Biomedical subjects

S Oparil

Publications and source records attributed to S Oparil.

At least 199 records · Page 11Linked to original sources

PubMed1989

Dietary NaCl loading enhances antihypertensive effect of guanabenz in spontaneously hypertensive rats.

Our previous studies demonstrated that high dietary NaCl intake causes increases in blood pressure and plasma norepinephrine (NE) levels and a decrease in NE release associated with local upregulation of alpha 2-adrenoceptor number in the anterior hypothalamic area (AHA) of NaCl-sensitive spontaneously hypertensive rats (SHR-S). Further, acute microinjection of clonidine into the AHA of SHR-S fed a high NaCl diet resulted in greater depressor and bradycardic responses than in SHR-S receiving a normal NaCl diet. The current study tested the hypothesis that the antihypertensive effect of chronic systemic administration of guanabenz (0.24 micrograms/kg/min, IV) is enhanced in SHR-S maintained on a high (8%) NaCl diet than in control rats on a normal (1% NaCl) diet. After two weeks on the diets, mean arterial pressure (MAP) and heart rate (HR) were measured and blood for NE and epinephrine (E) assay was collected from intra-arterial cannulas in conscious, unrestrained rats. The ratio of left ventricle and septum to body weight (LV + S/BW) was determined. Chronic infusion of guanabenz significantly decreased MAP (P less than .05), HR (P less than .01) and LV + S/BW (P less than .01) in 8% NaCl fed SHR-S, but not in 1% NaCl fed SHR-S (P greater than .1). Guanabenz tended to reduce plasma NE levels in 8% NaCl fed SHR-S (.1 greater than P greater than .05), but not in 1% NaCl fed rats (P greater than .1).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Central mechanisms of hypertension.

Central monoaminergic neurons, particularly noradrenergic neurons, are involved in the pathogenesis of hypertension. Dietary NaCl supplementation in NaCl-sensitive spontaneously hypertensive rats (SHR-S) elevates blood pressure, increases peripheral sympathetic nervous system activity, and depresses endogenous noradrenaline stores and noradrenaline release in the anterior hypothalamus (AHA). NaCl-resistant spontaneously hypertensive rats (SHR-R) and normotensive Wistar-Kyoto (WKY) rats are resistant to the NaCl-induced alterations in blood pressure and central and peripheral noradrenergic activity, whereas uninephrectomized Sprague-Dawley rats treated with DOCA + NaCl and Dahl-S rats receiving dietary NaCl supplementation develop NaCl-induced increments in blood pressure, but not depressed AHA noradrenaline release. The AHA is a major cardiovascular regulatory region, and depressor responses elicited by pharmacological (alpha 2-adrenoceptor) stimulation of this area are exaggerated in SHR-S fed a high NaCl diet compared to SHR-S fed a basal diet and SHR-R and WKY fed a high or basal NaCl diet. alpha 2-Adrenoceptors in the AHA are increased in number in SHR-S fed a high NaCl diet, presumably reflecting upregulation in response to reduced local noradrenaline release. These findings are consistent with the hypothesis that decreased noradrenergic activity of sympathoinhibitory neurons in the AHA may mediate the exacerbation in hypertension that occurs in SHR-S during dietary NaCl supplementation.

Animals↗

PubMed1989

Vasopressin lowers pulmonary artery pressure in hypoxic rats by releasing atrial natriuretic peptide.

The authors previously demonstrated that arginine vasopressin (AVP) lowers pulmonary artery pressure in rats with hypoxic pulmonary hypertension by activation of the V1 receptor. The pulmonary depressor effect of AVP in hypoxia-adapted rats is not due to its effect on cardiac output. The current study tested two alternative hypotheses: that AVP lowers pulmonary artery pressure in the hypoxia-adapted lung by (1) dilating pulmonary vasculature directly, or (2) releasing atrial natriuretic peptide (ANP) from the heart. The first hypothesis was tested by injecting AVP into the pulmonary arteries of isolated, buffer perfused lungs and monitoring pulmonary artery pressure, and by exposing preconstricted pulmonary artery rings to graded doses of AVP and monitoring the tension generated. AVP caused minimal vasodilation in perfused lungs and only a small vasodilator effect in pulmonary artery rings. The second hypothesis was tested by injecting AVP (160 ng/kg) or vehicle intravenously in conscious hypoxia-adapted (4 weeks) or air control rats and measuring ANP in arterial blood and atria, and by testing pretreatment with the V1 receptor antagonist d(CH2)5 Tyr(Me)AVP (130 micrograms/kg) on the AVP-induced increase in plasma ANP. AVP produced a 7-fold increase in plasma ANP (209 +/- 33 to 1346 +/- 233 pg/ml; p less than 0.05) in hypoxia-adapted rats and a 5-fold increase in ANP (122 +/- 22 to 573 +/- 174 pg/ml; p less than 0.05) in air controls. ANP release was abolished by pretreatment of both groups with d(CH2)5 Tyr(Me)AVP. The AVP-induced ANP release came mainly from left atrium. These data strongly suggest that the pulmonary depressor effects of AVP in hypoxia-adapted rats is due to augmented V1 receptor-induced release of ANP from left atrium.

Animals↗

PubMed1989

Atrial natriuretic peptide lowers pulmonary arterial pressure in patients with high altitude disease.

The authors' previous studies have demonstrated that IV administration of atrial natriuretic peptide (ANP) produces a dose dependent decrease in pulmonary arterial pressure in rats adapted to chronic hypoxia. To examine the effects of ANP on chronic hypoxic pulmonary hypertension in man, alpha-human ANP (200 micrograms) was infused (20 micrograms/min X 10 min) into the right atrium via a Swan-Ganz catheter in four patients with pulmonary hypertension of high altitude. Following the infusion, pulmonary arterial pressure fell gradually and remained depressed for 1 hour. Peak reductions in pulmonary arterial systolic pressure (PASP) and mean pulmonary arterial pressure (MPAP) were 23% and 30%, respectively. Systemic arterial pressure, cardiac output and cardiac index also tended to decrease, but these changes did not reach statistical significance. The data suggest that ANP is useful in the treatment of chronic hypoxic pulmonary hypertension in man.

Aldosterone↗

PubMed1989

Hypoxia stimulates endothelial cell angiotensin-converting enzyme antigen synthesis.

Previous studies from our laboratory indicate that exposure of the rat to chronic normobaric hypoxia reduces stores of active angiotensin-converting enzyme (ACE) in the lung. This study assesses directly the effects of hypoxia on ACE synthesis in cultured porcine pulmonary artery endothelial cells. Confluent cultures were exposed to hypoxia [2.5% O2 at 1 atmosphere (atm)] in a triple gas incubator; controls were cultured in normoxic conditions. After 24-, 48-, and 72-h exposure to hypoxic or normoxic conditions, followed by incubation with [35S]methionine for an additional 24 h under the same conditions, newly synthesized radiolabeled ACE was quantitated. Radiolabeled ACE was isolated by an immunobead procedure using either anti-ACE (porcine lung) immunoglobin G (IgG) or nonimmune IgG. A single radiolabeled peak (150 kDa) with the same electrophoretic mobility as purified porcine lung ACE was observed. There was a significant time-dependent increase in endothelial cell ACE antigen synthesis without a concomitant change in either cell number or total trichloroacetic (TCA)-precipitable protein in hypoxic cells compared with normoxic controls. In contrast, ACE activity, assessed by conversion of 125I-labeled angiotensin I to 125I-labeled angiotensin II was unchanged in cultures exposed to hypoxia (2.5% O2). This suggests that an inactive form of ACE is synthesized by cultured pulmonary artery endothelial cells under hypoxic conditions.

Anaerobiosis↗

PubMed1989

Hemodynamic effects of arginine vasopressin in rats adapted to chronic hypoxia.

Acute and chronic pulmonary and systemic hemodynamic responses to arginine vasopressin (AVP) were examined in 4-wk hypoxia-adapted and air control rats. AVP, administered intravenously as bolus injections or sustained infusions, produced major dose-dependent V1-receptor-mediated reductions in mean pulmonary arterial pressure in hypoxia-adapted rats. These effects were comparable in pentobarbital-anesthetized, thoracotomized animals and in conscious, intact rats. Chronic infusions of AVP induced a sustained reduction in mean pulmonary arterial pressure and partially prevented the development of pulmonary hypertension without changing systemic arterial pressure. AVP induced significant decreases in cardiac output in both groups; the cardiac output response was not significantly different in hypoxia-adapted and air control animals. AVP induced almost no change in MPAP in air control rats. Furthermore the systemic pressor effects of AVP were significantly blunted in hypoxia-adapted rats compared with air controls. We conclude that the pulmonary depressor and blunted systemic pressor effects of AVP observed in hypoxia-adapted rats may be related to release of a vasodilator, such as endothelium-derived relaxing factor, vasodilator prostaglandins, or atrial natriuretic peptides. Further study is needed to elucidate these mechanisms and assess the usefulness of AVP and/or its analogues in the treatment and prevention of hypoxia-induced pulmonary hypertension.

Adaptation, Physiological↗

PubMed1989

Renal nerve contribution to NaCl-exacerbated hypertension in spontaneously hypertensive rats.

Previous studies demonstrate that bilateral renal denervation enhances urinary sodium excretion and delays the onset of hypertension in young (7-week-old) spontaneously hypertensive rats (SHR) maintained on ordinary laboratory chow. We interpret these data as suggesting that increased renal nerve activity in this model contributes to hypertension by causing excess sodium retention. More recent studies show that dietary NaCl supplementation increases blood pressure and peripheral sympathetic nervous system activity in NaCl-sensitive SHR (SHR-S). The present study tests the hypothesis that the renal nerves contribute to the rise in arterial pressure caused by dietary NaCl supplementation in this model. SHR-S were fed a high (8%) or basal (1%) NaCl diet beginning at age 7 weeks. Bilateral renal denervation was carried out 2 weeks after the initiation of the diets, at which time systolic blood pressure was significantly higher in the high (compared with the basal) NaCl group. Systolic blood pressure was reduced slightly less in denervated SHR-S on the high (compared with basal) NaCl diet during the following 5 weeks. Renal denervation performed 1 week before initiation of the diets attenuated the subsequent development of hypertension equally in both groups. Both renal denervation and the high NaCl diet increased alpha 2-adrenergic receptor numbers in the kidney; renal denervation caused an approximately equal increase in alpha 2-adrenergic receptor binding in SHR-S on high and basal NaCl diets. The high NaCl diet increased plasma noradrenaline concentration, and renal denervation lowered mean arterial pressure but did not decrease circulating catecholamines in either diet group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Atrial natriuretic factor in NaCl-sensitive and NaCl-resistant spontaneously hypertensive rats.

Our previous studies demonstrated that chronic dietary NaCl supplementation is associated with significant increases in plasma atrial natriuretic factor in Wistar-Kyoto (WKY) rats but not in NaCl-sensitive spontaneously hypertensive rats (SHR-S). The current study tested the hypotheses that 1) acute volume-induced atrial natriuretic factor release is impaired in SHR-S compared with control NaCl-resistant SHR (SHR-R) and WKY rats maintained on basal (1%) NaCl diets; 2) dietary NaCl supplementation (8% NaCl for 2 weeks) alters acute volume-dependent atrial natriuretic factor release in these strains; and 3) replacement of the deficiency in circulating atrial natriuretic factor seen in NaCl-supplemented SHR-S can reverse the NaCl-sensitive component of hypertension. SHR-S and control SHR-R and WKY rats were placed on 1% or 8% NaCl diets at age 7 weeks; 2 weeks later, right atrial pressure and plasma atrial natriuretic factor were measured in conscious rats before and after acute volume expansion (7, 20, and 60 ml/kg, 5% dextrose, for 1 minute). The slopes of the right atrial pressure x plasma atrial natriuretic factor linear regression for the SHR-S fed both 1% and 8% NaCl were significantly shallower (p less than 0.01) than those of 1% NaCl-fed SHR-R or WKY rats. Dietary NaCl supplementation did not alter right atrial pressure in any strain and blunted acute volume-induced atrial natriuretic factor release in WKY rats, but not in SHR-S or SHR-R, suggesting the dietary NaCl-induced elevation in plasma atrial natriuretic factor levels in WKY rats may be related to impaired clearance, as well as enhanced release, of the peptide. The plasma levels of exogenous atrial natriuretic factor required to abolish the NaCl-induced pressor effect in SHR-S were 12-fold greater than endogenous plasma atrial natriuretic factor levels in 8% NaCl-fed WKY rats, suggesting that impairment of atrial natriuretic factor release does not play a major role in the pathogenesis of NaCl-sensitive hypertension in SHR-S.

Animals↗

PubMed1989

Impaired reflex response to volume expansion in NaCl-sensitive spontaneously hypertensive rats.

Abnormal baroreceptor reflex function that antedates or is a consequence of NaCl loading could contribute to the NaCl-induced exacerbation of hypertension in NaCl-sensitive spontaneously hypertensive rats (SHR-S). The current study tested the hypothesis that an impairment in cardiopulmonary baroreceptor reflex function exists in SHR-S before NaCl loading. The reflex response to volume expansion was compared in SHR-S, NaCl-resistant SHR (SHR-R), and normotensive Wistar-Kyoto (WKY) and Sprague-Dawley rats maintained on a normal NaCl diet. Conscious, free-moving SHR-S, SHR-R, WKY, and Sprague-Dawley rats were volume expanded with whole blood to 15% of blood volume within 6 minutes, and mean arterial pressure, heart rate, and lumbar sympathetic nerve activity were recorded. Heart rate and lumbar sympathetic nerve activity decreased significantly in SHR-R, WKY, and Sprague-Dawley rats after volume expansion. In contrast, in SHR-S neither heart rate after volume expansion nor lumbar sympathetic nerve activity was significantly different from levels before volume expansion. The blunted reflex response of heart rate and lumbar sympathetic nerve activity to volume expansion suggests impaired cardiopulmonary volume receptor function in SHR-S. This likely contributes to NaCl-induced hypertension in SHR-S on a high NaCl diet.

Animals↗

PubMed1989

Dietary Ca2+ supplementation prevents the exaggerated responsiveness of anterior hypothalamic alpha 2-adrenoceptors in NaCl-loaded spontaneously hypertensive rats.

Our previous studies demonstrated that (a) dietary Ca2+ supplementation prevents the rise in blood pressure, activation of sympathetic outflow, and reductions in anterior hypothalamic norepinephrine (NE) content and release induced in NaCl-sensitive spontaneous hypertensive rats (SHR-S) by dietary NaCl loading; and (b) stimulation of alpha 2-adrenoceptors by microinjection of clonidine into the anterior hypothalamic area (AHA) results in an exaggerated depressor response in SHR-S fed a high NaCl diet as compared with SHR-S on a basal diet. The current study tested the hypothesis that dietary Ca2+ supplementation prevents these NaCl induced defects in AHA noradrenergic neurons. SHR-S were placed on diets containing: (a) high NaCl; (b) high Ca2+; (c) high Ca2+, high NaCl; or (d) basal NaCl, basal Ca2+ (control). Two weeks later, clonidine (0.6, 1.2, or 2.5 micrograms) was microinjected into the AHA of conscious rats. Clonidine caused dose-dependent decreases in mean arterial pressure (MAP) and heart rate (HR) that were greater in SHR-S on the high NaCl diet than on the control diet. Ca2+ supplementation prevented the exaggerated depressor response to clonidine in high NaCl-fed SHR-S, but did not reduce the response in SHR-S on the basal NaCl diet. Ca2+ supplementation had no effect on blood pressure (BP) or HR responses to clonidine in control NaCl-resistant SHR (SHR-R) or in normotensive Wistar Kyoto (WKY) rats.

Animals↗

PubMed1989

Dietary Ca2+ prevents NaCl-induced exacerbation of hypertension and increases hypothalamic norepinephrine turnover in spontaneously hypertensive rats.

Dietary calcium (Ca2+) supplementation lowers blood pressure in many forms of genetically mediated and experimentally induced hypertension. The present study tested the hypothesis that neuronal mechanisms underlie the blood pressure-lowering effect of dietary Ca2+ in NaCl-sensitive spontaneously hypertensive rats (SHR-S). SHR-S were fed one of the following diets: control (0.75% NaCl/0.68% Ca2+); high NaCl (8.00% NaCl/0.68% Ca2+); high Ca2+ (0.75% NaCl/2.00% Ca2+), and high NaCl/high Ca2+ (8.00% NaCl/2.00% Ca2+). SHR-S on the 8% NaCl diet for 2 weeks displayed significantly elevated blood pressure (161 +/- 4 mmHg) compared with those on the control diet (139 +/- 3 mmHg). Ca2+ supplementation prevented a rise in blood pressure in rats on the high-NaCl diet but did not alter blood pressure in rats consuming 0.75% NaCl. Plasma norepinephrine stores and turnover in the hypothalamus (anterior and posterior regions), brainstem (pons and medulla) and thoracic spinal cord were assessed using the dopamine-beta-hydroxylase inhibitor 1-cyclohexyl-2-mercapto-imidazole. The 8% NaCl diets reduced anterior hypothalamic region norepinephrine stores and turnover. Concomitant Ca2+ supplementation restored norepinephrine turnover to normal, but did not alter norepinephrine stores in the anterior hypothalamic region. In other regions, no significant differences in norepinephrine content or turnover were observed among groups. In SHR that are resistant to high-NaCl diets (SHR-R), the diets did not alter blood pressure, and neither dietary NaCl nor Ca2+ supplementation affected norepinephrine turnover in any brain region studied. These data indicate that in SHR-S on a diet high in NaCl, Ca2+ supplementation may prevent the NaCl-induced exacerbation of hypertension by increasing norepinephrine turnover in the hypothalamus.

Administration, Oral↗

PubMed1988

Effect of steric exclusion on the separation of proteins by hydrophilic size-exclusion chromatography.

On the basis of studying the retention and band broadening of proteins on the TSK SW column, diffusion coefficients (Ds) of solute in stationary phase were obtained which elucidate the hydrodynamic process of chromatographic resolution of proteins by hydrophilic size-exclusion chromatography (SEC). After calculating the correlation between Ds and the molecular weight of the solute, the molecular dimensions of proteins in the process of chromatographic separation can be predicted. Deviations in diffusion coefficient of a protein from the calculated value reflect differences of measured molecular dimensions from molecular volumes predicted from the calibration curve of the SEC column. This study illustrates a convenient method for estimating the purity of proteins by SEC. Deviations from 2 lambda dp (where dp is the particle diameter) in the intercept of the theoretical plate height (H) versus flow-rate (U) curve from the band broadening equation H = CsU + 2 lambda dp + f(alpha M)T (where CsU represents mass transfer resistance caused by solute diffusion in the stationary phase and f(alpha M)T an added term for polydisperse solutes as proposed by Knox and McLennan [Chromatographia, 10 (1977) 75]) reflect impurities in the proteins.

Animals↗

PubMed1988

High NaCl diet increases anterior hypothalamic alpha 2-adrenoceptors in SHR.

Previous studies carried out in our laboratories demonstrated that dietary NaCl supplementation induced an increase in blood pressure associated with a reduction in noradrenaline release in the anterior hypothalamic region of NaCl-sensitive spontaneously hypertensive rats (SHR). The present study tested the hypothesis that this reduction in noradrenaline release induces a compensatory increase in alpha 2-adrenoceptor number in the anterior hypothalamic region of SHR. Low affinity p-[3H]aminoclonidine (alpha 2-adrenoceptor agonist) binding in the anterior hypothalamic region was increased significantly in SHR, but not in normotensive Wistar-Kyoto (WKY) rats on a high (compared to a basal) NaCl diet. Increased p-[3H]aminoclonidine binding was present at 1 and 2 weeks following initiation of the diets. In contrast, in the posterior hypothalamic region of SHR, alpha 2-adrenoceptors were significantly reduced following 1 week on the high (compared to basal) NaCl diet, and no difference between groups was observed following 2 weeks on the diets. The high NaCl diet did not alter alpha 2-adrenoceptors in the medulla, nor did it affect alpha 1- or beta-adrenoceptors in any brain region studied in either SHR or WKY. In SHR, dietary Ca2+ supplementation diminished the blood pressure elevation associated with high NaCl diets, and simultaneously prevented the NaCl induced increase in alpha 2-adrenoceptors in the anterior hypothalamic region. These data support the hypothesis that, in susceptible individuals, changes in noradrenergic transmission in the anterior hypothalamic region contribute to the cardiovascular effects of dietary NaCl loading and Ca2+ supplementation.

Animals↗

PubMed1988

Lung MK 351A uptake after hypoxia adaptation and subsequent hyperoxia exposure.

This study investigated the effects of hypoxia adaptation (10% O2 for 4 days) on rat lung angiotensin-converting enzyme (ACE) content before and after hyperoxia exposure (greater than 95% O2 for 2 days). The rationale for this investigation was that hyperoxia exposure decreases lung ACE, while hypoxia adaptation produces tolerance (improved survival) to oxygen toxicity in rats. Rats were exposed to air, hypoxia, hyperoxia alone, or hypoxia followed immediately by hyperoxia. The lungs were then excised and perfused in vitro at 12 ml/min with buffer. Lung ACE content was quantitated by measuring the single-pass binding of an iodinated ACE inhibitor, 125I-MK 351A, a derivative of lisinopril. We showed previously that 125I-MK 351A binding correlates quantitatively with ACE activity in lung homogenates and isolated, perfused lungs. Lung internal surface area was estimated by measuring the mean alveolar diameter of 5 micron hematoxylin and eosin sections from lungs fixed in inflation (25 cmH2O transpulmonary pressure). Hypoxia adaptation per se had no effect on 125I-MK 351A binding or estimated alveolar surface area, while hyperoxia exposure caused a significant decrease in both 125I-MK 351A binding and alveolar surface area. These hyperoxia-induced decreases were prevented partially by hypoxia adaptation, indicating a protective effect on both ACE content and surface area. 125I-MK 351A binding in isolated perfused lungs changed in parallel with histologically estimated surface area. These results indicate that hypoxia preadaptation minimizes the oxygen-induced decrease in lung microvascular ACE content.

Animals↗

PubMed1988

Central serotonergic alterations in deoxycorticosterone acetate/NaCl (DOCA/NaCl)-induced hypertension.

The present study investigated the metabolism of serotonin (5-HT) in rats made hypertensive by treatment with DOCA/NaCl. 5-Hydroxytryptamine and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were significantly elevated in a number of regions of the brain in rats treated for 2 weeks with DOCA/NaCl. Elevations in levels of 5-HIAA were present with 4 weeks of treatment with DOCA/NaCl but levels of 5-HT were not altered. No changes in the metabolism of 5-HT were detectable with 5 weeks of treatment with DOCA/NaCl. Levels of tryptophan were also elevated in a number of regions of the brain by treatment with DOCA/NaCl. Alterations in norepinephrine (NE) in the brainstem were present with 2, 4 or 5 weeks of treatment with DOCA/NaCl. The neurochemical effects of muscimol, a GABA agonist, were also investigated in rats treated with DOCA/NaCl for 4 weeks. Significant increases in levels of 5-HIAA and 5-HT were present in rats treated with DOCA/NaCl but not in controls, 15 min after intraventricular administration of muscimol (1.0 microgram/300 g body weight). Sixty min after muscimol, 5-HIAA was increased in both rats treated with DOCA/NaCl and control rats, but 5-HT was only increased in the hypothalamus. Treatment with DOCA/NaCl produced changes in the metabolism of 5-HT that may be important in the genesis of hypertension, but are not required for the maintenance of elevated arterial pressure. A disturbance of GABA-5-HT interactions between GABA and 5-HT in brainstem sites may also contribute to the pathogenesis of hypertension induced by DOCA/NaCl.

Animals↗

PubMed1988

Purification of an angiotensin II binding protein by using antibodies to a peptide encoded by angiotensin II complementary RNA.

We have generated a monospecific antibody to a synthetic peptide encoded by an RNA complementary to the mRNA for angiotensin II (AII) and determined whether this antibody recognizes the AII receptor. We demonstrate that the antibody competes specifically with 125I-labeled AII for the same binding site on rat adrenal membranes. Furthermore, we show that this antibody inhibits the secretion of aldosterone from cultured rat adrenal cells, suggesting that the antibody recognizes the biologically relevant AII receptor. Finally, we demonstrate that antibody to the complementary peptide can be used to immunoaffinity-purify a protein of Mr 66,000 that specifically binds radiolabeled AII.

Adrenal Glands↗

PubMed1988

The neural basis of salt sensitivity in the rat: altered hypothalamic function.

Dietary NaCl supplementation in NaCl-sensitive spontaneously hypertensive rats (SHR-S) elevates blood pressure, increases peripheral sympathetic nervous system activity and depresses endogenous noradrenaline stores and noradrenaline release in the anterior hypothalamus. NaCl-resistant spontaneously hypertensive rats (SHR-R) and normotensive Wistar Kyoto (WKY) rats are resistant to the NaCl-induced alterations in blood pressure and central and peripheral noradrenergic activity, suggesting that the alterations observed in the SHR-S during NaCl loading are genetically mediated. The anterior hypothalamus is a major cardiovascular regulatory region, and depressor responses elicited by pharmacologic (alpha 2 adrenoceptor) stimulation of this area are exaggerated in SHR-S fed a high NaCl diet compared with SHR-S fed a basal diet and compared with SHR-R and WKY fed a high or basal NaCl diet. Membrane-binding techniques confirm that alpha 2 adrenoceptors in the anterior hypothalamic area are increased in number in SHR-S fed a high NaCl diet, presumably reflecting upregulation in response to reduced local noradrenaline release. These findings are consistent with the hypothesis that decreased noradrenergic activity of sympathoinhibitory neurons in the anterior hypothalamic area may mediate the exacerbation in hypertension that occurs in SHR-S during dietary NaCl supplementation.

Animals↗

PubMed1988

Exaggerated depressor response to 6-iodoamiloride in NaCl-sensitive spontaneously hypertensive rats.

The current study tested the hypothesis that NaCl-sensitive hypertension may result from increased membrane sodium channel activity. The effect of 6-iodoamiloride, and analog of the sodium channel blocker amiloride, on mean arterial pressure (MAP) was examined in conscious, freely moving NaCl-sensitive spontaneously hypertensive rats (SHR-S) fed high (8%) or normal (1%) NaCl diets. SHR-S and age-matched NaCl-resistant SHR (SHR-R) and normotensive Wistar-Kyoto (WKY) control rats were studied at 9 weeks of age after 2 weeks on either high (8%) NaCl or control (1%) NaCl diets. 6-iodoamiloride was infused intravenously in doses of 0.38 or 0.76 mg/100 g body weight, and MAP and heart rate (HR) were monitored from a femoral arterial cannula for 2 hours. The 8% NaCl diet caused a significant elevation in MAP in SHR-S but not in SHR-R or WKY. Administration of 6-iodoamiloride (both doses) produced a significant, sustained decrease in MAP in both SHR-S and SHR-R. Maximal depressor responses to high dose 6-iodoamiloride were significantly enhanced in SHR-S fed 8% NaCl (31.2 +/- 3.7 mm Hg) compared to SHR-S fed 1% NaCl (14.8 +/- 2.4 mm Hg) or SHR-R fed either 8% or 1% NaCl diets (15.6 +/- 4.2 and 10.2 +/- 3.0 mm Hg, respectively). In contrast, feeding an 8% NaCl diet had no significant effect on the depressor responses to 6-iodoamiloride in either SHR-R or WKY rats. In WKY, these doses of 6-iodoamiloride had no significant effect on MAP in either diet group. 6-iodoamiloride had no significant effect on heart rate in any group. These results support the hypothesis that the exacerbation of hypertension in SHR-S fed a high NaCl diet may result from increased membrane sodium channel activity.

Amiloride↗