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)

Twenty-three patients with severe hypertension and impaired renal function were included in an open study of the efficacy and tolerance of felodipine treatment over 6 months. All patients were previously treated with a diuretic, a beta blocker, and a vasodilator, and eight of them also received an ACE inhibitor. At the start of felodipine treatment the previously used vasodilator was withdrawn. In nine patients the concomitant antihypertensive treatment was reduced during the study. The glomerular filtration rate (GFR), as 51Cr EDTA clearance, was determined before and at the end of the study. The blood pressure (BP) and heart rate (HR) were recorded at all clinical visits in the morning 12 hours after the evening dose of felodipine and 2 hours after the morning dose. Plasma concentrations of felodipine were measured at every visit before the morning dose and 2 hours after dose. The BP was reduced after felodipine was substituted for the previously used vasodilator. A significant additional anti-hypertensive effect was recorded 2 hours after the dose and amounted to -37 +/- 22/-15 +/- 12 mmHg (p = 0.0001/p = 0.0002) at 6 months. The effect measured 12 hours after the dose was less pronounced and was -11 +/- 28/-6 +/- 10 mmHg (p = 0.15/p = 0.03). Mean GFR was unchanged during the study, 38 +/- 19 versus 38 +/- 19 ml/min (n = 16). There was a sixfold interindividual variation in the trough plasma concentrations at steady state at the same drug dosage. Higher plasma concentrations seemed to be required to achieve the same antihypertensive effects as in patients with less severe hypertension and normal renal function.(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiovasc Drugs Ther 1990 Feb
PMID:Felodipine in the treatment of patients with severe hypertension and impaired renal function. 228 18

It seems established that hypertension, to some degree, is a frequent consequence of cardiac transplantation. The hypertension occurs de novo and is not related to whether hypertension was present in association with the heart disease that led to the need for transplantation. The etiology of this hypertension is multifactorial and varies depending on the time that has ensued after transplantation. Acutely, it is primarily a problem related to intravascular volume expansion and persistently increased systemic vascular resistance. Although it may be modest in severity, it seems to be particularly resistant to therapy with most antihypertensive drugs. Moreover, the total "hyperbaric impact" of the hypertension is rendered greater because the blood pressure and heart rate in these patients with denervated hearts fails to show the usual 10 to 15 percent fall when recumbent/asleep at night, which occurs in normotensive individuals and in most with hypertension of other etiologies. The major factor in the persistence of the hypertension through the later stages post-transplantation appears to be the cyclosporine that is used as an immunosuppressive. Although cyclosporine has been the major contributor to reduced rejection in these individuals, and to their increasingly prolonged survival, it inevitably produces slowly progressive impairment of renal function. The damage to the kidney is reflected both in tubular as well as glomerular and vascular damage, with a steady fall in glomerular filtration and a rise in creatinine. From our studies it appears that the renal alterations are associated with a gradual rise in plasma renin activity and angiotensin II, which perhaps further damages the kidney and causes persistence of the increased systemic vascular resistance. The use of lower doses of cyclosporine during the ischemic phase in the kidney that immediately follows surgery and of reduced doses over time, often with azathioprine added, seems to minimize the renal damage, or at least to stabilize it and to slow progression of the renal dysfunction and hypertension. Treatment of the hypertension with conventional drugs has definite but limited value. Diuretics and vasodilators have been the mainstay of our approach during the early phases of the hypertension but our recent data indicate that ACE inhibitors may become relatively specific in management during the later phases of the post-transplantation period as PRA levels rise in response to vascular damage by cyclosporine. ACE inhibitors have inherent dangers that require careful monitoring.(ABSTRACT TRUNCATED AT 400 WORDS)
Cardiovasc Clin 1990
PMID:Hypertension following orthotopic cardiac transplantation. 240 98

Studies on spontaneously hypertensive rats (SHR), which represent a model of genetically determined arterial hypertension, revealed that cardiac hypertrophy can be controlled by blood pressure normalization by use of various antihypertensive drugs such as hydralazine, captopril, metoprolol, guanethidine, and alpha-methyldopa. Adrenergic influences seem to play a part except for left ventricular (LV) systolic unloading on cardiac hypertrophy, because LV hypertrophy was quantitatively less expressed after a combined therapy with both metoprolol and hydralazine than after a single hydralazine treatment, although blood pressure was not different between the groups. To study whether nifedipine can cause an already existing cardiac hypertrophy to regress, 20-week-old SHR were treated with nifedipine for a period of 20 weeks. After nifedipine treatment, LV muscle mass/body weight ratio was significantly less than before therapy (2.13 +/- 0.18 vs. 2.37 +/- 0.30 mg/g; p less than 0.05). Mass to volume ratio, i.e., quotient of LV muscle mass and LV end-diastolic volume, dropped from 3.40 +/- 0.66 to 3.07 +/- 0.30 mg/microliters (p less than 0.05) after therapy. Accordingly, an antihypertensive treatment with the calcium channel blocker nifedipine can cause an already existing LV hypertrophy in SHR to regress. Because blood pressure reduction resulting from therapy with beta-receptor-blockers, vasodilators, sympatholytic drugs, angiotensin converting enzyme inhibitors, and calcium channel blockers has qualitatively similar effects with respect to causing regression of hypertrophy, reversal of cardiac hypertrophy seems to be mainly related to the reduced LV systolic load. Specific pharmacodynamic effects may only modulate the extent of LV mass reduction along with blood pressure normalization.
J Cardiovasc Pharmacol 1985
PMID:Regression of cardiac hypertrophy after therapy in animal hypertension. 240 72

The purpose of this study was to compare the effect of intrarenal angiotensin converting enzyme (ACE) inhibition with that of systemic ACE inhibition in conscious, instrumented dogs. Intrarenal ACE inhibition was achieved by infusing the potent ACE inhibitor MK-422 into the renal artery in a dose (0.32 micrograms/kg/min) that in dogs fed a normal sodium (n = 11) and low sodium (n = 10) diet markedly attenuated the renal blood flow response to intrarenal arterial angiotensin I (0.4 and 0.8 micrograms, respectively). Intrarenal arterial infusion of MK-422 decreased the responses by 76 and 72% in the normal and low sodium groups, respectively, but only decreased renal vascular resistance slightly (-9 and -8%, respectively) in the infused kidney. Following termination of intrarenal arterial infusion of MK-422, the inhibitor was administered intravenously, 0.2 mg/kg. This dose of MK-422 maximally inhibited systemic ACE, as evidenced by the complete abolition of the renal blood flow response to intravenous angiotensin I; the responses were decreased by 95 and 96% in the normal and low sodium groups, respectively. In contrast to the negligible reduction in renal vascular resistance seen during intrarenal arterial infusion of MK-422, systemically administered inhibitor decreased renal vascular resistance by 16 and 39%, respectively, in the normal and low sodium groups. These results lend additional support to our contention that systemically rather than intrarenally formed angiotensin II is mainly responsible for regulation of renal vascular resistance.
J Cardiovasc Pharmacol
PMID:Comparison of systemic and intrarenal converting enzyme inhibition by MK-422 on renal hemodynamics in conscious dogs. 241 Jul 13

Angiotension II is the effector molecule of the renin-angiotensin system. Therefore, agents directed at the receptor that mediates its actions are likely to represent the most physiologically specific inhibitors of the system. We suggest here an approach to such drugs based on an operational analogy between peptidases and peptide hormone receptors and on the development of inhibitors of angiotensin-converting enzyme. The rationale that led to captopril, enalapril, and related inhibitors of this peptidase required identification of its cognitive and functional properties, i.e., what amino acid sequences it preferentially recognizes and its Zn2+ -dependent dipeptidyl carboxypeptidase activity. Purification of the enzyme was necessary to obtain this information. We speculate that this type of information may be equally useful for developing a receptor antagonist. As progress toward this objective, we describe briefly purification of rabbit hepatic angiotensin II receptor using chemical and immunoaffinity ligands. We hope to determine the cognitive and functional properties of this purified protein, i.e., what residues it preferentially recognizes in defined peptides and the molecular mechanism by which binding of ligand is transduced into a cellular response.
J Cardiovasc Pharmacol 1985
PMID:Angiotensin receptor is a desirable locus for physiologically specific inhibition of the renin-angiotensin system. 241 17

The hemodynamic effects of enalaprilat (MK-422) and lisinopril (MK-521) were compared with the calcium channel blocker felodipine in dogs with ischemic left ventricular (LV) failure. The combination of nitrendipine plus enalapril was also examined in ischemic failure and in rats with spontaneous hypertension. In anesthetized dogs coronary embolization with 50 micron plastic microspheres reduced cardiac output and LV dP/dt max by approximately 40%, and LV end-diastolic pressure increased to greater than 13 mm Hg. Enalaprilat and lisinopril reduced mean arterial pressure by a maximum of 20 mm Hg and total peripheral resistance by approximately 30%. Left ventricular dP/dt:LVP, which was substantially decreased by embolization, was slightly increased by both angiotensin converting enzyme (ACE) inhibitors. The calcium entry blockers felodipine and nitrendipine qualitatively produced many of the same hemodynamic effects as the ACE inhibitors, but, in addition, they markedly reduced coronary resistance, increased myocardial blood flow, and did not alter cardiac contractility (LV dP/dt max). In spontaneously hypertensive rats single doses of nitrendipine (1.25 to 5.0 mg/kg per os) and enalapril (0.3 and 3.0 mg/kg per os) reduced mean arterial pressure, but differences were observed in the onset (enalapril 2 h versus nitrendipine 0.5 h), the duration of action, and magnitude of effect. In terms of blood pressure lowering, nitrendipine, 5.0 mg/kg per os, was clearly additive to 3.0 mg/kg per os of enalapril, but other combinations (enalapril, 3 mg/kg per os plus 0.625 mg/kg of nitrendipine or enalapril, 0.3 mg/kg per os plus 0.625 mg/kg nitrendipine) were not.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1986
PMID:Enalapril in experimental hypertension and acute heart failure: comparison with calcium channel blockers. 242 87

The increasing number of angiotensin converting enzyme (ACE) inhibitors means that compounds with different enzyme kinetics, pharmacokinetics, bioavailability, and pharmacodynamics will appear. They will, however, all inhibit ACE, and their hypotensive effect will be a consequence of this action. Enalapril (MK-421) is an esterified prodrug, which in man is converted by the liver to the bioactive potent ACE inhibitor enalaprilate (enalaprilic acid, MK-422). This probably accounts for the slower plasma appearance of MK-422 and the longer duration of action of enalapril. The clinical significance of deesterification by the liver needs further study but minor abnormalities of liver function, such as occur in congestive heart failure, do not affect the rate of deesterification and hence the plasma enalaprilat levels. A close relationship between the plasma drug level, degree of ACE inhibition, and the hormonal and hypotensive effect can be demonstrated after both acute and chronic enalapril administration to hypertensive patients. Chronic therapy with enalapril leads to induction of ACE but in humans this is not sufficient to lead to resistance or tolerance to the drug. Enalapril offers an exciting new approach to the treatment of hypertension with some distinct advantages over conventional antihypertensive therapy.
J Cardiovasc Pharmacol 1986
PMID:Evaluation of angiotensin converting enzyme (ACE) in the pharmacokinetics and pharmacodynamics of ACE inhibitors. 242 95

The effects of the angiotensin converting enzyme (ACE) inhibitors captopril, enalapril, HOE 498, and its prodrug on reperfusion arrhythmias after 15 min of coronary ligation were investigated in the isolated rat heart. Drug concentrations were equipotent in their effect on angiotensin I pressor response. Furthermore, the effect of indomethacin on ACE inhibition with captopril was studied. Upon reperfusion, ventricular fibrillation occurred in all untreated hearts, in all prodrug HOE 498-treated hearts (15 micrograms/ml), and in 4 of 6 of the enalapril-treated (8 micrograms/ml) hearts. In contrast, in only 2 of 6 (p less than 0.002) of the HOE 498-treated hearts (15 micrograms/ml) and in none (p less than 0.001) of the captopril-treated hearts (80 micrograms/ml) did ventricular fibrillation occur. A massive purine overflow was observed in untreated hearts upon reperfusion. This overflow was significantly reduced by captopril and HOE 498, whereas enalapril and prodrug HOE 498 had no significant effect. Concomitantly, the pressure-rate index was severely impaired after 30 min of reperfusion in the untreated, enalapril, and prodrug HOE 498 groups (33 +/- 9, 52 +/- 11, and 48 +/- 12% of initial values, respectively), but captopril and HOE 498 significantly reduced the impairment of mechanical function (124 +/- 9% and 98 +/- 9%, respectively). In contrast to enalapril and prodrug HOE 498, captopril and HOE 498 markedly reduced noradrenaline overflow during the first minutes of reperfusion. No angiotensin II was detectable in the coronary effluent of untreated hearts.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol
PMID:Reduction of reperfusion arrhythmias in the ischemic isolated rat heart by angiotensin converting enzyme inhibitors: a comparison of captopril, enalapril, and HOE 498. 242 10

SQ 27,786 and SQ 28,853 were designed to possess both angiotensin converting enzyme (ACE) inhibitory and diuretic properties. Both compounds were given to conscious male Sprague-Dawley rats and mongrel female dogs to determine ACE inhibitory and diuretic activities. All animals had previously been equipped with indwelling arterial and venous catheters. Both compounds resulted in dose-related inhibition of an angiotensin I pressor response in rats after i.v. administration. The maximum response and duration of effect of both compounds were similar to that seen with equimolar doses of captopril. Oral doses of SQ 28,853 (50.0 mumol/kg) and SQ 27,786 (15.0 mumol/kg) resulted in 15 and 64% inhibition of ACE, respectively. In conscious normotensive dogs, both compounds (2.0 mg/kg, i.v.) resulted in complete inhibition of ACE. Urine volume was increased by 153 and 667% after SQ 27,786 and SQ 28,853, respectively. Similarly, sodium excretion was increased by 336% after SQ 27,786 and by 650% after SQ 28,853. SQ 27,786 and SQ 28,853 increased potassium excretion by 54 and 115%, respectively. No significant changes in blood pressure were observed with either compound in either species. These results demonstrate that both SQ 27,786 and SQ 28,853 are potent ACE inhibitors and diuretic agents in vivo.
J Cardiovasc Pharmacol 1987 Feb
PMID:SQ 27,786 and SQ 28,853: two angiotensin converting enzyme inhibitors with potent diuretic activity. 243 92

On the isolated perfused rat kidney, the angiotensin converting enzyme (ACE) activity was evaluated with two approaches: one, pharmacological, through the vasoconstrictor response to angiotensin I (ANG I), and the other, biochemical, through the measurements of the enzymatic activity on renal homogenate. ANG I and angiotensin II (ANG II) induced a concentration-dependent renal vasoconstriction (EC50 = 10.5 +/- 1.8 X 10(-9) and 1.1 +/- 0.5 X 10(-9) M, respectively). Both responses were competitively antagonized by an ANG II receptor antagonist, saralasin (pA2 = 8.65 +/- 0.63 and 8.94 +/- 0.28, respectively). The effects of ACE inhibitors were studied in vitro after addition of captopril and ramiprilat (10(-5) M) directly to the perfusion medium, and ex vivo, after pretreatment of the rats with ramipril (50 mg/kg, i.p. the day before or 10 mg/kg/day, per os, over 3 weeks). In spite of the high doses of ACE inhibitors used, the ANG I concentration-response curve was only shifted to the right by a factor of 4, although renal tissue ACE activity was completely inhibited. Saralasin (10(-5) M) totally abolished the ANG I-induced vasoconstriction elicited in the presence of ACE inhibitors, this response being therefore linked to a generation of ANG II from ANG I. Our results suggest that, on the isolated perfused rat kidney, ANG II may be formed from ANG I by a peptidyl dipeptidase different from the ACE.
J Cardiovasc Pharmacol 1986
PMID:Effect of angiotensin converting enzyme inhibitors on the vasoconstrictor action of angiotensin I on isolated rat kidney. 243 82


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