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Aldosterone regulates blood pressure (BP) through water and sodium balance. In our study, we studied if continuous treatment with a mineralocorticoid receptor antagonist, spironolactone (30 mg/kg/day) for 20 days can: 1) attenuate hypertension development and restore inverted 24-h BP rhythm in hypertensive transgenic (mRen-2)27 rats (TGR) measured by telemetry; 2) improve function of the kidneys and heart; 3) be protective against high salt load (1% in water) by mitigating oxidative injury and improving kidney function. Spironolactone decreased albuminuria and 8-isoprostane in normal and salt load conditions in BP-independent effects. Salt load increased BP, impaired autonomic balance, suppressed plasma aldosterone level and increased natriuresis, albuminuria and oxidative injury in TGR. Spironolactone did not restore the inverted 24-h rhythm of BP in TGR, therefore, mineralocorticoids are not crucial in regulation of BP daily profile. Spironolactone improved kidney function, decreased oxidative stress and was protective against high salt load in the BP-independent manner.
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Expression of the nerve growth factor NGF is increased in pulmonary hypertension (PH). We have here studied whether oxidative stress and inflammation, two pathological conditions associated with transforming growth factor-β1 (TGF-β1) in PH, may trigger NGF secretion by pulmonary arterial (PA) cells. Effects of hydrogen peroxide (H2O2) and interleukin-1β (IL-1β) were investigated ex vivo on rat pulmonary arteries, as well as in vitro on human PA smooth muscle (hPASMC) or endothelial cells (hPAEC). TβRI expression was assessed by Western blotting. NGF PA secretion was assessed by ELISA after TGF-β1 blockade (anti-TGF-β1 siRNA, TGF-β1 blocking antibodies, TβRI kinase, p38 or Smad3 inhibitors). TβRI PA expression was evidenced by Western blotting both ex vivo and in vitro. H2O2 or IL-1β significantly increased NGF secretion by hPASMC and hPAEC, and this effect was significantly reduced when blocking TGF-β1 expression, binding to TβRI, TβRI activity, or signaling pathways. In conclusion, oxidative stress and inflammation may trigger TGF-β1 secretion by hPASMC and hPAEC. TGF-β1 may then act as an autocrine factor on these cells, increasing NGF secretion via TβRI activation. Since NGF and TGF-β1 are relevant growth factors involved in PA remodeling, such mechanisms may therefore be relevant to PH pathophysiology.
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Maturation of the cardiovascular system is associated with crucial structural and functional remodeling. Thickening of the arterial wall, maturation of the sympathetic innervation, and switching of the mechanisms of arterial contraction from calcium-independent to calcium-dependent occur during postnatal development. All these processes promote an almost doubling of blood pressure from the moment of birth to reaching adulthood. This review focuses on the developmental alterations of potassium channels functioning as key smooth muscle membrane potential determinants and, consequently, vascular tone regulators. We present evidence that the pattern of potassium channel contribution to vascular control changes from Kir2, Kv1, Kv7 and TASK-1 channels to BKCa channels with maturation. The differences in the contribution of potassium channels to vasomotor tone at different stages of postnatal life should be considered in treatment strategies of cardiovascular diseases associated with potassium channel malfunction.
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Previous data showed hypertensive rats subjected to chronic intracerebroventricular (ICV) infusion of angiotensin-(1-7) presented attenuation of arterial hypertension, improvement of baroreflex sensitivity, restoration of cardiac autonomic balance and a shift of cardiac renin-angiotensin system (RAS) balance toward Ang-(1-7)/Mas receptor. In the present study, we investigated putative central mechanisms related to the antihypertensive effect induced by ICV Ang-(1-7), including inflammatory mediators and the expression/activity of the RAS components in hypertensive rats. Furthermore, we performed a proteomic analysis to evaluate differentially regulated proteins in the hypothalamus of these animals. For this, Sprague Dawley (SD) and transgenic (mRen2)27 hypertensive rats (TG) were subjected to 14 days of ICV infusion with Ang-(1-7) (200 ng/h) or 0.9% sterile saline (0.5 μl/h) through osmotic mini-pumps. We observed that Ang-(1-7) treatment modulated inflammatory cytokines by decreasing TNF-α levels while increasing the anti-inflammatory IL-10. Moreover, we showed a reduction in ACE activity and gene expression of AT1 receptor and iNOS. Finally, our proteomic evaluation suggested an anti-inflammatory mechanism of Ang-(1-7) toward the ROS modulators Uchl1 and Prdx1.
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The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.
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Prenatal hypoxia (PH) has negative consequences on the cardiovascular system in adulthood and can affect the responses to additional insults later in life. We explored the effects of PH imposed during embryonic day 20 (10.5% O 2 for 12 h) on circadian rhythms of systolic blood pressure (BP) and heart rate (HR) in mature male rat offspring measured by telemetry. We evaluated: (1) stability of BP and HR changes after PH; (2) circadian variability of BP and HR after 2 and 5 weeks of exposure to artificial light at night (ALAN; 1–2 lx); and (3) response of BP and HR to norepinephrine. PH increased BP in the dark (134 ± 2 mmHg vs. control 127 ± 2 mmHg; p = 0.05) and marginally in the light (125 ± 1 mmHg vs. control 120 ± 2 mmHg) phase of the day but not HR. The effect of PH was highly repeatable between 21- and 27-week-old PH male offspring. Two weeks of ALAN decreased the circadian variability of HR ( p < 0.05) and BP more in control than PH rats. After 5 weeks of ALAN, the circadian variability of HR and BP were damped compared to LD and did not differ between control and PH rats ( p < 0.05). Responses of BP and HR to norepinephrine did not differ between control and PH rats. Hypoxia at the end of the embryonic period increases BP and affects the functioning of the cardiovascular system in mature male offspring. ALAN in adulthood decreased the circadian variability of cardiovascular parameters, more in control than PH rats.
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The mineralocorticoid receptor (MR) was originally identified as a regulator of blood pressure, able to modulate renal sodium handling in response to its principal ligand aldosterone. MR is expressed in several extra-renal tissues, including the heart, vasculature, and adipose tissue. More recent studies have shown that extra-renal MR plays a relevant role in the control of cardiovascular and metabolic functions and has recently been implicated in the pathophysiology of aging. MR activation promotes vasoconstriction and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Aging is associated with increased arterial stiffness and vascular tone, and modifications of arterial structure and function are responsible for these alterations. MR activation contributes to increase blood pressure with aging by regulating myogenic tone, vasoconstriction, and vascular oxidative stress. Importantly, aging represents an important contributor to the increased prevalence of cardiometabolic syndrome. In the elderly, dysregulation of MR signaling is associated with hypertension, obesity, and diabetes, representing an important cause of increased cardiovascular risk. Clinical use of MR antagonists is limited by the adverse effects induced by MR blockade in the kidney, raising the risk of hyperkalaemia in older patients with reduced renal function. Therefore, there is an unmet need for the enhanced understanding of the role of MR in aging and for development of novel specific MR antagonists in the context of cardiovascular rehabilitation in the elderly, in order to reduce relevant side effects.
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Key points: In mammals, the mother-offspring interaction is essential for health later in adulthood. The impact of altered timing and quality of maternal care on the offspring's circadian system was assessed using a cross-strain fostering approach. Better maternal care facilitated the development of amplitudes of Bmal1 clock gene expression in the central clock, as well as the clock-driven activity/rest rhythm, and also its entrainment to the external light/dark cycle. Worse maternal care impaired entrainment of the central clock parameters in the Wistar rat during the early developmental stages. Better maternal care remedied the dampened amplitudes of the colonic clock, as well as cardiovascular functions. The results provide compelling evidence that the circadian phenotype of a foster mother may affect the pathological symptoms of the offspring, even if they are genetically programmed. Abstract: In mammals, the mother-offspring interaction is essential for health later in adulthood. Maternal care is determined by the circadian phenotype of the mother. The impact of altered timing and quality of maternal care on the circadian system was assessed using a cross-strain fostering approach, with 'abnormal' (i.e. circadian misaligned) care being represented by spontaneously hypertensive rats (SHR) and 'normal' care by Wistar rats. The SHR mothers worsened synchrony of the central clock in the suprachiasmatic nuclei with the light/dark cycle in Wistar rat pups, although this effect disappeared after weaning. The maternal care provided by Wistar rat mothers to SHR pups facilitated the development of amplitudes of the Bmal1 expression rhythm in the suprachiasmatic nuclei of the hypothalamus, as well as the clock-driven activity/rest rhythm and its entrainment to the external light/dark cycle. The peripheral clocks in the liver and colon responded robustly to cross-strain fostering; the circadian phenotype of the Wistar rat foster mother remedied the dampened amplitudes of the colonic clock in SHR pups and improved their cardiovascular functions. In general, the more intensive maternal care of the Wistar rat mothers improved most of the parameters of the abnormal SHR circadian phenotype in adulthood; conversely, the less frequent maternal care of the SHR mothers worsened these parameters in the Wistar rat during the early developmental stages. Altogether, our data provide compelling evidence that the circadian phenotype of a foster mother may positively and negatively affect the regulatory mechanisms of various physiological parameters, even if the pathological symptoms are genetically programmed.
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Objective A high salt intake causes hypertension and leads to cardiovascular disease. Therefore, a low salt diet is now recommended to prevent hypertension and cardiovascular disease. However, it is still unknown whether an excessively low salt diet is beneficial or harmful for the heart. Methods Wistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) received normal salt chow (0.9% salt diet) and excessively low salt chow (0.01% salt diet referred to as saltless diet) for 8 weeks from 8 to 16 weeks of age. The effects of the excessively low salt diet on the cardiac (pro) renin receptor, renin-angiotensin-aldosterone, and sympatho-adrenal systems were investigated. Results The excessively low salt diet did not affect the systolic blood pressure but significantly increased the heart rate both in WKYs and SHRs. The excessively low salt diet significantly elevated plasma renin activity, plasma angiotensin I, II and aldosterone concentrations, and plasma noradrenaline and adrenaline concentrations both in WKYs and SHRs. Cardiac expressions of renin, prorenin, (P)RR, angiotensinogen, and angiotensin II AT1 receptor and phosphorylated (p)-ERK1/2, p-HSP27, p-38MAPK, and TGF-ß1 were significantly enhanced by the excessively low salt diet in both WKYs and SHRs. The excessively low salt diet accelerated cardiac interstitial and perivascular fibrosis and increased the cardiomyocyte size and interventricular septum thickness in WKYs and SHRs but the extent was greater in SHRs. Conclusion An excessively low salt diet damages the heart through activation of plasma renin-angiotensin-aldosterone and sympatho-adrenal systems and activation of cardiac (P)RR and angiotensin II AT1 receptor and their downstream signals both in WKYs and SHRs.
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This study was undertaken to examine the effects of angiotensin II-induced structural changes in the aortic wall on the dynamic mechanical properties of the vessel in the rat. Wistar rats were infused s.c. with 250 ng/kg/min angiotensin II (Ang II) for 14 days (ANG). Both ANG and control rats (CON) were equipped with an arterial catheter for measurement of arterial blood pressure. Thoracic aorta diameter, compliance coefficient (CC), and distensibility coefficient (DC) were determined non-invasively in pentobarbital-anesthetized animals using a B-mode imager attached to a vessel wall tracking system. After sacrifice, medial cross-sectional area (CSA), and elastin and collagen densities were determined by morphometry on cross-sections. Media thickness (Mt) and wall-to-lumen ratio (W/L) were subsequently calculated. Ang II infusion significantly increased mean arterial blood pressure in conscious rats (122 +/- 3 mmHg CON vs. 157 +/- 4 mmHg ANG). This was normalized when the rats were anesthetized, thus making it possible to determine CC and DC under isobaric conditions where the diastolic diameters were also similar. Two-week infusion of Ang II induced a significant increase in CSA from 0.48 +/- 0.02 mm2 in CON to 0.61 +/- 0.03 mm2. Mt and W/L were likewise increased, but collagen and elastin densities remained unchanged. CC and DC were not effected by this increase in aortic wall mass (CC: 0.143 +/- 0.009 CON, 0.147 +/- 0.014 mm2/kPa ANG; DC: 0.052 +/- 0.005 CON, 0.051 +/- 0.004 kPa-1 ANG). An increase in aortic wall mass resulting from chronic infusion of angiotensin II does not alter the dynamic compliance of the vessel under isobaric conditions.
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We describe a non-profit software package for the computerized analysis of ambulatory blood pressure monitoring (ABPM) recordings, in order to make it available to researchers in cardiovascular physiology, pharmacology and medicine. The first program, ABPM-FIT, can load data from several ABPM devices directly as they are stored on disk, making complicated data conversion steps unnecessary. The program performs conventional linear analyses of ABPM data automatically by calculation of mean, SD, load (the percentage of data above a chosen limit), and highest and lowest readings in user-defisned day and night periods. In addition, the area under the parameter-time curve (AUC) and the weighted mean (AUC/time) is calculated for all parameters monitored. In a second step, ABPM-FIT performs a rhythm analysis by fitting partial Fourier series to the data. Only those hormonics are included which significantly reduce the residual variance of the fit. The parameters of these functions (mesor, amplitudes, acrophases), values derived from the composed curves (maximum and minimum, AUC) and their slopes (e.g. maximal increase and decrease) are calculated automatically and, if desired, saved on disk. The second program, CV-SORT, loads groups of result files saved by ABPM-FIT, allows the extraction of parameters of interest for further analyses and creates spreadsheets containing the selected values from groups of patients. In addition, CV-SORT performs simple statistics, and calculates group mean circadian blood pressure and heart rate profiles from individual Fourier curves, with SD, confidence intervals or percentiles. The features of both programs are shown in exemplary analyses of ABPM recordings.
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TGR(mREN2)27 (TGR) rats are transgenic animals with an additional mouse renin gene, which leads to overactivity of the renin-angiotensin system. Adult TGR rats are characterized by fulminant hypertension, hypertensive end-organ damage, and an inverse circadian blood pressure pattern. To study the ontogenetic development of cardiovascular circadian rhythms, telemetric blood pressure transmitters were implanted in male Sprague-Dawley (SPRD, n = 5) and heterozygous, transgenic TGR rats before 5 weeks of age. The TGR received either drinking water or enalapril 10 mg/L in drinking water (n = 5 per group). Drug intake was measured throughout the study by computerized monitoring of drinking volume. Circadian patterns in blood pressure and heart rate were analyzed from 5 to 11 weeks of age. In the first week after transmitter implantation, blood pressure did not differ among SPRD, untreated, and enalapril-treated TGR rats. In parallel with the rise in blood pressure of untreated TGR rats, a continuous delay of the circadian acrophase (time of fitted blood pressure maximum) was observed, leading to a complete reversal of the rhythm in blood pressure at an age of 8 weeks. Enalapril reduced blood pressure at night, but was less effective during the day, presumably due to the drinking pattern of the animals, which ingested about 90% of their daily water intake during the nocturnal activity period. After discontinuation of treatment, blood pressure returned almost immediately to values found in untreated TGR rats. In conclusion, the inverse circadian blood pressure profile in TGR rats develops in parallel with the increase in blood pressure. Direct effects of the brain renin-angiotensin system may be involved in the disturbed circadian rhythmicity in TGR(mREN2)27 rats.
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The intrauterine and early postnatal periods represent key developmental stages in which an organism is highly susceptible to being permanently influenced by maternal factors and nutritional status. Strong evidence indicates that either undernutrition or overnutrition during development can predispose individuals to disease later in life, especially type 2 diabetes mellitus and obesity, a concept known as metabolic programming. Adipose tissue produces important signalling molecules that control energy and glucose homeostasis, including leptin and adiponectin. In addition to their well-characterized metabolic effects in adults, adipokines have been associated with metabolic programming by affecting different aspects of development. Therefore, alterations in the secretion or signalling of adipokines, caused by nutritional insults in early life, might lead to metabolic diseases in adulthood. This Review summarizes and discusses the potential role of several adipokines in inducing metabolic programming through their effects during development. The identification of the endocrine factors that act in early life to permanently influence metabolism represents a key step in understanding the mechanisms behind metabolic programming. Thus, future strategies aiming to prevent and treat these metabolic diseases can be designed, taking into consideration the relationship between adipokines and the developmental origins of health and disease.
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Aortic stiffness increases with advancing age more than doubling during the human lifespan and is a robust predictor of cardiovascular disease (CVD) clinical events independent of traditional risk factors. The aorta increases in diameter and length to accommodate growing body size and cardiac output in youth, but in middle- and older age the aorta continues to remodel to a larger diameter thinning the pool of permanent elastin fibers increasing intramural wall stress resulting in the transfer of load bearing onto stiffer collagen fibers. While aortic stiffening in early middle-age may be a compensatory mechanism to normalize intramural wall stress and therefore theoretically 'good' early in the lifespan, the negative clinical consequences of accelerated aortic stiffening beyond middle-age far outweigh any earlier physiological benefit. Indeed, aortic stiffness and the loss of the "Windkessel effect" with advancing age results in elevated pulsatile pressure and flow in downstream microvasculature that is associated with subclinical damage to high flow, low resistance organs such as brain, kidney, retina and heart. The mechanisms of aortic stiffness include alterations in extracellular matrix proteins (collagen deposition, elastin fragmentation), increased vasodilator tone (oxidative stress and inflammation-related reduced vasodilators and augmented vasoconstrictors; enhanced sympathetic activity), arterial calcification, vascular smooth muscle cell stiffness and extracellular matrix glycosaminoglycans. Given the rapidly aging population of the U.S., aortic stiffening will likely contribute to substantial CVD burden over the next 2-3 decades unless new therapeutic targets and interventions are identified to prevent the potential avalanche of clinical sequelae related to age-related aortic stiffness.
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The sympathetic nervous system prepares the body for ‘fight or flight’ responses and maintains homeostasis during daily activities such as exercise, eating a meal or regulation of body temperature. Sympathetic regulation of bodily functions requires the establishment and refinement of anatomically and functionally precise connections between postganglionic sympathetic neurons and peripheral organs distributed widely throughout the body. Mechanistic studies of key events in the formation of postganglionic sympathetic neurons during embryonic and early postnatal life, including axon growth, target innervation, neuron survival, and dendrite growth and synapse formation, have advanced the understanding of how neuronal development is shaped by interactions with peripheral tissues and organs. Recent progress has also been made in identifying how the cellular and molecular diversity of sympathetic neurons is established to meet the functional demands of peripheral organs. In this Review, we summarize current knowledge of signalling pathways underlying the development of the sympathetic nervous system. These findings have implications for unravelling the contribution of sympathetic dysfunction stemming, in part, from developmental perturbations to the pathophysiology of peripheral neuropathies and cardiovascular and metabolic disorders. The sympathetic regulation of bodily functions relies on precise connections between sympathetic neurons and peripheral organs. In this Review, Scott-Solomon and colleagues discuss the mechanisms underlying the development of the sympathetic nervous system and provide insight into disorders regulated by this branch of the nervous system.
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The benefits of consuming soy and its protein have been reported in many studies. However, its phytoestrogen content raises concerns about consumption during lactation and gestation We therefore examined the effects of soybean or soy protein isolate on the parameters-related cardiovascular pathophysiology in lactating mothers and their offsprings at weaning and adulthood. Lactating rats were divided: casein control (C); soy protein isolate (SPI); and soybean (S). At weaning, half of the litter received commercial ration up to 150 days. The levels of 17-β-estradiol and superoxide dismutase were low in the S mothers. For the SPI mothers, we observed a reduction of thiobarbituric acid reactive substances (TBARS). At weaning, atherogenic indices [1 = total cholesterol (TC)/HDL; 2 = LDL/HDL; 3 = TC-HDL/HDL)] decreased in the S and SPI offsprings compared to the casein control group; TBARS and antioxidant enzymes increased in the S offspring, while reduced/oxidized glutathione ratio increased in the SPI offspring, indicating lower oxidative stress. In adulthood, the SPI offspring showed an increase in liver cholesterol and atherogenic index 1 and 3 (vs. C and S) and 2 (vs. S). In addition, we found a decrease in catecholamines in the adrenal medulla and an increase in caffeine-stimulated secretion, but tyrosine hydroxylase expression remained constant. Maternal consumption of SPI during lactation worsened atherogenic indices of the offsprings in adulthood, which was associated with increased liver cholesterol and decreased catecholamines in the adrenal medulla. Soy consumption had no consistent long-term effects on the evaluated parameters compared to casein consumption. The data suggest that the consumption of SPI during lactation should be done with caution.
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Arterial stiffness, a leading marker of risk in hypertension, can be measured at material or structural levels, with the latter combining effects of the geometry and composition of the wall, including intramural organization. Numerous studies have shown that structural stiffness predicts outcomes in models that adjust for conventional risk factors. Elastic arteries, nearer to the heart, are most sensitive to effects of blood pressure and age, major determinants of stiffness. Stiffness is usually considered as an index of vascular aging, wherein individuals excessively affected by risk factor exposure represent early vascular aging, whereas those resistant to risk factors represent supernormal vascular aging. Stiffness affects the function of the brain and kidneys by increasing pulsatile loads within their microvascular beds, and the heart by increasing left ventricular systolic load; excessive pressure pulsatility also decreases diastolic pressure, necessary for coronary perfusion. Stiffness promotes inward remodeling of small arteries, which increases resistance, blood pressure, and in turn, central artery stiffness, thus creating an insidious feedback loop. Chronic antihypertensive treatments can reduce stiffness beyond passive reductions due to decreased blood pressure. Preventive drugs, such as lipid-lowering drugs and antidiabetic drugs, have additional effects on stiffness, independent of pressure. Newer anti-inflammatory drugs also have blood pressure independent effects. Reduction of stiffness is expected to confer benefit beyond the lowering of pressure, although this hypothesis is not yet proven. We summarize different steps for making arterial stiffness measurement a keystone in hypertension management and cardiovascular prevention as a whole.
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Blood pressure follows a daily rhythm, dipping during nocturnal sleep in humans. Attenuation of this dip (nondipping) is associated with increased risk of cardiovascular disease. Renal control of sodium homeostasis is essential for long-term blood pressure control. Sodium reabsorption and excretion have rhythms that rely on predictive/circadian as well as reactive adaptations. We explore how these rhythms might contribute to blood pressure rhythm in health and disease.
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Suboptimal conditions during prenatal and early postnatal development can increase risk of hypertension later in life. We studied consequences of a changed perinatal environment by initiating the cross-fostering of homozygous Ren-2 transgenic rat (TGR) offspring to normotensive, transgene-negative control mothers, and vice versa. We hypothesized that cross-fostering to a normotensive female can attenuate the development of malignant hypertension in TGR offspring (TGRx) and change their salt-sensitive response. Blood pressure (BP) was monitored by the telemetry system under normal salt intake, and BP responses to increased salt intake in the phase of established hypertension. Under normal salt conditions, BP was not markedly different in cross-fostered animals compared with controls. However, BP responses to 2% salt intake led to a stronger BP response in TGRx during the active phase when compared with the control TGR group. The TGRx also exhibited increased albuminuria, lower sodium excretion, and creatinine clearance under higher salt intake compared with control salt intake. Higher salt intake resulted in a significant increase of aldosterone concentrations only in the TGRx group; moreover, TGRx rats exhibited more pronounced renal injury compared with controls. In conclusion, our data indicate that cross-fostering in TGR not only did not attenuate the development of hypertension but, on the contrary, led to the deterioration of BP regulation, particularly due to exaggerated salt sensitivity and sodium retention in TGRx. Results underline the important role of the mother during lactation in postnatal development of the offspring, since these changes reflected different ion content in milk of a particular strain of rats.
Article
Background The aim of this study was to investigate the effect of long-term low salt diet on blood pressure and its underlying mechanisms. Methods Male Sprague-Dawley (SD) rats were divided into normal salt diet group (0.4%) and low salt diet group (0.04%). Blood pressure was measured with the non-invasive tail-cuff method. The contractile response of isolated mesenteric arteries was measured using a small vessel myograph. The effects on renal function of the intrarenal arterial infusion of candesartan (10 μg/kg/min), an angiotensin II receptor type 1 (AT1R) antagonist, were also measured. The expressions of renal AT1R and mesenteric arterial α1A, α1B, and α1D adrenergic receptors were quantified by immunoblotting. Plasma levels of angiotensin II were also measured. Results Systolic blood pressure was significantly increased after 8 weeks of low salt diet. There were no obvious differences in the renal structure between the low and normal salt diet groups. However, the plasma angiotensin II levels and renal AT1R expression were higher in low than normal salt diet group. The intrarenal arterial infusion of candesartan increased urine flow and sodium excretion to a greater extent in the low than normal salt diet group. The expressions of α1A and α1D, but not α1B, adrenergic receptors, and phenylephrine-induced contraction were increased in mesenteric arteries from the low salt, relative to the normal salt diet group. Conclusion Activation of the renin-angiotensin and sympathetic nervous systems may be involved in the pathogenesis of long-term low salt diet-induced hypertension.
Article
Activation of the mineralocorticoid receptor (MR) in the distal nephron by its ligand, aldosterone, plays an important role in sodium reabsorption and blood pressure regulation. However, expression of the MR goes beyond the kidney. It is expressed in a variety of other tissues in which its activation could lead to tissue injury. Indeed, MR activation in the cardiovascular (CV) system has been shown to promote hypertension, fibrosis, and inflammation. Pharmacological blockade of the MR has protective effects in several animal models of CV disease. Furthermore, the use of MR antagonists is beneficial for heart failure patients, preventing mortality and morbidity. A better understanding of the implications of the MR in the setting of CV diseases is critical for refining treatments and improving patient care. The mechanisms involved in the deleterious effects of MR activation are complex and include oxidative stress, inflammation, and fibrosis. This review will discuss the pathological role of the MR in the CV system and the major mechanisms underlying it.
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Systemic arterial hypertension is the most important modifiable risk factor for all-cause morbidity and mortality worldwide and is associated with an increased risk of cardiovascular disease (CVD). Fewer than half of those with hypertension are aware of their condition, and many others are aware but not treated or inadequately treated, although successful treatment of hypertension reduces the global burden of disease and mortality. The aetiology of hypertension involves the complex interplay of environmental and pathophysiological factors that affect multiple systems, as well as genetic predisposition. The evaluation of patients with hypertension includes accurate standardized blood pressure (BP) measurement, assessment of the patients’ predicted risk of atherosclerotic CVD and evidence of target-organ damage, and detection of secondary causes of hypertension and presence of comorbidities (such as CVD and kidney disease). Lifestyle changes, including dietary modifications and increased physical activity, are effective in lowering BP and preventing hypertension and its CVD sequelae. Pharmacological therapy is very effective in lowering BP and in preventing CVD outcomes in most patients; first-line antihypertensive medications include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, dihydropyridine calcium-channel blockers and thiazide diuretics.
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Accumulating evidence indicates that maternal high fat diet (HFD) is associated with metabolic syndrome and cardiovascular disease in adult offspring. The present study tested the hypothesis that maternal HFD modulates the brain renin-angiotensin system (RAS), oxidative stress and proinflammatory cytokines that alter angiotensin II and tumor necrosis factor-α (TNF-α) actions and sensitize the angiotensin II-elicited hypertensive response in adult offspring. All offspring were cross-fostered by dams on the same or opposite diet to yield 4 groups: offspring from normal fat control diet (CD)-fed dams suckled by CD-fed dams (OCC) or by HFD-fed dams (OCH), and offspring from HFD-fed dams fed HFD suckled by CD-fed dams (OHC) or by HFD-fed dams (OHH). RT-PCR analyses of the lamina terminalis (LT) and paraventricular nucleus (PVN) indicated upregulation of mRNA expression of several RAS components, NADPH oxidase and proinflammatory cytokines in 10-week old male offspring of dams with HFD during either pregnancy, lactation or both (OHC, OCH and OHH). These offspring also showed decreased cardiac baroreflex sensitivity and increased pressor responses to intracerebroventricular microinjection of either angiotensin II or TNF-α. Furthermore, chronic systemic infusion of angiotensin II resulted in enhanced upregulation of mRNA expression of RAS components, NADPH oxidase and proinflammatory cytokines in the LT and PVN and an augmented hypertensive response in the OHC, OCH and OHH groups when compared to the OCC. The results suggest that maternal HFD blunts cardiac baroreflex function and enhances pressor responses to angiotensin II or proinflammatory cytokines through upregulation of the brain RAS, oxidative stress and inflammation.
Article
The number of patients with adrenal aldosterone-producing adenomas (APAs) has gradually increased. However, even after adenoma resection, some patients still suffer from high systolic blood pressure (SBP), which is possibly due to great arterial remodeling. Moreover, mineralocorticoid receptors (MRs) were found to be expressed in vascular smooth muscle cells (VSMCs). This study aims to determine whether MR antagonism protects the aorta from aldosterone-induced aortic remolding. Male rats were subcutaneously implanted with an osmotic minipumps and randomly divided into four groups: control; aldosterone (1 μg/h); aldosterone plus a specific MR antagonist, eplerenone (100 mg/kg/day); and aldosterone plus a vasodilator, hydralazine (25 mg/kg/day). After 8 weeks of infusion, aortic smooth muscle cell proliferation and collagen deposition, as well as the MDM2 and TGF-β1 expression levels in the aorta, were examined. Model rats with APAs were successfully constructed. Compared with the control rats, the model rats exhibited (1) marked SBP elevation, (2) no significant alteration in aortic morphology, (3) increased VSMC proliferation and MDM2 expression in the aorta, and (4) enhanced total collagen and collagen III depositions in the aorta, accompanied with up-regulated expression of TGF-β1. These effects were significantly inhibited by co-administration with eplerenone but not with hydralazine. These findings suggested that specific MR antagonism protects the aorta from aldosterone-induced VSMC proliferation and collagen deposition.
Article
Physiological variables such as heart rate (HR) and blood pressure (BP) exhibit long-term circadian rhythms, which can be disturbed by shift work. On the other hand, short-term oscillations in HR and BP have a high prognostic value. Therefore, we aimed to determine if the short-term variability, complexity and entropy of HR and BP would be affected by a regular light/dark (LD) cycle and phase delay shifts of the LD cycle, leading to chronodisruption. Telemetry-monitored rats were exposed first to the regular LD cycle and then to shifts in LD for 8 weeks. On the basis of long-term HR and BP recording and evaluation, we found circadian rhythms in HR and BP variability, complexity and entropy under regular LD cycles. Short-term exposure to shifts disturbed circadian rhythms of HR and BP variability, complexity and entropy, indicating chronodisruption. The power of circadian rhythms was suppressed after 8 weeks of phase delay shifts. Long-term exposure to shifts increased variability (p = 0.007), complexity (p < 0.001) and dark-time entropy (p = 0.006) of HR but not BP. This is the first study demonstrating long-term recording and estimation of HR and BP variability, complexity and entropy in conscious rats exposed to irregular lighting conditions. After long-term phase delay shifts, short-term variability of HR was less predictable than in controls. This study suggests that changes in short-term HR and BP oscillations induced by long-term shift work can negatively affect cardiovascular health.
Article
Arsenic exposure can cause several cardiovascular diseases, including hypertension, atherosclerosis and microvascular disease. Earlier, we reported that arsenic-mediated enhancement of angiotensin II (AngII) signaling can impair vascular physiology. Here, we investigated whether the AT1 receptor (AT1R) blocker candesartan can ameliorate the arsenic-induced hypertensive vascular remodeling in rats and whether the amelioration could relate to attenuation in vascular AngII and TGF-β signaling. Rats were exposed to sodium arsenite (50 ppm) through drinking water for 90 consecutive days. Candesartan (1 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. Non-invasive blood pressure was recorded weekly in conscious rats, while AngII-induced change in mean arterial pressure in anaesthetized rats was measured by invasive method on the 91st day. On this day, blood was collected from other animals for measuring AngII level. Western blot of AT1, AT2 and TβRII receptors; ELISA of PTK, RasGAP, ERK-1/2, TGF-β and CTGF; immunohistochemistry of phosphorylated Smad3, Smad4 and collagen III, hydroxyproline/total collagen estimation, collagen deposition by Masson’s trichrome staining and histomorphometry were carried out in thoracic aorta. Arsenic increased non-invasive systolic, diastolic and mean arterial pressure. Further, AngII caused concentration-dependent incremental change in mean arterial pressure in the arsenic-exposed rats. Arsenic upregulated AT1 and TβRII receptor proteins; elevated the levels of PTK, ERK-1/2, TGF-β and CTGF, decreased RasGAP level and augmented the immunoreactivities of Smad3, Smad4 and collagen III. Arsenic also increased hydroxyproline/total collagen level, proliferation of collagen fibres and thickness of aortic wall and collagenous adventitia. Candesartan normalized blood pressure, regularized receptor expressions, MAP kinase and TGF-β signaling, restored collagen deposition and regressed aortic thickness. Our results demonstrate that candesartan can ameliorate the arsenic-mediated systemic hypertension and vascular remodeling in rats by regularizing the signaling pathways of AngII and TGF-β.
Article
Decreased oxygenation during pregnancy and early periods of ontogeny can affect normal body development and result in diseases in adulthood. The aim of this study was to use the model of prenatal intermittent hypoxia (PIH) and evaluate the effects of short-term hypoxia at the end of gestation on blood pressure (BP) control in adulthood. Wistar rats were exposed daily to PIH for 4 h during gestational day 19 and 20. In adult male rats, heart rate (HR), systolic BP and pulse pressure (PP) were acquired by radiotelemetry during 1 week. On the basis of HR variability and BP variability, sympathovagal balance (LF/HF) and spontaneous baroreflex sensitivity (sBRS) were evaluated. Systolic BP and PP were significantly elevated in PIH rats in comparison with control rats during the light and dark phase of the day, while LF/HF increased only during the light phase of the day. In contrast, sBRS tended to decrease only during the dark phase in PIH rats. In all measured and calculated parameters, significant circadian rhythms were present and were not affected by PIH. In conclusion, our data suggest that short intermittent hypoxia at the end of gestation can increase BP and PP via significant changes in LF/HF, which occur especially during the passive phase of the day. Results suggest that minor changes in the autonomous nervous system activity induced by environmental conditions during the perinatal period may contribute to development of hypertension in adulthood.Hypertension Research advance online publication, 25 February 2016; doi:10.1038/hr.2016.21.
Article
Background— Previous studies have demonstrated the development of cardiac fibrosis in aldosterone (Aldo)–salt hypertensive rats. Our aim was to determine the effects of Aldo and the Aldo receptor antagonist eplerenone (Epl) on in vivo mechanical properties of the carotid artery using echo-tracking system. Methods and Results— Aldo was administered (1 μg/h) in uninephrectomized Sprague-Dawley rats (SD) receiving a high-salt diet from 8 to 12 weeks of age. Uninephrectomized control SD rats received a normal salt diet without Aldo. Three groups of Aldo-salt rats were treated with 1, 10, or 30 mg/kg⁻¹ · d⁻¹ of Epl by gavage. Elasticity was measured by elastic modulus (Einc)-wall stress curves using medial cross-sectional area (MCSA). The structure of the arterial wall was analyzed by histomorphometry (elastin and collagen), immunohistochemistry (EIIIA fibronectin, Fn), and Northern blot (collagens I and III). Aldo produced increased systolic arterial pressure, pulse pressure, Einc, MCSA, and EIIIA Fn with no change in wall stress or elastin and collagen densities compared with controls without Aldo. No differences in collagen mRNA levels were detected between groups. Epl blunted the increase in pulse pressure in Aldo rats and normalized Einc-wall stress curves, MCSA, and EIIIA Fn. These effects were dose dependent and not accompanied by a reduction in wall stress. Conclusions— Aldo is able to increase arterial stiffness associated with Fn accumulation, independently of wall stress. The preventive effects of Epl suggest a direct role for mineralocorticoid receptors in mechanical and structural alterations of large vessels in rat hyperaldosteronism.
Article
Cardiovascular diseases (CVD) and diabetes still represent the main cause of mortality and morbidity in the industrialized world. Low birth weight (LBW), caused by intrauterine growth restriction (IUGR), was recently known to be associated with increased rates of CVD and non-insulin dependent diabetes in adult life (Barker's hypothesis). Well-established animal models have shown that environmentally induced IUGR (diet, diabetes, hormone exposure, hypoxia) increases the risk of a variety of diseases later in life with similar phenotypic outcomes in target organs. This suggests that a range of disruptions in fetal and postnatal growth may act through common pathways to regulate the developmental programming and produce a similar adult phenotype. The identification of all involved signaling cascades, underlying the physiopathology of these damages in IUGR fetuses, with their influence on adult health, is still far from satisfactory. The endothelium may be important for long-term remodeling and in the control of elastic properties of the arterial wall. Several clinical and experimental studies showed that IUGR fetuses, neonates, children and adolescents present signs of endothelial dysfunction, valuated by aorta intima media thickness, carotid intima media thickness and stiffness, central pulse wave velocity, brachial artery flow-mediated dilation, laser Doppler skin perfusion and by the measure of arterial blood pressure. In utero identification of high risk fetuses and long-term follow-up are necessary to assess the effects of interventions aimed at preventing pregnancy-induced hypertension, reducing maternal obesity, encouraging a healthy life style and preventing childhood obesity on adult blood pressure and cardiovascular disease in later life. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Article
Fetal development is a critical period for shaping the lifelong health of an individual. However, the fetus is susceptible to internal and external stimuli that can lead to adverse long-term health consequences. Glucocorticoids are an important developmental switch, driving changes in gene regulation that are necessary for normal growth and maturation. The fetal hypothalamic-pituitary-adrenal (HPA) axis is particularly susceptible to long-term programming by glucocorticoids; these effects can persist throughout the life of an organism. Dysfunction of the HPA axis as a result of fetal programming has been associated with impaired brain growth, altered behaviour and increased susceptibility to chronic disease (such as metabolic and cardiovascular disease). Moreover, the effects of glucocorticoid-mediated programming are evident in subsequent generations, and transmission of these changes can occur through both maternal and paternal lineages.
Article
Primary and secondary hypertension differ with regard to circadian blood pressure (BP) profiles. To evaluate the contribution of the renin-angiotensin system (RAS) to circadian BP regulation, we studied cardiovascular effects of the angiotensin II (AII) receptor antagonist losartan and the angiotensin-converting enzyme (ACE) inhibitor enalapril in animal models of primary and secondary hypertension after morning and evening dosing. Systolic/diastolic BP (SBP/DBP) and heart rate (HR) were measured telemetrically in spontaneously hypertensive rats (SHR) and transgenic hypertensive rats (TGR[mRen-2]27). Losartan (0.3 to 30 mg/kg) or enalapril maleate (10 mg/kg) were injected intraperitoneally (i.p.) either at 0700 or 1900 h. Baseline SBP/DBP and HR showed significant circadian rhythmicity in both strains. The 24-h means in SBP/DBP were 190/127 mm Hg in SHR and 200/139 mm Hg in TGR. TGR showed a reversed circadian profile in BP, with peaks occurring during the daily resting period, whereas HR peaked at night. Losartan reduced BP dose dependently; reductions in TGR were significantly greater and obtained at 30-fold lower doses than in SHR. Maximum decreases induced by losartan were similar to those induced with enalapril 10 mg/kg. Both drugs reduced BP in TGR more effectively when applied at 0700 than at 1900 h, resulting in a normalized circadian BP profile. Our results demonstrate that the RAS is involved in both the pathomechanism of hypertension and in the inverse circadian BP pressure pattern in TGR.
Article
PRIMARY hypertension is a polygenic condition in which blood pressure is enigmatically elevated; it remains a leading cause of cardiovascular disease and death due to cerebral haemorrhage, cardiac failure and kidney disease. The genes for several of the proteins involved in blood pressure homeostasis have been cloned and characterized1-8, including those of the renin-angiotensin system, which plays a central part in blood pressure control9-10. Here we describe the introduction of the mouse Ren-2 renin gene3,11-13 into the genome of the rat and demonstrate that expression of this gene causes severe hypertension. These trans-genic animals represent a model for hypertension in which the genetic basis for the disease is known. Further, as the transgenic animals do not overexpress active renin in the kidney and have low levels of active renin in their plasma, they also provide a new model for low-renin hypertension.
Article
Neurohumoral control of fetal, neonatal, and adult cardiovascular functions have been reviewed. Resting fetal heart rate remains fairly constant but neonatal heart rate declines progressively, reaching adult levels within six to eight weeks; systemic arterial pressure rises while pulmonary pressure falls to adult levels within the first week after birth. Sympathetic and parasympathetic control of circulatory functions matures at different rates during fetal and neonatal development; the sympathetic system becomes active earlier in fetal life than does the parasympathetic system. After birth, the parasympathetic tone of the resting heart rate rises to adult levels while adrenergic tone decreases. Despite changing autonomic activities, resting heart rate is set at given levels through alterations in intrinsic control. In the fetus, peripheral circulation is under neurohumoral tone of increasing magnitude; after birth, neurohumoral tone declines progressively, reaching levels comparable to those of adult nonpregnant sheep. Fetal cardiovascular response to neurotransmitters increases with age because of maturation of the effector system. The pulmonary bed responds primarily to acetylcholine whereas the systemic circulation responds to norepinephrine. After birth, the neonatal cardiovascular system becomes four to five times more sensitive to the action of neurotransmitters mainly because of closure of vascular shunts and elimination of umbilicoplacental circulation. In the neonate and adult, the pulmonary vascular bed loses its reactivity to neurotransmitters.
Article
The ontogeny of functional sympathetic neural, adrenal medullary, and extra-adrenal components of adrenergic control of heart rate was investigated in borderline hypertensive rats exposed to either high or low sodium chloride (NaCl) from conception through weaning. Borderline hypertensive rats were produced by mating spontaneously hypertensive females with normotensive Wistar-Kyoto males. Females were maintained on diets containing either low (0.12% NaCl) or high (3% NaCl) dietary NaCl throughout pregnancy and lactation. At 28 days of age, baseline heart rates recorded from awake and unrestrained pups did not differ between low and high NaCl-exposed pups. Overall sympathetic tone, inferred from heart rate change after beta 1-adrenergic blockade with atenolol, did not differ between high and low NaCl-exposed pups. Early NaCl exposure did not alter the neural component of sympathetic control of heart rate as inferred from heart rate decrease after bretylium tosylate. Parasympathetic nervous system control, as reflected by tachycardic response to muscarinic receptor blockade with atropine methyl nitrate was also unchanged by early NaCl exposure. The adrenal catecholamine component of sympathetic control of heart rate was inferred from bradycardia following administration of the ganglion blocking agent, chlorisondamine, to pups pretreated with bretylium and atropine methyl nitrate. Pups exposed to low NaCl showed increased adrenal control of heart rate compared to high NaCl-exposed pups. The influence of residual catecholamines on heart rate was inferred from bradycardia following administration of the beta 1-adrenergic receptor blocking agent, atenolol, in pups pretreated with bretylium, atropine methyl nitrate, and chlorisondamine. Residual catecholamine influence was greater in rats exposed to high NaCl.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Brattleboro rats without diabetes insipidus were subjected to sodium chloride enrichment (20-fold increase in dietary salt) at various stages of their development. Salt supplementation in the adult rat produced higher systolic blood pressure (SBP), particularly in males (142 +/- 3 versus 110 +/- 3 mmHg in control. The blood pressures of females on salt-supplemented diets during pregnancy decreased from 136 +/- 1 to 121 +/- 2 mmHg, although throughout this period the blood pressures for these rats were greater than for the control pregnant rats. Pregnant females on salt-supplemented diets also showed higher sodium concentrations in the amniotic fluid compared with controls (155 +/- 3.4 versus 134.1 +/- 6.0 mmol/l). Salt supplemented lactating mothers produced milk with similar sodium concentrations to those of the controls, but the urinary sodium concentrations of pups suckling on the former were greater than in the controls. It is concluded that the suckling pups were also salt-enriched. Rats were submitted to salt-enriched regimes in utero, during suckling, post-weaning and post-pubertally, or permutations thereof. Salt supplementation post-weaning led to consistent elevation in arterial blood pressure with males being more susceptible than females. The degree of elevation was increased if the salt-supplement was present during suckling (132 +/- 1 versus 112 +/- 1 mmHg) and was greatest when the salt-supplemented regime was administered both in utero and during the post-weaning period (154 +/- 2 versus 112 +/- 1 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The role of the renin-angiotensin system in the stimulation and termination of dehydration-induced drinking was examined in the rat. Rats dehydrated for 48 h had significantly elevated renin, angiotensin II, plasma Na+ concentration, osmolality, and hematocrit when compared with replete controls. Although plasma Na+ concentration, osmolality, and hematocrit of dehydrated rats had returned to control replete levels by 2-4 h after the return of water, the plasma renin and angiotensin II levels exhibited a further increase on rehydration and remained significantly above dehydration levels for 2-4 h after the return of water. The levels of renin and angiotensin II in rehydrated rats were maintained at levels in excess of the dipsogenic threshold for circulating angiotensin II during the 8-h period after rehydration, indicating that termination of the drinking is not dependent on a reduction of circulating angiotensin II. Finally, rehydrated rats did not drink significantly more than replete controls in the 1- to 8-h postrehydration period despite plasma angiotensin II levels in excess of that of the dipsogenic threshold for angiotensin II, indicating that mechanisms exist which override the dipsogenic action of circulating angiotensin II.
Article
We investigated the dose-dependent cardiovascular effects of enalaprilat at different dosing times in two animal models of hypertension. Blood pressure (BP) and heart rate (HR) were measured telemetrically in 5 spontaneously hypertensive rats (SHR) and in 5 transgenic hypertensive rats (TGR) after intraperitoneal (i.p.) injection of enalaprilat either at 700 h or at 1900 h. In SHR, dosing of enalaprilat at the beginning of the resting period, i.e., at 700 h, significantly reduced BP but did not influence HR. After dosing at 1900 h, BP was unchanged, whereas HR increased, which might have resulted from reflexly increased sympathetic tone. In TGR, enalaprilat at either dosing time decreased BP dose dependently and to a higher extent than in SHR, but the effects were more pronounced after morning than after evening dosing. These findings demonstrate that in two animal models of hypertension the antihypertensive effects of enalaprilat depended on the time of drug dosing.
Article
The purpose of this study was to test the hypothesis that chronic infusion of angiotensin II (ANG II) in rabbits shifts or resets baroreflex control of heart rate to a higher pressure level via a mechanism that is independent of the hypertension that is produced. The baroreflex relationship between arterial pressure and heart rate was assessed by first infusing progressively increasing doses of nitroprusside (3, 6, 12, 24, and 48 micrograms.kg-1 x min-1) to lower pressure and then increasing doses of phenylephrine (0.5, 1, 2, 4, and 8 micrograms.kg-1 x min-1) to raise pressure. Two weeks of intravenous ANG II infusion (20 ng.kg-1 x min-1) increased plasma ANG II levels from 9 +/- 1 to 146 +/- 24 pg/ml (P < 0.05), increased arterial pressure from 62 +/- 2 to 95 +/- 2 mmHg (P < 0.05), and transiently increased heart rate. The baroreflex was shifted to a higher pressure level after 30 min and 1, 3, 7, 9, and 14 days of ANG II infusion. Thirty minutes after the ANG II infusion on days 1, 7, and 14 was stopped, arterial pressure decreased, and the baroreflex shifted back to control, indicating that ANG II was required for the resetting that was produced. However, when the ANG II infusion was continued and arterial pressure was instead reduced for 30 min by infusing nitroprusside on days 3 and 9, the baroreflex relationship between arterial pressure and heart rate remained positioned at a higher pressure level.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The expression of the sarcoplasmic reticulum (SR) Ca(2+)-ATPase gene and the SR Ca2+ pump function were investigated in thoracic aortas of 5- and 17-week-old normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). The relative level of the two isoforms of SR Ca(2+)-ATPase mRNA expressed in the aorta (i.e., SERCA 2a and SERCA 2b) was determined by quantitative S1 nuclease protection analysis and normalized to the level of alpha-smooth muscle (alpha-Sm) actin mRNA. The level of alpha-Sm actin mRNA itself was normalized to the level of 18S ribosomal RNA using slot-blot hybridization assays. Total SR Ca2+ pump activity was estimated by measuring the rate of oxalate-supported Ca2+ uptake in homogenates. At 5 weeks, the amount of SERCA 2a and SERCA 2b mRNA, normalized to 18S ribosomal RNA, and the ratio of alpha-Sm actin mRNA to 18S RNA were identical in SHR and WKY rats. The Ca2+ pump activity was similar in the two strains of rats at 5 weeks. From 5 to 17 weeks, the amount of SERCA 2a mRNA increased in both strains while the level of SERCA 2b mRNA remained constant. The Ca2+ pump activity was unchanged in SHRs and tended to decrease in WKY rats. Accordingly, the change in the ratio of the SR Ca(2+)-ATPase mRNA isoforms does not appear to influence SR function. The level of alpha-Sm actin mRNA and SERCA 2a mRNA increased in parallel from 5 to 17 weeks in both strains.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Although rapid growth of the heart during early postnatal development ceases with maturation of the organism, the potential for cardiomyocyte growth is not lost and may be observed even in senescent hearts. Rapid developmental heart growth is accompanied by a proportional growth of capillaries but not always of larger vessels, and thus coronary vascular resistance gradually increases. Growth of adult hearts can be enhanced by thyroid hormones, catecholamines and the renin-angiotensin system hormones, but these do not always stimulate growth of coronary vessels. Likewise, chronic exposure to hypoxia leads to growth, mainly of the right ventricle and its vessels but without vascular growth elsewhere in the heart. On the other hand, ischaemia is a potent stimulus for the release of various growth factors involved in the development of collateral circulation. Heart hypertrophy develops in response to training, pressure or volume overload. Training usually leads to growth of larger coronary vessels but little growth of capillaries, except in young animals. However, growth of the capillary bed, but not the resistance vasculature capacity, can be induced by either increased coronary blood flow, bradycardia (electrically or pharmacologically induced) or increased inotropism, all of which are involved in the training stimulus. Thus, what actually promotes growth of larger vessels as opposed to capillaries in training is unclear. Pressure overload hypertrophy is mediated by both the renin-angiotensin system and the response of cardiomyocytes to stretch; both lead to activation of early oncogenes (c-fos, c-jun, c-myc) and angiotensin II activates several protein kinases involved in cell growth. In this condition, growth of larger vessels is inadequate, although some capillary growth may occur. Volume overload leads to cardiomyocyte hypertrophy and hyperplasia and some increase in vascular supply. Deficits in capillary supply in pressure or volume overload hypertrophy can be reversed by chronic administration of ACE inhibitors, dipyridamole, the bradycardic drug alinidine or pacing-induced bradycardia respectively, but in neither case is training effective. Mechanical and humoral factors are involved in growth of cardiomyocytes and vessels. For cardiomyocytes, stretch is most important, activating oncogenes, protein kinases and possibly the inositol phosphate pathway, but not ion channels, with regulation by the balance of angiotensin II, TGF-beta 1 and IGF-1, but not FGFs. For vessels, growth is stimulated by stretch and shear stress, possibly with involvement of VEGF. Increased shear stress disrupts the glycocalyx on the luminal side of vessels and releases plasminogen activator and metalloproteinases which disrupt the basement membrane and enable endothelial cell migration and proliferation. It also causes rearrangement of the endothelial cytoskeleton and transmission of mechanical signals to the abluminal side disturbing extracellular matrix and causing distortion of capillary basement membrane. Stretch acting from the abluminal side has a similar effect resulting also in basement membrane disruption and endothelial cell proliferation.
Article
The hypothesis that endogenous angiotensin II (Ang II) chronically supports baroreflex control of lumbar sympathetic nerve activity (LSNA) and heart rate (HR) via AT1 but not AT2 receptors was tested in conscious, normotensive rats. Rats were fed either a sodium deficient diet (LS) to increase circulating Ang II or a high-sodium diet (HS) for 2 to 3 weeks. One to two days after surgery to implant catheters and nerve electrodes, baroreflex curves were produced before and 40 minutes after intravenous administration of the AT1 antagonist losartan (10 mg/kg) or the AT2 antagonist PD123319 (500 micrograms/kg + 50 micrograms.kg-1.min-1). Mean arterial pressure (MAP) after losartan was maintained at basal levels with methoxamine. Forty minutes after losartan in LS rats, LSNA (46 +/- 5 to 22 +/- 1% max) and HR (414 +/- 7 to 387 +/- 8 bpm) were decreased (P < .05). Losartan decreased reflex control of LSNA more in LS than in HS rats (P < .05), as indicated by reductions in maximum LSNA (98 +/- 2 to 78 +/- 3% max) and minimum LSNA (42 +/- 5 to 21 +/- 5% max). Losartan also shifted reflex control of LSNA to a lower pressure in both groups, but the effect was larger in LS rats (-21 +/- 3 [LS] versus -9 +/- 2 [HS] mm Hg at basal LSNA; P < .05). Maximum gain was unaltered in either group. Similarly, losartan reduced maximum HR (534 +/- 6 to 495 +/- 9 bpm) and shifted the HR curve leftward (114 +/- 5 to 105 +/- 4 mm Hg) in LS but not in HS rats. In general, no changes were observed in MAP or baroreflex control of LSNA and HR after PD123319 in LS rats. These results suggest that in conscious, normotensive LS rats, endogenous Ang II supports LSNA and HR over a wide MAP range via AT1 but not AT2 receptors.
Article
1. The aim of the present study was to compare electrolyte handling in naturally reared neonatal spontaneously hypertensive rats (SHR) with those reared by a Wistar-Kyoto (WKY) rat foster mother (denoted SHRX), as cross-fostering SHR pups to a WKY rat dam lowers adult blood pressure in the SHR. 2. The electrolyte content of WKY rat and SHR dams’ milk was determined and electrolyte intake and urinary excretion rates were calculated in both naturally reared and cross-fostered WKY rat and SHR pups. 3. The milk sodium concentration fell in both strains (WKY rat: 31.8 ± 2.0 to 15.2 ± 1.2 mmol/L; SHR 31.9 ± 2.5 to 18.2 ± 1.6 mmol/L; P < 0.001), as did potassium (P < 0.001), over lactation, but there were no differences between strains. Calcium and magnesium concentrations increased (P< 0.001), although SHR dam's milk contained less calcium (P < 0.001) than that of WKY rat dams during the third week of lactation. 4. Spontaneously hypertensive rat pups ingested less milk (P<0.05) than WKY rat pups; therefore, their cumulative sodium intake over postnatal days 4–15 was significantly lower than that of WKY rat pups (WKY rat vs SHR: 84.4 ± 3.6 vs 59.7 ± 2.6 μmol/g bodyweight, respectively; P < 0.05) and fostered SHRX pups (77.7 ± 7.0 μmol/g bodyweight; P < 0.05). Potassium and magnesium intakes were comparable between SHR, WKY rat and SHRX pups, but SHR pups ingested significantly less calcium than either WKY rat pups (136.1 ± 6.4 vs 200.1 ± 9.5p, mol/g bodyweight, respectively; P<0.05) or SHRX pups (200.0 ± 18.0 μmol/g bodyweight; P<0.05). 5. These data show that the neonatal SHR experiences a period of sodium deficiency during the developmental stage when cross-fostering is effective in lowering blood pressure. This is consistent with the reported up-regulation of the renin-angiotensin system observed in SHR at this time and may have a long-term influence on blood pressure.
Article
Saanen goats were used to determine the effect of the alteration of the intramammary Na to K ratio on milk secretion. Udders were infused via the teat with an isosmotic solution that was high in Na or K to increase or decrease, respectively, the intramammary Na to K ratio. Control glands received an isosmotic sucrose solution. To ensure that the results were not confounded by a decrease in milk secretion as a result of enhanced permeability of mammary tight junctions, the latter was monitored throughout the experiments. An increase in the Na to K ratio caused a significant transient reduction in milk secretion. Therefore, an increase in Na and a decrease in K in milk, commonly observed as a result of the leakiness of tight junctions, may at least partially explain the reduction in milk secretion when the permeability of tight junctions was increased. These experiments further showed that the adverse effects on secretion were not due to a high intracellular concentration per se but were related to a change in the Na to K ratio because a reduction in the ratio also lowered milk secretion. These data support the evidence for activity of Na(+)-K(+)-ATPase in the basolateral secretory cell membranes and passive movement of these ions across the apical cell membranes.
Article
1. Multiple sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and two types of sarcoplasmic reticulum Ca2+ channels, the ryanodine receptor and the inositol 1,4,5 triphosphate (IP3) receptor are expressed. The heterogeneity of the Ca2+ pumps and Ca2+ channels in vascular cells will be discussed. 2. An age-related change in expression of the SERCA isoforms is observed in smooth muscle cells. 3. The sarcoplasmic reticulum Ca2+-uptake rate and the level of SERCA 2 mRNA are different in thoracic than in abdominal aortas and in aortas from spontaneously hypertensive rats than from normotensive rats. 4. Proliferation of vascular smooth muscle cells is associated with major changes in intracellular Ca2+-handling mechanisms.
Article
The reactivity of old hypertensive rat aortas has not been investigated in relation to each phenotype of the blood pressure curve, mean arterial pressure (MAP), and pulse pressure (PP). Aortic reactivities from 3- to 78-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were studied with the use of organ chambers and invasive blood pressure, carotid diameter, and histomorphometry. MAP and PP were elevated in SHR, but at 78 weeks, a selective increase of PP without further MAP increase was observed for the same carotid diameter as WKY. Aortic relaxation in response to carbamylcholine decreased similarly with age in both strains. With (+) or without (-) endothelium (E), maximal developed tension (MDT) under KCl increased linearly with age in SHR, proportionally to wall thickness and MAP increase. Under norepinephrine (NE), MDT of E(-) aortas from SHR and controls increased with age and reached plateaus at 12 weeks, whereas MDT of E(+) aortas from SHR increased linearly with age. Because the NE-induced MDT was higher for E(-) than E(+), the difference estimated endothelial function. This difference reached plateaus from 12 to 78 weeks in WKY but was abolished beyond 12 weeks in SHR, a finding also observed under NO-synthase inhibition. In old hypertensive rats, (1) increased KCl reactivity is endothelium independent but influenced by the MAP-dependent aortic hypertrophy with resulting increased vascular smooth muscle reactivity, whereas (2) increased NE reactivity is endothelium dependent in association with increased PP, altered endothelial function, and extracellular matrix, with resulting enhanced intrinsic arterial stiffness.
Article
To determine the effects of physiological alterations in endogenous angiotensin II activity on basal renal sympathetic nerve activity (RSNA) and its arterial baroreflex regulation, angiotensin II type 1 receptor antagonists were microinjected into the rostral ventrolateral medulla of anesthetized rats consuming a low, normal, or high sodium diet that were instrumented for simultaneous measurement of arterial pressure and RSNA. Plasma renin activity was increased in rats fed a low sodium diet and decreased in those fed a high sodium diet. Losartan (50, 100, and 200 pmol) decreased heart rate and RSNA (but not mean arterial pressure) dose-dependently; the responses were significantly greater in rats fed a low sodium diet than in those fed a high sodium diet. Candesartan (1, 2, and 10 pmol) decreased mean arterial pressure, heart rate, and RSNA dose-dependently; the responses were significantly greater in rats fed a low sodium diet than in those fed a normal or high sodium diet. [D-Ala(7)]Angiotensin-(1-7) (100, 200, and 1000 pmol) did not affect mean arterial pressure, heart rate, or RSNA in rats fed either a low or a high sodium diet. In rats fed a low sodium diet, candesartan reset the arterial baroreflex control of RSNA to a lower level of arterial pressure, and in rats with congestive heart failure, candesartan increased the arterial baroreflex gain of RSNA. Physiological alterations in the endogenous activity of the renin-angiotensin system influence the bradycardic, vasodepressor, and renal sympathoinhibitory responses to rostral ventrolateral medulla injection of antagonists to angiotensin II type 1 receptors but not to angiotensin-(1-7) receptors.
Article
Many factors are involved in the development of orthostatic intolerance after real or simulated weightlessness. The aim of our study was to compare the effects of 7-day head-down bed rest (HDBR) in eight women and eight men on the spontaneous baroreflex sensitivity (standard spectral method and new time-frequency algorithm) during lower body negative pressure (LBNP) tests. Results obtained before HDBR have shown in women, compared to men, higher heart rate, lower blood pressure, higher parasympathetic modulation at rest and greater decrease in baroreflex sensitivity with greater increase in sympathetic activity during LBNP. After HDBR, we observed in both men and women a dramatic decrease in orthostatic tolerance (7.0 min at R + 1 vs. 10.0 min, p<0.05, at BDC-1 in men; 5.4 vs. 9.0 min, p<0.05, in women) together with a decrease in plasma volume (-9.1 +/- 0.9% in men, -9.5 +/- 1.4% in women) and in spontaneous baroreflex sensitivity without gender effect. After HDBR, at the highest level of LBNP, diastolic blood pressure increased in men (+5.6 +/- 1.3 mm Hg) and decreased in women (-1.0 +/- 2.7 mm Hg) with a gender difference (p<0.05). This result suggests impaired vasoconstriction in women after HDBR. Neither endocrine response nor alterations to the cardiac baroreflex can explain gender differences in orthostatic tolerance after HDBR as reported by previous studies. Further studies need to be conducted in order to obtain a more precise analysis of gender difference in arteriolar vasoconstriction after HDBR. The time frequency method we developed to study changes in spontaneous baroreflex might be applied to the analysis of LBNP tests.