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We compared the therapeutic effects of various low-molecular-weight enzyme inhibitors on dystrophic mice. Leupeptin, bestatin, forphenicinol and forphenicine significantly affected the enzymatic activities in the dystrophic muscles. The pattern of enzymatic changes in the muscles of forelimb and hindlimb caused by these inhibitors were similar in spite of the variety of their inhibitory spectra in vitro. However, comparing the pattern of enzymatic changes in spleen, forphenicinol differed from the other inhibitors tested. This may be related to the peculiar effects of this inhibitor on immunologically responsive cells.
The angiotensin I-converting enzyme (peptidyl-dipeptide hydrolase, EC 3.4.15.1) inhibitor, ramiprilat (2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-Ala]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid), is shown to exist in tow conformational isomers, cis and trans, which interconvert around the amide bond. The two conformers were separated by reversed-phase high-performance liquid chromatography. The conformers were identified by nuclear Overhauser effect measurements. From line shape analysis the isomerization rate constants were determined to be kcis----trans = 15 s-1 and ktrans----cis = 5 s-1 at 368 K in [2H]phosphate buffer (p2H 7.5). By enzyme kinetic studies using 3-(2-furylacryloyl)-L-Phe-Gly-Gly as substrate, the trans conformer was found to be the most potent enzyme inhibitor, whereas the cis conformer had a very low inhibitory effect. A new inhibition mechanism is presented for this type of slow, tight-binding inhibitors that contain an amide bond. This mechanism involves an equilibrium between the two conformers and the enzyme-bound inhibitor complex.
Enzymes catalyze a rich variety of metabolic transformations, and do so with very high catalytic rates under mild conditions, and with high reaction regioselectivity and stereospecificity. These characteristics make biocatalysis highly attractive from the perspectives of biotechnology, analytical chemistry, and organic synthesis. This review, containing 128 references, focuses on the use of separation techniques in the elucidation of enzyme-inhibitor and enzyme-substrate interactions. While coverage of the literature is selective, a broad perspective is maintained. Topics considered include chromatographic methods with soluble or immobilized enzymes, capillary electrophoresis, biomolecular interaction analysis tandem mass spectrometry (BIA-MS), phage and ribosomal display, and immobilized enzyme reactors (IMERs). Examples were selected to demonstrate the relevance and application of these methods for determining enzyme kinetic parameters, ranking of enzyme inhibitors, and stereoselective synthesis and separation of chiral entities.
Coformycin, which is an inhibitor of adenosine deaminase, significantly inhibited in vitro blastogenic responses of human lymphocytes to both phytohaemagglutinin (PHA) and pokeweed mitogen (PWM), whereas blastogenic responses to bacterial lipopolysaccharide (LPS) were rather enhanced by the addition of coformycin. Blastogenic responses of lymphocytes to PHA and PWM were markedly suppressed by the addition of adenosine, which is a substrate of adenosine deaminase. Allopurinol, which is an inhibitor of xanthine oxidase, inhibited blastogenic responses of human lymphocytes to PHA, PWM, and bacterial LPS. Inosine (a substrate of purine nucleoside phosphorylase) and hypoxanthine (a substrate of xanthine oxidase) showed no or only a small effect on blastogenic responses of human lymphocytes. These results suggest that adenosine deaminase activity is associated with the T-cell response but not with the B-cell response and that the impaired T-cell response in adenosine deaminase deficiency is the result of intracellular retention of adenosine in T cells. The results also suggest that purine nucleoside phosphorylase or xanthine oxidase activity is associated with both T- and B-cell responses.
The direct effects of a renin inhibitor, N-acetyl-pepstatin and five angiotensin converting enzyme inhibitors, captopril and the active diacid forms of enalapril, ramipril, cilazapril, and CS-622, on the vascular renin-angiotensin system were examined in isolated perfused rat mesenteric arteries. Vascular renin activity and angiotensin II (Ang II) released into the perfusate were determined. Infusion of N-acetyl-pepstatin (5 X 10(-8)-5 X 10(-6) M) suppressed vascular renin activity and Ang II release dose dependently. Isoproterenol (10(-6) M) induced a 135 +/- 30% increase in Ang II release from the basal value. N-Acetyl-pepstatin (5 X 10(-6) M) suppressed isoproterenol-induced Ang II release. Infusions of 5 X 10(-6) M captopril and the diacid forms of enalapril, ramipril, cilazapril, and CS-622 by themselves had little effect on Ang II release, but concomitant infusion of isoproterenol with these angiotensin converting enzyme inhibitors significantly decreased Ang II release (71 +/- 21%, 51 +/- 40%, 8 +/- 21%, 69 +/- 24%, and 44 +/- 29% increase, respectively, from the basal values). These results indicate that N-acetyl-pepstatin suppresses the vascular renin-angiotensin system. This effect may in part contribute to the hypotensive actions of renin inhibitors. Although angiotensin converting enzyme inhibitors also suppress locally generated Ang II, the mechanism and physiological significance still remain to be clarified.
OBJECTIVES: To examine whether the progression of early diabetic renal disease to end-stage renal failure may be slowed by the use of angiotensin converting enzyme inhibitors for reasons other than their antihypertensive properties, so that they have value in the treatment of normotensive diabetics with microalbuminuria. SEARCH STRATEGY: MEDLINE was searched for English language reviews and randomised controlled trials. Personal reference lists, and reference lists of retrieved studies were also used. SELECTION CRITERIA: Randomised controlled trials with separate identifiable results for initially normotensive diabetic patients, who received angiotensin converting enzyme inhibitors for at least one year and were compared with controls. DATA COLLECTION AND ANALYSIS: Meta-analyses were performed on the results of 11 randomised controlled trials with a variety of patient inclusion and exclusion criteria. MAIN RESULTS: Albumin excretion rate fell for patients on angiotensin converting enzyme inhibition in 10 of the 11 studies but did so for only two of the 11 groups on placebo. Treatment provided a significant reduction in albumin excretion rate in both insulin dependent diabetes mellitus and non insulin dependent diabetes mellitus. Treatment with either captopril, enalapril or lisinopril reduced albumin excretion rate in comparison with control patients. A greater lowering of blood pressure was experienced by initially normotensive patients in the angiotensin converting enzyme inhibitor than in the placebo group. Pooled end-of-study mean blood pressures for the treated group were significantly lower than for the untreated group, although this was not so for all individual studies. The apparent (treatment - placebo) 'effect' on systolic and diastolic pressures had a larger standard error for longer lasting studies. Average haemoglobin fell a little in the treated patients and rose in the controls but neither this nor the difference in changes in glomerular filtration rate reached statistical significance. REVIEWER'S CONCLUSIONS: Inhibition of angiotensin converting enzyme can arrest or reduce the albumin excretion rate in microalbuminuric normotensive diabetics, as well as reduce or prevent an increase in blood pressure. But, given the drop in blood pressure in patients on angiotensin converting enzyme inhibitors, it is not possible to be certain that the reduction of albumin excretion rate is due to a separate renal effect. A direct link with postponement of end-stage renal failure has not been demonstrated. There appear to be no substantial side effects.
BACKGROUND: Aldosterone (ALDO) exerts profibrotic effects, acting via the mineralocorticoid receptors in cardiovascular tissues. Aldosterone antagonism in combination with angiotensin-converting enzyme inhibition may better protect against the untoward effects of ALDO than angiotensin-converting enzyme inhibition alone. METHODS: In a double-blind randomized study, the tolerability and efficacy of canrenoate (25 mg/d) plus captopril versus captopril alone were evaluated in 510 patients with an acute anterior myocardial infarction (MI), a serum creatinine concentration < 2.0 mg/dL, and a serum potassium level < 5.0 mmol/L. Three hundred forty-one patients received captopril and 25-mg canrenoate (group A). Group B (346 patients) received captopril and placebo. At baseline and at 10, 90, and 180 days after admission, Doppler echocardiography was performed. RESULTS: Clinical and demographic aspects were similar in both groups. In addition, baseline cardiac enzyme levels, left ventricular function, and incidence of surgical interventions and angioplasty were comparable. Overall, creatinine, blood urea, and serum potassium levels did not show significant differences between groups. However, in 18 patients in group A, increases in serum potassium levels to > 5.5 mEq/L and creatinine levels to > 2.0 mg/L after 10 days of treatment were observed. At 180 days, the mitral E-wave-A-wave ratio was higher (P = .0001) and left ventricular end-systolic volume was smaller (P = .0001) in patients treated with canrenoate than in those receiving placebo. No further side effects were observed during the study period. CONCLUSIONS: Our data suggest that the combination of captopril plus canrenoate is well tolerated after an acute MI and has beneficial effect on systolic and diastolic parameters and may decrease post-MI remodeling.
An adverse interaction between aspirin and angiotensin-converting enzyme (ACE) inhibitors is suspected in patients with heart failure, but the effect of combined therapy with these agents on hospital readmission rates is unknown. Our study found that combining aspirin with ACE inhibitors is associated with higher early readmission rates than use of ACE inhibitors alone, particularly in patients with depressed ejection fraction and in those without coronary artery disease.
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Matrix metalloproteinases and their tissue inhibitors are key enzymes degrading myocardial collagen in acute myocardial infarction (AMI). The aim of the present study was to determine whether angiotensin-converting enzyme inhibitors (ACEI) influence collagenase-1 (MMP-1) and their tissue inhibitor (TIMP-1) activity in AMI patients. Plasma levels of MMP-1, TIMP-1 and MMP-1/TIMP-1 complex were measured in 24 patients (aged 58.4 +/- 13.9 years) with AMI. Thirteen patients received perindopril 4 mg/day (group A) and 11 did not (group B). Plasma samples collected on admission and at 0, 3, 6, 9, 12, 18, 24, 36 and 48 hours and on days 3, 4, 5, 7, 15 and 30 thereafter were analyzed by relevant ELISA kits. Ejection fraction (EF) was assessed by ventriculography and end-diastolic diameter (EDD) echo-study on days 6 and 30. Values of collagenolytic enzymes of group A compared with those in group B were on average lower by 34%, 18.3% and 40%, respectively. The difference in values between groups at 0 h, 3 h and 9 h was significant (p < 0.048). ANOVA repeated measurement analysis showed significance within subjects for MMP-1 alone (p < 0.043) and for MMP-1 and ACEI (p < 0.046), while for TIMP-1 and MMP-1/TIMP-1 complex significance was only p < 0.0009. Regarding EDD changes, patients in group A showed minimal or no changes (51.23 +/- 1.8 mm to 51.6 +/- 2.13 mm), their EF was 38.8% and infarct size was medium to large. In contrast, group B showed a trend to increase EDD (41 +/- 0.78 mm to 42.33 +/- 0.59 mm), their EF was 50.5% and infarct size was small to medium. In conclusion, early initiation of ACEI treatment reduces collagenolytic activity. This effect may be considered an alternative mechanism for beneficial effects on postinfarction remodeling.
The hemodynamic effects of varying oral doses of the long-acting converting enzyme inhibitor lisinopril were studied in an acute, single-blind, parallel fashion in 55 patients with moderate to severe congestive heart failure. Doses of 2.5, 5.0, and 10 mg produced a significant increase in cardiac index and significant reductions in pulmonary capillary wedge, right atrial, pulmonary arterial, and systemic arterial pressures and systemic vascular resistance. The changes were present up to 24 hours after dosing for most parameters. There was a clear-cut dose-response relationship observed. Forty-seven patients were followed over a 3-month period, during which functional status and exercise tolerance improved. Although 26% showed some evidence of renal dysfunction with lisinopril, these changes could be normalized by decreasing either the lisinopril or the diuretic dose. These data demonstrate that the hemodynamic changes with the long-acting converting enzyme inhibitor lisinopril can be modulated with dose adjustment in patients with congestive heart failure. They also suggest that renal function changes may be normalized by adjustment of either the dose of lisinopril or the diuretic dose.
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AIM: To compare the effects of angiotensin converting enzyme (ACE) inhibitors, renin inhibitors and angiotensin II (Ang II) antagonists. METHOD: Survey of data from recent studies. DISCREPANCY BETWEEN BLOOD PRESSURE REDUCTION INDUCED BY ACE INHIBITORS AND PLASMA ANG II LEVELS: Studies on the effects of ACE inhibition in hypertensive subjects have suggested that with chronic ACE inhibitor treatment, blood pressure remains lowered even when plasma Ang II returns to normal. However, this discrepancy may be largely an artefact related to difficulties in measuring low Ang II levels in the presence of high angiotensin I (Ang I) levels. Even with modern sensitive and specific Ang II assays it can be difficult to monitor in vivo ACE inhibition (Ang II:I ratio in plasma) because of ex vivo Ang II formation. Recently, in measuring 24-h blood pressure responses to ACE inhibitor treatment, we have obtained good correlations between the time-course of the blood pressure response and the change in circulating Ang II. PROBLEMS IN MEASURING RENIN ACTIVITY: Routine assays of renin activity in plasma can lead to an overestimate of the degree of in vivo inhibition during renin inhibitor treatment, because some protease inhibitors that are used in these assays can cause an ex vivo displacement of protein-bound renin inhibitor, thereby increasing its free concentration. This must be taken into account when using the ratio of enzymatically active renin to immunoreactive renin as an index of in vivo renin inhibition. BLOOD PRESSURE RESPONSE AND ANG II LEVELS WITH RENIN INHIBITORS AND ANG II ANTAGONISTS: Results published so far seem to indicate that with these drugs, as with the ACE inhibitors, the magnitude of the blood pressure effect is correlated with the decrease in the 'effective' Ang II concentration at the receptor sites. However, the time-course of the two effects may be different; with the renin inhibitors, the maximum effect on pressure was delayed compared with the effect on Ang II. CONCLUSIONS: Further studies are needed to establish the exact time-course of renin and Ang II changes and their relationship to blood pressure. Only with rigorously controlled assays will it be possible to answer the question whether, for a given change in 'effective' Ang II concentration at the receptor sites, the effect on blood pressure is different with the three classes of anti-renin-angiotensin drugs.
Converting enzyme inhibitors (CEIs) are widely used in treatment of essential hypertension. Large-scale clinical studies have shown that CEIs are well tolerated and cause fewer side effects than most other antihypertensive agents. The latter observation is fundamental for compliance with long-term treatment. There do exist, however, some side effects which although rare are not negligible. It is necessary though to distinguish between side effects linked to the class of therapeutic agents and those associated with particular structural features. Three types of side effects have been seen: 1) manifestations linked to inhibition of angiotensin II with systemic vasodilation (hypotension, vertigo) and decreased glomerular pressure (functional renal impairment) with preferred onset in renovascular hypertension; 2) potentiation of the bradykinin-prostaglandin system which causes cutaneous eruptions and for reasons still poorly understood a cough which may justify discontinuance of treatment: 3) side effects for which the sulfydryl group is essentially responsible (rash, dysgeusia, neutropenia, proteinuria) and which basically appear to be linked to the use of high doses of captopril. In general terms, and bearing in mind the frequently dose-dependent character of the side effects, it is advisable to prescribe low doses of CEIs, and this therapeutic approach is strengthened by the possibility of concomitant use of a thiazide diuretic allowing improved antihypertensive effects, coupled to better reciprocal tolerance of the drugs. The end result is a better quality of life for the hypertensive subject, and hence improved compliance with long-term treatment.
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