Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vasodilating drugs such as angiotensin converting enzyme (ACE) inhibitors may extend life expectancy in patients with congestive heart failure (CHF). The purpose of this study was to evaluate whether long-term therapy (365 days) with enalapril (ENAL, an ACE inhibitor), would prolong life in rats with a healed myocardial infarction (MI), an experimental model with hemodynamic characteristics of CHF. Seven days after sham or coronary ligation, when the healing phase of MI was well underway, 132 rats (75 sham, 57 MI) were randomized to receive either enalapril in the drinking water (17-25 mg/L, approximately 1.0 mg/kg/day) or tap water. The date of spontaneous death was recorded, and heart weight and MI size (by planimetry) were determined. Serum ENAL, total ACE concentration, and angiotensin and methoxamine pressor responses were quantified in 12 survivors. Long-term enalapril prolonged survival (p = 0.014) with a median 50% survival of 164 (164-165) days, compared to 84 (64-104) days in rats receiving tap water. There were twice as many MI rats alive at the end of one year on angiotensin converting enzyme inhibition (ACEI) therapy as compared to the untreated group. The average MI size (39-40%) was not different between groups, and there was a significant inverse correlation between date of death and MI size (r = 0.7-0.8) in both treatment groups. Cardiac hypertrophy was evident in all MI rats. Serum ENAL levels, after one year, were at the clinically relevant concentration (2.3 ng/ml) and total serum ACE (inhibitor removed) doubled to 4,300 nmol/h/ml.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increased survival in rats with congestive heart failure treated with enalapril. 245 Feb 32

Serial determinations of protein excretion rate and systolic blood pressure (SBP) were made in spontaneously hypertensive rats (SHR) uninephrectomized (UNX) at six weeks of age and given tap water (CON), or water with hydrochlorthiazide, hydralazine and reserpine (HHR), captopril (CAP) or enalapril (ENP). Compared to CON, significant hypertension was prevented, kidney weight was lower and there was less proteinuria in HHR, CAP and ENP rats followed for 30 weeks after UNX. Morphologic studies of these four groups revealed that antihypertensive therapy reduced the incidence of glomerular sclerosis in UNX SHR by 50%. Despite complete absence of systemic hypertension, there was striking medial thickening of lobular arteries and arterioles of rats given the angiotensin converting enzyme (ACE) inhibitor, captopril. These vascular abnormalities were present to a lesser degree in rats given ENP, but were entirely absent in untreated animals or in those ingesting the HHR combination. Micropuncture studies performed five weeks after UNX in four additional groups of CON, HHR, CAP and ENP rats revealed that glomerular capillary pressure was elevated in CON and reduced by all three drug regimens. These studies support the hypothesis that glomerular capillary hypertension and/or nephron hypertrophy predispose to glomerular injury in this model of hypertension and reduced renal mass. ACE inhibitors and HHR are equivalent in their ability to prevent glomerular hypertension and damage in these rats, but the former, and in particular captopril, produce abnormalities of cortical vessels via a mechanism not dependent on the presence of systemic hypertension.
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PMID:Renal vascular effects of antihypertensive therapy in uninephrectomized SHR. 254 Mar 76

1. Antihypertensive agents normalize blood pressure and restore depressed endothelium-dependent relaxations in experimental models of hypertension, but little is known regarding whether antihypertensive agents themselves can directly modulate responses to agonists of endothelium-dependent or independent relaxations, or contractions. 2. Normal rats were treated with either tap water, captopril, hydralazine or enalapril in their drinking water for 2 weeks, following which endothelium-dependent and endothelium-independent relaxations were tested with acetylcholine and sodium nitroprusside, respectively, in aortic rings suspended in organ chambers. 3. All antihypertensive agents caused slight but similar potentiation of sodium nitroprusside-induced relaxations. However, their effects on acetylcholine-induced relaxations were quite different: captopril had a marked potentiating effect, hydrazaline a slight potentiating effect, and enalapril had no significant effect on these relaxations. 4. The relaxations induced by acetylcholine and potentiated by captopril were not altered when indomethacin was included in the tissue bath. However, pyrogallol, an inhibitor of endothelium-derived relaxing factor (EDRF), markedly inhibited these relaxations suggesting that captopril's effect may involve EDRF. 5. SQ 14,534, a stereoisomer of captopril which is 100 fold less potent in inhibiting angiotensin converting enzyme, also significantly enhanced acetylcholine induced relaxations. Thus the effects of both captopril and SQ 14,534 upon EDRF appear independent of the effects of these compounds on the angiotensin converting enzyme. 6. We conclude that certain antihypertensive agents may modulate endothelium-dependent relaxations in response to agonists, and that these properties may be of therapeutic importance in cardiovascular diseases.
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PMID:Effects of antihypertensive agents on endothelium-dependent and endothelium-independent relaxations. 255 77

Previous studies have shown that the spontaneously hypertensive rat (SHR) has a preference for 0.9% NaCl solution over water as a drinking fluid. This preference was decreased by chronic treatment of SHR with intracerebroventricular captopril (an angiotensin converting enzyme inhibitor). Although other strains of rats were compared to SHR, no studies, that we are aware of, have been reported in renal hypertensive rats. Wistar-Kyoto rats were sham operated or had a silver clip (i.d., 0.20 mm) placed on the left renal artery to produce renovascular hypertension. Three weeks later the rats were operated upon again to implant osmotic minipumps to deliver captopril or saline either into the right lateral brain ventricle (i.c.v.) or into the peritoneal cavity (i.p.). The rats had a choice of 0.9% NaCl or tap water during the study. Blood pressures were measured by a tail plysmographic method in the conscious rats. The rats that became hypertensive showed a marked preference for saline. Treatment with captopril i.p. (24 mumol/kg/day) stimulated preference for saline but i.c.v. treatment (24 mumol/kg/day) decreased the preference for saline despite reductions in blood pressure in both groups of renal hypertensive rats. These changes were not seen in renal hypertensive rats infused with saline. The results suggest that captopril's antihypertensive effect in this model of renal hypertension may be independent of the effects of the drug on preference to drink saline.
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PMID:Central angiotensin converting enzyme blockade and salt preference in renovascular hypertensive rats. 298 3

Two studies were designed to examine the effect of the angiotensin converting enzyme inhibitor, captopril, on the sympathetic nervous system. In the first study, blood pressure (BP), heart rate (HR), and norepinephrine (NE) concentrations in the heart were measured in rats which had been given the agent orally in tap water (0.5 mg/ml) for 2, 9, 19, 29, and 58 days. BP and HR were measured using a tail-microphone to which a tachometer to record HR was connected in the unanesthetized and unrestricted condition. Heart NE was extracted with perchrolic acid and measured with the THI method on a high pressure liquid chromatography. The same study was also done in the control rats. The BP of the rats which had been given captopril for 9 days or more was significantly lower than in the control rats, while HR was not different between the two groups of rats. The ratio of heart weight/body weight was significantly lower in the captopril rats than in the control rats 58 days after the captopril administration. The ratio was significantly correlated with BP in these captopril and control rats (r = 0.59, p less than 0.01). In contrast to the control rats, the NE concentrations in the heart gradually increased in the captopril rats, thus being significantly higher in the latter than in the former after 29 and 58 days of captopril administration (p less than 0.01 for both observations). In addition, the lower the BP was, the higher the NE concentrations in the heart was in all the rats (r = 0.52, p less than 0.001). In the second study, BP, HR, and NE concentrations in plasma, heart, brain and the left kidney were measured in rats which had been on captopril for 2 and 29 days. Renal renin content (RRC) was also measured in the right kidney. In this study, BP and HR were recorded through a carotid catheter which had been inserted 4 hrs previously under light ether anesthesia. BP was significantly lower and NE concentrations in the heart was higher in the captopril rats than in the control rats after 29 days of captopril administration. There was a significant negative correlation between BP and NE concentrations in the heart in the captopril and the control rats (r = -0.88, p less than 0.001). No difference in HR was found between the 2 groups. NE concentrations in plasma, brain and kidney showed no significant differences between the captopril and the control rats in either of the stages of sacrifice. RRC was markedly reduced in the rats with 2 days of captopril, while it increased in the rats with 29 days of captopril. However, the RRC had no definite relationship with the NE concentrations in plasma or that in the kidney. The results show that chronic administration of captopril reduces the heart weight in normotensive rats. This effect points on the one hand to a decrease in "cardiac after-load" and on the other to changes of humoral factors such as plasma angiotensin II induced by captopril...
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PMID:[The effects of the angiotensin converting enzyme inhibitor, captopril, on catecholamine concentrations in rat plasma, heart, brain and kidneys (author's transl)]. 627 7

Blockade of the renin-angiotensin system was studied in male Sprague-Dawley rats during long-term inhibition of nitric oxide synthase. Nitro-L-arginine-methyl ester (L-NAME) was placed in the drinking water for 4 weeks (approximately 100 mg/kg per day). Separate groups of rats were coadministered the angiotensin II antagonist A-81988 in the drinking water ranging from approximately 0.001 to 1 mg/kg per day. Control groups received only tap water or A-81988 alone. Each week, rats were placed in metabolic cages, and tail-cuff blood pressures and blood samples were taken. L-NAME produced a sustained elevation in tail-cuff pressure that was completely prevented by A-81988. No changes in creatinine clearance, sodium excretion, plasma creatinine concentration, or blood urea nitrogen were observed. Food and water intakes were identical in all groups. Water excretion was significantly increased in L-NAME-treated animals regardless of additional inhibitor treatment, suggesting a possible role for nitric oxide synthase in the control of water excretion; this effect was independent of blood pressure. Although less potent than A-81988, the angiotensin II antagonist losartan and the angiotensin converting enzyme inhibitor enalapril also blocked L-NAME-induced hypertension. In a separate series of experiments, rats were not given A-81988 until 2 weeks after hypertension had fully developed in L-NAME-treated rats. Within 1 week of treatment with the angiotensin II antagonist, tail-cuff pressure returned to normal. We conclude from these studies that long-term inhibition of endogenous nitric oxide production produces an angiotensin II-dependent form of hypertension.
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PMID:Angiotensin blockade reverses hypertension during long-term nitric oxide synthase inhibition. 768 26

In Wistar rats just after weaning, 5/6 of renal parenchyma were removed surgically. Thereafter, the rats were fed either a "high-protein" (21%) or two types of a "low-protein" (6%) diet; in one of the latter the lack of protein was substituted by saccharide, in the other by fat, making the substitution "isocaloric" in either case. In all three diet groups, subgroups were formed drinking either tap water or water containing either the ACE inhibitor enalapril (Ena) or the calcium antagonist diltiazem (Dil), or both (Ena + Dil). In the high-protein diet group, increases in the weight of kidney remnants, in proteinuria and in systolic blood pressure (SBP) were seen. This was prevented by feeding either type of the low-protein diet but also by Ena and Ena + Dil. Ena and Ena + Dil not only prevented the increase in SBP but actually lowered it significantly. Dil alone also had a SBP-lowering action but offered no protection from kidney hypertrophy and proteinuria. No additive protective action of Ena + Dil or Ena + low protein or Ena + Dil + low protein was seen, suggesting that a bottom limit of these protective action was reached by the low-protein diet alone. There was no substantial difference between either type of the low-protein diet except a small and transient decrease in body weight in the first week of fat-rich diet administration.
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PMID:A comparison of the effect of feeding a low-protein diet and of pharmacological intervention on the course of ablation nephropathy in the rat. 777 Jun 41

The effect of inhibiting the renin-angiotensin system was evaluated in male Sprague-Dawley rats with reduced renal mass produced by right nephrectomy and infarction of two-thirds of the left kidney. Separate groups of rats were then administered the angiotensin receptor antagonists, A-81988 or losartan (DuP 753), the angiotensin converting enzyme inhibitor, enalapril, or vehicle (tap water) in their drinking water for 4 weeks. Tail cuff blood pressures and blood samples were obtained weekly. Excretory function during week 4 was evaluated using metabolic cages. Rats with reduced renal mass were characterized by a significant elevation in systolic blood pressure and urinary protein excretion along with a reduced urine osmolality. At 1 mg/kg/day, A-81988 prevented the hypertension and the development of proteinuria. A-81988 administration also improved urinary concentrating ability because urine osmolality was significantly higher in this group compared to untreated controls. The same dose of losartan or enalapril was ineffective at controlling the development of the hypertension, indicating that A-81988 is more potent in vivo. Despite the maintenance of systemic hypertension, losartan significantly blunted the proteinuria compared to vehicle-treated controls. At a dose of 10 mg/kg/day, losartan and enalapril also prevented the increase in systolic blood pressure and proteinuria and produced an increase in urine osmolality. These data support the hypothesis that angiotensin receptor antagonists have beneficial effects in forms of renal failure associated with proteinuria and diminished concentrating ability.
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PMID:Angiotensin II receptor blockade improves renal function in rats with reduced renal mass. 824 38

We profiled the concentrations of angiotensin I (Ang I), angiotensin II (Ang II), and angiotensin(1-7) [Ang(1-7)] by the combination of radioimmunoassay and high performance liquid chromatography in the blood of 14-week-old male Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) drinking either tap water or a solution containing ceranapril (30 mg/kg) or lisinopril (20 mg/kg) for 14 days. Differences in the chemical and pharmacokinetic properties of the two converting enzyme inhibitors ruled out class-related effects. Plasma renin activity, angiotensin converting enzyme (ACE) activity, and plasma levels of Ang I and Ang II were the same in vehicle-treated WKY and SHR. In contrast, plasma levels of both Ang(1-7) and vasopressin in SHR were 3.7-fold and 2.6-fold higher, respectively (p < 0.05). Angiotensin converting enzyme inhibition reduced the blood pressure of WKY and SHR, and augmented their intake of water and output of urine. These changes were associated with increases in renin activity and plasma levels of Ang I and Ang(1-7). In both WKY and SHR, lisinopril had a greater effect in inhibiting plasma and cerebrospinal fluid ACE, reducing levels of plasma angiotensinogen, and increasing the concentrations of authentic Ang II. The principal finding of this study is that plasma Ang(1-7) is the sole component of the circulating angiotensin system that is elevated in the established phase of genetic hypertension. The finding that chronic inhibition of ACE augments circulating levels of Ang(1-7) evidenced the existence of functional pathways for the alternate processing of Ang I.
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PMID:Angiotensin(1-7) in the spontaneously hypertensive rat. 828 65

An atheroma-like neo-intima was produced by positioning a flexible collar around the common carotid arteries of normocholesterolaemic rabbits. Vessel segments taken from the mid-region of the collared and control region of the same artery were studied 7 days after surgery. Placebo rabbits were provided ab libitum with regular tap water, and treated animals were supplied with water containing perindopril (0.3 mg/kg/day) for 14 days. Perindopril treatment reduced plasma angiotensin converting enzyme (ACE) activity by 88%, but did not significantly alter arterial blood pressure or heart rate. In control rings from placebo rabbits perindoprilat in vitro (0.1-1.0 microM) reduced the sensitivity to angiotension I up to 20-fold but did not affect that of angiotensin II. In placebo rabbits, the collared arterial segments were approximately five-fold more sensitive to the vasoconstrictor action of 5-HT (P < 0.05) than the corresponding control segments. Perindopril treatment did not prevent the supersensitivity of the collared vessels to 5-HT. Development of the lesion in placebo or perindopril-treated rabbits did not alter the vascular sensitivity to either angiotensin I (10(-9)-10(-5)M) or angiotensin II (10(-10)-10(-6)M). The vasorelaxant action of sodium nitroprusside was similar in collared and control rings, whereas the maximum endothelium-dependent vasorelaxant response to acetylcholine was reduced from 68 +/- 5% in control rings, to 44 +/- 8% (mean +/- S.E.M., n = 9, P < 0.05) in collared rings of placebo-treated rabbits. In the perindopril-treated animals, this impairment of relaxation was restored in collared vessels and was no longer significantly different from the control sections. In contrast, perindoprilat in vitro (1.0 microM) did not alter the vasorelaxant response to acetylcholine in control or collared rings in a separate series of placebo rabbits. Morphologically, vessel segments taken from the centre of the collared artery of all placebo rabbits showed a thickened intima filled with cells that had the appearance of synthetic-state smooth muscle. The intimal/medial cross-sectional area ratio was reduced from 0.11 +/- 0.02 (n = 10) in placebo rabbits to 0.05 +/- 0.01 (n = 9) in perindopril-treated rabbits, whereas cross-sectional area of media of the collared vessels was similar in the two groups. Thus ACE may have important roles in the initiation and progression of atheroma-like lesions. Inhibition of ACE with perindopril reduces intimal thickening and restores the defective vasodilatation induced by the endothelial-dependent vasodilator, acetylcholine.
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PMID:Perindopril treatment prevents the loss of endothelial nitric oxide function and development of neo-intima in rabbits. 889 57


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