarii of the rat

Article

Apr 2001

Angiotensin II (ANGII) acting on ANGII type 1 (AT1) receptors in the solitary tract nucleus (NTS) depresses the baroreflex. Since ANGII stimulates the release of nitric oxide (NO), we tested whether the ANGII-mediated depression of the baroreflex in the NTS depended on NO release. In a working heart-brainstem preparation (WHBP) of rat NTS microinjection of either ANGII (500 fmol) or a NO donor (diethylamine nonoate, 500 pmol) both depressed baroreflex gain by -56 and -67 %, respectively (P < 0.01). In contrast, whilst ANGII potentiated the peripheral chemoreflex, the NO donor was without effect. NTS microinjection of non-selective NO synthase (NOS) inhibitors (L-NAME; 50 pmol) or (L-NMMA; 200 pmol) prevented the ANGII-induced baroreflex attenuation (P > 0.1). In contrast, a neurone-specific NOS inhibitor, TRIM (50 pmol), was without effect. Using an adenoviral vector, a dominant negative mutant of endothelial NOS (TeNOS) was expressed bilaterally in the NTS. Expression of TeNOS affected neither baseline cardiovascular parameters nor baroreflex sensitivity. However, ANGII microinjected into the transfected region failed to affect the baroreflex.Immunostaining revealed that eNOS-positive neurones were more numerous than those labelled for AT1 receptors. Neurones double labelled for both AT1 receptors and eNOS comprised 23 +/- 5.4 % of the eNOS-positive cells and 57 +/- 9.2 % of the AT1 receptor-positive cells. Endothelial cells were also double labelled for eNOS and AT1 receptors. We suggest that ANGII activates eNOS located in either neurones and/or endothelial cells to release NO, which acts selectively to depress the baroreflex.

Cytokines and the central nervous system

Article

Apr 2001
BRAIN RES BULL

Judit dr. Szelényi

Cytokines are involved both in the immune response and in controlling various events in the central nervous system, that is, they are equally immunoregulators and modulators of neural functions and neuronal survival. On the other hand, cytokine production is under the tonic control of the peripheral and the central nervous system and the cytokine balance can be modulated by the action of neurotransmitters released from nonsynaptic varicosities [131]. The neuroimmune interactions are therefore bidirectional-cytokines and other products of the immune cells can modulate the action, differentiation, and survival of neuronal cells, while the neurotransmitter and neuropeptide release play a pivotal role in influencing the immune response. Cytokines and their receptors are constitutively expressed by and act on neurons in the central nervous system, in both its normal and its pathological state, but cytokine overexpression in the brain is an important factor in the pathogenesis of neurotoxic and neurodegenerative disorders. Accordingly, it can be accepted that the peripheral and central cytokine compartments appear to be integrated, and their effects might synergize or inhibit each other; however, it should always be taken into account that they are spatiotemporally differentially regulated. New concepts are reviewed in the regulation of relations between cytokine balance and neurodegeneration, including intracellular receptor-receptor, cell-cell, and systemic neuroimmune interactions that promote the further elucidation of the complexities and cascade of the possible interactions between cytokines and the central nervous system.

Sympathetic Nervous System Activation in Essential Hypertension, Cardiac Failure and Psychosomatic Heart Disease

Article

Feb 2000

Regional sympathetic activity can be studied in humans using electrophysiological methods measuring sympathetic nerve firing rates and neurochemical techniques providing quantification of noradrenaline spillover to plasma from sympathetic nerves in individual organs. Essential hypertension: Such measurements in patients with essential hypertension disclose activation of the sympathetic outflows to skeletal muscle blood vessels, the heart and kidneys, particularly in younger patients. This sympathetic activation, in addition to underpinning the blood pressure elevation, most likely also contributes to left ventricular hypertrophy, and to the commonly associated metabolic abnormalities of insulin resistance and hyperlipidaemia. Antihypertensive drugs, such as moxonidine, which act primarily by inhibiting the sympathetic nervous system, should have additional clinical benefits beyond those attributable to blood pressure reduction, in protecting against hypertensive complications. Obesity-related hypertension: Understanding the neural pathophysiology of hypertension in the obese has been difficult. In normotensive obesity, renal sympathetic tone is doubled, but cardiac noradrenaline spillover (a measure of sympathetic activity in the heart) is only 50% of normal. In obesity-related hypertension, there is a comparable elevation of renal noradrenaline spillover, but without suppression of cardiac sympathetics (cardiac sympathetic activity being more than double that of normotensive obese and 25% higher than in healthy volunteers). Increased renal sympathetic activity in obesity may be a 'necessary' cause for the development of hypertension (and predisposes to hypertension development), but apparently is not a 'sufficient' cause. The discriminating feature of the obese who develop hypertension is the absence of the adaptive suppression of cardiac sympathetic tone seen in the normotensive obese. Heart failure: In cardiac failure, the sympathetic nerves of the heart are preferentially stimulated. Noradrenaline release from the failing heart at rest in untreated patients is increased as much as 50-fold, similar to the level seen in the healthy heart during near-maximal exercise. Activation of the cardiac sympathetic outflow provides adrenergic support to the failing myocardium, but at a cost of arrhythmia development and progressive myocardial deterioration. Psychosomatic heart disease: No more than 50% of clinical coronary heart disease is explicable in terms of classical cardiac risk factors. There is gathering evidence that psychological abnormalities, particularly depressive illness, anxiety states, including panic disorder and mental stress, are involved here, 'triggering' clinical cardiovascular events, and possibly also contributing to atherosclerosis development. The mechanisms of increased cardiac risk attributable to mental stress and psychiatric illness are not entirely clear, but activation of the sympathetic nervous system seems to be of prime importance.

Neurotransmission of the Cardiovascular Reflexes in the Nucleus Tractus Solitarii of Awake Rats

Article

Jul 2001

Benedito H Machado

Chemoreflex activation with potassium cyanide (i.v.) produces pressor and bradycardic responses in awake rats. Microinjection of AP-5, a selective NMDA receptor antagonist, into the nucleus tractus solitarii (NTS) produced a dose-dependent blockade of the bradycardic response; while microinjection of DNQX, a selective non-NMDA receptor antagonist, or kynurenic acid, a nonselective ionotropic receptor antagonist, produced only a partial reduction in the pressor response, indicating that the bradycardic component of the chemoreflex is mediated by NMDA receptors and that the sympathoexcitatory component may involve neurotransmitters other than excitatory amino acids. With respect to the baroreflex, we verified that the gain of baroreflex bradycardia in response to phenyleprine (Phe) infusion was significantly reduced in a dose-dependent manner by microinjection of AP-5 into the NTS, indicating that the parasympathetic component of the baroreflex is mediated mainly by NMDA receptors. However, in a series of experiments involving the electrical stimulation of the aortic depressor nerve (ADN) we observed that the maximal bradycardic response was almost blocked by the combination of microinjection of NMDA and non-NMDA receptor antagonists into the NTS, while the depressor response was only partially reduced. These data indicate that the bradycardic response produced by the activation of the baroreflex with Phe is mediated by mechanisms differing from those in response to the electrical stimulation of the ADN because phenylephrine also activates carotid and aortic baroreceptors, while unilateral electrical stimulation of the ADN involves only one specific set of baroreceptor afferents. These data also indicate that the sympatho inhibitory component of this response may involve neurotransmitters other than L-glutamate. We discuss the possibility that two different afferent systems of arterial baroreceptors are involved in the modulation of parasympathoexcitation and sympathoinhibition: one activated within the normal range of pulsatile arterial pressure (on a pulse-to-pulse basis) and the other acting under circumstances of challenge to the pulsatile arterial pressure above the normal range.

Increased level of YKL-40 in sera from patients with early rheumatoid arthritis: A new marker for disease activity

Article

Aug 2001

YKL-40 is a newly discovered major secretory protein of human chondrocytes and synoviocytes. We measured serum levels of YKL-40 in 52 patients with early onset rheumatoid arthritis (RA) by enzyme-linked immunosorbent assay (ELISA) during a 2-year prospective follow-up, correlating values with laboratory and clinical variables and radiographic progression. Levels at baseline before antirheumatic therapy were significantly higher in patients than in healthy controls. The levels of YKL-40 correlated with laboratory and clinical markers of disease activity both at baseline and during follow-up. Baseline YKL-40 values correlated with baseline Larsen scores but did not predict radiographic progression. Baseline and mean YKL-40 values did not differ between fast and slow radiological progressions. Mean YKL-40 levels correlated with the number of swollen joints but were not predictors of radiographic progression. These results suggest that in early RA, serum YKL-40 is an inflammatory marker correlating with disease activity. However, its levels do not predict clinical course or radiographic progression.

Immune function of astrocytes

Article

Nov 2001

Astrocytes are the major glial cell within the central nervous system (CNS) and have a number of important physiological properties related to CNS homeostasis. The aspect of astrocyte biology addressed in this review article is the astrocyte as an immunocompetent cell within the brain. The capacity of astrocytes to express class II major histocompatibility complex (MHC) antigens and costimulatory molecules (B7 and CD40) that are critical for antigen presentation and T-cell activation are discussed. The functional role of astrocytes as immune effector cells and how this may influence aspects of inflammation and immune reactivity within the brain follows, emphasizing the involvement of astrocytes in promoting Th2 responses. The ability of astrocytes to produce a wide array of chemokines and cytokines is discussed, with an emphasis on the immunological properties of these mediators. The significance of astrocytic antigen presentation and chemokine/cytokine production to neurological diseases with an immunological component is described.

Unloading arterial baroreceptors causes neurogenic hypertension

Article

Apr 2002

T N Thrasher

We developed a new model to examine the role of arterial baroreceptors in the long-term control of mean arterial pressure (MAP) in dogs. Baroreceptors in the aortic arch and one carotid sinus were denervated, and catheters were implanted in the descending aorta and common carotid arteries. MAP and carotid sinus pressure (CSP) averaged 104 +/- 2 and 102 +/- 2 mmHg (means +/- 1 SE), respectively, during a 5-day control period. Baroreceptor unloading was induced by ligation of the common carotid artery proximal to the innervated sinus (n = 6 dogs). MAP and CSP averaged 127 +/- 7 and 100 +/- 3 mmHg, respectively, during the 7-day period of baroreceptor unloading. MAP was significantly elevated (P < 0.01) compared to control, but CSP was unchanged. Heart rate and plasma renin activity increased significantly in response to baroreceptor unloading. Removal of the ligature to restore normal flow through the carotid resulted in normalization of all variables. Ligation of the carotid below a denervated sinus (n = 4) caused a significant decrease in CSP but no systemic hypertension. These results indicate that chronic unloading of carotid baroreceptors can produce neurogenic hypertension and provide strong evidence that arterial baroreceptors are involved in the long-term control of blood pressure.

Sympathetic neural mechanisms in white-coat hypertension

Article

Aug 2002
J AM COLL CARDIOL

This study planned to establish whether sympathetic hyperactivity exists in white-coat hypertension (WHT) in the clinical setting, relative to matched groups with normotension (NT) and untreated essential hypertension (EHT). White-coat hypertension differs from EHT by the presence of normal ambulatory blood pressure. Sympathetic hyperactivity exists in patients with EHT in the clinical setting and is believed to contribute to the development of target organ damage. Similar organ damage has been reported in WHT, yet little is known about sympathetic neural activity in this condition. Using microneurography, we examined groups of 12 matched subjects with WHT, EHT and NT during the same clinical setting to quantify muscle sympathetic nerve activity as multiunit discharge (MSNA) and single units (s-MSNA). The s-MSNA in WHT (54 +/- 4.2 impulses/100 beats) was greater (p < 0.05) than in NT (37 +/- 5.4 impulses/100 beats) despite similar age and body mass index (BMI). The EHT values of s-MSNA (73 +/- 5.2 impulses/100 beats) were significantly (p < 0.05) greater than in WHT despite similar age, BMI and blood pressure levels. The MSNA followed a similar trend. White-coat hypertension had a similar cardiac baroreceptor reflex sensitivity to NT, but this was impaired in EHT relative to both NT and WHT. It was shown, in the clinical setting, that central sympathetic hyperactivity exists in WHT, albeit to a lesser degree than EHT. These findings suggest that WHT may not be entirely benign and that the observed sympathetic hyperactivity may be responsible for development of target organ damage in this group of patients.

Collagen I and III mRNA gene expression and cell growth potential of skin fibroblasts in patients with essential hypertension

Article

Aug 2002

Despite the claimed disregulation of extracellular matrix synthesis and the increased proliferation rate of different cell types in experimental models of hypertension, very few data are available on collagen synthesis and the proliferation rate of fibroblasts in essential hypertensive patients. We measured collagen I, collagen III, histone H3 mRNA gene expression, collagen protein concentration and thymidine incorporation in fibroblasts from 17 essential hypertensive patients (EH) and 13 healthy normotensive control subjects (NC). A Northern blot analysis was performed on fibroblasts in culture obtained from skin biopsies. Collagen protein concentration and DNA synthesis were measured by means of incorporation of tritiated proline and tritiated thymidine, respectively. In cultivated fibroblasts from hypertensives, the expression of collagen III mRNA after addition of fetal calf serum was significantly increased in comparison with that of normotensive-derived cells. After addition of fetal calf serum, collagen protein was statistically increased in cultures from EH patients as compared to NC. In hypertensives, the expression of histone H3 mRNA as well as tritiated thymidine incorporation were both increased as compared to normotensives. Our data suggest that cultivated fibroblasts from essential hypertensive patients are characterized by an increased expression of type III collagen mRNA and collagen protein synthesis in response to fetal serum, as compared to normotensive-derived cells. Cells from hypertensives are characterized by an increased rate of proliferation after addition of fetal serum, as ascertained by increased thymidine incorporation and increased histone H3 mRNA gene expression, as compared to normotensive-derived cells. This phenotype could be genetically determined and may have an important role in the pathogenesis of essential hypertension.

Augmented Upregulation by c- fos of Angiotensin Subtype 1 Receptor in Nucleus Tractus Solitarii of Spontaneously Hypertensive Rats

Article

Oct 2002
Hypertension

Our laboratory demonstrated previously that spontaneously hypertensive rats (SHR) exhibited an elevated basal Fos expression in the nucleus tractus solitarii (NTS), the terminal site for primary baroreceptor afferents, and that Fos protein is required for the re-expression of angiotensin subtype 1 receptor (AT1R) mRNA in the NTS after baroreceptor activation. The present study evaluated the hypothesis that this re-expression of AT1R is augmented in SHR and is promoted by the heightened Fos expression. Reverse transcription-polymerase chain reaction analysis revealed that baroreceptor activation via sustained increase in systemic arterial pressure resulted in a discernible reduction in the expression of AT1R mRNA at the dorsomedial medulla of SHR and normotensive Wistar-Kyoto rats. However, SHR manifested an appreciably larger magnitude of decline, followed by a faster time course of re-expression in AT1R mRNA. Parallel findings were obtained from the pressor response induced by microinjection unilaterally of angiotensin II (40 pmol) into the NTS. Whereas the re-expression of AT1R at both transcriptional and functional expression levels after baroreceptor activation was discernibly blunted by prior bilateral application into the NTS of an antisense c-fos oligonucleotide (50 pmol), the suppression in SHR was again significantly more intense. Control pretreatment with the corresponding sense or scrambled c-fos oligonucleotide was ineffective. We conclude that the heightened Fos expression in SHR is causatively related to the augmented re-expression of AT1R in the NTS at both transcriptional and functional levels.

TGF-ßS and Their Roles in the Regulation of Neuron Survival

Article

Feb 2002
ADV EXP MED BIOL

Transforming growth factor-betas (TGF-betas) are a still growing superfamily of cytokines with widespread distribution and diverse biological functions. They fall into several subfamilies including the TGF-betas 1, 2, and 3, the bone morphogenetic proteins (BMPs), the growth/differentiation factors (GDFs), activins and inhibins, and the members of the glial cell line-derived neurotrophic factor family. Following a brief description of their general roles and signaling in development, maintenance of homeostasis, and disease, we shall focus on their distribution in the CNS and their involvement in regulating neuron survival and death.

Early autonomic malfunction in normotensive individuals with a genetic predisposition to essential hypertension

Article

Nov 2003

One of the primary pathologies associated with hypertension is a complex autonomic dysfunction with evidence of sympathetic hyperactivity and/or vagal withdrawal. We investigated the possibility for early detection of essential hypertension on the basis of the analysis of heart rate (HR) and blood pressure fluctuations, which reflect autonomic control. Young adult normotensive offspring of one hypertensive parent (KHT; n = 12) and normotensive offspring of two normotensive parents (YN; n = 14) participated in this study. ECG, continuous blood pressure, and respiration were recorded during steady-state conditions and under various autonomic challenges. Time-frequency decomposition of these signals was performed with the use of a continuous wavelet transform. The use of the wavelet transform enables the extension of typical HR variability analysis to non-steady-state conditions. This time-dependent spectral analysis of HR allows time-dependent quantification of different spectral components reflecting the sympathetic and parasympathetic activity during rapid transitions, such as an active change in posture (CP). During an active CP from the supine to standing position, KHT demonstrated a significantly greater increase in the low-frequency fluctuations in HR than YN, indicating enhanced sympathetic involvement in the HR response to CP, and a reduced alpha-index, indicating decreased baroreceptor sensitivity. On recovery from handgrip, vagal reactivation was more sluggish in KHT. These results indicate the early existence of malfunctions in both branches of autonomic control in individuals at increased risk of hypertension.

Okamoto K, Aoki KDevelopment of a strain of spontaneously hypertensive rats. Jpn Circ J 27:282-293

Article

Apr 1963

A male rat with spontaneously high systolic blood pressures of 150 to 175 mmHg persisting for more than one month and a female rat with blood pressures slighty above the average, 130 to 140 mmHg, were selected from among 68 Wistar strain rats in normal condition and mated to obtain F1 rats. Of these F1 rats, males and females with hypertension (blood pressure exceeding 150 mmHg) persisting for more than a month (mostly over 2 months) were mated to produce F2 rats. The procedure was repeated to obtain F3, F4, F5 and F6 rats totaliag 380 animals. The weights and blood pressures (by the tail-water-plethysmographic method) were measured once weekly biginning at 4 weeks of age, and the results can be summarized as follows : 1. In body weight, the F rats showed little difference from the normal controls. 2. The blood pressures of F rats rose with age and from generation to generation, increasing significantly above those of normotensive controls of the same age after 20 weeks of age among female F1, after 15 weeks among male F1 and also male and female F2, and after 10 weeks among all F3 to F6 rats. E. g., the average systolic blood pressure of F5 at 25 weeks of age was 206+__-18.5 mmHg in the male and 193+__-20.5 mmHg in female rats. The blood pressures of normotensive controls remained at 131 to 136 mmHg in the male and 130 to 135 mmHg in female rats after 10 weeks of age. 3. Many F rats showed spontaneous hypertension. The incidence of the spontaneous occurrence of hypertension increased, and the development of hypertension occurred at younger ages from generation to generation. All of the F3 to F6, rats developed spontaneous hypertension within 15 weeks of age. Severe hypertension with blood pressures exceeding 200 mmHg began to observed among F2. The incidence of such severe hypertension increased with each generation, so that among male animals it inceased from only 9% in F2 to 35% in F3, 42% in F4, and 56% in F5, and in female animals from 3% in F2, 16% in F3, 33% in F4, and 37% in F5. The authors have named this Wistar strain of rats with spontaneous occurrence of hypertension as "spontaneously hypertensive rats (Okamoto-Aoki)". 4. The blood pressures of β-line rats from parents with very high blood pressures were significantly higher than among α-line rats from parents with moderately high blood pressures at the same age. 5. There was no difference in the blood pressures of offsprings resulting from inbreeding and those from cross breeding. The male blood pressure averaged about 10.6 mmHg above the female value in spontaneous hypertension, and hypertension developed at lower ages in the male. 6. It is a question for future study whether the spontaneous hypertension induced in rats in this Study is comparable in characteristics with essential hypertension in man.

Broadly Altered Gene Expression in Blood Leukocytes in Essential Hypertension Is Absent During Treatment

Article

Jun 2004
Hypertension

We assessed whether large-scale expression profiling of leukocytes of patients with essential hypertension reflects characteristics of systemic disease and whether such changes are responsive to antihypertensive therapy. Total RNA from leukocytes were obtained from untreated (n=6) and treated (n=6) hypertensive patients without apparent end-organ damage and from normotensive controls (n=9). RNA was reverse-transcribed and labeled and gene expression analyzed using a 19-K oligonucleotide microarray using dye swaps. Samples of untreated and of treated patients were pooled for each sex and compared with age- and sex-matched controls. In untreated patients, 680 genes were differentially regulated (314 up and 366 down). In the treated patients, these changes were virtually absent (4 genes up, 3 genes down). A myriad of changes was observed in pathways involved in inflammation. Inflammation-dampening interleukin receptors were decreased in expression. Intriguingly, inhibitors of cytokine signaling (the PIAS family of proteins) were differentially expressed. The expression of several genes that are involved in regulation of blood pressure were also differentially expressed: angiotensin II type 1 receptor, ANP-A receptor, endothelin-2, and 3 of the serotonin receptors were increased, whereas endothelin-converting enzyme-1 was decreased. Strikingly, virtually no changes in gene expression could be detected in hypertensive patients who had become normotensive with treatment. This observation substantiates the long-standing idea that hypertension is associated with a complex systemic response involving inflammation-related genes. Furthermore, leukocytes display differential gene expression that is of importance in blood pressure control. Importantly, treatment of blood pressure to normal values can virtually correct such disturbances.

Specific inflammatory condition in nucleus tractus solitarii of the SHR: Novel insight for neurogenic hypertension?

Abstract

No full-text available

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