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PubMed1987

Evidence against a pressor role for vasopressin in spontaneous hypertension.

The hypothesis that the vasoconstrictor action of vasopressin may contribute to the development of hypertension in spontaneously hypertensive rats (SHR) was tested by chronic infusion of a specific antagonist of the vascular effects of vasopressin. From 4 to 13 weeks of age, SHR and Wistar-Kyoto rats (WKY) received subcutaneously either isotonic saline or the vasopressin pressor antagonist, d(CH2)5Tyr(Me)arginine vasopressin by osmopump. Systolic blood pressure was measured by tail cuff from 5 to 11 weeks of age. In SHR, the vasopressin analogue did not alter the rate or magnitude of increase in systolic blood pressure. In WKY, systolic blood pressure in the vasopressin analogue group was slightly reduced compared with the saline infusion values until 10 weeks of age (F1, 10 = 10.18, p = 0.008). At 12 to 14 weeks of age, all animals were prepared with indwelling arterial and venous catheters. Resting mean arterial pressure was not altered significantly by the vasopressin analogue infusion in either strain, but the response to an acute vasopressin infusion of 5, 15, or 50 ng/kg body weight was markedly attenuated by the analogue treatment, indicating that plasma levels of the vasopressin analogue were sufficient to block pressor effects of endogenous vasopressin. A bolus injection of the angiotensin II converting enzyme inhibitor teprotide (SQ 20881) resulted in a decrease in mean arterial pressure (p less than 0.05) that was comparable in all groups, and serum renin concentration was not elevated in the vasopressin analogue-treated rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

Acute renovascular hypertension in conscious dogs. Interaction of the renin-angiotensin system and sympathetic nervous system in systemic hemodynamics and regional blood flow responses.

The effects of acute renovascular hypertension on the sympathetic nervous system, regional blood flow and cardiac function were studied in conscious dogs submitted to renal artery occlusion by inflation of a cuff implanted previously around one renal artery. We then compared the alterations in plasma renin and catecholamine levels and in the various hemodynamic parameters induced by those maneuvers in intact dogs, to those in dogs pretreated with alpha- and beta-adrenergic receptor blockers. Subsequently, the converting enzyme inhibitor teprotide was administered to inhibit angiotensin formation in both experiments. Our results suggest that both the renin-angiotensin system and the sympathetic system contribute to the rise in blood pressure. The hemodynamic changes and alterations in regional blood flows accompanying this acute hypertension appear to be due mostly to the increase in plasma angiotensin, since prior adrenoceptor blockade only attenuated their magnitude but did not alter their direction. However, angiotensin-induced coronary vasoconstriction was observed only in adrenergically blocked but not intact animals, probably because of the protective effect of baroreceptor-mediated reflex sympathetic coronary vasodilation.

Acute Disease↗
PubMedDate not supplied

Reversal of experimental acute cerebral vasospasm by angiotensin converting enzyme inhibition.

We tested the hypothesis that cerebral arteriospasm developing after rupture of a subarachnoid aneurysm may be due to the vasoconstrictor effect of locally generated angiotensin II. Ten dogs had subarachnoid hemorrhage simulated by intracisternal introduction of 2 ml autologous blood, and were followed by cineangiography. Thirty minutes later, when acute arteriospasm was established, seven dogs received injection of the angiotensin converting enzyme inhibitor teprotide and 3 control dogs received normal saline. Repeat angiography at 30 and 90 minutes after injection, showed total or partial release of spasm in the experimental dogs and no change or further intensification of spasm in the control animals. We concluded that angiotensin converting enzyme inhibition may be a potentially useful approach for the reversal or prevention of cerebral arteriospasm after subarachnoid hemorrhage.

Acute Disease↗
PubMed1983

Interference by inhibitors of the renin-angiotensin system with neurogenic vasoconstriction.

In the pithed rat preparation captopril, enalapril, teprotide and saralasin given intravenously attenuated pressor responses to both spinal sympathetic nerve stimulation and exogenous noradrenaline, indicating that angiotensin has a potent adrenergic facilitating action. Bi-lateral nephrectomy abolished the effects of captopril on nerve stimulation but responses to noradrenaline were still inhibited following nephrectomy, indicating that part of the post-junctional actions of captopril might not be angiotensin dependent. Both phenylephrine and clonidine are also inhibited by captopril in the pithed rat. It is thus not clear whether captopril is interacting with post-junctional alpha 1- or alpha 2-adrenoceptors. Vasoconstrictor responses to nerve stimulation are greater in SHR than WKY and captopril is more effective at inhibiting responses in the SHR than it is in WKY. These interactions between captopril and the sympathetic nervous system could explain the effectiveness of ACE inhibitors as antihypertensive agents.

Animals↗
PubMed1981

Reversal of experimental delayed cerebral vasospasm by angiotensin-converting enzyme inhibition.

Delayed cerebral vasospasm is an important determinant of the clinical outcome after subarachnoid hemorrhage, but its prevention and treatment has met with limited success. Since cerebral arteries were found to be sensitive to the vasoconstrictor effect of angiotensin II, the possibility of angiotensin's contribution to this vasospasm was investigated. Delayed cerebral arterial spasm was documented angiographically 72 hours after introduction of blood in the subarachnoid space of dogs. Following injection of the angiotensin-converting enzyme inhibitor, teprotide, repeat cineangiograms at 30, 60, and 90 minutes demonstrated partial or total release of spasm of the basilar artery and its branches. It is concluded that angiotensin II participates in the delayed cerebral vasospasm after hemorrhage, and that angiotensin inhibition may release the spasm and prevent cerebral ischemia.

Angiography↗
PubMed1979

Converting enzyme inhibition in hypertensive emergencies.

The diagnostic and therapeutic value of the angiotensin converting enzyme inhibitor teprotide (SQ 20881) was assessed in 18 patients with hypertensive emergencies. Mean blood pressure fell 31 +/- 18 mm Hg in the 10 subjects who responded to 1 mg/kg body weight administered intravenously, whereas it fell 5 +/- 3 mm Hg in the eight nonresponders. In patients who had received no previous drug treatment, log baseline plasma renin activity and change in mean blood pressure after SQ 20881 correlated significantly (r = 0.651, P less than 0.05). After acute therapy with SQ 20881, the patients who had a satisfactory response to the drug were treated with propranolol and a relatively normal sodium intake (88 meq/day). Nonresponders were treated with diuretics and sodium restriction (10 meq/day), and intermediate responders were given combination therapy. Mean blood pressure responded favorably within 24 h to the chosen regimen for each group from 152 +/- 47 to 102 +/- 31 mm Hg. SQ 20881 allows prompt evaluation of the role of renin in hypertensive emergencies and permits early choice of appropriate therapy based on the prevailing mechanism.

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↗
PubMed1991

Inhibition of human platelet aggregation by endothelium-derived relaxing factor, sodium nitroprusside or iloprost is potentiated by captopril and reduced thiols.

We have examined whether inhibitors of angiotensin-converting enzyme-containing sulfhydryl groups such as, captopril (CPT) or SQ 14,534, the nonsulfhydryl-containing angiotensin-converting enzyme inhibitors, teprotide (TPR) or enalaprilat (ENA) and other structurally unrelated sulfhydryl-containing compounds, N-2-mercaptopropionylglycine (MPG) or N-acetyl-L-cysteine (NAC), could influence platelet aggregation. Incubation of human washed platelets with CPT, SQ 14,534, TPR, ENA, MPG or NAC (0.1-0.5 mM) did not modify their aggregatory responses to thrombin. However, the antiaggregatory properties of endothelial cells cultured from bovine aorta were potentiated by CPT, SQ 14,534, MPG or NAC but not by TPR or ENA (40-100 microM). CPT (100-500 microM) or NAC (50-200 microM) but not ENA (100 and 500 microM) also potentiated the antiaggregatory effects of sodium nitroprusside (1.0 microM) or iloprost (0.2 nM). The ability of the thiol-containing compounds (CPT or NAC) to potentiate the antiaggregatory effects of sodium nitroprusside or iloprost was not associated with an elevation of platelet cyclic GMP or cyclic AMP levels, respectively. Thus, CPT and other sulfhydryl-containing compounds can synergize with antiplatelet compounds, thereby enhancing the ability of endothelial-derived autocoids to inhibit platelet aggregation. The mechanism responsible for this potentiating effect of thiols on platelet aggregation is not known, but may relate to the ability of thiol-containing compounds to act as intracellular scavengers of oxygen-derived free radicals.

Acetylcysteine↗
PubMed1983

Converting enzyme inhibition to identify and treat renin-mediated or sodium-volume related forms of increased peripheral resistance in hypertension and in congestive heart failure.

Ten years of experience with three different converting enzyme inhibitors (CEI; teprotide, captopril and enalapril) in over 300 hypertensive patients reveals that CEI act largely to block renin-angiotensin mediated vasoconstriction. Thus, their effectiveness or lack of it is predicted by the baseline plasma renin measurement. Accordingly, responses to these pharmacological agents can be used to identify and quantify renin-mediated vasoconstriction in the spectrum of hypertensive diseases. The converse is also generally true. Patients failing to respond to CEI exhibit low renin values and their increased peripheral resistance appears related to other mechanisms, possibly involving a subtle increase in total body sodium. Thus, low renin states such as low-renin essential hypertension, primary aldosteronism, and anephric man exhibit little or no response to CEI. The relationship between the renin system activity and effectiveness of CEI reflects a specific interference with a particular pathogenic mechanism which is further supported by the fact that two other types of renin system inhibitors (beta-blockers and saralasin) are similarly effective or ineffective according to the operant renin profile also by studies in patients with congestive heart failure without hypertension in whom the same relationships can be demonstrated. Like hypertensives, heart failure patients exhibit a broad spectrum of renin activity values, and their pretreatment renin levels predict the responses to CEI. We have also found that plasma renin values in heart failure are dependent on sodium intake. When salt is administered, renin falls and patients then become unresponsive to CEI.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1980

Angiotensin inhibitors for hypertension.

Inhibition of the angiotensin-converting enzyme emerges as a new promising approach to the treatment of hypertension. The intravenously administered teprotide appears to be suitable as a diagnostic test and for initial treatment of certain hypertensive emergencies. The oral inhibitor captopril is effective for chronic maintenance of blood pressure control in various types of hypertension but has been associated with a number of adverse reactions.

Administration, Oral↗
PubMed1982

[Characteristics, assay and semeiologic value of angiotensin converting enzyme (ACE)].

Serum angiotensin conversion enzyme (serum ACE) is a dipeptidylcarboxypeptidase which activates angiotensin I to angiotensin II and inactivates bradykinine. It is a glycoprotein with an MW of 126,000 to 480,000. It is produced by all endothelial cells, and is located on the cell membrane. It is inhibited by EDTA (chelator of Zn-- cofactor), teprotide (snake venom nonapeptide) and captopril. Estimation of ACE has greatly benefitted from the use of synthetic tripeptides. An example is the method of Cushman and Cheung using hippuryl histidyl leucine. A raised serum ACE level in sarcoidosis has been demonstrated by Liebermann in 1975. The diagnostic value is limited by the existence of high levels in other pulmonary diseases (asbestosis, silicosis). Serum ACE levels in sarcoidosis are all higher when the disease is diffuse from a pulmonary and extrapulmonary standpoint. They decrease when the disease regresses spontaneously and rise if it worsens. Radiological improvement in pulmonary sarcoid lesions under the influence of corticosteroid therapy is accompanied by a fall in serum ACE levels. Persistence of this normalization as the dose is decreased is a favourable sign, whilst the reappearance of a high serum level may either reflect simple and isolated biological "rebound" or may accompany a recurrence of signs of the disease. Serum ACE measurement is thus an important factor in the surveillance of cases of treated sarcoidosis when the dose of corticosteroids is to be reduced.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1982

Converting enzyme inhibition: implications for renal perfusion and function.

1. Substantial but circumstantial evidence has suggested an important role for angiotensin in the control of renal perfusion and function. A local, intrarenal action may have been angiotensin's first role in phylogeny, additional actions on the adrenal and the systemic vasculature having arisen later. 2. Converting enzyme inhibitors, both teprotide and captopril, induce a potentiated renal vascular response in patients with essential hypertension, associated with a consistent increase in sodium excretion and occasionally an increase in glomerular filtration rate. In patients with advanced congestive heart failure resistant to other vasodilators, a similar triad occurs. 3. It is not yet clear in which settings the renal response to converting enzyme inhibition reflects a reduction in angiotensin II formation thus implicating the reninangiotensin system in the pathogenesis; or an additional action, such as a potentiation of the local actions of bradykinin or enhanced prostaglandin formation. 4. Under some circumstances, especially where a qualitatively and quantitatively similar response occurs to angiotensin antagonists and converting enzyme inhibitors or where an angiotensin antagonist prevents an additional response to a converting enzyme inhibitor, the specific action of the converting enzyme inhibitor of angiotensin II formation is clearly responsible. Unfortunately, for most responses in animal models and all responses in patients such rigorous evidence is not yet available.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1985

The design and properties of N-carboxyalkyldipeptide inhibitors of angiotensin-converting enzyme.

Angiotensin-converting enzyme inhibitors promise to make important therapeutic contributions to the control of hypertension and congestive heart failure. The nonapeptide teprotide was the first of these inhibitors to be tested clinically. It was followed by orally active inhibitors, captopril in 1977 and enalapril in 1980. The latter is representative of a new design for the inhibition of metallopeptidases and is the subject of this review. The best of the N-carboxyalkyldipeptide inhibitors inhibits angiotensin-converting enzyme with a Ki of 7.6 X 10(-11) M. This compound is the most potent competitive inhibitor of a metallopeptidase yet to have been reported. The basis of this high potency is beginning to be understood and in part is considered to involve precisely arranged multiple interactions within the enzyme active site. X-ray crystallography of a thermolysin-inhibitor complex has been achieved. Assuming that similar interactions within the active site of angiotensin-converting enzyme are mechanistically probable, the authors hypothesize the binding of enalaprilat to converting enzyme as shown in Figure 24. Such interactions are consistent with kinetic studies (Section V) with the understanding that binding to the enzyme is not sensitive to the inhibitor's state of NH protonation. The reason for this surprising conclusion has not been established. Perhaps counterbalancing factors are involved in the energetics of binding or there may be compensating adjustments made in the enzyme which permit NH protonated and nonprotonated inhibitor to bind equally well. Figure 24 also summarizes present understanding of the conformation of enalaprilat when bound to angiotensin-converting enzyme. From studies on conformationally defined analogs of enalaprilat, it seems likely that the Ala-Pro segment of enalaprilat binds in a conformation that is close to a minimum energy conformer. This situation no doubt contributes to the potency of enalaprilat, since little binding energy would be needed to induce conformational changes in this part-structure of enalaprilat when it is bound to the enzyme. The phenethyl group of enalaprilat is believed to be near the alpha-hydrogen of the L-Ala residue in the enzyme-inhibitor complex. However, the synthesis of conformationally restricted analogs to establish this point has not yet been reached. The N-carboxyalkylpeptide design was developed from Wolfenden's collected product inhibitors of carboxypeptidase-A. Whether or not N-carboxyalkyldipeptides should be classified as collected product or transition state inhibitors is unclear.(ABSTRACT TRUNCATED AT 400 WORDS)

Aldosterone↗
PubMed1989

Selective expression of des-Arg9-BK sensitive (B1) receptors in vivo and in vitro by angiotensin converting enzyme inhibitors.

LPS (E. Coli), captopril, enalapril, teprotide and BK-infusion induced after 18 h in rabbits an increased hypotensive response to the selective B1-receptor agonist des-Arg9-BK. A similar selective increase in responsiveness and sensitivity of the in vitro aortic strip to des-Arg9-BK taken from pretreated animals was also seen. These results suggest that angiotensin converting enzyme inhibitors may elevate endogenous kinin levels which may contribute towards the inflammatory side-effects seen with this group of drugs.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

Renal hemodynamics in essential and renovascular hypertension. Influence of captopril.

Among vascular beds, that of the kidney is especially responsive to angiotensin II, perhaps a reflection of the fact that the renin-angiotensin axis is normally a volume-control rather than a pressure-control system. The dose of angiotensin required to induce renal vasoconstriction in a normal subject receiving a typical, liberal sodium intake, for example, is about an order of magnitude lower than that required to induce a pressor response. Indeed, compelling arguments can be made for a local, intrarenal role as angiotensin's first action in phylogeny, with additional cardiovascular and endocrine responses arising later. In patients with essential hypertension, in whom renal vascular tone is commonly increased, converting enzyme inhibitors such as teprotide and captopril induce a potentiated acute renal vascular response: renal blood flow increases more than it does in normal subjects. The result is a consistent, early increase in sodium excretion and an occasional increase in glomerular filtration rate. Reduced aldosterone release consequent to the block of angiotensin II formation also contributes to the natriuresis and results in positive potassium balance. With long-term therapy, renal function tends to be very well maintained. In renal artery stenosis the situation is more complex: as perfusion pressure distal to the stenosis falls, typically afferent arteriolar dilatation exists and glomerular capillary pressure tends to be maintained by an increase in postglomerular resistance. To the extent that this increase is angiotensin-mediated, suppression of angiotensin formation with captopril can reduce glomerular capillary pressure and thus filtration rate. This is well tolerated in the patient with unilateral stenosis and a healthy contralateral kidney, but can provoke renal failure when the stenosis is bilateral or involves a solitary kidney. The available evidence suggests that the converting enzyme inhibitor's influence on the kidney primarily reflects reduced angiotensin II formation, although reduced kinin degradation or increased prostaglandin synthesis may also have an influence. Whatever the mechanism responsible for the renal response, there are compelling reasons for suspecting that the salutary action of captopril on the kidney makes a substantial contribution to its over-all efficacy in the treatment of hypertension.

Acute Kidney Injury↗
PubMed1983

[3H]Captopril binding to membrane associated angiotensin converting enzyme.

[3H]Captopril binding to membrane fractions of rat tissues is saturable and reversible with a KD of 2.4 nM. [3H]Captopril binding and angiotensin converting enzyme measured with hippuryl-L-histidine-L-leucine are distributed in parallel between different tissues and brain regions, with highest levels in the choroid plexus, lung and corpus striatum. Captopril, N-(1(S)-carboxy-3-phenyl-propyl)-L-alanyl-L-proline, N-(1(S)-carboxy-3-phenyl-propyl)-L-lysyl-L-proline, teprotide, thiorphan and S-acetylcaptopril each have similar potencies for inhibition of [3H]captopril binding and of angiotensin converting enzyme. These data strongly indicate that [3H]captopril binds selectively to angiotensin converting enzyme. [3H]Captopril binding evaluation should help clarify the localization and function of angiotensin converting enzyme and assist in defining pharmacologic actions of captopril.

Animals↗