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 in vitro binding of [3H]SR42128 (Iva-Phe-Nle-Sta-Ala-Sta-Arg), a potent inhibitor of human renin activity, to purified human renin and a number of other aspartic proteases was examined. SR42128 was found to be a competitive inhibitor of human renin, with a Ki of 0.35 nM at pH 5.7 and 2.0 nM at pH 7.4; it was thus more effective at pH 5.7 than at pH 7.4. Scatchard analysis of the interaction binding of [3H]SR42128 to human renin indicated that binding was reversible and saturable at both pH 5.7 and pH 7.4. There was a single class of binding sites, and the KD was 0.9 nM at pH 5.7 and 1 nM at pH 7.4. The association rate was 10 times more rapid at pH 5.7 than at pH 7.4, but there was no difference between the rates of dissociation of the enzyme-inhibitor complex at the two pHs. The effect of pH on the binding of [3H]SR42128 to human renin, cathepsin D, pepsin, and gastricsin was also examined over the pH range 3-8. All the aspartic proteases had a high affinity for the inhibitor at low pH. However, at pH 7.4, [3H]SR42128 was bound only to human renin and to none of the other aspartic proteases. Competitive binding studies with [3H]SR42128 and a number of other inhibitors on human renin or cathepsin D were used to examine the relationships between structure and activity in these systems.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A potent radiolabeled human renin inhibitor, [3H]SR42128: enzymatic, kinetic, and binding studies to renin and other aspartic proteases. 332 2

Pepstatin analogues corresponding to the general formula A-X-Y-Sta-Ala-Sta-R were synthesized in solution phase. Various changes in the nature of the A, X, and Y groups were made to improve the inhibitory potency against human plasma renin activity. The results were interpreted by use of the active-site model based on the sequence of human angiotensinogen. The tert-butyloxycarbonyl group and the isovaleryl group were found to be the most effective acyl groups (A). The analogues having a Phe residue in place of Val1 (X) and His or amino acid with an aliphatic side chain such as norleucine or norvaline in the Y position showed the highest inhibition of human plasma renin activity with IC50 values of about 10(-8)M. Esterification or amidification of the carboxyl group of the C-terminal statine did not change the inhibitory potency. The selectivity for rat, dog, pig, and monkey plasma renin of the most interesting compounds was studied.
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PMID:Pepstatin analogues as novel renin inhibitors. 354 58

An angiotensin II antagonist, [1-sarcosine, 8-alanine]-angiotensin II, was given intravenously to anesthetized dogs with thoracic caval constriction and ascites to investigate the role of angiotensin II in the control of arterial pressure. The antagonist produced a striking fall in arterial pressure and in aldosterone secretion and an accompanying increase in plasma renin activity. In a control experiment, normal anesthetized dogs were given the angiotensin analog, but it failed to reduce arterial pressure or to influence plasma renin activity. In conscious dogs with caval constriction, the antagonist produced essentially the same drop in arterial pressure as observed in anesthetized animals. These results suggest an important role for angiotensin II in the maintenance of arterial pressure by its action on specific receptor sites in arteriolar smooth muscle and in the adrenal cortex.
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PMID:Angiotensin. II. Important role in the maintenance of arterial blood pressure. 434 66

A "bolus" dose (110 microgram) of the angiotesin II (A II)-blocker 1-Sar-8-Ala-A II (Saralasin, S) followed by its slow rate infusion (5 microgram/min/rat) for thirty min, was injected before and after the complete ganglionic blockade by pentolinium (P) in unanaesthetized unilaterally clipped renal hypertensive rats (the opposite kidney remained untouched). Pentolinium was also injected like a "bolus" dose (3 mg) followed by slow infusion (0.1 mg/min/rat) for thirty min. The observations were made until the fifth week after clipping the left renal artery. A consistent maximal hypotensive response was observed after the "bolus test" with both drugs. When S was the first drug injected, an inverse correlation was found between the percent decrease in arterial pressure (BP) by S and the percent decrease in BP by P (r = --0.83, P < 0.01, n = 8). Thus whenever a greater hypotensive effect was obtained by S, a smaller neural pressor component remained to be blocked by P. On the other hand, when P was the first drug injected a lesser A II pressor component remained to be blocked by S in the hypertensive rats. The results suggest that a considerable A II pressor effect in two-kidney renovascular hypertension is mediated via neurogenic mechanisms from the first week. A direct pressor vasoconstriction was found to be significant in cases with very high plasma-renin activity.
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PMID:Humoral and neurogenic factors in two-kidney renovascular hypertension. 615 37

1 The effect of the angiotensin converting enzyme inhibitor, MK 421 (N-((S)-1-(ethoxycarbonyl)-3-phenylpropyl)L-Ala-L-Pro), on the blood pressure of two-kidney Goldblatt hypertensive rats has been investigated in relation to he initial plasma renin activity (PRA) and the initial blood pressure of the individual animals. 2 Blood pressure was monitored by an indirect tail-cuff method at 1, 3, 6 and 24 h after dosing. MK 421 produced a fall in blood pressure in the majority of animals, but the extent of this reduction varied considerably between individuals. 3 The change in blood pressure showed a significant correlation with both the initial PRA and the initial blood pressures of the animals. However, only a modest correlation was found between the initial PRA and the degree of hypertension. 4 MK 421 (10 mg/kg, orally) produced a mean blood pressure change which was statistically significant (P less than 0.001) at all times tested. 5 It is concluded that the degree of antihypertensive activity of MK 421 is related to the degree of activity of the renin-angiotensin system which, in this model at least, is reflected by the PRA.
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PMID:Relation of plasma renin activity to the antihypertensive effect of MK 421 in the rat. 628 72

Enalapril maleate (MK-421), an ethyl ester, is an angiotensin-converting enzyme (ACE) inhibitor from a novel series of substituted N-carboxymethyldipeptides. The parent diacid (MK-422) N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro of MK-421 inhibited hog plasma ACE with an I50 of 1.2 nM. Because deesterification occurs slowly or not at all in vitro, the in vitro I50 for enalapril was 1200 nM. However, both enalapril and MK-422 were potent inhibitors of ACE by the i.v. and oral routes in rats and dogs. In rats with experimental hypertension, enalapril was most potent in those models in which the renin-angiotensin system plays a dominant role (salt restriction, two-kidney Grollman) and in models rendered renin dependent by diuretics, although blood pressure reduction did occur in low or normal renin models such as spontaneously hypertensive rats, in which inhibition of ACE as measured by the blockade of angiotensin I pressor responses bore little temporal relationship to the later fall in blood pressure after enalapril.
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PMID:Pharmacological properties of the converting enzyme inhibitor, enalapril maleate (MK-421). 629 19

This study was designed to investigate the central action of circulating angiotensin II on the regulation of blood pressure in sodium depleted states. The effects of intravertebral arterial infusion of angiotensin II and [Sar-1, Ala-8] angiotensin II (saralasin) on plasma norepinephrine (NE) were studied in alpha-chloralose anesthetized dogs. Intravertebral arterial infusion of angiotensin II (10 ng/kg/min) increased mean arterial pressure (MAP), heart rate (HR) and plasma NE. Plasma NE was decreased by intravertebral arterial infusion of saralasin (0.40 +/- 0.05 to 0.28 +/- 0.04 ng/ml, p less than 0.05) in normal dogs. The administration of furosemide produced significant increases in plasma NE (142.4 +/- 23.7%, p less than 0.01), plasma renin activity (PRA) (158.6 +/- 26.3%, p less than 0.01) and HR (32.3 +/- 6.0 beats/min, p less than 0.01). A slight rise in mean blood pressure (3.9 +/- 1.2 mmHg, p less than 0.05) was observed during the furosemide administration. Saralasin infused into the vertebral artery significantly suppressed the furosemide-induced increases in plasma NE, HR and PRA, and lowered mean arterial blood pressure. Intravenous infusion of the same dose of saralasin produced no changes in arterial blood pressure, HR and plasma NE. These results suggest that the central sympathetic potentiation induced by circulating angiotensin II may contribute to the regulation of blood pressure in sodium and volume depleted states produced by furosemide.
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PMID:Changes in plasma norepinephrine after intravertebral artery infusion of saralasin in sodium depleted dogs. 633 71

We have studied the contribution of circulating renin of renal origin to renin-like activity within the arterial wall and to blood pressure. Bolus injections of renin sufficient to elevate blood pressure by 44.7 mm Hg caused aortic renin to rise from 0.13 to 1.48 ng angiotensin I/100 mg/hr in nephrectomized rats. Elevation of aortic renin was still present at 6 hours, and this was associated with significant blood pressure elevation (p less than 0.05) which could be reversed by infusion of sarcosine, alanine, angiotensin II (saralasin). Prevention of the pressor effect by pretreatment with the converting enzyme inhibitor captopril did not reduce renin uptake. When kidneys were left in situ, although significant uptake of renin could be demonstrated 1 hour after injection, the increase at 3 hours was no longer significant (p greater than 0.05) and blood pressure returned to normal by 1 1/2 hours. This change in blood pressure may be related to the much more rapid clearance of circulating renin in the presence of normal kidneys or to other renal factors influencing the blood pressure response. The present studies demonstrate therefore that most of the renin-like activity within the aortic wall is derived from plasma renin and it seems probable that this component of the renin-angiotensin system plays an important role in blood pressure maintenance in the nephrectomized rats injected with renin. The relationship is less obvious in the presence of normal kidneys where additional influences may come into play.
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PMID:Arterial wall uptake of renal renin and blood pressure control. 635 78

The effects of acute hypoxemia and hypercapnic acidosis were examined in five unanesthetized dogs in which sodium intake was controlled at 80 mEq/24 hours for 4 days prior to study. Each animal was studied during combined acute hypoxemia and hypercapnic acidosis (Pao2 = 36 +/- 1 mm Hg, Paco2 = 52 +/- 1 mm Hg, pH = 7.18 +/- 0.02), acute hypoxemia alone (Pao2 = 32 +/- 1 mm Hg, Paco2 = 32 +/- 1mm Hg, pH = 7.34 +/- 0.01), and acute hypercapnic acidosis alone (Pao2 = 82 +/- 2 mm Hg, Paco2 = 51 +/- 1 mm Hg, pH = 7.18 +/- 0.02). Although mean arterial pressure, cardiac output, and heart rate increased during combined hypoxemia and hypercapnic acidosis, effective renal plasma flow and glomerular filtration rate decreased. In addition, filtered sodium load and urinary sodium excretion decreased during combined hypoxemia and hypercapnic acidosis. Either acute hypoxemia or hypercapnic acidosis alone resulted in increased mean arterial pressure, cardiac output, and heart rate. However, in contrast to their combined effects, renal hemodynamic function was unchanged and natriuresis was observed. Measurement of plasma renin activity and angiotensin II concentrations indicated that hypoxemia or hypercapnic acidosis alone resulted in moderate activation of the renin-angiotensin system. Moreover, combined hypoxemia and hypercapnic acidosis acted synergistically resulting in major renin-angiotensin activation. Systemic angiotensin II blockade using 1-sarcosine, 8-alanine, angiotensin II (2 micrograms/kg per min) during combined acute hypoxemia and hypercapnic acidosis resulted in decreased renal hemodynamic function. We conclude that acute hypoxemia and hypercapnic acidosis act synergistically to increase mean arterial pressure, diminish renal hemodynamic function and activate the renin-angiotensin system. Systemic angiotensin inhibition studies suggest activation of the renin-angiotensin system maintains renal hemodynamic function during combined hypoxemia and hypercapnic acidosis, instead of mediating the renal vasoconstriction.
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PMID:Synergistic effects of acute hypoxemia and hypercapnic acidosis in conscious dogs. Renal dysfunction and activation of the renin-angiotensin system. 641 80

We designed aldehyde derivatives of small peptides representing the C-terminal portion of angiotensin I sequence as an inhibitor of human renin. Among compounds that we synthesized, benzyloxycarbonyl (Z)-Phe-His-Leucinal (compound V), Z-Pro-Phe-His-Leucinal (Compound IV) and Z-[3-(1'-naphthyl)Ala]-His-Leucinal (compound VII) markedly inhibited human renin (IC50, 7.5 X 10(-7), 3.2 X 10(-7) and 8.0 X 10(-8) mol/l, respectively). Compound VII was shown to be noncompetitive (Ki = 2.4 X 10(-7) mol/l). It did not inhibit either cathepsin D or pepsin. Compound V had slight or no inhibitory effect at the concentration of 10(-5) mol/l on six animal renins except for monkey and rabbit renins. Results obtained show that these aldehyde compounds are highly selective and species specific inhibitors for human and monkey renins.
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PMID:Highly potent and specific inhibitors of human renin. 642 31


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