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University of Groningen Risk Factors, Endothelial Function, and Clinical University of Groningen Risk factors, endothelial function, and clinical outcome after coronary bypass surgery Voors, Adriaan Alexander IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 1997 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Voors, A. A. (1997). Risk factors, endothelial function, and clinical outcome after coronary bypass surgery. s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 03-10-2021 Chapter 10 Drug differences between ACE-inhibitors in experimental settings and clinical practice. Adriaan A. Voors1,2, J.Herre Kingma1,2, and Wiek H. van Gilst1 1. Department of Clinical Pharmacology, University of Groningen, the Netherlands. 2.Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands : J Cardiovasc Risk 1995;2:413-22. 98 chapter 10 Summary In recent years years, growing evidence has suggested a beneficial effect from the use of ACE-inhibitors after myocardial infarction. Since important differences between structure and effects of the various ACE-inhitors exist, differences in outcome can be expected. This review discusses the structural, pharmacodynamic and pharmacokinetic differences between ACE-inhibitors administered after myocardial ischemia, both in experimental settings and in clinical practice. Introduction In the first days after acute myocardial infarction, the renin-angiotensin system (RAS) is activated.1 In some patients, this activation continues, which may cause harmful effects. Angiotensin-converting enzyme (ACE)-inhibitors have been described to influence this activation beneficially. Therefore, administration of ACE-inhibitors after acute myocardial infarction could lead to a reduction in morbidity and fatal events. Indeed, experimental studies have revealed protective effects of ACE-inhibitors after myocardial ischemia.2,3 However, there has been considerable variability in the type, structure and dose of the ACE-inhibitor used. Studies comparing the effects of different ACE- inhibitors after myocardial ischemia have consequently resulted in controversial outcomes. In the experimental setting, some studies showed equally beneficial effects for all drugs tested,4-7 other studies did not find any beneficial effects of ACE-inhibitors after myocardial infarction,8,9 and some studies reported only beneficial effects for ACE- inhibitors containing a sulphydryl-group.10 The majority of clinical studies on the effects of ACE-inhibitors after acute myocardial infarction have resulted in decreased morbidity and mortality. However, when ACE- inhibitors were started early after acute myocardial infarction in a non-selected patient group, the results remained controversial.11 ACE-inhibitors after acute myocardial infarction have been postulated to act through different mechanisms. Most of their effects contribute substantially to the risk of subsequent clinical events.12 Because of this heterogeneity, the overall clinical outcome may be a result of both beneficial and harmful aspects. Besides the use of different ACE-inhibitors and the heterogeneous effects of these drugs, there may be other explanations for the contradictory results: for example, differences in experimental settings. In clinical studies, the selection of patients and the time at which the therapy was started could have seriously affected the outcome. This review discusses structural, pharmacodynamic and pharmacokinetic differences between various ACE-inhibitors in view of the contradictory results of ACE-inhibitors administered after myocardial infarction. differences between ACE-inhibitors 99 Local vs. Circulating RAS It was initially thought that the RAS was an enzymatic cascade that acted only as a circulating endocrine system. Circulating renin is formed by the juxta-glomerular cells of the kidney and converts angiotensinogen to angiotensin I. Finally, in the plasma, ACE cleaves off two aminopeptides, rendering the effector angiotensin II. However, studies have demonstrated that chronic administration of ACE-inhibitors lowers blood pressure when plasma renin activity is not elevated,13 or even low, as in anephric subjects.14 Also, in asymptomatic cardiac dysfunction, increased plasma renin activity was either not associated with clinical outcome,15 or not related to the beneficial effects of the ACE- inhibitor captopril.16 Thus, the clinical effects of ACE-inhibitors might not be related to the activity of the plasma renin. Meanwhile, renin-like enzymes were found in the heart, the blood vessels and many other tissues.17 These findings led to the hypothesis that ACE inhibition may additionally act through inhibition of tissue RAS, rather than just inhibition of the circulating RAS. Cohen and Kurz18 were the first to describe how, in spontaneously hypertensive rats, administration of an ACE-inhibitor could inhibit ACE in various tissues, including the vascular wall. They also demonstrated that the antihypertensive action was associated with persistent ACE inhibition in the kidney and the vascular wall, whereas it was not related to ACE inhibition in the plasma. Additionally, Johnston et al.19 and Hirsch et al.20 reported an increased activation of tissue cardiac ACE after experimental myocardial infarction, suggesting that some of the harmful effects might originate from local activation of the RAS. Therefore, based on these data, it seems reasonable to conclude that, after myocardial infarction, the effects of ACE-inhibitors on the local RAS may be more important than the effects on the circulating RAS. Consequently, tissue penetration of different ACE-inhibitors is probably a crucial determinant of each drug's ability to inhibit ACE in the tissue, and could be more important than their kinetic properties in the plasma. Structural differences between ACE-inhibitors The ACE-inhibitors can be divided in three groups21-23: (1) ACE-inhibitors that contain a sulphydryl-group, such as captopril, zofenopril and alacepril; (2) carboxyl containing compounds such as enalapril, ramipril, perindopril, cilazapril and quinapril; and (3) the phosphorus containing inhibitors, such as fosinopril and ceranapril. In general, carboxyl containing inhibitors are more potent than captopril, but may have a limited bioavailability.24 This problem has been largely overcome by developing prodrugs, which have to be converted into the active form. The potencies of the relatively new class of phosphorus containing ACE-inhibitors are comparable with captopril but they have a longer duration of action. Independent of their ACE inhibiting property, the sulphydryl-containing inhibitors may exert cardiac effects due to the presence of the thiol moiety. It has been suggested that the sulphydryl group acts as a scavenger of free radicals and/or as antioxidant agent. These actions may play an important role after myocardial infarction because of their beneficial effects on 100 chapter 10 reperfusion-induced depression of contractility and reperfusion arrhythmias.25,26 Another effect of the sulphydryl group is vasodilatation, either by a direct effect or by potentiation of nitrovasodilatators.27,28 The variation in lipophilicity between ACE- inhibitors might affect their ability to inhibit tissue ACE. Single oral doses of captopril, fosinopril and particularly zofenopril were found to produce striking and long-lasting inhibition of cardiac ACE, whereas equivalent doses of ramipril and enalapril only induced minimal inhibition.29 This selective inhibition was confirmed by Frohlich and Horinaka,30 when they compared effects of six ACE-inhibitors on cardiovascular structure and function and systemic hemodynamics in rats. Although all ACE-inhibitors (except quinapril) reduced ventricular mass, pumping ability remained unchanged at the reduced pressure loads with both quinapril and captopril. Pumping ability was diminished with CGS-16617, enalapril, and utibapril, whereas the performance curve improved with cilazapril. Whether these dissociated responses were due to pharmacodynamic (e.g., enzyme binding) or pharmacokinetic differences (e.g., lipophilicity), remains uncertain. Differences in tissue penetration between ACE- inhibitors will mainly depend on molecular size and lipophilicity. However, differences between ACE-inhibitors in tissue ACE inhibition are also due to different enzyme binding properties. Other pharmacokinetic characteristics of different ACE-inhibitors might also be important, such
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