Active Angiotensin-converting Enzyme Research Articles

Effects of prolonged administration of the angiotensin converting enzyme inhibitor CGS 16617 in normotensive volunteers

A new, orally active angiotensin converting enzyme (ACE) inhibitor, CGS 16617, has been evaluated in normotensive subjects during acute and prolonged administration. Single ascending doses of CGS 16617 20 to 100 mg were given to 9 normotensive volunteers at one week intervals and the changes in blood pressure, plasma ACE and renin activity were examined up to 72 h after drug intake. Also, CGS 16617 50 mg/day or placebo were given for 30 days to 8 and 6 normotensive subjects, respectively, maintained on an unrestricted salt diet. Blood pressure was measured daily in the office and ambulatory blood pressure profiles were also obtained before, during and after therapy, using the Remler M 2000 blood pressure recording system. CGS 16617 was an effective and long lasting ACE inhibitor. It did not induce a consistent change in blood pressure, but, the individual responses were very variable and several subjects experienced a clear decrease in the average of the blood pressures recorded during the daytime.

P-127 - Antihypertensive effects of a novel orally active angiotensin converting enzyme (ACE) inhibitor altiopril calcium (MC-838) in several hypertensive rat models

P-127 - Antihypertensive effects of a novel orally active angiotensin converting enzyme (ACE) inhibitor altiopril calcium (MC-838) in several hypertensive rat models

Effects of the angiotensin converting enzyme inhibitor, ramipril, in isolated ischaemic rat heart are abolished by a bradykinin antagonist.

To elucidate the role of bradykinin in the cardiac actions of angiotensin converting enzyme (ACE) inhibitors, experiments were performed in isolated ischaemic hearts from guinea pigs and rats treated with the ACE inhibitor ramipril and the bradykinin-antagonist D-Arg[Hyp2,Thi5,8,D-Phe7]BK. In guinea pig hearts bradykinin increased coronary flow. Single oral pretreatment with ramipril (10 mg/kg) potentiated but perfusion with the bradykinin antagonist abolished this effect. In ischaemic working rat heart preparations perfusion with ramiprilat (2.58 x 10(-7) mol/l) or single oral pretreatment with ramipril (1 mg/kg) protected the heart from the ventricular fibrillations that invariably occurred upon reperfusion after ischaemia. Lactate dehydrogenase and creatine kinase activities, as well as lactate formation, were decreased in the venous effluent of pretreated hearts. Moreover, ACE inhibition in the heart improved cardiodynamic and metabolic parameters; left ventricular pressure, (dp/dt)max and coronary flow were increased and myocardial tissue levels of glycogen, ATP and creatine phosphate were elevated. A comparable array of changes was seen when rat hearts were perfused with bradykinin (1 x 10(-10) mol/l), which reduced enzymatic activities in the perfusate and improved the metabolic parameters in the myocardium. These cardioprotective effects produced by both the ACE inhibitor ramipril and bradykinin were completely abolished when the bradykinin-antagonist (1 x 10(-5) mol/l) was added to the perfusate. They were only partially attenuated when indomethacin (1 x 10(-6) mol/l) was perfused. Higher concentrations of bradykinin (1 x 10(-7) mol/l) or ramiprilat (2.58 x 10(-5) mol/l) overcame the actions of the bradykinin-antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Cimetidine on the Pharmacokinetics and Pharmacodynamics of Enalapril in Normal Volunteers

The possible effects of cimetidine on the pharmacokinetics and pharmacodynamics of enalapril, a pro-drug requiring hepatic de-esterification to an active angiotensin-converting enzyme (ACE) inhibitor enalaprilat, were assessed in a randomized, crossover study. Cimetidine (400 mg) or placebo was administered orally every 12 h for 3 days and on the day of a single oral administration of enalapril maleate (10 mg) to seven healthy male subjects. Serum ACE, plasma renin activity (PRA), plasma aldosterone concentration (PAC), and alpha-human atrial natriuretic peptide (alpha-hANP) were measured before and 4 h after the enalapril dosing. There were no significant differences in any serum- and urine-derived kinetic parameters of enalapril and enalaprilat, nor in hemodynamics, PAC, or alpha-hANP between the two treatment trials. ACE decreased and PRA increased to a similar extent in the two trials. Serum enalaprilat concentration correlated significantly (p less than 0.001) with percentage of inhibition of ACE activity. The results suggest that the pharmacokinetics and pharmacodynamics of enalapril are unaffected by preadministration of cimetidine. Thus, cimetidine does not appear to alter hepatic esterase activity toward enalapril.

Angiotensin-converting enzyme inhibition in mild to moderate congestive heart failure: an evolving approach.

As a result of the understanding of the factors governing myocardial performance achieved in the physiology laboratory, vasodilator therapy was introduced for patients with refractory heart failure nearly two decades ago. Ten years later, investigations began with the first orally active angiotensin-converting enzyme inhibitor (ACEI), captopril, in patients with severe congestive heart failure (CHF). Subsequent studies have definitively demonstrated that ACEIs produce symptomatic and exercise tolerance improvement in patients with moderate and severe CHF. This favorable experience led to the investigation of captopril in patients with milder symptoms in whom the goals of treatment must be defined more rigorously. An optimal agent for this patient group would not only reduce symptoms, but improve prognosis and have demonstrable advantages over existing treatments. A growing body of investigational data and clinical experience indicates that the ACEIs achieve these goals. As a result, they are being used with increasing frequency in patients with milder grades of heart failure.

Urinary mannitol: lactulose excretion ratios and jejunal mucosal structure.

A dual sugar (mannitol, lactulose) absorption test was evaluated using an iso-osmolar oral dose in two groups of children: a study group of 43 children divided into five subgroups, based on severity of mucosal damage, and a control group of 53 children with histologically normal jejunal biopsy specimens. After an oral dose, the three hour urinary mannitol: lactulose ratios in the control group showed a highly significant positive correlation with body surface area. After correction for the body surface area relationship, a control lower limit was defined by the mean -2SD of the log10 transformed control mannitol: lactulose ratios. Specificity and sensitivity for severe villous atrophy was 98% and 95% respectively but the sensitivity declined rapidly with decreasing degrees of mucosal damage, and the test would not therefore be an adequate screening procedure for all enteropathies. In sequential studies in 18 children, the changes in the mannitol: lactulose ratio were consistent with the changes in mucosal structure induced by gluten challenge or gluten withdrawal. The test may therefore have a role in any sequential study of lesions of the mucosa of the small intestine.

Effect of renal impairment on disposition of pentopril and its active metabolite.

Disposition of pentopril was studied in 15 male volunteers with varying renal functions. Mild to moderate compromise in renal function did not demonstrate any appreciable changes in plasma concentration of pentopril, the prodrug ester of the active angiotensin-converting enzyme (ACE) inhibitor CGS 13934. This is consistent with the known elimination pattern for pentopril, which is eliminated primarily by hydrolysis to the active inhibitor. In contrast, the plasma concentration of the active ACE inhibitor was sensitive to moderate changes in renal function. Because of the reciprocal relationship of AUC and clearance, AUC did not change to any appreciable extent until creatinine clearance (CLCR) dropped to about 50 ml/min. Below 50 ml/min of CLCR, AUC and half-life increased sharply with reduced kidney function. Because of the significant contribution of the renal secretion process to total renal elimination of both pentopril and the active metabolite, prediction of renal clearance from CLCR was poor at relatively normal kidney function (CLCR greater than 80 ml/min). However, renal secretory clearances for both pentopril and metabolite were well correlated to p-aminohippuric acid clearance. In patients with moderately compromised renal function (glomerular filtration rate less than 40 ml/min), tubular secretion rate of creatinine approaches its glomerular filtration rate and hence CLCR could be used as a predictor of renal clearance and other disposition parameters. Plasma ACE activity also demonstrated prolonged inhibition with decreased renal function. Based on the prolonged blockade of plasma ACE activity, some correction in dose or dosing interval is anticipated in patients with moderately compromised renal function (CLCR less than 50 ml/min).

Oxidation-induced increase in activity of angiotensin converting enzyme in the rat kidney

The activity of angiotensin converting enzyme(ACE) in crude extracts of the rat renal cortex was increased when the oxidizing agent diamide was added to the extract. The maximal activity was obtained at concentrations over 1 mM, and the value was twice or more the activity in the absence of the pretreatment. The activity of ACE was also increased by the diamide-pretreatment of the isolated membrane fraction of the renal cortex, thereby indicating that the increase in activity was not due to oxidation of endogenous glutathione (GSH) that may lower the ACE activity, but rather that ACE itself was oxidized. When O2 was included in the extract for 2 h, the ACE activity also increased to about twice the original activity. Lineweaver-Burk plots analysis demonstrated that, after oxidation with diamide and O2, the Vmax was increased but the Km remained unchanged. We conclude that the action of ACE in the kidney functions may differ in relation to oxidation of the tissue.

Lisinopril pharmacokinetics in chronic renal failure.

1. Lisinopril, a new orally active angiotensin converting enzyme inhibitor, was given to eight patients with stable chronic renal failure, in a dose of 5 mg 24 h-1 for 1 week. Creatinine clearance of the subjects ranged from 0.22 to 1.11 ml s-1. Lisinopril pharmacokinetics were studied over 8 days. 2. There was a close correlation between creatinine clearance and total 'area under the curve' over the 8 days of study (r = -0.88, P less than 0.05), and plateau lisinopril concentration and creatinine clearance (r = -0.77, P less than 0.05). 3. Serum angiotensin converting enzyme activity was inhibited in proportion to log serum lisinopril concentration (r = -0.99, P less than 0.001). Calculated IC50 was 47 ng lisinopril ml-1. from pooled data, with individual patients IC50 ranging from 20 to 70 ng lisinopril ml-1. 4. Creatinine clearance was unaltered by treatment. Serum potassium rose to over 5 mmol 1-1 in four patients, without adverse clinical effect.

New Drugs: Angiotensin converting enzyme inhibitors

The development of angiotensin converting enzyme inhibitors is often cited as a prime example of task oriented research. The truth is far from this, and, as so often, chance played a large part in the development of this group of drugs. Some 25 years ago a group of Brazilian pharmacologists was searching for substances that would block the inactivation of bradykinin, a process subsequently shown to take place in man in the pulmonary vascular bed. It was shown that this was also the site for the conversion of angiotensin I to the potent vasoconstrictor angiotensin II, and the two processes were controlled by enzymes that, if not the same, were very similar. It has been appreciated for many years that the renin-angiotensin aldosterone system is important in the control of blood pressure. Most early stratagems to lower blood pressure clinically, however, were based on manipulating the sympathetic nervous system, and attempts to perturb the renin-angiotensin-aldosterone system came much later. The use of effective orally active angiotensin converting enzyme inhibitors depended on translating the experiences of pharmacologists, who were interested primarily in the breakdown of bradykinin, to physiologists, who were interested in the mechanisms of controlling blood pressure, and then using the skills of medicinal chemists and clinical pharmacologists to design and test suitable compounds. A recent review by Ferreira, an important figure in the early development of this subject, details this interesting story.1 There are currently two orally active angiotensin converting enzyme inhibitors available in the United Kingdom, captopril and enalapril. Some 20 compounds that have a similar pharmacological activity are in, various stages of development, several of them having been already given to volunteers and patients. This review will concentrate on the two marketed products because, as will be seen below, a risk-benefit analysis for angiotensin converting enzyme inhibitors can be made only after extensive exposure of patients, and any assessment of new members of the group is difficult. I will therefore compare captopril and enalapril with respect to their pharmacology, relative efficacy, and relative toxicity.

Mechanisms of action of estrogen to pressor response and its facilitates the inhibitory action of angiotensin converting enzyme in SHR

Mechanisms of action of estrogen to pressor response and its facilitates the inhibitory action of angiotensin converting enzyme in SHR

Post marketing surveillance of captopril (for hypertension): a preliminary report.

1 The methodology and interim results of a post marketing surveillance of captopril, the first orally active angiotensin converting enzyme inhibitor are presented. 2 Utilising viewdata technology, details of hypertensive patients were entered directly into a mainframe computer. This allowed day to day monitoring of events; a facility not available with paper-based methods. 3 The design of the study allowed analysis of results including some details of efficacy, concomitant therapy, any disease symptoms and reasons for withdrawal. These factors could be categorised according to sex and age. 4 This preliminary report is based on the first 13,295 patients entered from July 1983 with follow-up until January 1985. The results of the study confirm the safety of captopril in the patients studied.

Monoclonal antibody to human lung angiotensin-converting enzyme.

The hybridoma producing monoclonal antibody (IgG1) to human angiotensin-converting enzyme (ACE) has been prepared by fusion of murine myeloma P3O1 with spleen cells of BALB/c mice immunized with a purified human lung ACE preparation. A high specificity of monoclonal antibody (MAb) binding to immobilized ACE has been demonstrated by enzyme-linked immunosorbent assay and that of soluble ACE by an immunoadsorption test. The latter technique permits the use of impure ACE preparations for the screening procedure. This MAb did not affect ACE activity. We believe this antibody will be useful not only for immunoassay and immunopurification of ACE, but also as a tool for the investigation of the tissue distribution of the enzyme as well as for the study of the structure and mechanism of action of ACE.

A unique geometry of the active site of angiotensin-converting enzyme consistent with structure-activity studies.

Previous structure-activity studies of captopril and related active angiotensin-converting enzyme (ACE) inhibitors have led to the conclusion that the basic structural requirements for inhibition of ACE involve (a) a terminal carboxyl group; (b) an amido carbonyl group; and (c) different types of effective zinc (Zn) ligand functional groups. Such structural requirements common to a set of compounds acting at the same receptor have been used to define a pharmacophoric pattern of atoms or groups of atoms mutually oriented in space that is necessary for ACE inhibition from a stereochemical point of view. A unique pharmacophore model (within the resolution of approximately 0.15 A) was observed using a method for systematic search of the conformational hyperspace available to the 28 structurally different molecules under study. The method does not assume a common molecular framework, and, therefore, allows comparison of different compounds that is independent of their absolute orientation. Consequently, by placing the carboxyl binding group, the binding site for amido carbonyl, and the Zn atom site in positions determined by ideal binding geometry with the inhibitors' functional groups, it was possible to clearly specify a geometry for the active site of ACE.

Converting Enzyme Inhibitors in the Treatment of Hypertension

The renin-angiotensin system has a wide range of physiological actions, and thus interference with the system has attractive therapeutic potential. The orally active angiotensin converting enzyme (ACE) inhibitors have so far been the most successful drugs in this area. They lower arterial pressure both in renovascular and essential hypertension, and their effects are enhanced by concomitant diuretic therapy or dietary salt restriction. Since, in renovascular hypertension, the affected kidney depends on enhanced local generation of angiotensin II to help preserve its function, the circulation and excretory capacity of this kidney may be compromised with ACE inhibition. ACE inhibitors can improve exercise tolerance and diminish cardiac ventricular arrhythmias in patients with heart failure. Because these drugs lower plasma aldosterone, they tend to correct potassium deficiency and hypokalemia, which may have been induced by diuretic treatment. Hypotension can occur with the first dose of ACE inhibitor, especially in sodium-depleted subjects; in patients on prior antihypertensive therapy, particularly if this includes a diuretic; and in the elderly. Not all of the actions of ACE inhibitors are necessarily due to lowering of plasma angiotensin II: accumulation of kinins may be responsible for some of the effects and side effects. Common to all ACE inhibitors are occasional rashes, cough, and, more rarely, angioedema. Apparently peculiar to captopril, and less often seen with the lower doses now employed, are taste disturbance, proteinuria, and marrow depression. ACE inhibitors, should not be used in pregnant women.

MC-838 (altiopril calcium): a novel orally active angiotensin converting enzyme inhibitor.

MC-838, calcium (-)-N-[(S)-3-(N-cyclohexylcarbonyl-D-alanyl) thio]-2-methylpropionyl]-L- prolinate, is a new orally active angiotensin converting enzyme (ACE) inhibitor in which the mercapto-group is taken up in a stable thiolester linkage. The linkage was relatively resistant against enzymatic hydrolysis by rat liver homogenates. The ACE prepared from rabbit lung was inhibited by MC-838 in a concentration-dependent manner. In isolated rat aortic ring and guinea-pig ileum preparations, MC-838 was highly specific in suppressing the contractile response to angiotensin-I (A-I) an in augmenting the contractile one to bradykinin. However, the ACE inhibitory activity of MC-838 was 30-100 times less potent than that of captopril. In conscious two-kidney (2 KG), renal hypertensive rats and spontaneously hypertensive rats (SHRs), MC-838 (3 and 10 mg/kg) given orally caused a long-lasting hypotensive effect with a slow onset. When compared on a weight basis (3 mg/kg), the antihypertensive effect of MC-838 was comparable to that of captopril in magnitude, but the duration of action of MC-838 was approximately 2 times longer than that of captopril.

P-361 - CV-S975, a highly potent, long acting angiotensin converting enzyme (ACE) inhibitor

P-361 - CV-S975, a highly potent, long acting angiotensin converting enzyme (ACE) inhibitor

Effect on blood pressure and the renin-angiotensin system of repeated doses of the converting enzyme inhibitor CGS 14824A

A new, orally active angiotensin converting enzyme (ACE) inhibitor, CGS 14824A, was evaluated in 12 healthy male volunteers. Two groups each of 6 volunteers were given 5 or 10 mg once daily p.o. for 8 days. Four hours after the first and the last morning doses, plasma angiotensin II, aldosterone and plasma converting enzyme activity had fallen, while blood angiotensin I and plasma renin activity had risen. Throughout the study, more than 90% inhibition of ACE was found immediately before giving either the 5 or 10 mg dose and 50% blockade was still present 72 h following the last dose. Based on the determination of ACE, there was no evidence of drug accumulation. No significant change in blood pressure or heart rate was observed during the course of the study. CGS 14824A was an effective, orally active, long-lasting and well tolerated converting enzyme inhibitor.

Single and repeated dosing of the converting enzyme inhibitor perindopril to normal subjects.

The new orally active angiotensin converting enzyme (ACE) inhibitor perindopril (S9490-3) was evaluated in 18 normotensive men. In three subjects the pressor response to exogenous angiotensin I was tested. A 8 mg oral dose reduced the pressor response by greater than 80%. Single oral perindopril doses of 2, 4, 8, and 16 mg were given to groups of five subjects each. Eight and 16 mg decreased plasma ACE activity within 4 hours to less than 10% of control; 72 hours later, plasma ACE activity was still reduced by at least 40%. Doses of 4 and 8 mg po once a day were then given for 8 days to two groups of six subjects. Four hours after the first and the last morning doses, plasma angiotensin II, aldosterone, and plasma ACE activity fell significantly, whereas blood angiotensin I and plasma renin activity rose. There was no evidence of drug accumulation. No significant change in blood pressure or heart rate was observed. Thus in normotensive subjects, perindopril seems an effective, orally active, long-lasting ACE inhibitor.

Adverse reactions with angiotensin converting enzyme (ACE) inhibitors.

Teprotide, a nonapeptide isolated from the venom of a Brazilian pit viper, Bothrops jararaca, was the first angiotensin converting enzyme (ACE) inhibitor to be discovered and tested. It was found to be an effective, non-toxic antihypertensive agent as well as an afterload-reducing agent for patients with congestive heart failure (CHF). The primary activity of teprotide resulted from blockade of the angiotensin I converting enzyme--the pivotal step in the renin-angiotensin-aldosterone system (RAAS), and consequent reductions in angiotensin II levels. There was limited clinical testing for teprotide because of: its scarcity; the need for parenteral administration; and the subsequent discovery and synthesis of captopril, the first orally active angiotensin converting enzyme inhibitor. Captopril is the prototype oral angiotensin converting enzyme inhibitor and has been extensively studied since the initiation of formal studies in 1976. Perhaps one of the most closely researched drugs in modern times, the experience with captopril now includes more than 12,000 patients studied in formalized trials and over 4,000,000 patients treated world-wide by physicians for hypertension and congestive heart failure. Enalapril (MK421) is the first of what appears to be a growing number of analogues which are structurally and pharmacodynamically different from captopril; yet, they possess the same capacity for inhibiting the activity of angiotensin converting enzyme. The side effect profile of enalapril (and presumably future) angiotensin converting enzyme inhibitors appears to be similar to captopril, though clearly more experience is needed with newer agents. The initial use of captopril was troubled by a relatively high incidence of side effects which will form the focus of this discussion. Partially the result of incomplete pharmacokinetic information, captopril was administered in early studies at dosages now recognised to be far in excess of those necessary for drug action. In addition, dosages were given without regard for deficiencies of renal function, now known to be the main excretory route of captopril. The population of those patients studied frequently had chronic, treatment-resistant hypertension, often associated with concomitant end-organ disease (especially renal disease); and many additional factors further complicating the clinical setting, e.g. a relatively high incidence of collagen vascular disease and immunosuppressive treatments.(ABSTRACT TRUNCATED AT 400 WORDS)