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 experiments describe the endothelin-1 (ET-1) antagonist activity of BQ123 (cyclic D-Asp-L-Pro-D-Val-L-Leu-D-Trp) in conscious Sprague-Dawley (SD) rats, and we also examined the effect blockade of ETA receptors had on blood pressure in four experimental models of hypertension. Rats were anesthetized with methoxyflurane and instrumented with femoral arterial and venous catheters. In SD rats, BQ123 (0.1-10.0 mg/kg i.v.) administered 5 or 60 min prior to ET-1 inhibited both the magnitude and duration of the ET-1 (0.25 nmol/kg i.v.) pressor response. In addition, BQ123 (10.0 mg/kg) inhibited the pressor response evoked by administration of the ET-1 precursor, proendothelin-1 (1.0 nmol/kg). However, BQ123 (10.0 mg/kg) had no effect on the pressor response evoked by ET-3 (0.75 nmol/kg). In Wistar-Kyoto rats, BQ123 (10.0 mg/kg) reversed the hypertension produced by an infusion of ET-1 (0.01 nmol/kg/min). Administration of BQ123 produced a mild antihypertensive effect in normal- to low-renin models of hypertension, but no blood pressure lowering was observed in high-renin models of hypertension. These studies demonstrated the selectivity of the ETA receptor antagonist, BQ123 for ET-1, but not ET-3-induced pressor responses. Furthermore, ET-1 does not appear to be a major contributing factor to the maintenance of elevated levels of blood pressure in four experimental models of hypertension.
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PMID:Pharmacologic characterization of an endothelinA (ETA) receptor antagonist in conscious rats. 128 97

Plasma levels of endothelin (ET), plasma renin activity (PRA) and angiotensin II (Ang II) were measured in anaesthetized marmosets exposed to acute aortic stenosis proximal to the renal arteries. In vehicle experiments, ET rose from 5 +/- 2 to 38 +/- 4 pg ml-1, PRA from 5 +/- 2 to 99 +/- 21 ng ml-1 h-1 and Ang II from 21 +/- 4 to 213 +/- 76 pg ml-1. Administration of renin inhibitor and angiotensin converting enzyme inhibitor reduced PRA and Ang II to control levels, while the plasma levels of ET increased further (51 +/- 10 and 71 +/- 16 pg ml-1, respectively). During aortic stenosis the two isoforms ET-1 and ET-3 appeared in the circulation, while in conscious control animals only ET-1 was found. It is concluded that the increased plasma levels of ET in our primate model could not be ascribed to the increased circulating levels of PRA and Ang II.
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PMID:Raised plasma concentrations of endothelin-1 and -3 in marmosets with acute aortic stenosis: no relation to the renin-angiotensin system. 134 44

The direct effects of rat endothelin (ET-3) on renal function and prostanoid levels were examined in the isolated, oncotically perfused kidney of the rat. ET-3 at 0.75 and 2.0 ng/ml produced sustained increases in perfusion pressure of 46 and 83 mm Hg, respectively, as compared with control kidneys. Glomerular filtration rate was significantly higher than control after additions of ET-3 as was the absolute and fractional excretion of water and electrolytes. ET-3 increased perfusate 6-keto-prostaglandin (PG)F1 alpha (breakdown product of PGI2) levels and stimulated greater urinary excretion of PGE2 and PGF2 alpha than 6-keto-PGF1 alpha. ET-3 did not affect urinary excretion or perfusate levels of thromboxane B2. Time-dependent increases in renin release were suppressed by ET-3. Indomethacin (10 microM) prevented ET-3-induced increases in urinary and perfusate prostanoids; however, renal vasoconstrictor and excretory responses were the same in the presence or absence of indomethacin. These results indicate that ET-3 acts directly on the perfused rat kidney to increase the release of prostanoids from the vascular and urinary compartments. A modulatory influence of prostaglandins on the acute renal hemodynamic and excretory effects of ET-3 was not observed under these conditions.
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PMID:Endothelin-3 effects on renal function and prostanoid release in the rat isolated kidney. 162 3

This study was conducted to determine the involvement of endogenous endothelin-1 (ET-1), a potent vasoconstricting peptide, in systemic and renal hemodynamics and in the renin-angiotensin system, by inhibiting ET-1 action with an infusion of specific ET-1 antiserum during altered sodium balance. Infusion of 1:50 diluted ET-1 antiserum, which completely inhibited renal vasoconstriction caused by exogenously administered ET-3 (0.25 to 1.0 nmol/kg), increased urinary sodium excretion (UNaV) and fractional excretion of sodium (FENa), and decreased the plasma renin concentration (PRC) without significant changes in blood pressure, heart rate, GFR, RPF, or urine volume (UV) in conscious rats fed a low-salt diet, but not those on a high-salt diet. A time-control study showed no significant changes in any of these parameters. These results suggest that during low salt intake, in comparison to high salt intake, endogenous ET is more potent. Endogenous ET may thus contribute to the adaptive modulation of sodium excretion by a renal tubular action, and of renin release in association with a change in sodium balance.
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PMID:Role of endogenous endothelin in renal function during altered sodium balance. 172 59

This study was performed to examine the effects of endothelin (ET)-1, ET-2, and ET-3 on renin secretion from cultured mouse renal juxtaglomerular (JG) cells. Although different ETs had no consistent effect on basal renin secretion, they equipotently inhibited adenosine 3',5'-cyclic monophosphate (cAMP)-stimulated renin release with a concentration of approximately 3 nM inhibiting 50% of maximal response. ETs did not significantly affect renin release stimulated by the nitric oxide donor sodium nitroprusside (100 microM) or that stimulated by low [2 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid] or high (3 mM CaCl2) extracellular calcium. The inhibitory effect of ETs on cAMP-dependent renin secretion was abolished by lowering extracellular calcium concentration to the nanomolar range. However, the action of ETs was not changed by the ETA receptor antagonist BQ-123 (100 nM) and was mimicked by ETB receptor agonists IRL-1620 (1 microM), sarafotoxin S6b (1 microM), and [Ala1,3,11,15]ET-1 (1 microM). All ETs induced calcium oscillations in JG cells that were dependent on extracellular calcium and were associated with prominent calcium-activated chloride currents. These findings suggest that ETs inhibit rather selectively the cAMP-activated pathway of renin secretion through a calcium-sensitive process. The action of ETs on renal JG cells appears to be mediated via ETB receptors and is presumably related to activation of phospholipase C and subsequent events.
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PMID:Effects of endothelins on renin secretion from isolated mouse renal juxtaglomerular cells. 784 Feb 46

The factors that regulate the synthesis and release of renin by human decidua and other extrarenal tissues are poorly understood. Recent studies have demonstrated that the potent vasoconstrictive peptide endothelin (ET) inhibits the release of renin from renal juxtaglomerular cells, probably by a calcium-dependent mechanism. To determine whether ET also influences the release of renin from decidual tissue, we have examined the effects of ET on the synthesis and release of renin by primary cultures of human decidual cells. Decidual cells exposed continuously to ET (10(-7) mol/L) for 96 h released significantly more renin than control cells. At 48, 72, and 96 h, the ET-exposed cells released 284, 645, and 1300% more renin, respectively, than control cells. Greater than 95% of the renin released into the medium was in the form of prorenin, the precursor of renin. The stimulation by ET was dose-dependent, with half-maximal stimulation at a concentration of 7 x 10(-9) mol/L. ET-2 and ET-3, as well as the precursor to ET (big ET), also stimulated renin release. The total amount of renin in the media and cells of ET-exposed decidual cells was significantly greater than that of control cells, indicating that the increase in renin release was accompanied by an increase in synthesis. In addition, Northern blot analysis of total RNA from cells exposed for 96 h to ET-1 (10(-7) mol/L) indicated that the renin messenger RNA content of ET-1-exposed cells was approximately 100 times greater than that of control cells. These results indicate that ET is a potent stimulus to the synthesis and release of prorenin from human decidua and that the effect of ET on decidual renin expression is opposite to that observed for the expression of renal renin.
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PMID:Endothelins stimulate the synthesis and release of prorenin from human decidual cells. 844 18

Using a preparation of isolated rat kidneys perfused at constant renal artery pressure (80 mmHG) we investigated the role of endothelins in the regulation of renin release. Addition of three related endothelins (ET-1, ET-2, ET-3) at a concentration of 10 pmol L(-1) tended to enhance renin secretion rates. Higher doses (100 pmol L(-1), 1 nmol L(-1)) of different ETs such as the selective ETB receptor agonist sarafotoxin S6c (100 pmol L(-1), 1 nmol L(-1)) inhibited renin release and increased renal vascular resistance with similar potency. These effects of ETs were blunted when calcium ions were removed from the perfusate. Renin release activated by isoproterenol (10 nmol L(-1)) was also significantly reduced with ET-1, -2 and -3 (1 nmol L(-1)). BQ-123 (500 nmol L(-1)), a selective ETA receptor antagonist, only attenuated, whilst the non-selective ET receptor blocker bosentan (Ro 47-0203, 10 micro mol L(-1)) almost abolished the renal vasopressor and renin inhibitory action of ET-1 and sarafotoxin S6c. BQ-123 and bosentan alone did not affect either perfusate flow or basal renin secretion rates in isolated perfused kidneys. These findings indicate that all three ET peptides equipotently inhibit renin secretion from the kidneys. Most of the vasopressor and renin inhibitory effect of ETs is mediated by ETB rather than ETA receptors involving a calcium-dependent signal transduction mechanism. Moreover, our results suggest that intrarenally released ETs do not contribute to the regulation of renin secretion from isolated perfused rat kidneys.
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PMID:Effects of endothelins on renin secretion from rat kidneys. 866 90

The aim of the present study was to investigate the relationship between ET plasma concentrations and other hormonal systems in acute volume regulation of patients with cirrhosis. Ten healthy controls and 10 cirrhotic patients, five without and five with ascites were studied after 1 h in a sitting posture and subsequently subjected to 1 h head-out water immersion. Blood was collected for determinations of ET-1, ET-3, ANF, aldosterone, renin activity and noradrenaline. In addition, in 10 patients with compensated cirrhosis the effect of loop diuretics on ET-3, aldosterone and renin was studied. ETs in cirrhosis were significantly (P < 0.01) higher than in controls both before (ET-1, 19.6 +/- 1.3 pgmL-1 vs. 11.8 +/- 0.4 pgmL-1; ET-3, 18.5 +/- 1.4 pgmL-1 vs. 9.5 +/- 0.5 pgmL-1) and after water immersion (ET-1, 18.6 +/- 1.2 pgmL-1 vs. 12.4 +/- 0.3 pgmL-1; ET-3, 18.7 +/- 1.7 pgmL-1 vs. 10.0 +/- 0.5 pgmL-1). In cirrhotic patients, basal and immersion concentrations of ET-1 were significantly correlated to noradrenaline plasma concentrations (r = 0.79, P < 0.05). ET-3 plasma concentrations in cirrhosis were correlated to renin activity (r = 0.65, P < 0.05). Furthermore, ET-3 in cirrhosis was inversely correlated to systolic and mean arterial blood pressure (r = -0.55, P < 0.01 and r = -0.50, P < 0.05; respectively). To investigate the effect of hypovolaemia in compensated cirrhosis, 10 patients without ascites were studied before and after treatment with loop diuretics. In compensated cirrhosis ET-3 was significantly increased 6h after oral diuretic treatment (17.9 +/- 1.0 pgmL-1 vs. 15.5 +/- 0.4 pgmL-1, P < 0.001). The presented data demonstrate relations of endothelins, particularly of ET-3 to neurohumoral systems in patients with cirrhosis of the liver.
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PMID:Relation of endothelins to volume regulating neurohumoral systems in patients with cirrhosis of the liver. 871 27

This review describes recent progress in the accumulation of knowledge about the endothelins (ETs), a family of vasoactive 21-amino acid polypeptides, in chronic liver disease. Particular prominence is given to the dynamics of ET-1 and ET-3 and their possible relation to the disturbed circulation and neurohumoral dysregulation found in cirrhosis. Recent studies have shown that the ET system is highly activated in most cirrhotic patients. Circulating ET-1 and ET-3 levels have a positive relation to the severity of the disease and fluid retention, with the highest values recorded in patients with functional renal failure. Studies on liver biopsies have revealed synthesis of ET-1 in hepatic endothelial and other cells, and recent investigations have identified the hepatosplanchnic system as a major source of ET-1 and ET-3 spillover into the circulation, with a direct relation to portal venous hypertension. In addition, marked associations with disturbance of systemic haemodynamics and with abnormal distribution of blood volume have been reported. Although the pathophysiological importance of the ET system in chronic liver disease is not completely understood, similarities to other vasopressive and antinatriuretic regulatory systems (i.e. the sympathetic nervous system, renin-angiotensin-aldosterone and vasopressin) are apparent, with respect to kinetics and haemodynamic dysregulation. Cirrhosis seems to be a pathophysiological condition with indications of the occurrence of ETs, not only as local modulators, but also as a system with potential importance for systemic regulation.
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PMID:Endothelins in chronic liver disease. 890 9

Endothelin-1, -2 and -3 (ET-1, -2, -3) have suppressive effects on the renin system in different experimental in vitro models, whereas a modulation of renin secretion or renin gene expression by endothelins (ETs) in in vivo studies has not so far been found. In a recent study we observed a significant stimulation of the renin system by acute hypoxia over 6 h in rats. In the study reported here, we investigated the more chronic effects of hypoxia (10% O2 for 4 weeks) on renin gene expression and the influence of the ET system on its regulation. Renin mRNA levels decreased after 2 weeks of hypoxia to 76% of control and after 4 weeks to 49% of control (p < 0.05). Concomitant administration of the ET(A)-receptor antagonist LU135252 led to a significant increase in renin gene expression compared to control or hypoxia alone. ET-1 mRNA increased to 120% after 2 weeks and 173% after 4 weeks of hypoxia (NS), while ET-3 was not affected by hypoxia. We therefore conclude that ETs have a suppressive effect on renal renin gene expression in the setting of chronic hypoxia in rats in vivo.
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PMID:Role of endothelins for the regulation of renal renin gene expression. 1107 73


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