Benedito H Machado

University of São Paulo | USP

There is evidence that astrocytes modulate synaptic transmission in the NTS interacting with glutamatergic and purinergic mechanisms. Here, using in situ working heart-brainstem preparations we evaluated the involvement of astrocyte and glutamatergic/purinergic neurotransmission in the processing of autonomic and respiratory pathways in the NTS of...

Hypoxia due to reduction in the partial pressure of oxygen in the arterial blood (PaO 2 ) activates the afferents of peripheral chemoreflex to produce cardiovascular and respiratory adjustments to bring PaO 2 back to the normal range. Herein we evaluated the possible changes of astrocytic modulation on glutamatergic transmission in NTS neurons of m...

Carotid body pathophysiology is associated with many cardiovascular–respiratory–metabolic diseases. This pathophysiology reflects both hyper‐sensitivity and hyper‐tonicity. From both animal models and human patients, evidence indicates that amelioration of this pathophysiological signalling improves disease states such as a lowering of blood pressu...

Sustained hypoxia (SH) in mice induces changes in the respiratory pattern and increase in the parasympathetic tone to the heart. Among adenosine G‐protein‐coupled receptors (GPCRs), the A2A receptors are especially important in mediating adenosine actions during hypoxia due to their expression in neurons involved with the generation and modulation...

The autonomic profile of mice submitted to sustained hypoxia (SH) was not yet fully evaluated. Herein, we characterized the cardiovascular and autonomic profile of conscious freely moving mice submitted to SH using two sequential experimental protocols to evaluate the parasympathetic and sympathetic tone to the heart and the sympathetic tone to the...

Twenty‐five years ago, a new physiological preparation called the working heart–brainstem preparation (WHBP) was introduced with the claim it would provide a new platform allowing studies not possible before in cardiovascular, neuroendocrine, autonomic and respiratory research. Herein, we review some of the progress made with the WHBP, some advanta...

Active expiration is essential for increasing pulmonary ventilation during high chemical drive (hypercapnia). The lateral parafacial (pFL) region, which contains expiratory neurones, drives abdominal muscles during active expiration in response to hypercapnia. However, the electrophysiological properties and synaptic mechanisms determining the acti...

We have considered some of the available evidence to account for the impact of SARS-CoV on the regulatory control of the autonomic nervous and respiratory systems. Apart from stimulating general interest in the subject, our hope was to provide putative explanations for some of the patients' symptoms based on described physiological and pathophysiol...

New findings: What is the central question of this study? Do mice submitted to sustained hypoxia present autonomic and respiratory changes similarly to rats? What is the main finding and its importance? Arterial pressure in the normal range, reduced baseline heart rate and tachypnoea were observed in behaving sustained hypoxia mice. Recordings in...

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). The two senior authors of this article would like to retract it after having conducted a thorough review of all original recordings and previous data analyses and found that the data were not a...

Short-term sustained hypoxia (SH) elicits active expiration, augmented late-expiratory (late-E) sympathetic activity, increased arterial pressure and ventilation, and amplified sympathetic and abdominal expiratory responses to chemoreflex activation in rats of the Wistar-Ribeirão Preto (WRP) strain. Herein, we investigated whether SH can differenti...

Short term sustained hypoxia (SH, FiO 2 0.1, 24 h) produces cardiovascular and respiratory changes mainly due to peripheral chemoreflex activation. SH alters the electrophysiological properties of neurons in the NTS, where the first synapses of chemoreflex afferents are located. In the present study we evaluated alterations produced by SH on neuron...

New findings: What is the central question of this study? Adrenomedullin in the rostral ventrolateral medulla (RVLM) increases sympathetic activity. Given that adrenomedullin is released during hypoxia, we explored its antagonism and agonism in the RVLM after chronic intermittent hypoxia (CIH) exposure. What is the main finding and its importance?...

New findings: What is the central question of this study? Chronic intermittent hypoxia (CIH) causes increased arterial pressure (AP), sympathetic overactivity, and changes in expiratory modulation of sympathetic activity. However, changes in short-term sleep-wake cycle pattern after CIH and their potential impact on cardiorespiratory parameters ha...

Key points Rats subjected to sustained hypoxia (SH) present increases in arterial pressure (AP) and in glutamatergic transmission in the nucleus tractus solitarius (NTS) neurons sending projections to ventrolateral medulla (VLM). Treatment with minocycline, a microglial inhibitor, attenuated the increase in AP in response to SH. The increase in the...

Sustained hypoxia (SH) activates chemoreceptors to produce cardiovascular and respiratory responses to bring the PaO 2 back to the physiological range. We evaluated the effect of SH (FiO 2 = 0.10 - 24 hours) on glutamatergic synaptic transmission and the interaction neuron-astrocyte in neurons of the nucleus tractus solitarius (NTS). Tractus solita...

Obstructive sleep apnea patients face episodes of chronic intermittent hypoxia (CIH), which has been suggested as a causative factor for increased sympathetic activity (SNA) and hypertension. Female rats exposed to CIH develop hypertension and exhibit changes in respiratory-sympathetic coupling, marked by an increase in the inspiratory modulation o...

Key points Acute hypoxia induces active expiration in rectus abdominis (RA) muscles in conscious freely moving rats, although its overall contribution is smaller than in internal oblique (IO) muscles. Tonically active and silent RA motoneurons were identified in in vitro preparations of rat spinal cords. Sustained hypoxia (SH) increased the synapti...

New findings: What is the central question of this study? After sino-aortic denervation (SAD) rats present normal levels of mean arterial pressure (MAP), high MAP variability and changes in breathing. However, mechanisms involved in SAD-induced respiratory changes and their impact on the modulation of sympathetic activity remain unclear. Herein, w...

At rest, inspiration is an active process while expiration is passive. However, high chemical drive (hypercapnia or hypoxia) activates central and peripheral chemoreceptors triggering reflex increases in inspiration and active expiration. The Locus Coeruleus contains noradrenergic neurons (A6 neurons) that increase their firing frequency when expos...

There is experimental evidence showing that pre‐sympathetic neurons in the ventrolateral medulla have their firing frequency modulated by the respiratory network. After baroreceptors afferents removal [sino‐aortic denervation (SAD)], awake rats present normal levels of sympathetic activity and mean arterial pressure. However, the mechanisms involve...

The sustained hypoxia (SH) is associated with changes in synaptic transmission in the nucleus tractus solitary (NTS) and also with inflammatory processes. In this study, we investigated the effects of anti‐inflammatory treatment on the excitatory synaptic transmission in the NTS neurons and the gene expression of pro‐inflammatory cytokines [interle...

Female rats submitted to chronic intermittent hypoxia (CIH) presented a reduced time of inspiration, sympathetic overactivity and hypertension. The increase in sympathetic nerve discharge in CIH‐female rats is associated to an increase in the inspiratory modulation of sympathetic activity. In this context, we hypothesized that inspiratory neurons a...

The cardiovascular and respiratory reflex responses to activation of the arterial chemoreceptors or baroreceptors are dependent on the phase of respiratory cycle. To determine if the respiratory modulation of the chemoreflex and baroreflex occurs within the nucleus tractus solitarii (NTS), whole cell patch clamp recordings of NTS neurons were obtai...

The carotid bodies are peripheral chemoreceptors and contribute to the homeostatic maintenance of arterial levels of O2, CO2 and [H+]. They have attracted much clinical interest recently because of the realisation that aberrant signalling in these organs is associated with several pathologies including hypertension. Herein, we describe data suggest...

O avanço da ciência, e sua relação com a formação de pessoal altamente qualificado na pós-graduação, geram pressões por desempenho e, em paralelo, dilemas éticos e conflitos de interesse entre os diversos atores envolvidos. A situação urge reflexões sobre quais são tais conflitos e como tratá-los, de forma a que sejam compatíveis com a formação de...

New findings: What is the central question of this study? Chronic intermittent hypoxia (CIH) and one-kidney, one-clip experimental models lead to sympathetic overactivity and hypertension. The present study explored the impact of previous exposure to CIH on one-kidney, one-clip renal hypertension; we hypothesized that CIH potentiates its developme...

Purpose of review: Surgical removal of the baroreceptor afferents [sino-aortic denervation (SAD)] leads to a lack of inhibitory feedback to sympathetic outflow, which in turn is expected to result in a large increase in mean arterial pressure (MAP). However, few days after surgery, the sympathetic nerve activity (SNA) and MAP of SAD rats return to...

Sympathetic activity displays rhythmic oscillations generated by brainstem inspiratory and expiratory neurons. Amplication of these rhythmic respiratory-related oscillations is observed in rats under enhanced central respiratory drive or during the development of neurogenic hypertension. Herein, we evaluated the involvement of ventral medullary sym...

Obstructive sleep apnea (OSA) is a complex disease in which humans face episodes of intermittent hypoxia and it affects men and women. Patients with OSA present hypertension and sympathetic overactivity among several other dysfunctions. Therefore, one important question remains: are the autonomic dysfunctions associated with OSA similar in male and...

New Findings What is the central question of this study? Sino‐aortic denervated (SAD) rats present normal levels of sympathetic activity and mean arterial pressure. However, neural mechanisms regulating the sympathetic activity in the absence of arterial baroreceptors remain unclear. Considering that respiration modulates the sympathetic activity,...

In spite of recent advances on the knowledgement of the neural control of cardiovascular function, the cause of sympathetic overactivity in neurogenic hypertension remains unknown. Studies from our laboratory point out that rats submitted to chronic intermittent hypoxia (CIH), an experimental model of neurogenic hypertension, present changes in the...

After recent very successful IUPS Congresses in San Diego (U.S., 2005), Kyoto (Japan, 2009), and Birmingham (UK, 2013), now it is the time for a new journey for the physiologists to stop in Rio de Janeiro (Brazil, 2017). The World Congress of the International Union of Physiological Sciences (IUPS)

Humans ascending to high altitudes are submitted to sustained hypoxia (SH), activating peripheral chemoreflex with several autonomic and respiratory responses. We analyzed the effect of short-term SH (24 hours, FIO210%) on the cardiovascular parameters in non-anesthetized rats and on the processing of cardiovascular and respiratory reflexes using i...

Although it is well known that chronic hypoxia induces muscle wasting, the effects of intermit-tent hypoxia on skeletal muscle protein metabolism remains unclear. We hypothesized that acute intermittent hypoxia (AIH), a challenge that activates the hypothalamic-pituitary-adrenal axis, would alter muscle protein homeostasis through a glucocorticoid-...

[This corrects the article on p. 424 in vol. 7, PMID: 27713705.].

Despite several studies describing the electrophysiological properties of RVLM presympathetic neurons, there is no consensus in the literature about their pacemaking property, mainly due to different experimental approaches used for recordings of neuronal intrinsic properties. In this review we are presenting a historical retrospective about the pi...

In view of the high proportion of individuals with resistance to antihypertensive medication and/or poor compliance or tolerance of this medication, new drugs to treat hypertension are urgently needed. Here we show that peripheral chemoreceptors generate aberrant signaling that contributes to high blood pressure in hypertension. We discovered that...

New Findings What is the central question of this study? The arterial baroreflex regulates arterial pressure within a narrow range of variation. After sino‐aortic denervation (SAD), rats show a large increase in arterial pressure variability, but mean arterial pressure levels remain similar to those of control rats. Considering that breathing influ...

New Findings What is the central question of the study? There are sex differences in the respiratory network and in the regulation of arterial blood pressure. Female rats develop hypertension after chronic intermittent hypoxia (CIH). In this context, we evaluated the respiratory‐related mechanism underlying the development of hypertension in CIH‐ex...

Chronic intermittent hypoxia (CIH) produces respiratory-related sympathetic overactivity and hypertension in rats. In this study, we tested the hypothesis that the enhanced central respiratory modulation of sympathetic activity after CIH also decreases the sympathoinhibitory component of baroreflex of rats, which may contribute to the development o...

It is well known that several days after sino‐aortic denervation (SAD) rats present normal levels of sympathetic activity and mean arterial pressure (MAP). However, the mechanisms involved in the modulation of the sympathetic activity after SAD remain unclear. Here we hypothesized that the respiratory network may contribute to the modulation of the...

During hypoxia condition the peripheral chemoreflex is activated and induces autonomic and respiratory responses. In this study we analyzed the effect of short‐term sustained hypoxia [(SH) 24 hours, FIO 2 10%] on the synaptic transmission of NTS. Using brainstem slices and whole‐cell patch clamp we observed that passive properties of NTS astrocytes...

Juvenile female rats exposed to chronic intermittent hypoxia (CIH) presented a significant reduction in the time of inspiration and increase in sympathetic activity during this phase of respiratory cycle, characterizing changes in the respiratory‐sympathetic coupling. There is evidence that the firing frequency of the pre‐sympathetic neurons is mod...

Short‐term sustained hypoxia (SH) is associated with cardiorespiratory changes and inflammatory process in the central nervous system. SH also promotes changes in excitatory synaptic transmission in the NTS. In this study we evaluated the possible role of inflammation triggered by SH on the excitatory synaptic transmission of NTS neurons sending pr...

Expiration is considered a passive process during resting breathing condition. There is a lack of information about the intrinsic electrophysiological properties of expiratory motoneurons and their possible changes in conditions in which the expiration becomes an active process, such as hypoxia. Considering that abdominal expiratory muscle activity...

Chronic intermittent hypoxia (CIH) produces expiratory‐related sympatho‐excitation in rats, which might contribute to the development of hypertension. We evaluated the role of sympatho‐excitatory cathecolaminergic medullary C1 neurons in the CIH‐induced expiratory‐related sympatho‐excitation and hypertension in rats. In awake rats in vivo and in in...

There is evidence that a reduction in the baroreflex gain contributes to the high blood pressure in SHR. In the present study performed in conscious freely moving rats, we hypothesized that the baroreflex gain was not altered in SHR. To address this question we used two methods for evaluation of the cardiac baroreflex: a) the sequence analysis tech...

Respiratory pattern is determined by chloride‐mediated conductances via GABAergic and glycinergic receptors. GABA and glycine act as inhibitory neurotransmitters in the adult central nervous system, but as excitatory neurotransmitters during postnatal development. In this study, we investigated the respiratory pattern, electrophysiological properti...

Obstructive Sleep Apnea (OSA) is known to be independently associated with several cardiovascular diseases including hypertension, myocardial infarction and stroke. To determine how OSA can increase cardiovascular risk, animal models have been developed to explore the underlying mechanisms and the cellular and end-organ targets of the predominant p...

Rats exposed to chronic intermittent hypoxia (CIH) develop hypertension, which is associated with changes in the coupling of sympathetic and respiratory activities. In this study we hypothesized that previous preconditioning to intermittent or sustained hypoxia would affect cardiovascular and respiratory changes produced by subsequent protocols of...

Humans ascending to high altitudes are submitted to sustained hypoxia (SH), activating peripheral chemoreflex with several autonomic and respiratory responses. Here we analyzed the effect of short-term SH (24 h, FIO210%) on the processing of cardiovascular and respiratory reflexes using an in situ preparation of rats. SH increased both the sympatho...

Why sympathetic activity raises in neurogenic hypertension remains unknown. It has been postulated that changes in the electrical excitability of medullary pre-sympathetic neurones are the main causal mechanism for the development of sympathetic over activity in experimental hypertension. Herein, we review recent data suggesting that enhanced sympa...

Sympathetic overactivity has been related to the pathogenesis of hypertension. Enhanced peripheral chemoreceptor sensitivity has been suggested as a possible mechanism for sympathetic overactivity. We compared both baseline and chemoreflex evoked carotid sinus nerve (CSN) activity, and the electrophysiological properties of petrosal ganglion cells...

New findings: What is the central question of this study? Chronic intermittent hypoxia (CIH) induces hypertension in male rats. There is evidence that the development of high blood pressure in females is attenuated in other models of hypertension. Due to the lack of information about the cardiovascular effect of CIH in female rats, we set out to d...

Key points: The respiratory control of the glottis by laryngeal motoneurones is characterized by inspiratory abduction and post-inspiratory adduction causing decreases and increases in upper airway resistance, respectively. Chronic intermittent hypoxia (CIH), an important component of obstructive sleep apnoea, exaggerated glottal abduction (before...

Abstract Respiratory modulation seen in the sympathetic nerve activity (SNA) implies that the respiratory and sympathetic networks interact. During hypertension elicited by chronic intermittent hypoxia (CIH), the SNA displays an enhanced respiratory modulation reflecting strengthened interactions between the networks. In this chapter, we review a s...

The respiratory modulation of sympathetic activity relies on the balance between excitatory and inhibitory inputs from the brainstem respiratory network to presympathetic neurons of the rostral ventrolateral medulla. This central respiratory-sympathetic contributes for the generation of respiratory-related rhythmical oscillations in heart rate and...

Major evolutionary trends in animal physiology have been heavily influenced by atmospheric O2 levels. Amongst other important factors, the increase in atmospheric O2 which occurred in the Pre-Cambrian and the development of aerobic respiration beckoned the evolution of animal organ systems that were dedicated to the absorption and transportation of...

Introduction The central nucleus of amygdala plays an important role mediating fear and anxiety responses. It is known that oxytocin microinjections into the central nucleus of amygdala induce hypergrooming, an experimental model of compulsive behavior. We evaluated the behavioral and cardiorespiratory responses of conscious rats microinjected with...

New Findings What is the central question of this study? What is the effect of chronic intermittent hypoxia (a neurogenic model of hypertension that also induces active expiration) on intrinsic electrophysiological properties of rostral ventrolateral medulla presympathetic and putative expiratory neurons recorded in brainstem slices of juvenile rat...

Rats exposed to chronic intermittent hypoxia (CIH) develop hypertension. In the present study we evaluated the effect of a previous protocol of CIH on the cardiovascular responses produced by a new protocol of CIH. Male Wistar rats (45 ‐ 50 g) were divided in 3 groups: Control group (n=24), maintained under normoxia during 35 days; CIH group (n=18)...

Chronic intermittent hypoxia (CIH) induces hypertension in juvenile and adult male rats due to an increase in sympathetic activity. There is experimental evidence that changes in respiratory network are driving the sympathetic overactivity in this model. Female rats are more resistant to the development of hypertension in several experimental model...

Rats submitted to sino‐aortic denervation (SAD) present normal basal sympathetic activity and mean arterial pressure (MAP) few days after the surgical procedure. In the present study, we evaluated the cardiovascular and respiratory changes 3 and 10 days after SAD. Male juvenile Wistar rats were submitted to SAD or sham surgery and four groups were...

The respiratory pattern generator modulates the sympathetic outflow which strength is enhanced by hypoxia. This coupling is due to the respiratory‐modulated pre‐sympathetic neurons in the RVLM, but the underlining electrophysiological mechanisms remain unclear. For a better understanding of the central generation of respiratory‐sympathetic coupling...

Our computational model predicts that post‐inspiratory (post‐I) neurons expressing the glycine transporter 2 (GLYT2) located in the Bötzinger Complex (BötC) suppress generation of abdominal and sympathetic late‐expiratory (late‐E) activities in eucapnia. Hypercapnia allows parafacial late‐E neurons to escape this inhibition. To test functional conn...

The variation of litter size from rodents in the early days of life, which results in neonatal overfeeding or undernutrition, is a very useful model for the obesity study since programs the animals to become obese adults. Moreover, several studies have demonstrated the importance of the angiotensin II (ANG II) in the pathophysiology of obesity and...

In this study we evaluated, in brainstem slices from adult rats, the effects of acute hypoxia (AH) on the firing rate of pre‐sympathetic neurons in rostral ventrolateral medulla sending projections to the intermediolateral column of spinal cord (RVLM‐IML neurons). Anesthetized male Wistar rats (PO 30) were submitted to microinjection of fluorescent...

Post‐inspiratory (post‐I)‐modulation of sympathetic outflows was increased in the pre‐hypertensive spontaneously hypertensive (SH) rats and this excitation can be reduced by carotid body denervation (CBD).In SH and Wistar rats (4‐6 week old), simultaneous recordings of sympathetic and respiratory nerves together with whole cell patch clamp recordin...