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S Oparil

Publications and source records attributed to S Oparil.

At least 271 records · Page 15Linked to original sources
PubMed1984

Mechanism of the depressor effect of bromocriptine in the spontaneously hypertensive rat.

Bromocriptine, a dopamine (DA) agonist which passes the bloodbrain barrier, has been shown to have a depressor effect in the spontaneously hypertensive rat of the Okamoto strain. To elucidate the mechanism of this depressor effect, the responses of mean arterial blood pressure and plasma epinephrine (EP), norepinephrine, prolactin and renin activity to i.v. administration of bromocriptine (500 micrograms/kg), alone and after pretreatment with i.v. metoclopramide, a DA antagonist which crosses the blood-brain barrier, and domperidone, a DA antagonist which does not cross the blood-brain barrier, were examined in conscious unrestrained spontaneously hypertensive rats. Metoclopramide attenuated the depressor action of bromocriptine in a dose-related manner, but domperidone had no effect. Neither metoclopramide nor domperidone given alone altered mean arterial blood pressure. Bromocriptine given alone decreased plasma prolactin and increased plasma EP without altering plasma norepinephrine or plasma renin activity. Pretreatment with either metoclopramide or domperidone completely blocked the EP-stimulating effects of bromocriptine. Neither DA antagonist given alone had an effect on plasma EP, norepinephrine or plasma renin activity; both agents stimulated prolactin release. These results suggest that the depressor action of i.v. administered bromocriptine is mediated mainly through a central dopaminergic mechanism rather than by peripheral effects and that plasma EP responses to bromocriptine do not directly contribute to its depressor action.

Animals↗
PubMed1983

Effect of hypoxia on the conversion of angiotensin I to II in cultured porcine pulmonary endothelial cells.

Earlier studies by other investigators have shown that acute exposure of cultured endothelial cells to hypoxic atmospheres inhibits the activity of the angiotensin converting enzyme in situ, resulting in severe but reversible depression of the rate of degradation of bradykinin. We exposed primary cultures of endothelial cells from the pulmonary artery of the pig to a range of hypoxic gas mixtures and measured the activity of the angiotensin converting enzyme in situ using angiotensin I as substrate. Each cell flask was exposed in random sequence to both hypoxic gas mixtures (PO2 29-69 torr) and room air for 40 min in Dulbecco's medium containing angiotensin I at concentrations of 1000 (N = 7), 500 (N = 8) or 100 ng/ml (N = 4). Angiotensin I disappearance rates and angiotensin II generation rates were linear. Recovery of immunoreactive peptide as either angiotensin I or II following 40 min of incubation was 86 +/- 17% (S.D.). The rate of increase in angiotensin II concentration in surface medium in room air experiments was 91 +/- 51 (S.D.) ng x ml-1 x hr-1. During hypoxia it was 85 +/- 42 ng x ml-1 x hr-1. The difference in rates was not significant by paired t analysis. The results of this study are consistent with earlier observations by the authors which suggest that hypoxia-induced depression of angiotensin I conversion in vivo is due to hemodynamic phenomena. Further studies are needed to clarify the role of cellular mechanisms in hypoxia-induced depression of angiotensin metabolism.

Angiotensin I↗
PubMed1983

Enalapril in low-renin essential hypertension.

The antihypertensive efficacy of N-[(S)-1-(ethoxycarbonyl)-3-phenyl-propyl]-L-alanyl-L-proline (enalapril maleate) was evaluated in a randomized, double-blind trial in 23 patients with mild low-renin essential hypertension ranging in age from 32 to 70 yr (20 were black and 3 were white). All underwent a 4-wk washout-placebo phase and were then assigned to a dosing schedule of either 10 mg enalapril once daily, 5 mg enalapril twice daily, or placebo twice daily for 12 wk. Conditional on diastolic pressure, the dose was increased at 4-wk intervals to a maximum of 40 mg daily or until control was achieved or the end of the study reached. At the end of the 12-wk titration phase, there was a follow-up period during which measurements were made after discontinuation of the medication. Mean supine diastolic pressure decreased from baseline (98.5 +/- 2.6 mm Hg) during the titration phase (86.3 +/- 4.6 mm Hg) in the group taking enalapril once daily. In three of the eight patients in the once-daily group and five of eight in the twice-daily group, supine diastolic pressures fell below 90 mm Hg. Neither supine nor standing systolic pressure nor standing diastolic pressure decreased significantly from pretreatment levels during enalapril once or twice daily. Heart rates measured after 5 min supine rest were not altered by enalapril. Enalapril induced inhibition of converting enzyme activity at all dose levels and with both dosing schedules. No adverse effect attributable to enalapril occurred during the study. The data indicate that once-daily enalapril is safe and effective treatment for mild low-renin essential hypertension.

Adult↗
PubMed1983

Central catecholamine depletion, vasopressin, and blood pressure in the DOCA/NaCl rat.

To determine whether impaired arginine vasopressin (AVP) release occurs when DOCA-NaCl hypertension is prevented following chemical sympathectomy with 6-hydroxydopamine (6-OHDA), male Sprague-Dawley rats treated with intraventricular injections of 6-OHDA (250 micrograms X 2) or Merlis solution received deoxycorticosterone acetate (DOCA) implants (100 mg/kg) and drank 0.5% saline. Systolic blood pressure in the 6-OHDA-treated DOCA/NaCl group (139 +/- 4 mmHg) was lower (P less than 0.001) than in the Merlis-DOCA/NaCl group (183 +/- 7 mmHg). 6-OHDA treatment produced widespread catecholamine depletion throughout the central nervous system, including the supraoptic and paraventricular nuclei, the cells of which are known to produce AVP, but hypothalamic, pituitary, and plasma AVP levels were similar in both experimental groups, the latter values averaging 1.5-2 times those of controls. Both groups of rats suppressed AVP secretion appropriately when water loaded. Such suppression, however, had no effect on blood pressure in the hypertensive animals and, furthermore, administration of the AVP antagonist d(CH2)5Tyr(Me)AVP produced small decrements in mean blood pressure of both groups that were not significantly different from responses seen in control normotensive rats. These data demonstrate that 6-OHDA does not prevent DOCA-NaCl hypertension by decreasing AVP levels and suggest that AVP is not necessary for the maintenance of hypertension in this model.

Animals↗
PubMed1983

Intrarenal angiotensin I conversion at normal and reduced renal blood flow in the dog.

Intrarenal conversion of angiotensin I (ANG I) to angiotensin II (ANG II) under conditions of normal and reduced renal blood flow (RBF) elicited by constriction of the renal artery was examined in pentobarbital-anesthetized dogs. In eight animals, tracer doses of 125I-ANG I (5-12 pmol) were injected into the renal artery and 125I-ANG I, 125I-ANG II, and 125I-labeled metabolites were measured in renal venous effluent by high-voltage paper electrophoresis. The mean conversion of ANG I to ANG II during a single passage through the kidney was 21.8 +/- 2.1% at control RBF. When RBF was decreased by 25 and 53%, percent ANG I conversion was not altered significantly. In six dogs percent conversion of 125I-[Sar1, Ile5]ANG I, an ANG I analogue refractory to hydrolysis by aminopeptidases, was 18.1 +/- 1.7% at control RBF and did not change significantly when the RBF was reduced by 55%. Although there were severalfold increases in renal renin secretion rate and net ANG I generation rate during reduced RBF, net renal ANG II formation rate did not change significantly. These data indicate that there is substantial conversion of ANG I in a single passage through the dog kidney and that intrarenal ANG I conversion is independent of RBF even under conditions in which renin secretion rate and ANG I generation rate are increased severalfold.

Angiotensin I↗
PubMed1983

Immunoreactive bradykinin and [des-Arg9]-bradykinin in low-renin essential hypertension--before and after treatment with enalapril (MK 421).

Bradykinin (BK) and [des-Arg9]-bradykinin (-9BK) concentrations in blood and urine samples from 18 normotensive subjects and 23 patients with low-renin essential hypertension were determined by radioimmunoassay. BK and -9BK levels in venous blood from normotensive subjects were 67.1 +/- 60.8 pg/ml and 204.1 +/- 44.5 (mean +/- S.D.), respectively, and levels in urine from normotensive subjects were 5.3 +/- 5.3 ng/ml and 1.6 +/- 1.2, respectively. The blood and urinary levels of BK and -9BK in low-renin essential hypertensives were not significantly different from those of normotensives and did not change when the hypertensives were treated with the new orally active angiotensin I-converting enzyme (ACE) inhibitor, enalapril (MK421). It has been proposed that BK levels do not change with ACE inhibition because under these conditions BK might be metabolized to -9BK by kininase I. Since -9BK levels did not increase with MK421 treatment, this possibility can be excluded. The absence of elevations in blood and urine BK and -9BK after administration of MK421 does not support an involvement of kinins in the mechanism of antihypertensive action of MK421 in these patients. On the basis of the data, it is not possible to exclude such an involvement, however, because local changes in kinin concentrations could occur that are not reflected by changes in circulating or urinary kinin levels.

Adult↗
PubMed1982

Effect of hypoxia on the conversion of angiotensin I to II in the isolated perfused rat lung.

Acute hypoxia in the intact animal and in cultured endothelial cells has been shown to be associated with a decrease in conversion of angiotensin I (AI) to angiotensin II (AII). Alterations in capillary surface and in contact time resulting from hemodynamic changes have been shown to influence the rate of pulmonary AI conversion. The dependency of AI conversion on hemodynamics complicates the interpretation of experiments showing changes in AI conversion in intact animals. We studied the effect of acute hypoxia on AI conversion in the isolated rat lung perfused at constant flow without recirculation of perfusate. Three levels of oxygenation were produced by ventilating lungs and equilibrating perfusate with a range of hypoxic gas mixtures. AI (1 microgram) was injected into the pulmonary artery, and the effluent was collected for measurement of AI and AII. Instead of the expected hypoxic inhibition, percent conversion of AI to AII increased slightly but significantly from 69.3 +/- 3.1 (mean +/- S.E.M.) at normal oxygenation to 74.4 +/- 3.0 at moderate hypoxia (P less than 0.005, paired t) and to 73.5 +/- 3.9 at severe hypoxia (P less than 0.01, paired t). Decreasing mean transit time of substrate through the lung (by increasing perfusate flow rate from 5 to 20 ml/min) resulted in a significant decrease in conversion of AI from 88.7 +/- 2.9 to 73.4 +/- 2.1% (P less than 0.001, paired t). These data confirm the effect of contact time on the rate of AI conversion in the lungs. The isolated rat lung preparation does not exhibit the phenomenon of hypoxia-induced inhibition of AI conversion. The authors speculate that hypoxia-induced inhibition of AI conversion in vivo may be secondary to the effects of hypoxia on hemodynamics.

Angiotensin I↗
PubMed1982

Gallium 67 citrate scanning and serum angiotensin converting enzyme levels in sarcoidosis.

Gallium 67 citrate scans and serum angiotensin converting enzyme (ACE) levels were obtained in 54 patients with sarcoidosis and analyzed in relation to clinical manifestations. 67Ga scans were abnormal in 97% of patients with clinically active disease (n = 30) and in 71% of patients with inactive disease (n = 24). Serum ACE levels were abnormally high (2 standard deviations above the control mean) in 73% of patients with clinically active disease and in 54% of patients with inactive disease. Serum ACE levels correlated significantly with 67Ga uptake score (r =.436; p less than .005). The frequency of abnormal 67Ga scans and elevated serum ACE levels suggests that inflammatory activity with little or no clinical expression is common in sarcoidosis. Abnormal 67Ga scans were highly sensitive (97%) but had poor specificity (29%) to clinical disease activity. The accuracy of negative prediction of clinical activity by normal scans (87%) was better than the accuracy of positive prediction of clinical activity by abnormal scans (63%). 67Ga scans can be used to support the clinical identification of inactive sarcoidosis.

Adult↗
PubMed1982

Differences between renal tubular processing of glucagon and insulin.

Renal processing of glucagon and insulin was compared. Iodinated glucagon (mol wt 3,674, linear molecule) or insulin (mol wt 6,000, two chains with disulfide bonds) was microinfused into surface nephrons of the rat kidney, and the radiolabel recovered in the urine was quantified and characterized. Proximal but not distal reabsorption of both peptides was observed, and uptake varied similarly as a function of tubular length. After proximal microinfusion, [125I]glucagon was largely degraded to [125I]tyrosine in the urine, but remained intact after distal infusion. [125I]Insulin was recovered as intact peptide following both proximal and distal microinfusion. Prolonged tubular sequestration of 125I label was observed following proximal microinfusion of [125I]insulin, with efflux requiring longer than 1 h for completion. No measurable cellular sequestration of [125I]glucagon was observed. Incubation of both peptides with rabbit renal microvilli membranes resulted in enzymatic hydrolysis of [125I]glucagon but relatively little or no degradation of [125I]insulin. It is concluded that glucagon and insulin are reabsorbed in the proximal tubule by predominantly different mechanisms.

Absorption↗
PubMed1982

Angiotensin-converting enzyme in serum and in bronchoalveolar lavage in sarcoidosis.

Angiotensin-converting enzyme (ACE) determinations were made in serum and in bronchoalveolar lavage fluid in 20 controls and in 28 patients with sarcoidosis. Serum ACE was significantly higher in patients with active sarcoidosis (54.3 +/- 19.0 SD nmol/ml/ min; n = 24) compared to controls (25.7 +/- 8.2; n = 20) or to patients with inactive sarcoidosis (23.6 +/- 7.3; n = 4). In contrast, ACE in bronchoalveolar lavage fluid was similar in nonsmoking controls (16.4 +/- 7.3 nmol/ml/min/macrophage; n = 8), smoking controls (10.4 +/- 11.9; n = 7); nonsmoking active sarcoidosis patients (16.7 +/- 14.6; n = 10), smoking sarcoidosis patients (17.9 +/- 8.4; n = 6) and inactive sarcoidosis patients (14.5 +/- 8.2; n = 3). Since ACE has been demonstrated by immunofluorescence in mononuclear phagocytes in granulomas, the authors speculate that macrophages recovered by alveolar lavage are not activated and do not reflect sarcoid alveolitis at the tissue level.

Bronchi↗
PubMed1982

Neuronal and adrenomedullary catecholamine release in response to cardiopulmonary bypass in man.

Cardiopulmonary bypass (CPB) alters systemic hemodynamics and affects several biochemical systems involved in cardiovascular regulation. We investigated the changes in levels of circulating epinephrine (E) and norepinephrine (NE) and related them to events during CPB. Twenty-eight patients undergoing various surgical procedures were studied. Plasma E and NE were determined by radioenzymatic assay at eight stages of the operation. A ninefold increase in arterial E (from 75 +/- 13 to 708 +/- 117.3 pg/ml) occurred from prebypass (stage 1) measurements to the end of aortic cross-clamping (stage 4). The values at stage 4 were significantly higher (p less than 0.05) than at all other stages. E decreased rapidly, to 360 +/- 84.3 pg/ml, after myocardial and pulmonary reperfusion (stage 5). Arterial NE increased twofold from stage 1 to stage 4 (from 426 +/- 66.9 to 825 +/- 84.2, p less than 0.05). The increase in NE from initial CPB values (stage 2) to 30 minutes of aortic cross-clamping (stage 3) was associated with an increase in mean blood pressure (r = 0.51, p = 0.02). The peak increases in catecholamines occurred when the heart and lungs were excluded from the circulation, which suggests that either or both contributed to the increase. Because the increase in E was markedly greater than that in NE, the predominant humoral response to CPB appears to be adrenomedullary release of E. This significant increase in catecholamines could jeopardize myocardial protective measures during CPB.

Adrenal Medulla↗
PubMed1982

Decrease in peripheral sympathetic nervous system activity following renal denervation or unclipping in the one-kidney one-clip Goldblatt hypertensive rat.

Increased sympathetic nervous system activity has been demonstrated in established one-kidney one-clip hypertension in the rat. We have found that renal denervation in this model results in an attenuation of hypertension, unassociated with alterations in sodium or water balance or renin activity. To determine whether the depressor effect of renal denervation is associated with changes in peripheral sympathetic nervous system activity, sham operation (n = 12), renal denervation (n = 13), or unclipping (n = 13) was carried out 2 wk after the onset of one-kidney one-clip hypertension. Normotensive unine-phrectomized age- and sex-matched rats were used as controls (n = 14). Renal denervation resulted in a significant decrease in systolic blood pressure (201+/-7 to 151+/-6 mm Hg), while unclipping lowered systolic blood pressure to normotensive levels (130+/-6 mm Hg). 8 d after operation plasma norepinephrine and mean arterial pressure before and after ganglionic blockade with 30 mg/kg hexamethonium bromide were measured in conscious, unrestrained, resting animals, as indices of peripheral sympathetic nervous system activity. Plasma norepinephrine was significantly higher in hypertensive sham-operated rats (422+/-42 pg/ml) compared with normotensive controls (282+/-25 pg/ml) (P < 0.01). Both renal denervation and unclipping restored plasma norepinephrine to normal levels (273+/-22 and 294+/-24 pg/ml, respectively). Ganglionic blockade in hypertensive sham-operated animals resulted in a significantly greater decrease in mean arterial pressure than occurred in renal denervated, unclipped, or control rats. The data suggest that the depressor effect of renal denervation or unclipping in the one-kidney one-clip hypertensive rat is associated with a decrease in peripheral sympathetic nervous system activity.

Animals↗
PubMed1982

Review of therapeutic modalities acting directly via central pathways.

The brain influences arterial pressure through central mediation of a variety of neurotransmitters, including norepinephrine, and translates this action into changes in peripheral autonomic tone. Two opposed adrenergic systems have been described in brain: a hypothalamic pathway in which adrenergic receptor stimulation raises arterial pressure and a brainstem pathway related to the baroreflex arc in which adrenergic receptor stimulation lowers arterial pressure. Antihypertensive drugs with primarily central effects, including clonidine and alpha methyldopa, act as alpha 2 adrenoceptor agonists. The central receptor involved in their antihypertensive action is of the alpha 2 type but is located postsynaptically. Activation of this receptor by either clonidine or alpha methylnorepinephrine, a metabolite of alpha methyldopa, engages the depressor pathway in the brainstem and leads to a decrease in norepinephrine release and a reduction in peripheral sympathetic tone. Clonidine and alpha methyldopa share a similar pattern of peripheral effects, including reductions in preganglionic sympathetic nerve traffic, bradycardia, decreases in plasma renin activity, reductions in blood pressure in the supine position and adverse effects such as depression, sedation and bad dreams. Because of the frequency and severity of these side effects, there is an ongoing search for new centrally acting antihypertensive agents which might be better tolerated.

Adrenergic beta-Antagonists↗
PubMed1982

Decrease in sympathetic nervous system activity and attenuation in response to stress following renal denervation in the one-kidney one-clip Goldblatt hypertensive rat.

We have found that renal denervation in the one-kidney one-clip Goldblatt hypertensive rat results in an attenuation of the hypertension associated with a decrease in sympathetic nervous system activity. To test further the hypothesis that the renal nerves (afferents) contribute to the maintenance of hypertension in this model by modulating sympathetic nervous system activity, plasma norepinephrine and epinephrine changes in response to stress were compared in hypertensive sham-operated (n = 6), renal denervated (n = 6) and control (n = 7) animals. Stress was produced in conscious resting unrestrained animals by administering two brief electrical stimulations to the hindlimb. Resting plasma norepinephrine was significantly higher (P less than 0.01) in hypertensive sham-operated (420 +/- 41 pg/ml) compared to renal denervated (289 +/- 23 pg/ml) or control (296 +/- 25 pg/ml) animals. There was no difference in resting plasma epinephrine among the groups. In response to stress there were significantly greater absolute increases in plasma norepinephrine and epinephrine in hypertensive sham-operated animals compared to renal denervated and control groups, suggesting that the one-kidney one-clip rat exhibits an enhanced sympathoadrenal response to stress. The response to stress in renal denervated rats was the same as that in the control group. Taken together, these data support the concept that the renal afferent nerves modulate sympathetic nervous system activity in the one-kidney one-clip hypertensive rat.

Animals↗
PubMed1982

Sodium-neural interactions in the development of spontaneous hypertension.

The influence of alterations in sodium intake on blood pressure and indices of peripheral sympathetic activity was studied during the development of hypertension in the SHR. Male SHRs were given a diet containing either low (0.05%), normal (0.29%) or high (3.4%) sodium content beginning at 7 weeks of age. Systolic blood pressure was measured weekly by the tail cuff method in conscious animals. Three weeks after initiation of the diets 24 hour urines were collected for analysis of catecholamines. Plasma catecholamines were measured and the blood pressure response to ganglionic blockade (hexamethonium bromide, 30 mgm/kg) determined. High sodium resulted in a marked increase in the severity of hypertension that was associated with an increase in plasma and urinary norepinephrine concentration and an exaggerated depressor response to ganglionic blockade. In addition, a highly significant positive correlation was seen between plasma norepinephrine concentration and systolic blood pressure. The results are compatible with the hypothesis that the increase in blood pressure in the SHR maintained on a high sodium intake is in part due to an increase in peripheral sympathetic activity.

Animal Feed↗
PubMed1981

Lofexidine and clonidine in moderate essential hypertension.

The efficacy, safety, and tolerability of lofexidine, a centrally acting imidazoline derivative, were compared to that of clonidine in a randomized double-blind trial in 28 patients with moderate essential hypertension. The study consisted of a washout phase, a placebo phase, a drug titration phase (0.2 to 1.6 mg/day, with hydrochlorothiazide added at 0.4 mg daily for supine and erect diastolic blood pressure above 90 mm Hg), and a maintenance phase lasting 3 mo. During the titration phase supine systolic and diastolic pressures fell in lofexidine patients from 143 +/- 4/98 +/- 3 to 122 +/- 3/81 +/- 2 mm Hg and in clonidine patients from 154 +/- 6/101 +/- 2 to 124 +/- 4/81 +/- 2 mm Hg (P less than 0.01), and erect systolic and diastolic pressures fell in lofexidine patients from 143 +/- 3/105 +/- 2 to 116 +/- 3/85 +/- 2 mm Hg and in clonidine patients from 156 +/- 6/104 +/- 2 to 117 +/- 4/82 +/- 2 mm Hg (P less than 0.01). Maximal doses of lofexidine and clonidine in combination with hydrochlorothiazide had equivalent antihypertensive effects, but when the effects of lofexidine and clonidine were compared at each dose level, larger doses of lofexidine patients in either the supine or erect position during the titration phase but heart rate fell in the clonidine patients (P less than 0.05) over the same period. Dry mouth and drowsiness were reported in both groups but were both less frequent and less severe in the lofexidine group than the clonidine group.

Adult↗