Showing papers by "Suzanne Oparil published in 1987"
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TL;DR: Peripheral renal denervation has a peripheral sympatholytic effect and alters the level of activation of central noradrenergic pathways but does not alter sodium or water intake or excretion, plasma renin activity or creatinine clearance, suggesting that efferent renal nerve function does not play an important role in the maintenance of this form of hypertension.
Abstract: The renal nerves play a role in the pathogenesis of hypertension in a number of experimental models. In the deoxycorticosterone acetate - salt (DOCA-NaCl) hypertensive rat and the spontaneously hypertensive rat (SHR) of the Okamoto strain, total peripheral renal denervation delays the development and blunts the severity of hypertension and causes an increase in urinary sodium excretion, suggesting a renal efferent mechanism. Further, selective lesioning of the renal afferent nerves by dorsal rhizotomy reduces hypothalamic norepinephrine stores without altering the development of hypertension in the SHR, indicating that the renal afferent nerves do not play a major role in the development of hypertension in this genetic model. In contrast, the renal afferent nerves appear to be important in one-kidney, one-clip and two-kidney, one-clip Goldblatt hypertensive rats (1K, 1C and 2K, 1C, respectively) and in dogs with chronic coarctation hypertension. Total peripheral renal denervation attenuates the severity of hypertension in these models, mainly by interrupting renal afferent nerve activity, which by a direct feedback mechanism attenuates systemic sympathetic tone, thereby lowering blood pressure. Peripheral renal denervation has a peripheral sympatholytic effect and alters the level of activation of central noradrenergic pathways but does not alter sodium or water intake or excretion, plasma renin activity or creatinine clearance, suggesting that efferent renal nerve function does not play an important role in the maintenance of this form of hypertension. Selective lesioning of the renal afferent nerves attenuates the development of hypertension, thus giving direct evidence that the renal afferent nerves participate in the pathogenesis of renovascular hypertension.
69 citations
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TL;DR: The BHR is discussed as a model for determining the triggers responsible for environmentally-induced hypertension, and plasma norepinephrine determinations revealed a significant response to cold stress in all groups, but only in WKY.
Abstract: The effect of high dietary sodium (8%) on blood pressure in spontaneously hypertensive (SHR), borderline hypertensive (BHR), and normotensive Wistar-Kyoto (WKY) rats was determined weekly by tail cuff plethysmography for one week of baseline and four weeks of diet. After 4 weeks, significant elevations in systolic blood pressure were found in SHR and BHR groups, but not in WKY. BHR studied an additional 4 weeks showed a further progression of hypertension, reaching levels nearly equal to control SHR. Direct measurement of arterial pressure in conscious animals in their home cage confirmed the elevation in pressure in both SHR and BHR groups. Metabolic studies revealed that the high sodium diet reduced body weight in SHR and BHR strains, but not in WKY. Although both urinary volumes and sodium excretion values were significantly lower in SHR and BHR compared with WKY, this effect disappeared when adjustments for body weight were made. Plasma norepinephrine determinations revealed a significant response to cold stress in all groups. Plasma epinephrine was elevated in all strains in response to cold stress; however, a consistent statistical elevation was seen only in WKY. The BHR is discussed as a model for determining the triggers responsible for environmentally-induced hypertension.
67 citations
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TL;DR: The depressor effects of intracerebroventricular captopril in SHR may be due, in part, to an attenuation in sympathetic vasoconstrictor tone.
Abstract: The cardiovascular effects of electrical stimulation of the posterior hypothalamus, intravenous administration of norepinephrine (NE), and direct sympathetic nerve stimulation (SNS) were compared in spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY) given captopril (osmotic minipump, 1.25 micrograms/h icv) or vehicle for 4 wk beginning at age 7 wk. Mean arterial pressure (MAP) and renal and mesenteric flows (pulsed Doppler flow probes) were monitored in anesthetized rats. Following chronic administration of captopril the MAP was 141 +/- 4 mmHg in SHR receiving captopril and 183 +/- 6 mmHg in SHR receiving vehicle. Posterior hypothalamic stimulation, intravenous NE, and SNS resulted in lesser increases in MAP and renal and mesenteric vascular resistances in SHR treated with captopril. Response curves were shifted to the right, and the initial slopes and rate of change of slopes of the curves were less in captopril-treated SHR than vehicle-treated rats. The decrease in sensitivity to posterior hypothalamic stimulation was greater than the decrease in response to NE or SNS. The decrease in vascular reactivity in captopril-treated SHR was not due to increased sensitivity of the baroreflex for control of vascular resistance nor to a decrease in arterial pressure per se. WKY treated with captopril also showed lesser increases in MAP and renal and mesenteric vascular resistances in response to posterior hypothalamic stimulation, intravenous NE, and SNS. The depressor effects of intracerebroventricular captopril in SHR may be due, in part, to an attenuation in sympathetic vasoconstrictor tone. This attenuation involves both a decrease in vascular smooth muscle responsiveness to NE as well as a decrease in central stimulation of sympathetic outflow.
58 citations
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TL;DR: To examine the hypothesis that abnormalities in the monoaminergic innervation of the hypothalamus and brain stem contribute to the NaCl-induced exacerbation of hypertension, the monoamine and monoamine metabolite contents of specific hypothalamic and brainstem regions thought to be involved in the pathogenesis of hypertension were determined.
Abstract: Spontaneously hypertensive rats (SHR) of the Okamoto strain exhibit a significant exacerbation in severity of hypertension when fed diets high in NaCl. To examine the hypothesis that abnormalities in the monoaminergic innervation of the hypothalamus and brainstem contribute to the NaCl-induced exacerbation of hypertension, the monoamine and monoamine metabolite contents of specific hypothalamic and brainstem regions thought to be involved in the pathogenesis of hypertension were determined in SHR fed a diet containing 8% or 1% NaCl for either 2 or 6 weeks beginning at age 8 weeks. SHR maintained on the 8% NaCl diet for 2 weeks displayed significant decreases in norepinephrine in both the anterior and posterior hypothalamic regions but not in other brainstem or hypothalamic regions, as compared with animals consuming 1% NaCl. In addition, stores of the principal terminal norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol were reduced in the anterior hypothalamic region of SHR fed an 8% NaCl diet for 2 weeks. After 6 weeks on the diets, SHR fed 8% NaCl showed small but statistically nonsignificant reductions in norepinephrine stores of the anterior hypothalamic region as compared with SHR fed a basal diet, while WKY fed 8% NaCl had significantly elevated norepinephrine stores in the anterior hypothalamic region as compared with WKY fed a basal diet. There was a significant group X diet interaction (p less than 0.05). After 6 weeks on the 8% NaCl diet, SHR (but not WKY) displayed a significant reduction in norepinephrine content of the posterior hypothalamic region. No NaCl-induced differences in norepinephrine stores were found in the pons or medulla of either strain.(ABSTRACT TRUNCATED AT 250 WORDS)
49 citations
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TL;DR: There was a significant relationship between the change in RSR and thechange in ANG II formation rate, and the amount of arterially delivered ANG II that escaped degradation was increased.
Abstract: In previous studies it has not been possible to determine net intrarenal formation of angiotensin II (ANG II) from arteriovenous ANG II concentrations because of the high intrarenal ANG II degradat...
45 citations
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TL;DR: It is demonstrated that diets high in chloride and moderate in sodium can increase blood pressure in salt-sensitive spontaneously hypertensive rats and suggested that this increase is related to a reduction in noradrenergic input to sympathoinhibitory neurons in the anterior hypothalamus.
Abstract: In salt-sensitive spontaneously hypertensive rats (SHR-S) of the Okamoto strain, dietary salt loading causes an exacerbation of hypertension that is associated with a decrease in noradrenergic input to the depressor neurons in the anterior hypothalamus. In the present study, the contribution of chloride to the salt-induced hypertensive response was examined in the SHR-S, in order to test the hypothesis that diets high in chloride but moderate in sodium elevate blood pressure in genetically predisposed subjects. SHR-S were fed diets high in NaCl (1.97% Na+, 2.93% Cl-; 5% NaCl), high in chloride (2.93%) but moderate in sodium (0.39%) or moderate in NaCl (0.39% Na+, 0.61% Cl-; 1% NaCl). After 2 weeks, rats on the high (5%) NaCl diet exhibited a significant elevation in blood pressure compared to rats on the moderate (1%) NaCl diet, and this elevation was maintained throughout the next 3 weeks. SHR-S on the high chloride diet were not significantly more hypertensive than 1% NaCl-fed SHR-S during the first 3 weeks, but during the fourth and fifth weeks, SHR-S on the high chloride diet displayed a significant exacerbation of hypertension. The diet-induced elevation in blood pressure in groups fed either the 5% NaCl or high chloride (compared to 1% NaCl) diets was associated with significant decreases in norepinephrine stores in the anterior hypothalamic region, but no other changes in monoamines or monoamine metabolites in this region or in the posterior hypothalamic region. The high chloride diet did not increase blood pressure in normotensive Wistar-Kyoto rats.(ABSTRACT TRUNCATED AT 250 WORDS)
35 citations
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TL;DR: Results indicate that the renal nerves do not provide a major contribution to hypertension in the Dahl NaCl-sensitive rat.
Abstract: In previous experiments we have demonstrated that the renal nerves play a significant role in all genetic and (or) induced models of hypertension that we have studied. The current experiments extended this research by investigating the contribution of the renal nerves to hypertension in the Dahl NaCl-sensitive rat. This was investigated by assessing the effect of bilateral phenol renal denervation carried out prior to initiation of a high NaCl (8% NaCl) diet. In two separate studies, renal denervation did not affect systolic blood pressure in either Dahl NaCl-sensitive rats or their normotensive counterparts, Dahl NaCl-resistant rats. Further, denervation did not increase absolute urinary sodium excretion, percent urinary sodium excretion, urinary volume output, or food or water intake; nor did it differentially alter creatinine clearance or body weight. Denervation was verified at the termination of each study by a greater than 80% depletion of renal noradrenaline stores. These results indicate that the ...
31 citations
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TL;DR: The results suggest that the pressor action of LY171555 in conscious LE rats is mediated by an increase in plasma AVP and by activation of sympathetic outflow through the central D2 dopaminergic system but not through thecentral vasopressinergic system.
Abstract: To elucidate the role of central and peripheral arginine vasopressin (AVP) in the cardiovascular action of LY171555 in conscious rats, we have examined the effects of LY171555 on mean arterial pressure, heart rate, plasma AVP and catecholamine levels in conscious, congenitally AVP-deficient Brattleboro (DI) rats and Long-Evans (LE) control rats. Administration of LY171555 (1 mg/kg i.v.) increased heart rate without altering mean arterial pressure in DI rats but increased both mean arterial pressure and heart rate in LE rats. After pretreatment with domperidone, LY171555 induced both a pressure response and a tachycardia in DI rats. Domperidone pretreatment enhanced the pressor action of LY171555 and attenuated the LY171555-induced tachycardia in LE rats. After pretreatment with phenoxybenzamine, LY171555 induced a depressor and bradycardic response that could be blocked by pretreatment with domperidone in DI rats. Pressor and bradycardic responses to LY171555 were attenuated by phenoxybenzamine pretreatment in LE rats. LY171555 administration increased plasma norepinephrine and epinephrine levels in both DI and LE rats but increased plasma AVP only in LE rats. The vasopressor effect of the alpha-1 adrenoceptor agonist phenylephrine was significantly attenuated in DI rats compared with LE rats, whereas the pressor action of angiotensin II was similar in both groups. These results suggest that the pressor action of LY171555 in conscious LE rats is mediated by an increase in plasma AVP and by activation of sympathetic outflow through the central D2 dopaminergic system but not through the central vasopressinergic system.(ABSTRACT TRUNCATED AT 250 WORDS)
22 citations
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TL;DR: The data indicate that the antihypertensive effect of enalapril in essential hypertension occurs in the absence of an active renin-angiotension system and is associated with increased excretion of 6-keto PGF1α but is not blunted by cyclooxygenase inhibitors.
20 citations
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TL;DR: The altered systemic and pulmonary pressor responsiveness to ANG I and ANG II in hypoxic rats is probably related to mechanisms specific to the renin-angiotensin system, such as inhibition of intrapulmonary angiotENSin-converting enzyme activity and down regulation of ANG II receptors in the systemic circulation.
Abstract: Systemic and pulmonary vascular reactivity to graded doses of angiotensin I (ANG I), angiotensin II (ANG II), and, as a control, phenylephrine were examined in 14- or 28-day hypoxia-exposed and air control rats. Hypoxic rats exhibited pulmonary hypertension that was reversible on return to room air, but systemic arterial pressure was not altered by hypoxia. Systemic pressor responses to ANG I and ANG II were significantly less in the hypoxic rats than in the control rats at 14 and 28 days but returned to control levels in hypoxic animals that were then returned to room air, demonstrating reversibility of the hypoxia-induced changes in vascular reactivity. Pulmonary pressor responses to ANG I were significantly less at 14 days, whereas responses to ANG II were significantly greater at 28 days, in hypoxic rats than in controls. There were no significant differences in systemic and pulmonary pressor responses to phenylephrine between the hypoxic and air control animals. The altered systemic and pulmonary pressor responsiveness to ANG I and ANG II in hypoxic rats is probably related to mechanisms specific to the renin-angiotensin system, such as inhibition of intrapulmonary angiotensin-converting enzyme activity and down regulation of ANG II receptors in the systemic circulation. Further study is needed to elucidate these mechanisms.
15 citations
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TL;DR: These studies demonstrated a relationship between renal NE content and renal α2-adrenergic receptors and the implications of this relationship and other salt-related changes in renal catecholamine metabolism were discussed as they pertained to hypertension and renal function.
Abstract: Increased dietary salt intake alters renal function which often leads to deleterious cardiovascular consequences. Studies were carried out to characterize the effects of high-salt diets on renal catecholamines and α2-adrenergic receptors. These parameters were evaluated in both genetic and acquired forms of hypertension and also in normotensive rats on high-salt diets. Renal catecholamine content was determined by high-performance liquid chromatography with electrochemical detection. Renal α2-adrenergic receptor-binding studies were performed on whole kidney homogenates using 3H-p-aminoclonidine to label both high- (0.5 nM) and low-affinity (5.0 nM) renal α2-adrenergic receptors. Increased salt intake elevated blood pressure, decreased renal norepinephrine stores and resulted in renal α2-adrenergic receptor up-regulation in deoxycorticosterone acetate salt hypertensive rats, Dahl-S rats and COX-SHR. The decreased renal stores of norepinephrine (NE) appeared to reflect increased renal NE utilization. In contrast, SHR (Charles River) had elevated NE stores and α2-adrenergic receptors while on normal salt diets. Short-term (10–14 days) exposure to high-salt diets had modest effects in normotensive rats or COX-SHR, although it was sufficient to increase low affinity renal α1-adrenergic receptor number. Renal dopamine metabolism was also altered by high-salt diets. These studies demonstrated a relationship between renal NE content and renal α2-adrenergic receptors. The implications of this relationship and other salt-related changes in renal catecholamine metabolism were discussed as they pertained to hypertension and renal function.
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TL;DR: The results of the present study demonstrate the multifarious nature of the alterations in CNS monoamine metabolism in SHr, a genetic model of hypertension and compared to its normotensive control.
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TL;DR: It was concluded that the increase in chondroitin sulfate and [35S]sulfate incorporation into proteoglycans occurred as a result of hypertension, regardless of genetic factors.
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TL;DR: The data suggest that O2 induced impairment in activity of angiotensin-converting enzyme at the endothelial membrane level has functionally significant effects on cardiovascular homeostasis, probably via reduced generation of endogenous AII.
Abstract: The effects of exposing rats to hyperoxia (100 percent O2) at normal atmospheric pressure for periods of 24-48 hours on components of the renin-angiotensin system and on blood pressure control were examined. Intrapulmonary conversion of angiotensin I (AI) to angiotensin (AII) was assessed using an isolated lung preparation perfused at constant flow. Exposure of rats to hyperoxia for 44-48 hours reduced single pass conversion of AI to AII in the pulmonary circulation from control levels of 82 ± 4 to 29 ± 5 percent (p < 0.001). AII levels in trunk blood of 44-48 hour O2 exposed animals were 5.2 ± 1.9 pg/ml, compared to 37.9 ± 10.0 pg/ml in controls (p < 0.001). Mean arterial pressure decreased significantly from 117 ± 4.3 to 103 ± 6.7 mmHg (p < 0.05) in the O2 exposed group despite a threefold increase in plasma renin activity. The pressor response to exogenous AI was significantly diminished by O2 exposure, while the pressor response to exogenous AII remained unchanged from control. Pulmonary angiotensin-c...
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TL;DR: LY171555 significantly reduced HVA and DOPAC levels in perfused striatum in both normotensive control and DOCA/NaCl-hypertensive rats, indicating that this mechanism may be altered in the desoxycorticosterone acetate (DOCA)/NaCl model of hypertension.
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TL;DR: The data suggest that continuous intravenous administration of quinpirole produces a transient centrally mediated pressor effect which is followed by a more sustained, peripherally mediated depressor response.
Abstract: Cardiovascular responses to sustained infusion of quinpirole (LY171555), a dopamine (DA) D2 receptor agonist, and bolus injection of quinpirole following sustained infusion were examined in conscious, unrestrained Sprague-Dawley rats to investigate the contributions of central and peripheral D2 receptors to the regulation of cardiovascular function. Continuous intravenous administration of quinpirole induced a transient pressor response followed by normalization of mean arterial pressure (MAP) and, at higher doses, a decrease in MAP below control levels. Intravenous bolus injections of quinpirole administered 30 min after termination of the infusion produced dose-dependent depressor responses which were blocked by pretreatment with domperidone, a peripheral D2 antagonist. The data suggest that continuous intravenous administration of quinpirole produces a transient centrally mediated pressor effect which is followed by a more sustained, peripherally mediated depressor response.
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TL;DR: There were no significant differences in pulmonary and systemic pressor responses to phenylephrine between the hypoxic and normoxic groups, and the effects of AVP on MSAP and MPAP were abolished by the specific AVP V1 receptor antagonist, indicating that these effects are V1 receptors mediated.
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TL;DR: Quinpirole resulted in a significant increase in DA stores and decrease in DOPAC stores in most brain regions examined in both DOCA/NaCl-hypertensive rats and normotensive controls, presumably by inhibiting DA release through a presynaptic mechanism.
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TL;DR: The enhanced YOH-induced renal NE depletion in SHR suggests an alteration in the presynaptic control of NE release in the genetically hypertensive rat, however, the effects of YOH in the SHR may be mediated by mechanisms unrelated to alpha 2-adrenergic receptors.
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TL;DR: All lines of evidence in this study indicate that two alpha 2-adrenoceptor binding sites exist in the rat kidney, and specific alpha 2 -adrenergic agonists exhibited greater binding affinity to both sites than did nonspecific drugs, and all drugs displayed greater affinity for the high- than the low-affinity binding site.
Abstract: [3H]p-aminoclonidine [3H]PAC, a specific alpha 2-adrenergic agonist, was used to characterize alpha 2-adrenoceptor binding in rat renal membranes. Rosenthal plots demonstrated two binding sites with Kds of approximately 1.7 and 14.2 nM and Bmaxs (maximum binding) of 47.3 and 218.8 fmol/mg protein for the high- and low-affinity sites, respectively. These characteristics were confirmed by estimate of Kd parameters based on association and dissociation experiments. Pseudo-Hill coefficients generated from drug inhibition experiments were all less than unity, suggesting differential binding at two alpha 2-adrenoceptor binding sites. Specific alpha 2-adrenergic agonists exhibited greater binding affinity to both sites than did nonspecific drugs, and all drugs displayed greater affinity for the high- than the low-affinity binding site. Both guanyl nucleotides and sodium chloride inhibited [3H]PAC binding more at the high-affinity than at the low-affinity site. Renal denervation resulted in significant upregulation of receptor density only at the high-affinity sites with no change in receptor affinity at either site, suggesting that a majority of the alpha 2-adrenoceptors in the kidney are postsynaptic. Thus all lines of evidence in this study indicate that two alpha 2-adrenoceptor binding sites exist in the rat kidney.
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TL;DR: The data suggest that the specific D2 agonist may effect its central pressor response by stimulating NE release from posterior hypothalamic area, a "pressor" region of hypothalamus, and that this D 2 agonist induced pressor mechanism may be blunted in DOCA/NaCl hypertension.