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)

Caffeine is a methylxanthine whose primary biologic effect is antagonism of the adenosine receptor. Its presence in coffee, tea, soda beverages, chocolate, and many prescription and over-the-counter drugs makes it the most commonly consumed stimulant drug. Initially caffeine increases blood pressure, plasma catecholamine levels, plasma renin activity, serum free fatty acid levels, urine production, and gastric acid secretion. Its long-term effects have been more difficult to substantiate. Most of the caffeine consumed in the United States is in coffee, which contains many other chemicals that may have other biologic actions. The consumption of coffee is a self-reinforcing behavior, and caffeine dependence and addiction are common. Coffee and caffeine intake have been linked to many illnesses, but definitive correlations have been difficult to substantiate. Initial trials showing coffee's association with coronary disease and myocardial infarction have been difficult to reproduce and have many confounding variables. Recent studies showing a larger effect over long follow-up periods and with heavy coffee consumption have again brought the question of the role of coffee in disease states to the fore. Caffeine in average dosages does not seem to increase the risk of arrhythmia. At present there is no convincing evidence that caffeine or coffee consumption increases the risk for any solid tumor. The intake of coffee and caffeine has clearly been decreasing in this country over the past two decades, largely brought about by the increasing health consciousness of Americans. Although there have been many studies that hint that the fears of increased disease with coffee drinking may be warranted, many questions have yet to be answered about the health effects of coffee and caffeine use.
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PMID:Wake up and smell the coffee. Caffeine, coffee, and the medical consequences. 144 96

Experiments were conducted in anesthetized dogs to evaluate the effects of adenosine receptor blockade on renal function and on autoregulation of total RBF and outer cortical blood flow. After control measurements, the adenosine receptor antagonist, 1,3-dipropyl-8-p-sulfophenylxanthine (PSPX) was infused intrarenally for 45 min at 2 or 6 microM/min. Responses to PSPX were compared with those obtained during infusions of either aminophylline or theophylline. PSPX infusion led to substantial increases in urine flow and sodium excretion (four- to fivefold). RBF increased significantly; however, outer cortical blood flow and GFR were not significantly altered. PRA increased twofold during PSPX infusion. The vasoconstrictor responses to bolus injections of 2-chloroadenosine (100 mumol) were attenuated by 58 and 86% during the low and high doses of PSPX and to a lesser extent with aminophylline/theophylline infusions. At renal arterial pressures above the inflection point, the slope of the average pressure-flow relationship during PSPX infusion was close to zero and was not significantly different from control. Similarly, autoregulatory capability was not altered during infusions of theophylline or aminophylline. These data provide further evidence that endogenous adenosine contributes substantially to the control of renin release but only modestly to the control of RBF and GFR and to renal autoregulatory capability. The natriuretic responses during adenosine blockade, which occurred in the face of elevated renin levels, support the hypothesis that endogenous adenosine enhances tubular sodium reabsorption rate.
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PMID:Influence of adenosine receptor blockade on renal function and renal autoregulation. 176 May 42

Intracellular Ca (Cai) is an inhibitory second messenger in renin secretion, and it has been hypothesized that some first messengers--especially angiotensin II [A-II] and antidiuretic hormone [ADH], and possibly A1-adenosine receptor antagonists as well--increase Cai and thereby inhibit renin secretion by causing the release or mobilization of Ca from intracellular sites of sequestration. The present experiments were designed to test this hypothesis, by using 3,4,5-trimethoxybenzoic acid 8-(diethylamino)-octyl ester (TMB-8), a putative antagonist of Ca release from intracellular sequestration sites. The rat renal cortical slices preparation was used. Basal renin secretory rate was unaffected by 1 and 10 microM TMB-8, but more than doubled in response to 100 microM TMB-8. Basal renin secretory rate was inhibited by A-II (1 microM), by ADH (200 units/1), by an A1-adenosine receptor agonist (N6-cyclohexyladenosine, or CHA; 0.5 microM), and by an alpha-adrenergic agonist (methoxamine; 10 microM). Only the inhibitory effect of methoxamine was blocked by 1 and 10 microM TMB-8, but these concentrations had no effect on basal secretory rate. At 100 microM, TMB-8 blocked the inhibitory effects of ADH as well as of methoxamine, but failed to block the inhibitory effects of CHA and A-II. However, these observations cannot be taken as evidence that methoxamine and ADH, but not CHA and A-II, inhibit renin secretion by a mechanism involving release of Ca from intracellular sequestration sites, because 100 microM TMB-8 clearly had non-specific effects. Among them, it completely blocked the inhibitory effect of K-depolarization on renin secretion. Collectively, at least three separate actions of TMB-8 must be invoked to explain the present results. Likely candidates are an Na-channel blocking effect and a Ca channel blocking effect in addition to antagonism of the release of Cai.
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PMID:Calcium-dependent inhibition of renin secretion: TMB-8 is a non-specific antagonist. 192 44

In the rat and dog, exogenous adenosine inhibits renin release and adenosine receptor blockade augments stimulated renin release, suggesting that endogenous adenosine contributes to the regulation of renin release. The present study examines the role of endogenous adenosine in the regulation of renin in humans. The ability of the adenosine receptor blocker, caffeine, to augment renin release in response to the vasodilator, diazoxide, has been investigated in eight normal subjects in a double-blind, placebo-controlled, cross-over study. During each arm of the study, subjects on a 150 mEq of sodium, xanthine-free diet received caffeine (250 mg 3 times daily) or placebo for 3 days before and on the study day, when they were given an i.v. loading dose of diazoxide (4 mg/kg) followed by a 3-hr continuous infusion (0.67 mg/kg/hour). PRA, caffeine and diazoxide levels were measured before, during and after the diazoxide infusion. PRA measurements were repeated with subjects standing, 6 hr after starting diazoxide. Administration of diazoxide resulted in a modest tachycardia and a small, but significant, decrease in BP. Supine PRA was elevated during and after the diazoxide infusion and rose further with standing. Although there was no difference in plasma diazoxide levels, maximal pulse or BP response to diazoxide between the two arms of the study, the renin response was significantly greater in the presence of caffeine. These data confirm that caffeine augments the PRA response to diazoxide and suggest that endogenous adenosine inhibits stimulated renin response in humans.
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PMID:Caffeine potentiates the renin response to diazoxide in man. Evidence for a regulatory role of endogenous adenosine. 198 69

Previous studies strongly suggest that adenosine receptors on juxtaglomerular cells function to restrain the secretion of renin induced by a variety of stimuli. The clinical significance of this is that caffeine, a widely consumed adenosine receptor antagonist, could augment renin release responses to diseases such as renovascular hypertension, liver cirrhosis and heart failure and to therapeutic maneuvers such as salt restriction, diuretics and vasodilators. Caffeine may be particularly troublesome in this regard because this methylxanthine has central nervous system effects and intracellular actions that also might contribute to the overall ability of caffeine to potentiate renin secretion. The purpose of this study was to document the effects of caffeine on renin release responses to a vasodilator and to investigate what mechanisms were responsible for any augmentation of vasodilator-induced renin secretion. Accordingly, we compared the effects of caffeine vs. 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX; a xanthine that we documented in this study not to significantly enter the brain or penetrate cell membranes) on base-line and hydralazine-induced renin release in both normal and beta adrenoceptor-blocked (propranolol, 15 mg/kg) rats. Both xanthines (at a dose of 10 mg/kg plus 150 micrograms/min) attenuated adenosine-mediated hypotension and bradycardia, and DPSPX was at least as effective as caffeine in antagonizing peripheral adenosine receptors. Caffeine and DPSPX increased base-line plasma renin activity to a similar extent regardless of whether the animals were pretreated with propranolol. In rats with an intact beta adrenergic system, caffeine, but not DPSPX, increased the renin release response to low-dose hydralazine (1 mg/kg). Although both xanthines augmented the renin release response to high-dose hydralazine (10 mg/kg), caffeine was more efficacious in this regard. In beta adrenoceptor-blocked rats, neither caffeine nor DPSPX augmented the renin release response to low-dose hydralazine, whereas both xanthines equally potentiated the renin release response to high-dose hydralazine. These data demonstrate that caffeine increases base-line renin release primarily by blocking peripheral (most likely renal), cell-surface adenosine receptors; however, caffeine potentiates vasodilator-induced renin secretion in part by blocking peripheral (most likely renal), cell-surface adenosine receptors and in part by additional central nervous system and/or intracellular mechanism(s) that involve the beta adrenergic system.
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PMID:Caffeine potentiates vasodilator-induced renin release. 200 84

This study compares the renal actions of the A2 selective adenosine agonist, CGS 21680A, with the A1 selective adenosine agonist, N6-cyclopentyladenosine (CPA), and the nonselective agonist, 5'-N-ethylcarboxamide adenosine (NECA), in the anesthetized dog. Initial receptor binding studies in dog brain demonstrated that CPA and CGS 21680A were selective for the A1 and A2 adenosine receptor, respectively, whereas NECA displayed slightly greater affinity for A1 than A2 adenosine receptors in the canine brain. Intravenous infusion of CGS 21680A (0.25 and 2.5 micrograms/kg/min) decreased blood pressure (BP) and increased heart rate (HR). CGS 21680A transiently increased renal blood flow (RBF) and either did not change or, at the highest dose infused, decreased glomerular filtration rate (GFR). Both urine volume (UV) and urinary sodium excretion (UNaV) also were decreased by CGS 21680A. At the lowest infusion rate (0.025 micrograms/kg/min) CGS 21680A produced a slowly developing increase in RBF, no change in GFR and a significant decrease in sodium excretion. Intravenous infusion of CPA (15 micrograms/kg/min) lowered BP and HR RBF and GFR. UNaV, UV and renin release also were inhibited by CPA. At a lower infusion rate (2.5 micrograms/kg/min), CPA markedly inhibited UNaV in the absence of a significant change in either BP or renal hemodynamic parameters. Infusion of NECA (0.01 and 0.1 micrograms/kg/min) lowered BP but did not change HR. Furthermore, RBF was increased by NECA, whereas UV and UNaV were inhibited in the absence of a change in GFR. These results may be explained by the relative selectivity of each analog for A1 or A2 adenosine receptors.
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PMID:Renal actions of a new adenosine agonist, CGS 21680A selective for the A2 receptor. 204 17

The purpose of this study was to test the hypothesis that endogenous adenosine functions to restrain the renin release response to pharmacological and pathophysiological stimuli. To achieve this objective, we examined the effects of an adenosine receptor antagonist, 1,3-dipropyl-8-(p-sulfophenyl)xanthine (DPSPX), on the renin release response induced by acute administration of hydralazine or by chronic clipping of the left renal artery (renovascular hypertensive rats). In conscious, unrestrained rats, DPSPX significantly increased plasma renin activity (PRA) in control rats, in rats treated with hydralazine, and in renovascular hypertensive rats. The effect of DPSPX on PRA was significantly greater in rats treated with hydralazine or in renovascular hypertensive rats compared with control rats. DPSPX did not influence arterial blood pressure in any group, did not affect the measurement of PRA, and did not alter the elimination of renin activity from the circulation. Additional experiments were performed in the in situ autoperfused kidney so that the effects of DPSPX on renal hemodynamics and renal excretory function could be assessed. In this experimental model, DPSPX also increased PRA in hydralazine-treated rats and in renovascular hypertensive rats without affecting arterial pressure, renal blood flow, or sodium excretion. In a final set of studies in conscious, unrestrained rats, adenosine deaminase increased PRA in a dose-dependent manner in hydralazine-treated rats and significantly increased the slope of the relation between PRA and the depressor response to hydralazine. We conclude: 1) Although the kidney has both A1 and A2 adenosine receptors mediating inhibitory and stimulatory actions, respectively, on renin release, the dominant effect of endogenous adenosine on renin release is inhibitory. 2) Even under basal physiological conditions, endogenous adenosine tonically inhibits renin release. 3) This inhibitory effect is augmented whenever the renin-angiotensin system is stimulated regardless of the approach used to activate renin release. 4) Endogenous adenosine negatively modulates renin release by a direct effect on juxtaglomerular cells.
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PMID:Endogenous adenosine restrains renin release in conscious rats. 240 69

The effects of different doses of dilazep on renal hemodynamics, urine formation, and renin release were studied in anesthetized dogs. Intrarenal arterial infusion of dilazep (1 microgram/kg/min) increased renal blood flow, with no change in systemic arterial blood pressure and renal venous plasma renin activity. Renal vasodilation induced by dilazep was completely inhibited by intrarenal arterial infusion of 3-isobutyl-1-methyl-xanthine (IBMX; 11.1 micrograms/kg/min), a potent adenosine receptor antagonist, but not by indomethacin (13 mg/kg i.v.). These results suggest that dilazep has a vasodilatory action in the kidney--one that is independent of the renal renin-angiotensin system. The inhibitory action of IBMX on the dilazep-induced renal vasodilation indicates that the renal vascular effects of dilazep may be exerted by augmentation of endogenous adenosine and mediated through adenosine receptors.
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PMID:Renal vascular effects of dilazep antagonized by 3-isobutyl-1-methyl-xanthine. 242 86

In a previous study we discovered that the adenosine receptor antagonist, caffeine, increases plasma renin activity and blood pressure in renin-dependent renovascular hypertension. The purpose of the present investigation was to determine whether methylxanthines augment the increase in renin secretion induced by a reduction in renal perfusion pressure and, if so, whether this effect is mediated by a direct action on juxtaglomerular cells. Accordingly, we examined the effects of infusions of caffeine and theophylline directly into the renal artery on the increase in renin secretion induced by suprarenal aortic constriction. All studies were conducted in dogs receiving an intravenous infusion of propranolol to prevent changes in renin secretion mediated indirectly via the sympathetic nervous system. Caffeine (5 mg/min) increased the renin response to suprarenal aortic constriction about 10-fold without significantly affecting renal hemodynamics or excretory function. Theophylline (5 mg/kg), on the other hand, did not significantly increase the renin response to a reduction in renal perfusion pressure, but did increase urine flow and sodium excretion about 10-fold. However, in the non-filtering, beta-adrenoceptor blocked, canine kidney, theophylline markedly increased the renin response to suprarenal aortic constriction. These results indicate that methylxanthines can potentiate the renin response to a reduction in renal perfusion pressure most likely by directly affecting the juxtaglomerular cells; however, since increased sodium delivery to the macula densa inhibits renin release, the extent to which methylxanthines affect the renin response to renal artery hypotension depends on how vigorous the diuretic response is to a given methylxanthine.
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PMID:Methylxanthines augment the renin response to suprarenal-aortic constriction. 257 Mar 68

The purpose of this study was to determine the role of endogenous adenosine in controlling renin release during both a normal and low sodium diet. To probe the involvement of endogenous adenosine in the control of renin release, we examined the effects of an adenosine receptor antagonist, 1,3-dipropyl-8-(p-sulfophenyl)xanthine (DPSPX), on renin release in rats fed either a normal or low sodium diet. All studies were conducted in the in situ autoperfused kidney. DPSPX significantly increased arterial and renal venous levels of renin in both groups of animals; however, statistical analysis of the data (2-factor analysis of variance) indicated that DPSPX increased aortic and renal venous levels of renin more in rats fed a low sodium diet compared to rats fed a normal sodium diet. Also, whereas DPSPX did not significantly increase the venoarterial difference of renin activity across the kidney or the calculated net secretion rate of renin in rats on a normal sodium diet, both of these indices of renin release were significantly increased by DPSPX in rats on a low sodium diet. The effects of DPSPX on renin release could not be explained by changes in renal hemodynamics or excretory function. Additional experiments with rats on a low sodium diet that were treated with propranolol demonstrated that the effects of DPSPX on renin release were independent of the sympathetic nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endogenous adenosine restrains renin release during sodium restriction. 265 49


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