Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was designed to characterize the developmental changes in the renal responses to dopamine DA1-receptor activation in chronically instrumented preterm (109-115 days) and near-term (130-140 days, full term 145 days) fetal sheep. Cumulative doses of the selective DA1-agonist fenoldopam increased mean arterial blood pressure (MABP) in both preterm (+16 +/- 3%) and near-term fetuses (+16 +/- 3%) but had no significant effect on renal blood flow velocity. Infusion of the DA1-antagonist SCH-23390 did not affect the increase in MABP, suggesting that the effect of fenoldopam on MABP was not directly related to activation of DA1-receptors. Fenoldopam infusion had no significant effects on renal function parameters in preterm fetuses. In near-term fetuses, however, fenoldopam increased urinary flow rate (82.6 +/- 20.9%, P < 0.003), glomerular filtration rate (GFR; 16.6 +/- 4.9%, P < 0.01), urinary sodium excretion (40.1 +/- 14.9%, P < 0.02), and fractional excretion of sodium (26.8 +/- 11.2%, P < 0.03). Infusion of the DA1-antagonist SCH-23390 blocked the fenoldopam-induced diuresis and natriuresis but had no significant effect on the rise in GFR. Fenoldopam infusion had no significant effects on plasma renin activity and plasma aldosterone concentration and on urinary prostaglandin (PG) excretion (PGE2, PGF2 alpha, and 6-keto-PGF1 alpha). Taken together, these results suggest that the renal effect of DA1-receptor activation is age dependent and that stimulation of DA1-receptor in near-term fetuses is associated with a diuresis and natriuresis that seem to be independent of renal hemodynamics and adrenal effects.
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PMID:Ontogeny of renal response to specific dopamine DA1-receptor stimulation in sheep. 135 89

This review discusses the localization of adrenergic- and dopaminergic-adrenoceptors within the cardiovascular system and describes the cardiovascular and renal changes produced following the activation of these receptors by appropriate agonists. Whereas the role of alpha- and beta-adrenergic agents in the treatment of heart failure is well recognized, recent studies with dopamine (DA)-receptor agonists indicate that they offer a novel approach in the therapy of congestive heart failure. DA-adrenoceptor agonists reduce afterload by causing vasodilation and promote sodium excretion via direct activation of DA1-adrenoceptors located on renal tubules. Fenoldopam is a selective DA1-adrenoceptor agonist found to be effective in heart failure. It reduces afterload by causing peripheral vasodilation and produces natriuresis and diuresis. Dopexamine is a DA1- and beta 2-adrenoceptor agonist, and its efficacy in heart failure is due to its ability to provide mild inotropic support and cause a reduction in afterload. Ibopamine is a prodrug that is converted into its active metabolite, epinine. This compound activates primarily DA1- and DA2-adrenoceptors. It is effective in heart failure, and the mechanism progresses via DA1- and DA2-adrenoceptor-mediated reduction in afterload. Agonists of DA2-adrenoceptors reduce afterload by decreasing the release of norepinephrine and by reducing the levels of renin-angiotensin-aldosterone system. Since both of these systems are active in heart failure, ibopamine offers a rational approach for therapy. The present review addresses the concept of pharmacologic intervention in adrenergic and dopaminergic influence in the cardiovascular and renal systems to produce changes that are desirable for the pharmacotherapy of congestive heart failure.
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PMID:Cardiovascular pharmacology of adrenergic and dopaminergic receptors: therapeutic significance in congestive heart failure. 167 49

To clarify the contribution made by the renin-angiotensin system activation to the short lived hypotensive response to fenoldopam, the haemodynamic effects of a combination of fenoldopam (100 mg) and enalapril (5 mg) were compared with fenoldopam alone, enalapril alone and placebo in a balanced, randomised, double blind, single dose study in eight hypertensive patients. Fenoldopam caused an acute fall in blood pressure which lasted approximately 3 h after dosing and was associated with a reflex tachycardia. Enalapril caused a more gradual fall in blood pressure (onset 2 h) without a reflex tachycardia. The combination of drugs produced greater reductions in blood pressure sustained for a longer period than fenoldopam alone and with a more rapid onset than enalapril alone. In combination the hypotensive effects of fenoldopam and enalapril were clearly additive and not synergistic. Activation of the renin-angiotensin system does not antagonise significantly the hypotensive effect of fenoldopam.
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PMID:A single dose study of the effects of fenoldopam and enalapril in mild hypertension. 167 67

Fenoldopam (SKF 82526 J) is a selective DA-1 receptor agonist and thus of a potential benefit for promoting afterload reduction, renal vasodilatation, and diuresis in congestive heart failure. To examine the acute effects of fenoldopam in heart failure, studies were performed in control rabbits (n = 6) and in rabbits with chronic congestive heart failure (CHF, n = 6) induced by adriamycin treatment. Cardiovascular variables and regional blood flows were determined before and after an infusion of fenoldopam (150 micrograms/kg total dose). Resting hemodynamics differed in CHF and control groups. In the CHF group, mean arterial pressure (MAP), cardiac output (CO), and stroke volume (SV) were reduced and right atrial pressure (RAP), left ventricular end-diastolic pressure (LVEDP), and total peripheral resistance (TPR) were increased. Renal blood flow was much reduced in the CHF as compared with the control group (5.1 +/- 0.8 vs. 9.1 +/- 0.6 ml/min.g, p less than 0.05). Similar falls in MAP were noted after fenoldopam in CHF (-13 +/- 2%) and control rabbits (-12 +/- 3%) due to falls in TPR. An increase in CO was observed in both groups, the rise being more pronounced in the CHF group (22 vs. 12%). Heart rate was unchanged by fenoldopam in CHF rabbits but increased in controls. After fenoldopam, CHF rabbits exhibited significantly greater increases in blood flow to each of the three vascular beds studied: renal (113 +/- 27% vs. 7 +/- 13%), mesenteric (249 +/- 60% vs. 15 +/- 19%) and cerebral (145 +/- 13% vs. 12 +/- 12%). Plasma renin and norepinephrine (NE) levels increased after fenoldopam in both control and CHF rabbits. These results show that acute administration of fenoldopam produces favourable systemic and regional hemodynamic responses in rabbits with low output heart failure. However, long-term benefit remains to be demonstrated, particularly considering the hormonal responses.
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PMID:Beneficial effects of fenoldopam on systemic and regional hemodynamics in rabbits with congestive heart failure. 245 54

In anesthetized dogs, a 15-min intravenous (i.v.) infusion of fenoldopam (2.0 micrograms/kg/min) produced a decrease in mean aortic blood pressure (MAP) and an increase in renal blood flow (RBF) and plasma renin activity (PRA). The hypotensive effect attained a maximum within 5 min and then waned by approximately 30% at the end of fenoldopam administration. The development of this "tolerance" phenomenon was prevented by enalapril or saralasin. The hypotension and the increase in PRA were not modified by either propranolol or chlorisondamine but were inhibited by SCH 23390, a DA1 antagonist. Fenoldopam (0.1 microgram/kg/min for 15 min) infused into the left renal artery (i.a.) in intact or ganglion-blocked dogs did not change MAP but increased PRA. This effect was antagonized by SCH 23390. In ganglion-blocked preparations in which an apparently maximal renal vasodilatation had been achieved by an i.a. acetylcholine, i.a. fenoldopam produced an increase in PRA which was again blocked by SCH 23390. In uninephrectomized dogs, blockade of alpha- and beta-adrenoceptors or inhibition of renal baroreceptor and macula densa mechanisms of renin release failed to prevent the fenoldopam-induced increase in PRA. In conclusion, the release of renin by fenoldopam is responsible for the development of tolerance to the hypotensive effects of fenoldopam. Furthermore, because the increase in PRA was blocked by SCH 23390 and occurred in the absence of either operational systemic or intrarenal regulatory mechanisms, we propose that it is mediated by stimulation of specific dopamine (DA1) receptors on the juxtaglomerular (JG) cells.
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PMID:Increase in plasma renin activity evoked by fenoldopam in dogs is directly mediated by dopamine1 receptor stimulation. 247 22

Direct effects of dopamine on renin release were examined using static incubations and perifusions of rat renal cortical slices. Dopamine (10(-5)M) significantly stimulated renin release compared with control. To determine which receptors are involved in dopamine-elicited renin release, studies were performed with specific dopamine-1 and dopamine-2 receptor agonists and antagonists, as well as with alpha- and beta-adrenergic antagonists. Fenoldopam, a dopamine-1 receptor agonist, dose dependently stimulated renin secretion both in static incubations and perifusions; whereas quinpirole (10(-7)-10(-5)M), a dopamine-2 receptor agonist, was ineffective. Phentolamine (10(-4)M), an alpha-adrenergic antagonist, did not alter dopamine- or fenoldopam-induced renin release. Similarly, propranolol, a beta-blocker, did not interfere with the renin stimulation of dopamine (10(-5)M) or fenoldopam (10(-6)M) incubations or perifusion experiments; whereas propranolol significantly blocked isoproterenol action. SCH 23390 (10(-5)M), a specific dopamine-1 antagonist, blocked dopamine- and fenoldopam-induced renin. In contrast, pimozide, a dopamine-2 receptor antagonist, was ineffective. These studies indicate that dopamine is a direct renin secretogogue, and its effects seem to be mediated by specific dopamine-1 receptor activation, as neither alpha- nor beta-adrenergic blockers nor dopamine-2 receptor antagonists altered dopamine actions. The results suggest that dopamine produced locally in the kidney may stimulate renin secretion directly by dopamine-1 receptor activation.
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PMID:Evidence that specific dopamine-1 receptor activation is involved in dopamine-induced renin release. 256 77

The effect of a single oral dose of 100 mg of fenoldopam on renal function and blood pressure was investigated in seven healthy male subjects in a double-blind placebo controlled study. Mean diastolic blood pressure fell by 10 mm Hg, 45 min after oral dosing and then gradually returned to baseline values. There was an increase in pulse rate and a delayed rise in systolic blood pressure. Measured from 30 to 120 min after drug ingestion, mean effective renal plasma flow increased to 158% of the value observed after placebo; mean glomerular filtration rate rose to 109% of the placebo value. Measured from 120 to 210 min after administration of the drug, effective renal plasma flow and glomerular filtration rate had returned to baseline values. Fenoldopam produced a small increase in the mean sodium excretion rate which was not significantly different from the fall after placebo. No change was detected in urine flow or potassium excretion rate. Mean plasma renin activity increased three-fold 1 h after oral dosing. Plasma aldosterone did not show a parallel increase although the plasma concentration at 1 h was significantly higher than after placebo. The results show a pronounced renal vasodilator effect lasting about 2 h. The findings are consistent with marked DA1 receptor agonist activity.
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PMID:The effect of oral fenoldopam (SKF 82526-J), a peripheral dopamine receptor agonist, on blood pressure and renal function in normal man. 285 15

A series of studies were undertaken to assess the effect of oral fenoldopam, a specific DA1 dopamine receptor agonist on blood pressure and renal function in patients with mild essential hypertension. Six patients with essential hypertension were entered into a dose-ranging study and received either placebo, 25, 50 or 100 mg fenoldopam. A significant, dose-related reduction in diastolic blood pressure, and increase in heart rate was demonstrated (both P less than 0.05), maximal at 45 min to 1 h. Fenoldopam increased plasma renin activity. In a double-blind study, seven patients received a single dose of fenoldopam 100 mg or placebo. Fenoldopam produced a significant fall in systolic (P less than 0.05) and diastolic (P less than 0.01) blood pressure and renal vascular resistance (P less than 0.01). Urine flow rate (P less than 0.05), sodium excretion (P less than 0.01), plasma renin activity (P less than 0.05) and plasma aldosterone (P less than 0.05) increased. Five patients underwent measurement of the above parameters following a single dose of fenoldopam 100 mg with a repeat of these measurements after they had taken fenoldopam 100 mg four times daily for 1 month. The acute response of blood pressure to the single dose appeared unchanged but tachyphylaxis was evident in the responses of heart rate, plasma renin activity and plasma aldosterone.
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PMID:Studies with fenoldopam, a dopamine receptor DA1 agonist, in essential hypertension. 286 48

The effect of fenoldopam, a selective DA1-agonist, on the plasma aldosterone response to metoclopramide was studied in six hypertensive patients included in a multicentre double-blind placebo controlled cross-over study of the antihypertensive effects of fenoldopam. Fenoldopam significantly increased baseline plasma renin activity (PRA); baseline plasma aldosterone levels rose slightly. Baseline PRL and the PRL response to metoclopramide were not altered by fenoldopam. After metoclopramide, a significant increase of plasma aldosterone was observed during treatment with fenoldopam, as well as in the placebo-period. The peak values were not significantly different and occurred at 15 min during both treatment periods. These results indicate that fenoldopam does not reduce metoclopramide-induced aldosterone secretion and therefore suggest that the adrenal dopamine receptor is not identical to the vascular DA1 receptor.
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PMID:Effect of fenoldopam on the aldosterone response to metoclopramide in man. 287 51

Whether the dopaminergic system may be involved in essential hypertension is of pathogenetic as well as therapeutic interest. Therefore, we investigated in eight hypertensive and 12 normal subjects cardiovascular, endocrine, and renal responses to fenoldopam, which has been characterized experimentally as an agonist of peripheral postsynaptic dopamine1 receptors. A single oral dose of fenoldopam, 100 mg, changed blood pressure (BP) in hypertensive subjects (from 163/103 to 147/76 mm Hg; p less than 0.01 for systolic and p less than 0.001 for diastolic BP) and normal subjects (from 121/81 to 123/65 mm Hg; p less than 0.001 for diastolic BP); percentage decreases in diastolic BP averaged -20 +/- 6 and -16 +/- 7%, respectively. Fenoldopam-induced effects on other variables were similar in the two groups. Heart rate rose (p less than 0.001) on average from 69 to 92 beats/min in hypertensive and from 64 to 84 beats/min in normal subjects. Effective renal plasma flow increased (from 552 to 765 and 634 to 937 ml/min/1.73 m2; p less than 0.01), while glomerular filtration rate tended to decrease (from 121 to 99 ml/min/1.73 m2 in the hypertensive and from 119 to 97 ml/min/1.73 m2; p less than 0.001 in the normal group). Fractional sodium clearance was elevated (from 2.8 to 5.2 and 1.7 to 3.8%; p less than 0.01), as was free water clearance (from -1.7 to 0.6 and -1.7 to 0.1 ml/min/1.73 m2; p less than 0.01). Potassium clearance was largely unchanged. Plasma renin activity increased about twofold (p less than 0.01 in normal subjects), and plasma aldosterone by 40% (NS). Plasma norepinephrine levels increased twofold to 2.5-fold (p less than 0.001), and urinary norepinephrine excretion fivefold to 10-fold (p less than 0.01). Fenoldopam-induced changes were not significantly modified by intravenous and/or oral pretreatment with the dopamine-receptor antagonist metoclopramide or the cyclooxygenase inhibitor indomethacin. These findings suggest that in humans, fenoldopam may acutely override the dopaminergic antagonism of metoclopramide given in clinical dosage and that its cardiovascular and renal effects are not prostaglandin-mediated. Although acute sympathetic stimulation may be partially antagonistic, the concomitant BP-lowering, renal vasodilating, and natriuretic actions of fenoldopam represent a desirable profile of a potential antihypertensive agent.
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PMID:Cardiovascular and renal profile of acute peripheral dopamine1-receptor agonism with fenoldopam. 288 68


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