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)

Adenosine is a potent inhibitor of renin release. It has therefore been suggested that endogenous adenosine may play a role in the regulation of renin release. Sodium-chloride transport at the level of the macula densa has been proposed as the primary source of endogenous adenosine. Evidence to support a modulatory role of adenosine on renin release in vivo is, however, limited. We therefore wanted to determine if: 1) adenosine modulates furosemide-induced renin release and 2) sodium-chloride reabsorption at the macula densa is essential for adenosine actions. To test these hypotheses, three groups of rats were pretreated either with saline or the adenosine receptor antagonists caffeine or 1,3-dipropyl-8-(p-sulfophenyl)xanthine (both at a dose of 30 mg/kg followed by 450 micrograms/kg/min). Rats then received furosemide (50 mg/kg i.v.). In the vehicle group, furosemide increased urinary volume, sodium and potassium excretion and increased plasma renin activity from 6 +/- 1 to 45 +/- 11 ngAl/ml/hr. Caffeine and 1,3-dipropyl-8-(p-sulfophenyl)xanthine potentiated the increase in plasma renin activity produced by furosemide (to 120 +/- 15 and 147 +/- 21 ng Al/ml/hr, respectively), whereas having no significant effects on urinary volume, sodium excretion or blood pressure. These results suggest that furosemide-induced renin release in vivo is restrained by endogenous adenosine. In as much as furosemide blocks sodium-chloride transport in the thick ascending limb of Henle's loop and the macula densa cells, it appears that under the conditions of this study sodium transport across these segments is not essential to initiate adenosine-mediated mechanisms.
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PMID:Caffeine potentiates the renin response to furosemide in rats. Evidence for a regulatory role of endogenous adenosine. 267 16

The effect of the specific alpha 2-adrenoceptor agonist BHT 933 on stimulated renin release was investigated in the isolated perfused rat kidney preparation. Renin release was stimulated with N-ethylcarboxamide adenosine (NECA) (3 microM) a specific A2-adenosine receptor agonist. alpha 2-Adrenoceptor stimulation with BHT 933 (1 microM) attenuated the stimulation of renin release by NECA. Yohimbine (300 nM) or prazosin (28 nM) at alpha 2- and alpha 1-adrenoceptor specific concentrations respectively, blocked this inhibition of renin release by BHT 933. In all groups studied there was no significant effect of these experimental treatments on renal hemodynamics or electrolyte excretion. The ability of yohimbine or prazosin, at alpha 2- and alpha 1-adrenoceptor specific concentrations respectively, to antagonize the effects of BHT 933 suggests a lack of agonist specificity for these receptor effect as previously suggested for the mesenteric artery.
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PMID:Inhibition of renin release by alpha-adrenoceptor stimulation in the isolated perfused rat kidney. 288 45

Previous studies by others have demonstrated that exogenous adenosine inhibits renin secretion in vivo. In the present experiments, we studied the effects of three adenosine receptor agonists [N6-cyclohexyladenosine (CHA), 2-chloroadenosine (2-CIA) and 5'-N-ethylcarboxamideadenosine (NECA)] on renin secretion of rat renal cortical slices. The effects were biphasic; submicromolar concentrations inhibited secretion concentration-dependently and the order of potency was CHA greater than 2-CIA greater than NECA. Micromolar and higher concentrations stimulated secretion concentration-dependently and the order of potency was reversed: NECA greater than 2-CIA greater than CHA. These results are consistent with the hypothesis that activation of A1 and A2 adenosine receptors produces inhibition and stimulation of secretion, respectively. Theophylline antagonized both the inhibitory effect of low concentrations of CHA and the stimulatory effect of higher concentrations, providing additional evidence for mediation by activation of cell-surface adenosine receptors. Calcium chelation abolished the inhibitory effect of CHA, suggesting that increased intracellular calcium mediates the inhibitory effect; on the other hand, the inhibitory effect was unaffected by membrane depolarization and calcium channel blockade, suggesting that CHA-induced inhibition is not due to calcium influx through voltage-sensitive calcium channels. Ouabain, vanadate and K-depolarization, all of which are believed to increase intracellular calcium, antagonized CHA- and NECA-stimulated renin secretion, suggesting that the stimulatory effect of these agonists is mediated by decreased intracellular calcium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A1 and A2 adenosine receptor activation inhibits and stimulates renin secretion of rat renal cortical slices. 298 63

This study was designed to examine: (a) the effects of adenosine and its analogues on renin release in the absence of tubules, glomeruli, and macula densa, and (b) whether adenosine may be involved in a macula densa-mediated renin release mechanism. Rabbit afferent arterioles (Af) alone and afferent arterioles with macula densa attached (Af + MD) were microdissected and incubated for two consecutive 30-min periods. Hourly renin release rate from a single arteriole (or an arteriole with macula densa) was calculated and expressed as ng AI X h-1 X Af-1 (or Af + MD-1)/h (where AI is angiotensin I). Basal renin release rate from Af was 0.69 +/- 0.09 ng AI X h-1 X Af-1/h (means +/- SEM, n = 16) and remained stable for 60 min. Basal renin release rate from Af + MD was 0.20 +/- 0.04 ng AI X h-1 X Af + MD-1/h (n = 6), which was significantly lower (P less than 0.0025) than that from Af. When adenosine (0.1 microM) was added to Af, renin release decreased from 0.72 +/- 0.16 to 0.24 +/- 0.04 ng AI X h-1 X Af-1/h (P less than 0.025; n = 9). However, when adenosine was added to Af + MD, no significant change in renin release was observed. N6-cyclohexyl adenosine (an A1 adenosine receptor agonist) at 0.1 microM decreased renin release from Af from 0.69 +/- 0.14 to 0.39 +/- 0.12 ng AI X h-1 X Af-1/h (n = 5, P less than 0.05). However, 5'-N-ethylcarboxamide adenosine (an A2 adenosine receptor agonist) either at 0.1 microM or at 10 microM had no effect. Theophylline, at a concentration (10 microM) that does not block phosphodiesterase but does block adenosine receptors, increased renin release from Af + MD from 0.21 +/- 0.03 to 0.46 +/- 0.08 ng AI X h-1 X Af + MD-1/h (P less than 0.05; n = 8). The results are consistent with the hypotheses that adenosine decreases renin release via the activation of A1 adenosine receptors, and that adenosine may be an inhibitory signal from the macula densa to juxtaglomerular cells.
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PMID:Possible role of adenosine in the macula densa mechanism of renin release in rabbits. 299 77

Exogenous adenosine affects renal hemodynamics, renal tubular transport processes, and the secretion of renin. However, adenosine is not a selective agonist; it activates both A1 and A2 cell-surface receptors and it binds to an intracellular P-site that inhibits adenylate cyclase activity. Recent in vitro studies have suggested that activation of A1- and A2- adenosine receptors results in opposite effects on renin secretion. The purpose of these experiments was to examine the renal effects of A1- and A2-adenosine receptor agonists in vivo. 5'-N-ethylcarboxamide adenosine (NECA), 2-chloroadenosine (2-CLA), and N6-cyclohexyladenosine (CHA) were infused intravenously at rates that produced comparable decreases in systemic arterial blood pressure. All three of these adenosine analogues produced comparable decreases in para-aminohippurate (PAH) and inulin clearances and in Na and K excretion rates. CHA, an A1-selective agonist, markedly decreased plasma renin concentration (PRC), whereas NECA, an A2-selective agonist, markedly increased PRC; 2-CLA, a nonselective agonist, produced a smaller increase in PRC. Taken together, these results suggest that occupation of A1- and A2-receptors inhibits and stimulates renin secretion in vivo, independently of the effects of these adenosine receptor agonists on arterial blood pressure, renal hemodynamics, and tubular Na and K transport.
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PMID:Renal effects of selective adenosine receptor agonists in anesthetized rats. 302 72

Adenylate cyclase activity in a tubular fraction obtained from rabbit renal cortex was stimulated by typical adenosine receptor agonists with a rank order of potency NECA (5'-(N-ethyl-carboxamido)-adenosine) (EC50 = 0.48 mumol/l) greater than R-PIA [(-)N6 (R-phenylisopropyl)-adenosine] (3.22 mumol/l). The stimulatory effect of NECA was competitively antagonized by 8-phenyltheophylline. Contamination of the tubular fraction with glomeruli and microvessels was less than 2%, as verified by tissue renin determination and could, therefore, be ruled out as being responsible for the observed effect. Tubular A2-adenosine receptors are probably involved in the control of renal electrolyte secretion and may represent the site of action of methylxanthines.
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PMID:Stimulation of adenylate cyclase activity via A2-adenosine receptors in isolated tubules of the rabbit renal cortex. 330 42

Previous studies have shown that activation of A1 and A2 adenosine receptors leads to inhibition and stimulation respectively of renin secretion by rat renal cortical slices. In the present studies, rat renal cortical slices were incubated in the presence of adenosine deaminase, to destroy any adenosine released from the preparation. N6-cyclohexyladenosine (CHA) had a biphasic effect on renin secretion: submicromolar concentrations inhibited concentration-dependently, and there was an inflection in the dose-response curve near 1 microM CHA such that higher concentrations produced a concentration-dependent relative stimulation, which became an absolute stimulation (i.e., secretory rate was higher than control) at 50 microM. These findings are consistent with A1 and A2 adenosine receptor-mediated inhibition and stimulation of renin secretion, respectively. Xanthine amine congener ["XAC," 8-(4-((2-aminoethyl)-aminocarbonylmethyloxy)phenyl-1,3-dipropyl xant hine] has been shown by others to be a very potent adenosine receptor antagonist with selectivity for A1 receptors. It antagonized both CHA-induced inhibition (Ki approximately 2 x 10(-9) M) and CHA-induced stimulation (Ki approximately 5 x 10(-8) M) of renin secretion. Thus, XAC exhibited a 25-fold selectivity for CHA-induced inhibition of renin secretion in comparison with CHA-induced stimulation. In comparison with previous results, XAC is approximately 3 orders of magnitude more potent than theophylline. In conclusion, occupation of adenosine receptors can lead either to inhibition (A1 receptor-mediated) or stimulation (A2 receptor-mediated) of renin secretion, and XAC is a very potent and selective antagonist of CHA-induced changes in renin secretion.
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PMID:XAC, a functionalized congener of 1,3-dialkylxanthine, antagonizes A1 adenosine receptor-mediated inhibition of renin secretion in vitro. 332 70

Numerous studies indicate that exogenous adenosine can inhibit renin release. However, the hypothesis that endogenous adenosine functions to restrain the renin response to physiological and/or pharmacological stimuli remains untested. To address this hypothesis, we examined the effects of a novel adenosine receptor antagonist, 1,3-dipropyl-8-para-sulfophenylxanthine (DPSPX), on renin release in rats on a normal versus a low salt diet. DPSPX did not affect renal blood flow, glomerular filtration rate, filtration fraction, urine volume, or sodium excretion in rats on either a normal or low salt diet. In contrast, in rats on a low salt diet, DPSPX significantly increased arterial and renal venous plasma renin activity and the gradient of plasma renin activity across the kidney. DPSPX did not alter these indices of renin release in rats on a normal salt diet. These data support the hypothesis that endogenous adenosine functions to restrain the renin response to salt depletion. Finally, if these findings are applicable to man, caffeine consumption could account for the variable antihypertensive effect of a low salt diet.
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PMID:Role of endogenous adenosine as a modulator of the renin response to salt restriction. 333 May 76

The effect of aminophylline on renin release from human chorion was investigated by perfusing the tissue with various concentrations of the drug. Buffer containing aminophylline (2 X 10(-6) mol/l) doubled the rate of active and total renin secretion, but a more concentrated solution (10(-5) mol/l) released proportionately less active and total renin although the result was statistically significant. Renin secretion was not altered by aminophylline (5 X 10(-5) mol/l). The pattern of renin release was modulated by concentrations of aminophylline which were at least a 100-fold lower than those required to inhibit cyclic adenosine 3',5'-monophosphate phosphodiesterase. However, as the methylxanthines are potent adenosine receptor antagonists, we suggest that in the human chorion adenosine is a mediator of renin release.
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PMID:The effect of aminophylline on renin release from human chorio-decidua. 352 15

Previous studies have shown that activation of A1 adenosine receptors results in renal vasoconstriction at submicromolar concentrations of N6-cyclohexyladenosine (CHA) followed by relative vasodilation at higher concentrations. The present data confirm these findings and demonstrate that Na loading enhances the vasoconstrictor effects of CHA in the isolated rat kidney perfused at constant flow. Furthermore, adenosine receptor antagonism with both theophylline and the A1-selective antagonist, xanthine amine congener (8-[4-[(2-aminoethyl)-aminocarbonylmethyloxy]phenyl]-1, 3-dipropylxanthine), produced a rightward and apparently parallel shift in the dose response to CHA. Determination of the inhibitory constants for both antagonists revealed that xanthine amine congener was three orders of magnitude more potent than theophylline in antagonizing CHA-induced renal vasoconstriction. Other investigators have hypothesized that angiotensin II mediates adenosine-induced renal vasoconstriction. However, we have been able to show that A1 receptor activation can result in renal vasoconstriction in the isolated perfused rat kidney devoid of renin substrate. Moreover, a competitive inhibitor of angiotensin II (saralasin) failed to attenuate the hemodynamic effects of CHA at doses that completely blocked the effects of angiotensin II itself. Taken together, these data are consistent with the hypothesis that A1 receptor activation in the kidney leads to vasoconstriction, a response that is enhanced by Na loading, and that A1 adenosine receptors and angiotensin II receptors are separate and distinct biochemical entities. Independent activation of either receptor leads to renal vasoconstriction, which can be prevented by its respective antagonist.
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PMID:Further characterization of the renovascular effects of N6-cyclohexyladenosine in the isolated perfused rat kidney. 355 83


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