High tissue affinity angiotensin-converting enzyme inhibitors improve endothelial function and reduce infarct size
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Enalaprilat
Endothelial Dysfunction
Angiotensin (Ang) I converting enzyme (ACE) inhibitors represent a major advance in the treatment of congestive heart failure, and tissue, rather than circulating ACE, may be their major site of action. However, assessments of tissue ACE inhibition in treated patients has not always supported this contention. In these studies, ACE activity was measured in homogenates of sampled tissue by biochemical methods. In the present study, using a model system, we have examined the validity of these tissue-sampling methods. Functional ACE activity was determined by comparing positive inotropic responses to [Pro10]Ang I in either vehicle-pretreated or ACE inhibitor-pretreated papillary muscles. [Pro10]Ang I elicits a response, which is entirely dependent on ACE-mediated conversion to Ang II. The ACE inhibitors studied were captopril, enalaprilat, lisinopril, and quinaprilat. In a parallel study, papillary muscle ACE activity was also measured in homogenates using [125I]MK-351A (a radiolabeled ACE inhibitor) binding. The studies indicate that the tissue-sampling method significantly underestimated functional ACE inhibition in hamster papillary muscles (p < 0.001). Kinetic studies indicated that the half-time for the dissociation of [3H]enalaprilat and [3H]lisinopril from hamster ventricular ACE was 4.5 and 6.2 minutes, respectively. The dissociation of [3H]quinaprilat was biphasic (half-time, 47 and 90 minutes), indicating that the two active sites of somatic ACE differ in their ability to bind to this inhibitor. The rapid rate of ACE inhibitor dissociation suggests that, during the time taken to assay ACE activity biochemically, the enzyme becomes "disinhibited," leading to an underestimation of functional ACE inhibition. ACE inhibitor dissociation rates were partially predictive of the duration of functional ACE inhibition in papillary muscles; other factors that appeared to contribute were "tissue trapping" of the inhibitor and de novo synthesis of ACE in papillary muscles. Quantification of tissue ACE inhibition and its relation to drug efficacy must, therefore, involve a careful consideration of these factors to avoid artifacts in clinical decision making and in assessments of pathogenic mechanisms involved in congestive heart failure.
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SUMMARY 1. Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II, and also metabolizes bradykinin‐(1–9) to bradykinin‐(1–7) and bradykinin‐(1–7) to bradykinin‐(1–5). Increases in endogenous kinin levels may contribute to the therapeutic effects of ACE inhibitors. 2. ACE inhibitors increase vascular levels of both bradykinin‐(1–9) and its ACE cleavage product bradykinin‐(1–7), at doses below the threshold for ACE inhibition, leading to the proposal that ACE inhibitors may also inhibit a non‐ACE kininase which cleaves both kinin peptides; this non‐ACE kininase may be the major pathway of kinin metabolism in the vasculature and some other tissues. 3. In support of this proposal, ACE inhibitors potentiate bradykinin‐(1–9) effects at doses which have little or no effect on ACE activity, as indicated by angiotensin I conversion to angiotensin II. ACE inhibitors also potentiate the actions of ACE‐resistant kinin analogues, which may be susceptible to metabolism by a non‐ACE kininase. 4. Identification and characterization of the putative non‐ACE kininase which is inhibited by ACE inhibitors may reveal novel approaches to the tissue‐specific modulation of kinin levels.
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Angiotensin converting enzyme (ACE) inhibitors have offered new perspectives in the treatment of hypertension. The development of new ACE inhibitors such as ramipril provides an opportunity to improve the knowledge on this class of drug, and to optimize the benefit/risk ratio for the patient. Ramipril was selected among several analogs because of its unique physicochemical properties. It is a nonsulfhydryl ACE inhibitor, and after oral absorption it is transformed in the liver into its active metabolite ramiprilat. which is at least 23 times more lipophilic than enalaprilat. Furthermore, the in vitro affinity of ramiprilat for the enzyme is 7 times higher than for enalaprilat and 47 times higher than for captopril. The ramiprilat-ACE complex is therefore very stable and dissociates 6 times more slowly than the enalaprilat-ACE complex and 22 times more slowly than the captopril-ACE complex. Ramipril possesses a favorable pharmacokinetic profile as a consequence of its physicochemical properties: its high potency allows the use of very low doses, and the slow dissociation of the ramipril-ACE complex explains the long duration of its action, permitting a once-daily treatment. Dose-finding studies have confirmed that very low doses of ramipril–2.5 mg once a day–can be used as a first-step treatment of hypertension. This dose can be increased up to 5 mg, and if necessary a low dose of a diuretic can be added. Using this therapeutic scheme, ramipril normalized blood pressure, insuring that each patient receives the smallest effective dose. Inhibition of the tissue renin-angiotensin system by ramipril has been described in recent studies on animal models. The effects of ramipril on the target organs of hypertension have been compared to those of other ACE inhibitors: possibly due to its lipophilicity, ramipril inhibits the renin-angiotensin system in the heart, kidney, and vascular wall, and the local production of angiotensin II is decreased by the treatment. In clinical trials, a rapid regression of cardiac hypertrophy was shown in hypertensive patients. Furthermore, ramipril is able to exert an antivaso-constrictor effect during infusion of angiotensin I in the brachial artery of healthy volunteers. Ramipril can also decrease blood pressure in binephrectomized hypertensive patients despite the absence of renin secreted by the kidney. These results provide indirect evidence that ramipril may exert an inhibitory effect on tissue renin-angiotensin systems in humans.
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To determine the short-term effects of angiotensin-converting enzyme (ACE) inhibition on hemodynamics and circulating levels of norepinephrine, angiotensin, and bradykinin, responses to enalaprilat and perindoprilat were examined at doses of 0.03, 0.3, and 1 mg/kg in permanently instrumented conscious dogs with pacing-induced heart failure (right ventricular pacing, 240-250 beats/min, 3 weeks). All doses of the two inhibitors produced similar decrease in mean aortic pressure and increase in cardiac output. Neither inhibitor affected plasma norepinephrine level. Both compounds induced a similar 60-80% decrease in blood angiotensin II level, a similar two- to eightfold increase in blood angiotensin I level, and a 80-95% decrease in the angiotensin II/angiotensin I ratio. There were also a fourfold to 10-fold increase in blood bradykinin-(1-9) level, a twofold increase in blood bradykinin-(1-7) level, and a 70-85% decrease in bradykinin-(1-7)/bradykinin-(1-9) ratio. In addition, the changes in total peripheral resistance induced by the two ACE inhibitors were weakly but significantly correlated with the changes in blood angiotensin II or blood bradykinin-(1-9). Thus whatever the specificity of enalaprilat and perindoprilat, both inhibitors produced similar acute hemodynamic effects in dogs with heart failure, which was associated with marked decrease in circulating angiotensin II level and increase in bradykinin-(1-9) level. This study, which measures for the first time in heart failure the blood bradykinin level after ACE inhibitors, indicates, in concert with angiotensin II reduction, a role for increased bradykinin-(1-9) level in mediating short-term hemodynamic effects of ACE inhibition in this model of heart failure.
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After oral administration, ramipril, a nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor, is transformed in the liver into its active metabolite ramiprilat. Because of its pentane ring it is at least 23 times more lipophilic than enalaprilat. The in vitro affinity for ACE is 7 times higher than for enalaprilat and 47 times higher than for captopril. The ramiprilat-ACE complex is therefore very stable and dissociates 6 times more slowly than the enalaprilat ACE complex and 72 times more slowly than the captopril ACE complex. Consequently, ramipril is pharmacologically more potent and has a longer duration of action than enalapril and captopril. The blood pressure lowering effect of ACE inhibitors is attributed to the decrease in angiotensin II in serum and locally in target organs of hypertension: heart, vessel wall, kidney and brain. Inhibition of tissue renin-angiotensin system by ramipril has been described in target organs of hypertension in animal models and in clinical studies. Possibly due to its high lipophilicity, and strong affinity to the converting enzyme a better tissue penetration and a more pronounced local ACE inhibition in the target organs has been observed, as compared to other ACE inhibitors. In a preliminary investigation a direct action of ramipril on the tissue RAS in hypertensive patients could also be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)
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Clinical Pharmacology & Therapeutics (1996) 59, 140–140; doi: 10.1038/sj.clpt.1996.61
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Angiotensin converting enzyme (ACE) inhibitors have offered new perspectives in the treatment of hypertension. The development of new ACE inhibitors such as ramipril provides an opportunity to improve the knowledge on this class of drug, and to optimize the benefit/risk ratio for the patient. Ramipril was selected among several analogs because of its unique physicochemical properties. It is a nonsulfhydryl ACE inhibitor, and after oral absorption it is transformed in the liver into its active metabolite ramiprilat, which is at least 23 times more lipophilic than enalaprilat. Furthermore, the in vitro affinity of ramiprilat for the enzyme is 7 times higher than for enalaprilat and 47 times higher than for captopril. The ramiprilat-ACE complex is therefore very stable and dissociates 6 times more slowly than the enalaprilat-ACE complex and 22 times more slowly than the captopril-ACE complex. Ramipril possesses a favorable pharmacokinetic profile as a consequence of its physicochemical properties: its high potency allows the use of very low doses, and the slow dissociation of the ramipril-ACE complex explains the long duration of its action, permitting a once-daily treatment. Dose-finding studies have confirmed that very low doses of ramipril--2.5 mg once a day--can be used as a first-step treatment of hypertension. This dose can be increased up to 5 mg, and if necessary a low dose of a diuretic can be added. Using this therapeutic scheme, ramipril normalized blood pressure, insuring that each patient receives the smallest effective dose. Inhibition of the tissue renin-angiotensin system by ramipril has been described in recent studies on animal models.(ABSTRACT TRUNCATED AT 250 WORDS)
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