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Labilization of the phosphoester linkage in enzyme-inhibitor complexes of aspartate aminotransferase.

Individual enzyme-inhibitor complexes with characteristic absorption spectra have been obtained as a result of the reaction of the apoenzyme of aspartate aminotransferase with Nalpha-(5'-phosphopyridoxyl)-L-glutamic acid, Nalpha-(5'-phosphopyridoxyl)-D-glutamic acid, and Nalpha-(5'-phosphopyridoxyl)-L-pyroglutamic acid. The stability of the enzyme-inhibitor complexes has been investigated under various conditions, viz., reactivation by the coenzyme, denaturation by urea, variations in the pH. It has been shown that the complexes formed by the last two inhibitors are reactivated by pyridoxal-5'-phosphate and that the inhibitor can be released under mild conditions. The enzyme-inhibitor complex formed by Nalpha-(5'-phosphopyridoxyl)-L-glutamic acid, on the other hand, was not reactivated by the coenzyme. Pyridoxylglutamic acid has been isolate in attempts to release the inhibitor. The dephosphorylation of the inhibitor has been associated both with the hydrolysis of a phosphate bond involving the enzyme and with the phosphorylation of aspartate aminotransferase. A 32P peptide containing 13 amino acids has been isolated from the tryptic hydrolysate of the enzyme-inhibitor complex (formed by a 32P inhibitor). The data obtained have been interpreted on the basis of an assumption that the phosphate group of the coenzyme has an active role in the enzymatic transamination reaction.

Apoenzymes↗
PubMed1978

Neoantigenic expression in enzyme-inhibitor complexes. A means to demonstrate activation of enzyme systems.

Human thrombin-antithrombin III and plasmin-antiplasmin, two enzyme-inhibitor complexes composed of four different molecules, contain antigenic structures not present in the parent molecules, which can be directly quantitated in plasma with the use of non-cross-reacting antisera. It is anticipated that this neonatigenic expression is a more general phenomenon, which could provide a simple means of measuring activation of enzyme systems in biological fluids.

Antigen-Antibody Reactions↗
PubMed1976

Estimating renin participation in hypertension: superiority of converting enzyme inhibitor over saralasin.

This study was designed to examine more closely the differences in blood pressure responses in hypertensive patients to two agents which block the renin-angiotensin system. Accordingly, 39 seated patients received under the same conditions both saralasin, an octapeptide competitive antagonist of angiotensin II, and the nonapeptide converting enzyme inhibitor, SQ20881, which blocks the generation of angiotensin II from angiotensin I. A second component of the study involved administration of these agents in 10 addtional studies in anephric subjects. Although both agents produced maximal responses in blood pressure that correlated well with each other (p less than 0.001) and with the pretreatment plasma renin levels (p less than 0.001), analysis of the results by renin subgroups revealed significant differences. Thus, both drugs lowered the diastolic pressures of patients with high renin levels, but but converting enzyme inhibitor produced changes of greater amplitude (p less than 0.05). In contrast, saralasin was consistently pressor in both patients with low renin levels and anephric patients in whom converting enzyme blockade preduced no significant changes in blood pressure. Another impressive disparity in the responses to the two agents occurred in the group with normal renin levels in whom saralasin produced either neutral or pressor responses (mean change was +2.0 +/- 1.5 standard error of the mean (SEM) per cent control diastolic pressure) whereas the converting enzyme inhibitor consistently induced depressor responses (mean change was -10.2 +/- 1.2 per cent, p less than 0.001). Altogether, the results suggest that converting enzyme inhibitor tests for angiotensin II-dependent blood pressure with more sensitivity than the partial agonist saralasin. Moreover, it is unlikely that the differences between the responses to the two agents were due to bradykinin accumulation, since depressor responses to converting enzyme inhibitor were not observed in the patients with low renin levels and the anephric patients.

Adolescent↗
PubMed1979

Inhibitors of the renin-angiotensin system in experimental hypertension, with a note on the measurement of angiotensin I, II and III during infusion of converting-enzyme inhibitor.

1 Prolonged infusion (11 h) of both saralasin and angiotensin-converting enzyme inhibitor (SQ20881) gradually lowered BP in two-kidney hypertensive rats to levels similar to that in normotensive rats infused with dextrose. 2 Saralasin did not lower BP in DOCA-salt hypertensive rats. 3 These observations support the notion that in chronic renal hypertension, angiotensin II may maintain hypertension by a slowly developing action. 4 Plasma angiotensin II in rats infused with SQ20881 was suppressed relative to renin, but was not eliminated. 5 Chromatography of angiotensin II extracts from dogs infused with converting enzyme inhibitor (SQ14,225) showed that the very high levels of angiotensin I achieved after treatment with SQ14,225 can lead to falsely high estimated angiotensin II levels as a result of angiotensin I cross-reacting with the angiotensin II assay.

Angiotensin I↗
PubMed1979

Effects of the converting enzyme inhibitor (SQ 20881) on the pulmonary circulation in man.

The effects of the converting enzyme inhibitor (SQ 20881) on the pulmonary circulation were investigated in 13 patients in whom systemic hypertension developed following coronary artery bypass surgery. Pulmonary vascular resistance was decreased by the inhibitor, from 128 +/¿ 19 to 92 +/- 20 dynes sec cm-5 (or by 30 +/- 7 per cent; P less than 0.005), and this resulted in a decrease in mean pulmonary artery pressure from 17 +/- 1 to 13 +/- 1 mm Hg (or by 23 +/- 3 per cent, P less than 0.005). Consequently, right ventricular work was decreased by the inhibitor by 30 per cent (P less than 0.01), despite an increase in cardiac output (increase in stroke volume) by 16 +/- 6 per cent (P less than 01). This increase occurred despite a 13 +/- 3 per cent decrease in right ventricular filling pressure. The changes in pulmonary vascular resistance correlated with the pretreatment plasma renin activity (r = 0.74, P less than 0.01), as did the decrease in mean pulmonary artery pressure (R = 0.82, P less than 0.001), but neither change was related to the decrease in left ventricular fillling pressure nor to changes in cardiac output or mean arterial pressure. These results indicate that blockade of the formation of angiotensin II by the converting enzyme inhibitor results in reductions in pulmonary vascular resistance and pulmonary artery pressure which are unrelated to alterations in left ventricular function. Thus, angiotensin inhibition may have therapeutic value in various clinical states characterized by pulmonary hypertension--especially if renin levels are high.

Adult↗
PubMed1976

Localization of radiolabeled enzyme inhibitors in the adrenal gland.

Tissue distribution studies were performed in rats and dogs at five time intervals between 10 min and 24 hr after the intravenous injection of one of the following radiolabeled adrenocortical enzyme inhibitors: 3H-amino-glutethimide, 125I-3-iodoaminoglutethimide, 3H-SKF-12185, 125I-3-SKF-12185, 3H-metyrapone. 3H-metyrapol. 3H-amphenone B, and 3H-SU-10603. In rats, 3H-SKF-12185 showed the highest uptake in the whole adrenal (3.5% kg dose/gm at 1 hr). In dogs, 3H-metyrapol showed the highest uptake in the adrenal cortex (9% kg dose/gm at 1 hr), and the peak cortex-to-liver concentration ratio was 57 at 2 hr. These peaks uptakes were comparable to those obtained with the conventional iodocholesterols, but they were reached much earlier, with elimination of most of the adrenal radioactivity by 24 hr. These properties would permit the use of 123I as the label and a higher tracer dose, resulting in a higher photon flux. Thus, the radiolabeled enzyme inhibitors show promise as adrenal-scanning agents, with a markedly shortened scanning procedure, a lower absorbed radiation dose, and better resolution.

Adrenal Gland Diseases↗
PubMed1979

Molecular orbital study on the reaction mechanism of irreversible enzyme inhibitors.

By means of the molecular orbital method, the reaction mechanism of the specific and irreversible enzyme inhibitors, such as cycloserine, L-2-amino-4-methoxy-trans-3-butenoic acid (AMB), and vinylglycine (2-amino-3-butenoic acid), was studied. Firstly, it was attempted to know which pathway is probable between the transamination process and the isomerization one. By comparing the energy increments for these two reactions, the transamination reaction was predicted to be energetically favorable, supporting the proposition of Rando. Upon complexing with the coenzyme-pyridoxal moiety of alanine racemase or aminotransferase, the reactivity of the inhibitors toward the nucleophile was found to be considerably increased due to the lowering of the lowest unoccupied molecular orbital (LUMO), and this was considered to be the reason why the inhibitors become bound with the enzyme irreversibly. The LUMO of aspartate, substrate of aspartate aminotransferase, is higher than those of the inhibitors in the free state, as well as in the pyridoxal-linked state. This difference in the energy of the molecular orbital between substrate and inhibitors was considered to be correlated with the difference in the complex-forming properties of these compounds toward the nucleophile in the enzyme.

Alanine Racemase↗
PubMed1979

Studies on the mechanism of the hypotensive action of SQ-14225, an angiotensin-converting enzyme inhibitor in anesthetized dogs.

Intravenous administration of SQ-14225, an angiotensin-converting enzyme inhibitor, to pentobarbital-anesthetized dogs resulted in significant decrease in the arterial blood pressure with no changes in the heart rate. Pressure-flow curves obtained in the perfused hind limb vasculature were shifted significantly to the right following SQ-14225 indicating a decrease in the hind limb vascular resistance. Neither the denervation of the hind limb nor bilateral nephrectomy prevented the decrease in the hind limb vascular resistance produced by SQ-14225 indicating that the vasodilator action of this agent was unrelated to either the sympathetic nervous system or the renal renin-angiotensin system. The reflex vasodilatation in the hind limb observed during the administration of pressor agents was significantly attenuated by SQ-14225. Similarly this agent also antagonized the reflex increases in the systemic blood pressure, hind limb perfusion pressure and heart rate observed during bilateral carotid occlusion. These results suggest that the hypotensive action of SQ-14225 in the pentobarbital-anesthetized dog may be unrelated to the renal renin-angiotensin system.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1978

Haemodynamics of orally-active converting enzyme inhibitor (SQ 14225) in hypertensive patients.

1. The haemodynamic effects of oral converting enzyme inhibitor (SQ 14225) were assessed in eight patients with severe essential or renovascular hypertension. 2. Mean arterial pressure fell (149 +/- 5 to 127 +/- 8 mmHg, P less than 0.02), because of a fall in total peripheral resistance (6.9 +/- 0.53 to 5.7 +/- 0.40 kPa 1(-1)s m2) without a significant change in cardiac index. Two of the eight patients were non-responders without pressure reduction or a haemodynamic change. Sodium restriction (10 mmol/day) while the same dose of SQ 14225 was continued further lowered arterial pressure (137 +/- 8 to 111 +/- 12 mmHg, P less than 0.05) through further resistance reduction (6.5 +/- 0.53 to 5.2 +/- 0.40 kPa 1(-1)s m2, P less than 0.05). 3. Haemodynamic responses to head-up tilt (increased heart rate and resistance, decreased cardiac index) were unaffected by SQ 14225 regardless of sodium intake. 4. The pattern of reduction in peripheral resistance, with unchanged cardiac index, was similar to that produced by vasodilators acting at both arteriolar and venular levels.

Adult↗
PubMed1978

Antihypertensive effect of the oral angiotensin converting-enzyme inhibitor SQ 14225 in man.

We investigated the antihypertensive effect of the angiotensin converting-enzyme inhibitor SQ 14225 in 12 hypertensive patients for periods of three to 24 weeks. Blood pressure decreased in all patients (from 177 +/- 8/110 +/- 2 to 136 +/- 6/88 +/- 2 mm Hg--mean +/- S.E.); oral doses ranged from 400 to 1000 mg daily. Concomitant effects noted were small increases in plasma potassium concentration and pulse rate. One patient experienced a transient febrile reaction. Plasma renin activity rose during treatment, plasma aldosterone decreased, and angiotensin-converting-enzyme activity was virtually eliminated. There was no significant correlation between pretreatment plasma renin activity and degree of blood-pressure fall with SQ 14225. The exact mechanisms contributing to the blood-pressure-lowering effect of this agent remain unclear. SQ 14225 is a promising new antihypertensive agent, effective in patients refractory to traditional medical therapy.

Administration, Oral↗
PubMed1979

Oral angiotensin-converting enzyme inhibitor in long-term treatment of hypertensive patients.

The antihypertensive effect of the orally active angiotensin-converting enzyme inhibitor captopril (SQ 14225) was assessed in 22 hypertensive patients of whom 17 were followed for periods ranging from 1 to 7 months. Of these, eight had essential hypertension, eight had renovascular hypertension, and six had hypertension associated with chronic renal failure. Blood pressure decreased markedly in all patients, including those with low renin levels. Nevertheless, the magnitude of blood pressure reduction correlated with the base-line plasma renin activity (r = 0.58, P less than 0.01). Increasing the dose of captopril from 25 to 200 mg did not enhance the amplitude of the antihypertensive effect but did increase its duration. Patients' blood pressure remained well controlled and free of side-effects with a maximal daily dose of up to 200 mg by mouth twice daily. Despite the blood pressure reduction, sodium excretion tended to increase, probably because of reduced aldosterone secretion. There was no evidence of orthostatic hypotension, and no escape from the antihypertensive effect was observed. These results indicate that chronic inhibition of the angiotensin-converting enzyme with an orally active compound offers a new, efficient, and well-tolerated approach to the treatment of hypertension.

Adult↗
PubMed1979

Reactive hyperreninemia in renovascular hypertension after angiotensin blockage with saralasin or converting enzyme inhibitor.

Baseline plasma renin activity and responses to saralasin and converting enzyme inhibitor SQ 20881 (teprotide) in 47 untreated patients with surgically correctable renovascular hypertension were compared to those in 100 patients with high- and normal-renin essential hypertension. All 32 renovascular patients on normal sodium intake had high renin-sodium profiles and renin values greater than or equal to 5 ng angiotensin I/mL.h, as compared to 20 of 64 with essential hypertension. Diagnostic discrimination was greatly enhanced by infusion of saralasin or SQ 20881, which elicited marked reactive hyperreninemia in 31 of 32 renovascular patients but in only two of 64 with essential hypertension. Reactive hyperreninemia appeared to be more a specific test for renovascular hypertension than depressor responses. Prior dietary sodium depletion abolished this specificity. The results suggest that after initial screening with renin measurements, testing with angiotensin blocking agents may be a useful secondary screening procedure for more invasive and definitive procedures.

Angiotensin II↗
PubMed1979

Treatment of moderate to severe hypertensive patients with an orally active converting-enzyme inhibitor.

Seventeen hypertensive patients were treated with captopril, an orally active inhibitor of converting-enzyme. All patients showed a fall in blood pressure (BP), although in some patients only after the addition of diuretics. In 2 patients a skin rash developed. One patient developed proteinuria. A renal biopsy revealed membranous glomerulopathy. Correlations were found between pretreatment plasma renin activity (PRA) and the decrease in BP, and between pretreatment PRA and the decrease in plasma aldosterone concentration (PAC). Filtration fraction (FF) fell, indicating a decrease in renal vascular resistance. Captopril decreased the sensitivity to exogenous angiotensin I (AI), dependent on the captopril dose used. The sensitivity to exogenous bradykinin increased impressively even on the lowest dose of the drug. These observations suggest extrapulmonary conversion of AI to angiotensin II (AII).

Administration, Oral↗
PubMed1979

A novel orally active converting-enzyme inhibitor YS 980: effects on blood pressure in spontaneously hypertensive rats.

1. The effects of long-term treatment with the angiotensin I converting-enzyme inhibitor YS 980 were examined in stroke-prone spontaneously hypertensive (sp-SH) rats. Development of hypertension was markedly blunted in the YS 980-treated animals. 2. Effective converting-enzyme inhibition was confirmed by significant increases in plasma angiotensin I (ANG I) and plasma renin concentration, inhibition of the pressor responses to intravenous ANG I and potentiation of the depressor responses to intravenous bradykinin. 3. Urinary free aldosterone excretion was decreased but no changes in urinary sodium and potassium excretion were observed. 4. The pressor responses to intravenous leucine-enkephalin were reduced. 5. The pressor responses to injection of ANG I and bradykinin into the lateral brain ventricle were unaltered. 6. We conclude that the antihypertensive action of YS 980 in sp-SH rats cannot be explained by the inhibition of the plasma renin-angiotensin system alone. Effects on other peptide systems must be considered.

3-Mercaptopropionic Acid↗
PubMed1979

Effect of an angiotensin converting enzyme inhibitor (SQ 14,225) on beta-adrenergic and angiotensin-induced thirsts.

The effect of acute administration of SQ 14,225, a new angiotensin converting enzyme inhibitor, on the drinking response of female rats administered either isoprenaline, angiotensin I, or angiotensin II was studied during 2 h after treatment. Administration of isoprenaline (25 micrograms/kg body wt) was accompanied by a significant increase in water intake when compared with saline-treated controls. Acute administration of a constant dose of isoprenaline (25 micrograms/kg body wt) and increasing doses of SQ 14,225 (5--50 mg/kg) was accompanied by a dose-related, linear decrease in water intake. Acute administration of either angiotensin I or angiotensin II (200 micrograms/kg body wt) was accompanied by a significant increase in water intake. The dipsogenic response to angiotensin II was not affected by acute administration of 35 mg SQ 14,225/kg body wt. However, at the same dose of SQ 14,225, angiotensin I-induced thirst was attenuated. Since isoprenaline-induced and angiotensin I-induced, but not angiotensin II-induced, thirsts are blocked by SQ 14,225, the results suggest that isoprenaline-induced thirst is mediated by way of the renin--angiotensin system.

Angiotensin I↗
PubMed1976

Response to angiotensins I and II and to AI-converting-enzyme inhibitor in a shark.

The spiny dogfish shark, which does not have renal juxtaglomerular cells, exhibits a strong pressor response to both angiotensin I and II. A nonapeptide, angiotensin I-converting-enzyme inhibitor, blocks the pressor response to angiotensin I in this fish. The pressor response to both angiotensin II and norepinephrine is completely blocked by the adrenergic blocking drug phentolamine.

Adrenergic alpha-Antagonists↗
PubMed1979

Effects of an orally active converting-enzyme inhibitor, SQ 14225, on pressor responses to angiotensin administered into the brain ventricles of spontaneously hypertensive rats.

1. Two hours after oral feeding of normotensive Wistar Kyoto rats with the converting-enzyme inhibitor SQ 14225 (1 and 10 mg/kg), an increase of angiotensin I plasma concentrations from 892 +/- 113 to 1660 +/- 167 and 2951 +/- 405 pg/ml was observed. 2. Administration of SQ 14225 with the drinking fluid overnight suppressed the pressor responses to intravenous angiotensin I, although the blood pressure increase after intravenous angiotensin II was not altered in normotensive and spontaneously hypertensive rats. No change of pressor effects after injections of angiotensin I and II into the brain ventricles was observed after oral SQ 14225. 3. Intracerebroventricular infusions of SQ 14225 in spontaneously hypertensive rats abolished the central pressor responses to angiotensin I. 4. The results show that SQ 14225 effectively blocked the conversion of endogenous and exogenous angiotensin I into angiotensin II in plasma, and the conversion of exogenous angiotensin I in brain. Under the conditions studied, SQ 14225 does not cross the blood-cerebrospinal fluid barrier in spontaneously hypertensive rats.

Administration, Oral↗