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)

Twenty-four conscious male Wistar rats with hypertension induced by left renal artery clipping (two-kidney hypertension) were infused intravenously with 1-Sar-8-Ala-angiotensin II a competitive angiotensin II antagonist. The spectrum of responses was wide, ranging from a mild elevation in blood pressure to a marked fall in blood pressure, despite effective and specific angiotensin blockade in all cases. The change in blood pressure during 1-Sar-8-Ala-AII infusion activity showed a significant correlation with the level of plasma renin prevailing immediately before the infusion (r = - 0.78, P less than 0.01) but not with the prevailing blood urea level (r = 0.27, 0.1 greater than P greater than 0.05), the drgree of hypertension (r = 0.42, 0.1 greater than P greater than 0.05), or the time since clipping (r = 0.02, P greater than 0.05). There was no significant correlation between the degree of hypertension and the plasma renin activity (r = 0.42, 0.1 greater than P greater than 0.05). In rats with blood pressure drops greater than 20 mm Hg in response to 1-Sar-8-Ala-AII, the final blood pressure level was still above the normotensive range. Excision of the clipped kidney reduced blood pressure to normal or to near normal within 24 hours in all of the rats tested. It is concluded that the degree of dependence of renal hypertension on the renin-angiotensin system is directly related to the increase in circulating angiotensin itself and not to an increase in sensitivity to angiotensin. Other factors appear to be involved in renal clip hypertension in addition to circulating renin and angiotensin, especially when the measured activity of plasma renin is normal.
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PMID:Effect of the angiotensin II blocker 1-Sar-8-Ala-angiotensin II on renal artery clip hypertension in the rat. 119 61

Clonidine was nonhypotensive in conscious unrestrained rats maintained on a normal sodium intake. In contradistinction, clonidine caused a dose-related hypotension in conscious unrestrained rats subjected to sodium depletion via furosemide. The plasma renin activity of normal and sodium-depleted rats was reduced after the administration of clonidine (100 mug/kg, iv) by 22.8% and 34.4%, respectively. Intravenous infusion of an angiotensin II antagonist, 1-Sar-8-Ala-angiotensin II, caused a significant reduction of arterial blood pressure in sodium-depleted rats but not in normal rats. Similarly, bilateral nephrectomy reduced arterial blood pressure and completely abolished the hypotensive effect of clonidine in sodium-depleted rats. Subcutaneous administration of chlorisondamine caused a significantly greater reduction of arterial blood pressure in sodium-depleted rats than it did in normal rats. Treatment of normal and sodium-depleted rats with 6-hydroxydopamine reduced the arterial blood pressure of both groups to approximately 85 mm Hg and completely abolished the hypotensive effect of clonidine in the sodium-depleted rats. The data presented in this paper are consistent with the conclusion that clonidine acts at some site in the sympathetic nervous system of sodium-depleted rats to inhibit renal nerve activity with a resultant suppression of renin secretion and a reduction of the angiotensin II-maintained arterial blood pressure. A similar sequence of events occurring in normal rats would not result in hypotension because their arterial blood pressure is not maintained by angiotensin II.
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PMID:Hypotensive effect of clonidine during sodium depletion in the rat. 119 71

We have assessed the capacity of an analogue of angiotensin II (A II), 1-Sar, 8-Ala A II (P113) in normal man to stimulate and block responses to A II in four systems: blood pressure was monitored directly from an arterial catheter, and renal blood flow was measured with 133Xe and arterial renin and aldosterone concentrations by radioimmunoassay. The 31 normal subjects were in balance on a daily intake of 200 meg sodium and 100 meq potassium to suppress endogenous renin. P113 administered intravenously induced a dose-related renal blood flow reduction, with a threshold dose of 0.1 mug/kg/min. This dose also induced a small but significant increase in arterial blood pressure and plasma aldosterone as well as a reduction in plasma renin activity. In contrast to its effect on the renal vasculature, no tendency to a progressive response in the latter three parameters was noted as the P113 dose was increased 30-fold, to 3.0 mug/kg/min. P113 also reduced the clearance of para-aminohippurate, creatinine, sodium, and potassium, a pattern similar to that induced by A II. P113 at 0.1 mug/kg/min reduced significantly the blood pressure and renal vascular and aldosterone responses to graded doses of A II. Higher P113 doses totally obliterated all three responses to A II infused at 10 ng/kg/min, a dose that provides arterial A II concentrations in the range found in angiotensin-mediated hypertension. When A II was infused first, to induce a pressor, renal vascular, and aldosterone response, P113 induced a dose-related reversal of the response in each system. In conclusion, P113 is a partial agonist in normal man, inducing an angiotensin-like response in settings in which endogenous A II is not playing a tonic role, and displaying dominant antagonist activity in settings in which A II is active. Moreover, the studies suggest that the receptors mediating the responses to A II are different in the renal vasculature and other systemic vascular beds. The adrenal receptor must also differ. This agent should be useful in dissecting the role of A II in diseases characterized by hypertension or abnormalities of renal and adrenal function.
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PMID:Blockade and stimulation of renal, adrenal, and vascular angiotensin II receptors with 1-Sar, 8-Ala angiotensin II in normal man. 124 2

The influence of barbiturate anesthesia on renal blood flow was assessed by the xenon washout method in trained dogs with catheters chronically implanted in the renal artery. Anesthesia induced with either thiopental sodium or pentobarbital sodium resulted in a striking reduction in renal blood flow (4.1 +/- 0.1 vs. 2.6 +/- 0.2 ml/g per min; P less than 0.001) without a change in arterial pressure. The reduction in blood flow was prevented by a high salt intake and partially reversed by agents which interrupt the renin-angiotensin system (BPF 9a; 1-Sar,8-Ala-angiotensin II; propranolol) but not by alpha-adrenergic blocking agents (phentolamine and phenoxybenzamine). Anesthesia blunted the renal vascular response to angiotensin II (P less than 0.0005) whereas responsiveness to norepinephrine was increased (P less than 0.05). We conclude that barbiturate anesthesia induces a major, angiotensin-mediated renal vascular response which must be considered in the interpretation of experiments performed under these conditions.
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PMID:The role of angiotensin in the canine renal vascular response to barbiturate anesthesia. 124 68

Angiotensin II and its heptapeptide fragment, Des-Asp-1-angiotensin II, produced a striking increase in aldosterone secretion in rats pretreated with dexamethasone and morphine to reduce ACTH release. 1-Sar-8-Ala-angiotensin II (10 mug/kg min-1) given simultaneously with angiotensin II (1 mug/min) blocked the aldosterone response to angiotensin II in rats pretreated to reduce ACTH release. In contrast, 1-Sar-8-Ala-angiotensin II at the same dose failed to block the steroid response to Des-Asp-1-angiotensin II (1 mug/min) but a larger dose of 50 mug/kg min-1 of the angiotensin II antagonist blocked completely both the aldosterone and the corticosterone responses to 1 mug/min of Des-Asp-1-angiotensin II. From these data it is suggested that the heptapeptide has a higher affinity for zona glomerulosa receptors than the octapeptide and that Des-Asp-1-angiotensin II mediates, at least in part, the steroidogenic response to the renin-angiotensin system in the rat. The pressor response to Des-Asp-1-angiotensin II was approximately 50% of that produced by the octapeptide in the rat, and 1-Sar-8-Ala-angiotensin II was as effective in partially blocking the pressor response to the octapeptide as in inhibiting the heptapeptide. The present observations indicate a dissociation of adrenal cortex and peripheral arteriolar receptors in their affinity for angiotensin.
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PMID:Des-Asp-1-angiotensin II. possible role in mediating the renin--angiotensin response in the rat. 125 Aug 43

Hypertension was produced in 25 rabbits by constricting the right renal artery and leaving the opposite kidney intact (two-kidney hypertension). After 30 days mean arterial pressure and plasma renin activity (PRA) were significantly elevated (P less than 0.01), and arterial pressure was correlated with PRA (r = 0.551, P less than 0.01); however, not all hypertensive rabbits had elevated PRA, and in animals in which sodium balance was monitored, only rabbits in negative sodium balance had increased levels of PRA. To investigate the role of angiotensin II (A-II) in the hypertension, [1-sarcosine,8-alanine]angiotensin II was infused at 6 mug/kg per min for 30 min in anesthetized hypertensive animals (n = 25). For the group, arterial pressure fell significantly (P less than 0.01), but several animals with minimal hypertension failed to give a depressor response. The declines in arterial pressure were highly correlated with PRA (r = 0.853, P less than 0.01). Aldosterone secretion in hypertensive animals was correlated with PRA (r = 0.851, P less than 0.01). Thus, two-kidney hypertension in the rabbit persists with normal PRA, but during periods of spontaneous sodium depletion, A-II plays a role in the maintenance of the hypertension.
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PMID:Renin-angiotensin-aldosterone system in experimental renal hypertension in the rabbit. 125 9

The effect of the specific angiotensin II antagonist (AIIA), [1-sarcosine-8-alanine]angiotensin II, on autoregulation of glomerular filtration rate (GFR) and renal blood flow (RBF) in an isolated dog kidney was examined. Infusing the AIIA into the renal artery at 1.9 mug/min inhibited the renal vasoconstrictor action of angiotension II infused simultaneously at 1.15 mug/min. Under conditions of constant renal arterial pressure the AIIA had no significant effect on sodium excretion, GFR, RBF, cortical blood flow distribution (microsphere method), or renin secretion in non-renin-depleted kidneys. Similarly, no agonist properties were observed when the AIIA was infused into renin-depleted kidneys. This dose of the AIIA did not impair the capacity of the isolated kidney to regulate GFR or RBF when renal arterial pressure was increased from 100 to 150 mmHg. Efficiency of autoregulation of GFR and RBF was 77 and 82% of that predicted for perfect autoregulation. These values are not significantly different from those of the isolated kidney not infused with the antagonist. It is concluded that the angiotensin II antagonist, [1-sarcosine-8-alanine]angiotensin II, has no significant agonist properties, that it antagonizes the renal vascular effects of exogenously administered angiotensin II, but does not impair renal autoregulation. These data provide no support for the hypothesis that the renin-angiotensin system mediates the autoregulation of GFR and RBF.
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PMID:Effect of an angiotensin II antagonist on autoregulation in the isolated dog kidney. 126 3

Circulating angiotensin II is said to inhibit renin release by a direct, intrarenal action. This effect of angiotensin was studied indirectly using the selective angiotensin II antagonist saralasin (1Sar-8-Ala-angiotensin II) in conscious normal, sodium-depleted, and sodium-loaded rats. Saralasin caused a dose-related increase in plasma renin concentration (PRC) in normal and sodium-depleted rats, but had no effect on PRC in sodium-loaded animals. However, saralasin was 300 times more active in sodium-depleted rats than in normal rats. Saralasin caused hypotension and tachycardia in sodium-depleted rats, but not in normals. Propranolol inhibited saralasin-induced renin release by 99% in normal rats and by 75% in sodium-depleted rats but not alter the hypotensive effect of saralasin in the latter. Saralasin potentiated phentolamine-induced renin release, hypotension, and tachycardia in normal rats, and this potentiated renin release was blocked by propranolol. We conclude that a portion of saralasin-elicited renin release in sodium-depleted rats is mediated by hypotensive activation of the carotid baroreceptor reflex which increases sympathetic nervous activity in the kidney. However, in sodium-depleted rats saralasin induced a 42-fold increase in PRC, whereas an equipotent hypotensive dose of the vasodilator hydralazine caused only a 3.5-fold increase in PRC. Thus, we find that saralasin appears to have a selective effect on renin release over and above its hypotensive effect, which suggests an angiotensin-mediated, feedback mechanism inhibitory to renin release. Thus, we have come to the conclusion that for part of saralasin-induced renin release appears to be caused by disinhibition of angiotensin suppression of renin secretion. This "short-loop" feed-back mechanism is closely associated with intrarenal beta-adrenergic receptors, since propranolol impaired saralasin-induced renin release under all circumstances in our experiments.
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PMID:The effects of altered sodium balance and adrenergic blockade on renin release induced in rats by angiotensin antagonism. 126 3

This investigation was designed to study (1) renal sodium handling after an oral protein load and (2) its relationship to some known determinants of the hemodynamic response (glucagon, insulin, growth hormone, renin, aldosterone, and plasma amino acid concentration). To this end of group of 8 adult subjects was studied before (three 30-min clearances) and after a meat meal (MM; five 30-min clearances at 30, 60, 90, 120 and 180 min). The MM provided 2 g/kg BW of protein. Within 30 min from the MM an hyperfiltration response was seen, which was paralleled by a 2-fold increase in plasma alanine concentration while total plasma amino acid concentration was not different from the baseline values. The hemodynamic response was associated with a normally operating tubuloglomerular feedback mechanism independent of renin-aldosterone activity, but possibly associated with an early increase in plasma glucagon concentration and later on with a modest increase in postmeal plasma insuling concentration.
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PMID:Renal handling of sodium after an oral protein load in adult humans. 137 47

The relatively fast artificial substrate Leu-Ser-rho-nitro-Phe-Nle-Ala-Leu-OMe generates a solvent isotope effect of 1.51 +/- 0.02 only on the maximal velocity of peptide hydrolysis catalyzed by porcine pepsin (EC 3.4.23.1). The absence of an isotope effect on V/K places the isotopically-sensitive step after peptide bond cleavage and the release of the first product. Reprotonation of the active site aspartic carboxyls is proposed as the most likely interpretation of this observation. Structural and kinetic similarities between pepsin and other aspartic proteinases, including the therapeutically important targets HIV protease and renin, suggest a similar slow reprotonation step after catalysis. This mechanistic feature has important implications regarding inhibitor design; if most of the enzymes are present in a product-release form during steady-state turnover, then perhaps inhibitors should be designed as product analogs instead of substrate analogs.
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PMID:Slow step after bond-breaking by porcine pepsin identified using solvent deuterium isotope effects. 201 46


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