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 beneficial effect of angiotensin-converting enzyme (ACE) inhibitors on myocardial mass and contractility in hypertension and, possibly, congestive heart failure (CHF) may be related to their ability to induce a decreased afterload. This has been assessed in four experimental models--renovascular hypertension, DOCA-salt hypertension, spontaneously hypertensive rats (SHR) and myocardial infarction (MI)--and in normotensive mature rats. In renovascular hypertension, ACE inhibitors normalized blood pressure as well as left ventricular hypertrophy and hypocontractility. In the DOCA-salt model, blockade of the renin-angiotensin system by ACE inhibitors did not decrease blood pressure and therefore had no effect on cardiac mass and contractility. In the SHR model, the arterial smooth muscle cell is functionally and structurally abnormal; as a result, cardiac overload led, over time, to a terminal, decompensated phase of CHF. ACE inhibitors, by decreasing blood pressure, reversed cardiac hypertrophy, hyperfibrosis and atrial natriuretic factor (ANF) oversecretion and prevented overload and time-induced CHF. In the MI model, ACE inhibitors decreased blood pressure and thereby decreased overload and reversed cardiac hypertrophy, hypocontractility, hyperfibrosis and ANF oversecretion. In normal ageing, heart function and structure are modified over time. ACE inhibitors, by blocking a 'normal' signal upstream, allowed a 'normal' effector system to decrease blood pressure and prevented the development of age-dependent cardiac hypertrophy.
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PMID:Relationship between decrease in afterload and beneficial effects of ACE inhibitors in experimental cardiac hypertrophy and congestive heart failure. 214 18

Quinapril hydrochloride, a new, orally active, nonpeptide, nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor, has been studied extensively in a variety of in vitro and in vivo animal models. Quinapril inhibits the contractile and pressor effects of angiotensin I in rabbit aorta and in rats, respectively, and lowers blood pressure in both high- and normal-renin rodent and diuretic-treated dog models of hypertension. No tolerance to the antihypertensive effects of quinapril was noted in spontaneously hypertensive rats treated with quinapril for up to 14 consecutive days. As with other ACE inhibitors, quinapril had virtually no effect on the development of hypertension in the renin-independent one-kidney deoxycorticosterone (DOCA)-salt hypertensive rat. Antihypertensive activity best correlates with the inhibition of tissue (vascular) ACE, and thus the reduction in peripheral vascular resistance associated with plasma and tissue ACE most likely accounts for the therapeutic benefit of quinapril. Preliminary data from a trial of quinapril in cardiomyopathic hamsters show that the drug prevents the anticipated decline in left ventricular contractile function and retards the temporal progression of left ventricular failure. ACE inhibitors have been found to have a lipid-neutral profile, unlike some other classes of antihypertensives. Quinapril is rapidly absorbed and extensively distributed to all tissues except brain. It is rapidly hydrolyzed to quinaprilat, its pharmacologically active diacid form. Metabolism to other compounds is not extensive. Quinapril's preclinical toxicologic profile is similar to that of other ACE inhibitors. Long-term toxicology studies show that quinapril is not teratogenic, carcinogenic, or mutagenic.
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PMID:Quinapril: overview of preclinical data. 218 23

Urinary digoxin-like factor, ADH, sodium and potassium excretion and urine osmolality were studied during the development of two pathogenically different models of hypertension, DOCA-salt (low-renin) and Gold-blatt 2 kidney-1 clip (renin-dependent). Urinary digoxin-like factor was increased in rats that were given saline (NaCl 1%) to drink, uninephrectomized-salt and DOCA-salt rats, with no significant differences between the two groups urinary ADH was elevated in DOCA-salt rats during the study, compared with uninephrectomized-salt rats. Urinary digoxin-like factor and urinary ADH were not significantly modified in Goldblatt 2 kidney-1 clip and sham-operated rats. In addition, positive correlations between digoxin-like factor urinary excretion and urinary ADH and also with sodium urinary excretion were found. These data suggest that: a) digoxin-like factor and ADH could play a role in the pathogenesis of DOCA-salt but not in Goldblatt 2 kidney-1 clip hypertension. b) A common mechanism may stimulate ADH and digoxin-like factor simultaneously. c) Digoxin-like factor plays a role in the control of urinary sodium excretion.
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PMID:Urinary excretion of digoxin-like factor (DLF) and ADH during DOCA-salt and Goldblatt 2 kidney-1 clip hypertension development. 219 65

Angiotensin II (ANG II) generation in the mesenteric arteries was studied in four groups of rats: deoxycorticosterone (DOCA)/salt treated, glucocorticoid treated, nephrectomized and control rats. Basal plasma renin activity (PRA) was undetectable in the nephrectomized group and suppressed in the DOCA/salt treated rats, but was increased in the rats treated with glucocorticoid. The Basal plasma ANG II concentration changed comparably with PRA in all four groups of rats. In the control rats, ANG II was released from the mesenteric arteries at a rate of 43.0 +/- 12.0 pg/h, and it was not decreased by nephrectomy. In DOCA/salt rats and glucocorticoid rats, ANG II release significantly decreased to 12.8 +/- 7.1 and 6.9 +/- 1.5 pg/h, respectively. Captopril treatment significantly reduced ANG II release from the mesenteric arteries in both controls and nephrectomized rats, but did not influence ANG II output in DOCA/salt rats or in glucocorticoid treated rats. In nephrectomized rats, captopril lowered blood pressure in association with a significant reduction in the mesenteric ANG II formation. These results indicate that the renal and vascular renin-angiotensin system (RAS) may be independently regulated, and in nephrectomized animals the vascular RAS contributes in part to the maintenance of blood pressure. The present results also suggest that volume expansion per se and/or pharmacological intervention by DOCA and glucocorticoid could modulate vascular ANG II generation.
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PMID:Angiotensin II generation in mesenteric arteries in rats: effects of nephrectomy, deoxycorticosterone and dexamethasone. 220 Jun 59

TA-6366 and its active metabolite 6366A inhibited swine renal angiotensin converting enzyme (ACE) activity with IC50s of 9900 and 2.6 nM, respectively. TA-6366 (0.05-0.5 mg/kg, p.o.) inhibited the angiotensin I (AT-I)-induced pressor response in rats. 6366A augmented bradykinin (BK)-induced contraction of guinea pig ileum more potently than captopril. However, when the augmentation on BK-induced hypotension in rats was used as an indicator, TA-6366 was less active than captopril. TA-6366 increased plasma renin activity and plasma AT-I concentration. Oral administration of TA-6366 lowered the blood pressure in two-kidney one-clip renal hypertensive rats at 0.5 to 2 mg/kg and in spontaneously hypertensive rats (SHRs) at 2 to 10 mg/kg. The antihypertensive effect of TA-6366 was approximately 5 times more potent than that of captopril and almost as potent as that of enalapril. In SHRs, the antihypertensive action of TA-6366 was intensified in potency when administered repeatedly. The duration of action was longer than those of captopril and enalapril. However, TA-6366 had no substantial effect on the blood pressure in DOCA/saline hypertensive rats. These results indicate that TA-6366 is a potent and long lasting antihypertensive agent and that its antihypertensive action is attributable to the inhibition of ACE.
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PMID:Pharmacological studies on (4S)-1-methyl-3-[(2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino] propionyl]-2-oxo-imidazolidine-4-carboxylic acid hydrochloride (TA-6366), a new ACE inhibitor: I. ACE inhibitory and anti-hypertensive activities. 220 Sep 18

The inhibition of the renin-angiotensin system (RAS) has important effects on different parameters of left ventricular function. Chronic inhibition of the RAS avoids hypokalemia and potassium losses by increasing aldosterone release. This potassium-sparing effect is likely to prevent cardiac arrhythmia. Inhibition of the RAS reverses cardiac hypertrophy in renovascular and in spontaneously hypertensive rats (SHR), but not in DOCA salt hypertensive rats. Inhibition of the RAS also reverses the decrease in myocardial contractility, as demonstrated by the reversion of isoenzyme profile of cardiac myosin in renovascular hypertensive rats. In DOCA salt hypertensive rats, RAS inhibition has no effect on blood pressure or on cardiac contractility. Despite its peripheral vasodilatory property, inhibition of the RAS does not increase heart rate in relation to a direct negative chronotropic effect of angiotensin II inhibition and to the absence of activation of the baroreflex system. When RAS is activated, its inhibition has a coronary vasodilatory effect, but this coronary vasodilation is associated with a decrease in perfusion pressure and with an increase in intrinsic cardiac contractility. These concomitant effects lead us to conclude that inhibition of RAS probably has no important beneficial effect on the oxygen demand/oxygen supply ratio in the myocardium distal to the coronary artery stenosis.
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PMID:Can inhibition of the renin-angiotensin system have a cardioprotective effect? 240 75

Kinins have been considered to be involved in the escape from the sodium retaining effects of mineralocorticoids. In a metabolic study in rats, the importance of the kallikrein-kinin system for sodium and potassium excretion was evaluated by aprotinin-induced kallikrein inhibition under basal conditions and during DOCA administration. Kallikrein inhibition was accompanied by a transient sodium retention. The escape from the sodium retaining effect of DOCA was not affected. However, the DOCA-induced potassium loss was enhanced. Kallikrein inhibition decreased urinary prostaglandin (PG) E2 and prevented the DOCA-induced rise in PGE2. Plasma renin activity was stimulated after 10 days of aprotinin administration. The kallikrein-kinin system is not an important mediator of the escape phenomenon but it may play a role in the regulation of sodium and potassium excretion.
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PMID:Mineralocorticoid escape during kallikrein inhibition. 241 76

Desoxycorticosterone-salt (DOC-salt) hypertension in the rat can be prevented by administration of nitrendipine. We have studied the effect of nitrendipine on exchangeable body sodium (NaE) in this model. Eighteen male Sprague-Dawley rats had a left nephrectomy and after 14 days received subcutaneous injections of deoxycorticosterone (Percorten, CIBA) 12.5 mg three times weekly for 4 weeks and were given 22Na-labeled 1% saline plus 0.2% KCl to drink. They were fed a sodium-free diet. NaE, systolic blood pressure, and body weight were measured weekly. The animals were divided into two groups of nine, one group being given subcutaneous nitrendipine 5 mg/kg twice daily, while the control group was given vehicle only. Blood samples from conscious animals were drawn at the start and at the end of the study for measurement of plasma renin concentration (PRC) and haematocrit, and at the end for atrial natriuretic peptide (ANP) measurement. Twenty-four hour urine was collected at the end of the study from eight rats of each group, and urine and blood samples were taken for biochemical analysis. In the control rats, blood pressure rose from an initial mean of 140.6 +/- 1.7 (SEM) mm Hg to 187.2 +/- 6.5 (p less than 0.001) at week 4. In the nitrendipine-treated rats, blood pressure fell from 143.9 +/- 2 at week 0 to 127.2 +/- 3.3 mm Hg at week 4 (p less than 0.001). However, body weight rose similarly in both groups and there was no difference in NaE between the groups throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of nitrendipine on blood pressure, plasma renin, and exchangeable sodium in DOC-salt hypertension in the rat. 245 17

To establish if physiological manipulations of the renin-angiotensin system modulates tissue angiotensin converting enzyme (ACE), rats were fed low, normal, or high salt diets, or high salt and DOCA, for 3 weeks, and then plasma and tissue ACE levels were determined by radioinhibitor binding studies. Urinary sodium excretion (mmol/24 h) was 0.03 +/- 0.01 (low salt), 0.58 +/- 0.09 (normal salt), and 10.4 +/- 1.3 (high salt), and plasma angiotensin II (pg/ml) was 73.5 +/- 8.6 (low salt), 49.3 +/- 8.5 (normal salt), 32.2 +/- 8.5 (high salt), and 6.9 +/- 0.6 (high salt plus DOCA) in the third week of dietary treatment. ACE was studied by Scatchard analysis of radioinhibitor binding in plasma and tissue homogenates. [125I]MK351A bound to ACE was measured under standardized conditions in the presence of MK351A (10(-13) to 10(-5) M) and MK351A binding sites and equilibrium dissociation constant calculated. There were no significant changes in binding site concentration in plasma, lung, aorta, epididymus, brain, or kidney preparations across the range of salt states studied. The equilibrium dissociation constant appeared uniform within organs, but varied between organs. Further studies were undertaken with captopril, enalapril, and cilazoprilic acid in kidney and lung preparations. Concentration of inhibitor required for equal displacement of bound [125I]MK351A was consistently greater for kidney than for lung. Binding studies of rat ACE using [125I]MK351A showed that manipulation of salt status did not influence rat tissue ACE. Binding data suggest ACE from different tissues may have variations at the active site.
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PMID:Tissue angiotensin converting enzyme (ACE) during changes in the renin-angiotensin system. 248 49

In the present study, the pressor activity of 19-hydroxyandrostenedione (19-OH-AD) (which is a kind of androgen) and the presence or absence of the possibility of its role as an amplifier of mineralocorticoid were investigated. 34 Wistar rats of 8 weeks of age were used as the experimental subjects. The rats were divided into 3 groups, the control group (n = 12), 19-OH-AD group (n = 12) and DOCA group (n = 10). The control group was given 0.2 ml of sesame oil, the 19-OH-AD group was given 10 mg of 19-OH-AD dissolved in 0.2 ml of sesame oil, and the DOCA group was given 10 mg of DOCA dissolved in 0.2 ml of sesame oil. This was subcutaneously administered three times a week for 4 weeks, and body weight and blood pressure were observed. At the termination of the experiment, blood was sampled by decapitation, and the serum sodium concentration, erythrocyte sodium content, plasma renin activity (PRA), plasma atrial natriuretic hormone (alpha-rANP), and contents of DOC, corticosterone and aldosterone in adrenal gland were determined. The following results were obtained. The blood pressure at the termination of the experiment was higher than that at the initiation of the experiment by 9.9 +/- 1.9 (S.E.), 31.3 +/- 1.7, and 46.2 +/- 2.0 mmHg in the control, 19-OH-AD and DOCA groups, respectively, where significant elevations were observed in both the 19-OH-AD and DOCA groups as compared with the control group. As to the serum sodium concentration, only the DOCA group showed a significant elevation (p less than 0.001) as compared with the other two groups. However, the erythrocyte sodium contents of both the 19-OH-AD and DOCA groups increased significantly as compared with the control group. Moreover, the increase of the DOCA group was significantly higher (p less than 0.001) than that of the 19-OH-AD, and a significant positive correlation between the elevation of blood pressure and the erythrocyte sodium content was observed (p less than 0.001). As to the PRA value, only the DOCA group showed a significant lowering as compared with the other two groups, whereas alpha-rANP value of the DOCA group showed a significant elevation as compared with the other two groups. As to the contents of steroid hormones in the adrenal gland, all of the steroid hormones were significantly lower in the DOCA group, while those of the 19-OH-AD group were unchanged as were those of the control group.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Studies on the pressor mechanism of 19-hydroxyandrostenedione]. 252 10


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