Summary
To assess whether pretreatment with the calcium antagonist anipamil protects the heart against ischemic and reperfusion damage and to establish how long the protection persists after cessation of the therapy, rabbits were injected subcutaneously twice daily for 5 days with 2 mg/kg body weight of this drug. The heart was then isolated 2, 6, or 12 hours after the last injection and was perfused by the Langendorff technique during a control period and 90 minutes of total ischemia (37°C), followed by 30 minutes ofreperfusion. Diastolic and developed pressure was monitored; coronary effluent was collected and assayed for creatine phosphokinase (CPK); mitochondria were harvested and assayed for respiratory activity, ATP production, and calcium content; and tissue concentration of adenosine triphosphate (ATP) and creatine phosphate were determined. The data obtained with anipamil were compared with those obtained with verapamil administered to the rabbit at the same dose and following the same procedure.
Pretreatment with anipamil induced a negative inotropic effect under normoxic conditions; reduced the rate and extent of depletion of ATP and creatine phosphate during ischemia, with an incomplete restoration of the nucleotides after reperfusion; maintained mitochondrial function and calcium homeostasis during ischemia and reperfusion; reduced the rate of CPK release; and improved the recovery of ventricular function on reperfusion. The protective effects of anipamil persisted for as long as 12 hours after the last administration. In contrast, the protective and negative inotropic effects of verapamil were no longer apparent in heart isolated 6 or 12 hours after the last dose of the drug.
It is concluded that anipamil pretreatment provides a protection against some of the deleterious effects of myocardial ischemia and reperfusion and that this effect is substantially longer than that of verapamil. The protective effect of anipamil (like that of verapamil) is probably secondary to a reduction of the rate of ATP hydrolysis during ischemia, although alternative mechanisms of action cannot be excluded.
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References
Shen AC, Jennings RB, Kinetics of calcium accumulation in acute myocardial injury.Am J Path 1972;67:441–449.
Nayler WG, Ferrari R, Williams A. Protective effect of pretreatment with verapamil, nifedipine and propranolol on mitochondrial function in the ischemic and reperfused myocardium.Am J Cardiol 1980;46:242–248.
Reimer KA, Jennings RB, Cobb FR, Murdock RH, Greenfield JC, Becker LC, Bulkey BH, Hutchins GM, Schwartz RP, Bailey KR, Passamani ER. Animal models for protecting ischemic myocardium: Results of the NHLBI cooperative study comparison of unconscious and conscious dog models.Circ Res 1985;56:651–655.
Melin JA, Becker LC, Hutchins GM. Protective effect of early and late treatment with nifedipine during myocardial infarction in the conscious dog.Circulation 1984;69:131–141.
Klein HH, Schubothe M, Nebendahl K, Kruezer H. The effects of two different diltiazem treatments on infarct size in ischemic, reperfused porcine hearts.Circulation 1984;69: 1000–1005.
Kloner RA, Braunwald E. Effects of calcium antagonists on infarcting myocardium.Am J Cardiol 1987;59:84B-94B.
Nayler WG, Panagiotopoulos S, Elz JS, Sturrock WJ. Fundamental mechanism of action of calcium antagonist in myocardial ischemia.Am J Cardiol 1987;59:75B-83B.
Kloner RA, Braunwald E. Review Observations on experimental myocardial ischemia.Cardiovasc Res 1980;14: 371–395.
Reimer KA, Jennings RB. Effects of calcium channel blockers on myocardial preservation during experimental acute myocardial infarction.Am J Cardiol 1985;55:107B-115B.
Thuesen L, Jorgenson JR, Kuistgaard JH, Sorensen JA, Vaeth M, Jensen EB, Jensen JJ, Hagerup L. Effect of verapamil on enzyme release after early intravenous administration in acute myocardial infarction: Double blind randomized trial.Br Med J 1983;286:1107–1108.
Hansen JF, Mellemgaard B, Sigurd E. Steinmetz L, Hageru PC. Verapamil in acute myocardial infarction.Eur Heart J 1984;5:516–528.
Sirnes Per A, Overskeid K, Pedersen TR, Bathen JB, Drivenes A, Froland GS, Kjekshus JK, Landmark K, Rokseth R, Sirnes KE, Sundoy A, Torjussen BR, Westlund KM, Wik BA. Evolution of infarct size during the early use of nifedipine in patients with acute myocardial infarction: The Norwegian nifedipine multicenter trial.Circulation 1984;70: 638–644.
Muller JE, Morrison J, Stone PH, Rude RE, Ronser B, Roberts R, Pearle DL, Turzi ZG, Schneider JF, Serfas DH, Tate C, Scheiner E, Sobel BE, Hennekens CH, Braunwald E. Nifedipine therapy for patients with threatened and acute myocardial infarction: A randomized double-blind, placebocontrolled comparison.Circulation 1984;69:740–747.
Hugenholtz PG, Surrys PW, Fleckenstein A, Nayler WG. Why calcium antagonists are most useful before or during early myocardial ischemia.Eur Heart J 1986;12:62–72.
Siddiqui MA, Ahmad J, Mirza MR. Effect of verapamil on infarct size in acute myocardial infarction (abstr).J Mol Cell Cardiol 1986;18 (Suppl 1):203.
Huey-Ming LO, Kloner RA, Braunwald E. Effect of intracoronary verapamil on infarct size in the ischemic, reperfused canine heart: Critical importance of the timing of treatment.Am J Cardiol 1985;56:672–677.
Watts JA, Maiorano LJ, Maiorano PC. Comparison of the protective effect of verapamil, diltiazem, nifedipine and buffer containing low calcium upon global myocardial ischemic injury.J Moll Cell Cardiol 1986;18:255–263.
Weishaar RE, Bing RJ. The beneficial effect of a calcium channel blocker, diltiazem, on the ischemic-reperfused heart.J Moll Cell Cardiol 1980;12:993–1009.
Nagao T, Matlib MA, Franklin D, Millard RW, Schwartz A. Effects of diltiazem, a calcium antagonist, on regional myocardial function and mitochondria after brief coronary occlusion.J Moll Cell Cardiol 1980;12:29–43.
Crottogini AJ, Depaoli JR, Barra JG, Fischer EC, Chatruc MR, Pichel RH, Fuente L. The effect of the new calcium antagonist nisoldipine (Bay K 5552) on myocardial infarct size limitation in conscious dogs.Am Heart J 1985;110:753–760.
Hamm CW, Opie LH. Protection of infarction myocardium by slow channel inhibitors: Comparative effects of verapamil, nifedipine and diltiazem in the coronary-ligated isolated working heart.Circ Res 1983;52 (Suppl 1):129–138.
Raschack M. Prolonged cardioprotective effects of anipamil, a new calcium antagonist (abstr).Eur Heart J 1984;5 (Suppl):14.
Ferrari R, Albertini A, Curello S, Ceconi C, Di Lisa F, Raddino R, Visioli O. Myocardial recovery during post-ischemic reperfusion: Effects of nifedipine, calcium and magnesium.J Mol Cell Cardiol 1986;18:487–498.
Ferrari R, Ceconi C, Curello S, Guarnieri C, Caldarera CM, Albertini A, Visioli O. Oxygen mediated myocardial damage during ischaemia and reperfusion: Role of the cellular defences against oxygen toxicity.J Moll Cell Cardiol 1985;17: 937–945.
Oliver TA. A spectrophotometric method for the determination of creatine phosphokinase and myokinase.Biochem J 1955;61:116–122.
Ferrari R, Williams AJ. The role of mitochondria in myocardial damage occurring on post-ischemic reperfusion.J Appl Cardiol 1986;1:501–519.
Sordhal LA, McCollum WB, Wodd WG, Schwartz A. Mitochondria and sarcoplasmic reticulum function in cardiac hypertrophy and failure.Am J Physiol 1973;244:497–502.
Peng GF, Rane JJ, Murphy ML, Straub KD. Abnormal mitochondrial oxidative phosphorylation of ischaemic myocardium reversed by calcium chelating agents.J Moll Cell Cardiol 1977;9:897–908.
Bradford MM. A rapid and sensitive method for the qualification of microgram quantities of protein utilizing the principle for protein binding.Anal Biochem 1978;72:248–254.
Lamprecht W, Trautschold E. Adenosine-5′-triphosphate determination with hexokinase and glucose-6-phosphate dehydrogenase. In: Bergmeyer HU (ed.)Methods of Enzymatic Analysis. New York: Academic Press, 1974:2101–2105.
Nayler WG, Fassold E. Yepez C. The pharmacological protection of mitochondrial function in hypoxic heart muscle. Effect of verapamil, propranolol and methylprednisolone.Cardiovasc Res 1978;42:217–225.
Brode E, Holz D, Kern R. Internally standardized determination of anipamil in human plasma by means of highpressure liquid chromatography.Meth and Find Exptl Clin Pharmacol 1985;7:427–433.
Dennis AR, Kingma JG, Hearse DJ, Downey JM, Yellon DM. Anipamil limits myocardial necrosis in the closed-chest dog during 24 hours of coronary artery occlusion (abstr).J Mol Cell Cardiol 1986;18 (Suppl 1):359.
Kirchengast M, Raschack M. Effects of anipamil on electrocardiogram, plasma creatine kinase, and reperfusion arrhythmias after coronary occlusion in closed-chest rats.J Cardiovasc Pharmacol 1989, 13 (Suppl 4):73–75.
Raschack M, Kirchengast M. Inhibition by anipamil of epicardial elevation and K liberation after coronary artery occlusion in pigs (abstr).J Mol Cell Cardiol 1986;18 (Suppl 1):142.
Kingma JG, Dennis AR, Hearse DJ, Downey JM, Yellon DM. Limitation of infarct size for 24 hours by combined treatment with allopurinol+ verapamil during acute myoardial infarction in the dog.Circulation 1987;75 (Suppl V):25–33.
Chaudhry A, Vohra MM. A reserpine-like action of verapamil on cardiac sympathetic nerves.Eur J Pharmacol 1984;97:156–158.
Chaudhry A, Vohra MM. Depletion of cardiac noradrenaline stores by the calcium-channel blocker D-600.Can J Physiol Pharmacol 1984;62:640–644.
Nayler WG, Scott EM. The effect of chemical sympathectomy on mitochondrial function in the ischaemic and reperfused myocardium.Br J Pharmacol 1982;77:707–715.
Kubler W, Spieckerman PC. Regulation of glycolysis in the ischaemic and the anoxic myocardium.J Mol Cell Cardiol 1970;1:351–371.
Kirkels JH, Ruigrok TJ, VanEchteld CJ, Meijler FL. Protective effect of pretreatment with the calcium antagonist anipamil on the ischaemic-reperfused rat myocardium: A phosphorus-31 nuclear magnetic resonance study.J Am Coll Cardiol 1988;11:1087–1093.
Curtis MJ, Walker MJA, Yaswack T. Actions of the verapamil analogues anipamil and ronipamil against ischaemia-induced arrhythmias in conscious rats.Br J Pharmacol 1986;88:355–361.
Brezinski ME, Darius H, Lefer AM. Cardioprotective actions of a new calcium channel blocker in acute myocardial ischaemia.Drug Res 1986;36:464–466.
Muller-Peltzer H, Brode E, Greger G, Lehmann HD, Hollmann M. Pharmacokinetic study on anipamil in volunteers.Cardiovasc Pharmacother International Symposium 1985; 204.
Rhodes DG, Sarmiento JG, Herbete LG. Kinetics of binding of membrane-active drugs to receptor sites. Diffusionlimited rates for a membrane approach of 1,4-pihtoroptridine calcium channel antagonists to their active sites.Mol Pharmacol 1985;27:612–623.
Katz AM, Pappano AJ, Messineo FC, Smilowitz H, Nash-Adler P. Calcium-channel blocking drugs. In: Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan HE (eds.)The Heart and Cardiovascular System. New York: Raven Press, 1986:1597–1611.
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Ferrari, R., Raddino, R., Ceconi, C. et al. Prolonged protective effect of the calcium antagonist anipamil on the ischemic reperfused rabbit myocardium: Comparison with verapamil. Cardiovasc Drug Ther 3, 403–412 (1989). https://doi.org/10.1007/BF01858111
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DOI: https://doi.org/10.1007/BF01858111