Summary
The effects of oral zofenopril pretreatment were investigated in a chronic closed-chest pig model of ischemia and reperfusion. Pigs (25–35 kg) were pretreated orally with zofenopril (15 mg/day) on the 2 days prior to ischemia, which was evoked by the inflation of a catheter balloon in the left anterior descending coronary artery over 45 minutes. The catheter was then removed and the myocardium was reperfused. After 2 weeks, infarct properties were assessed by signal averaging of the body surface electrocardiogram and the inducibility of malignant ventricular tachyarrhythmias was tested with a programmed electrical stimulation protocol.
A significant increase in the pressure-rate product (43±11%, mean±SEM), indicating the oxygen demand of the heart, was prevented by zofenopril (19±8%, p<0.05). Zofenopril reduced the peak efflux of adrenaline (1302±213 vs. 3201±760 pg/ml; p<0.05), noradrenaline (402±54 vs. 902±282 pg/ml; p<0.05), and of the adenosine catabolites inosine and hypoxanthine (56±4 vs. 78±9, pg/ml; p<0.05) in the coronary venous effluent. The efflux of the cytoplasmatic enzyme creatine phosphokinase was not significantly reduced after zofenopril (p=0.08). No difference in plasma renin levels between the groups were found. After 2 weeks, late potentials were found only in the surviving animals from the untreated group, i.e., the voltage vector magnitude was more reduced, and a prolongation of the QRS duration and of the terminal low-amplitude part of the high-frequency QRS were found. Moreover, zofenopril had caused a significant reduction of the inducibility of sustained ventricular tachyarrhythmias.
These findings support the view that catecholamine and purine efflux, and an adverse increase in the oxygen demand during early reperfusion are reduced by zofenopril pretreatment, leading to a higher electrophysiologic stability of the subsequently developed infarct after 2 weeks.
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References
Yusuf S. Interventions that potentially limit myocardial infarct size: Overview of clinical trials.Am J Cardiol 1987;60:11A-7A.
Sherry S. Tissue-plasminogen activator (t-PA). Will it fulfill its promise?N Engl J Med 1985;313:1014–1017.
Gruppo Italiano per lo Studio della Streptochinasi Nelli Infarto Miocardio (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction.Lancet 1986;1:397–401.
Nayler WG, Elz JS. Reperfusion injury: Laboratory artifact or clinical dilemma.Circulation 1986;74:215–221.
Kersschot I, Brugada P, Ramental M, et al. Effects of early reperfusion in acute myocardial infarction on arrhythmias induced by programmed stimulation. A prospective randomized study.J Am Coll Cardiol 1986;7:1234–1242.
van Gilst WH, Terpstra JA, de Langen CDJ. Ventricular arrhythmias and purine loss upon reperfusion of ischemic myocardium: Comparison of ZK 36 374 and diltiazem. In: Schrör K, ed.Prostaglandins and other eicosanoids in the cardiovascular system. Basel: Karger, 1985:207–212.
Forman MB, Puett DW, Virmani R. Endothelial and myocardial injury during ischemia and reperfusion: Pathogenesis and therapeutic implications.J Am Coll Cardiol 1989;13:450–459.
Hearse DJ. The protection of the ischemic myocardium: Surgical success versus clinical failure?Progr Cardiovasc Dis 1988;30:381–402.
Braunwald E. The path to myocardial salvage by thrombolytic therapy.Circulation 1987;76(Suppl 2):II2-II7.
Rochette L, Ribout C, Belichard P, et al. Protective effect of angiotensin converting enzyme inhibitors (CEI): Captopril and perindopril on vulnerability to ventricular fibrillation during myocardial ischemia and reperfusion in the rat.Clin Exper Hypertension Ther Pract A 9(2&3):365–368.
de Graeff PA, de Langen CDJ, van Gilst WH, et al. Protective effects of captopril against ischemia/reperfusion-induced ventricular arrhythmias in vitro and in vivo.Am J Med 1988;84(Suppl 3A):67–74.
Linz W, Schölkens BA, Han YF. Beneficial effects of the converting enzyme inhibitor, ramipril, in ischemic rat hearts.J Cardiovasc Pharmacol 1986;8(Suppl. 10):S91-S99.
Elfellah MS, Ogilvie RI. Effect of vasodilator drugs on coronary occlusion and reperfusion arrhythmias in anesthetized dogs.J Cardiovasc Pharmacol 1985;7:826–832.
de Langen CDJ, de Graeff PA, van Gilst WH, et al. Intervention before reperfusion of the ischemic heart with captopril reduces infarct size and prevents the inducibility of sustained ventricular tachycardia in the pig (abstract).Cardiovasc Drugs Ther 1987;1:225.
de Graeff PA, van Gilst WH, Bel KJ, et al. Concentration dependent protection by captopril against myocardial damage during ischemia and reperfusion in a closed chest pig model.J Cardiovasc Pharmacol 1987;9(Suppl 2):S37-S42.
Ertl G. Angiotensin converting enzyme inhibitors and ischaemic heart disease.Eur Heart J 1988;9:716–727.
DeForrest JM, Waldron TL, Krapcho J, et al. Preclinical pharmacology of zofenopril, an inhibitor of angiotensin I converting enzyme.J Cardiovasc Pharmacol 1989;13:887–894.
de Langen CDJ, de Graeff PA, van Gilst WH, et al. Effects of angiotensin II and captopril on inducible sustained ventricular tachycardia two weeks after myocardial infarction in the pig.J Cardiovasc Pharmacol 1980;13:186–191.
Nachlas MM, Shnitka TK. Macroscopic identification of early myocardial infarcts by alterations in dehydrogenase activity.Am J Pathol 1963;42:379–390.
de Jong JW, ed.Myocardial energy metabolism. Dordrecht: Nijhoff, 1988.
Simson MB. Use of signals in the terminal QRS complex to identify patients with ventricular tachycardia after myocardial infarction.Circulation 1981;64:235–242.
Gorgels AP, Vos MA, Letsch IS, et al. Usefulness of the accelerated idioventricular rhythm as a marker for myocardial necrosis and reperfusion during thrombolytic therapy in acute myocardial infarction.Am J Cardiol 1988; 61:231–235.
van Gilst WH, de Graeff PA, Kingma JH, et al. Captopril reduces purine loss and reperfusion arrhythmias in the rat heart after coronary occlusion.Eur J Pharmacol 1984; 100:113–117.
de Langen CDJ, Hanich RF, Michelson EL, et al. Differential effects of procainamide, lidocaine and acetylstrophanthidin on body surface potentials and epicardial conduction in dogs with chronic myocardial infarction.J Am Coll Cardiol 1988;11:403–413.
Keren A, Gillis AM, Freedman RA, et al. Heart transplant rejection monitored by signal-averaged electrocardiography in patients receiving cyclosporine.Circulation 1984;70 (Suppl I):I124-I129.
Simson MB. Signal averaging.Circulation 1987;75(Suppl III):III69-III72.
Breithardt G, Borggrefe M. Recent advances in the identification of patients at risk of ventricular tachyarrhythmias: Role of ventricular late potentials.Circulation 1987;75:1091–1096.
Antonaccio MJ, Kerwin L. Pre- and postjunctional inhibition of vascular sympathetic function by captopril in SHR.Hypertension 1981;3(Suppl I):I54-I60.
Kimura E, Hashimoto K, Furukawa S, Hayakawa H. Changes in bradykinin level in coronary sinus blood after the experimental occlusion of a coronary artery.Exp Lab Rep 1973;85(5):635–647.
Tio RA, van Gilst WH, Rett K, et al. The effect of bradykinin and the ischemic isolated rat heart.Hormone Metabol Res 1990;in press.
Pitt B, Mason J, Conti CR, Colman R. Activation of the plasma kallikrein system during myocardial ischemia. In: Secuteri F, Rocha de Silva M, Back N, eds.Advances in experimental medicine and biology, vol 8. New York: Plenum Press, 1970:403–410.
Gryglewski RJ, Moncada S, Palmer RML. Bioassay of prostacyclin and endothelium-derived relaxing factor (EDRF) from porcine aortic endothelial cells.Br J Pharmacol 1986;87:685–694.
Parratt JR. Cardioprotective effects of iloprost. In: Gryglewski RJ, Stock G, eds.Prostacyclin and its stable analogue iloprost. Berlin: Springer-Verlag, 1987;301–303.
de Langen CDJ, van Gilst WH, Wesseling H. Sustained protection by iloprost of the porcine heart in the acute and chronic phases of myocardial infarction.J Cardiovasc Pharmacol 1985;7:924–928.
Kingma JH, Louwerenberg HW, Six AJ, et al. Concomitant use of captopril during thrombolytic therapy in acute myocardial infarction. In: Sonnenblick EH, Laragh JH and Lesch M, eds.New frontiers in cardiovascular therapy: Focus on angiotensin converting enzyme inhibition. Princeton, Amsterdam: Excerpta Medica, 1989:277–285.
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Tio, R.A., de Langen, C.D.J., de Graeff, P.A. et al. The effects of oral pretreatment with zofenopril, an angiotensin-converting enzyme inhibitor, on early reperfusion and subsequent electrophysiologic stability in the pig. Cardiovasc Drug Ther 4, 695–703 (1990). https://doi.org/10.1007/BF01856557
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DOI: https://doi.org/10.1007/BF01856557