Summary
The antiarrhythmic effects of a new calcium channel blocking agent (SD-3211) and its stereoisomer with additional sodium channel blocking activity (SA3212), were compared with those of a known antiarrhythmic drug (bepridil), using the left coronary artery ligation- and reperfusion-associated arrhythmia models both in isolated rat hearts and in anaesthetized rats.
Isolated and perfused rat hearts were subjected to regional ischaemia for 15 min and subsequent reperfusion for 5 min. SD-3211 and SA3212 showed dose-dependently prolongations of the time interval between coronary ligation and first appearance of ventricular premature beats, reductions in the number of total ventricular premature beats during the ligation period and reductions in the incidence of reperfusion-induced ventricular fibrillation. The values of the negative logarithm of IC50 (mol/l) of SD-3211, SA3212 and bepridil were 7.97, 7.41 and 6.64 for the reduction of ventricular premature beats during ligation and 6.43, 7.49 and 6.17 for the reduction of ventricular fibrillation during reperfusion, respectively. In a separate study on force of concentration and coronary flow in perfused heart paced at 340–360 beats/min SD-3211 caused a significant negative inotropic effect between 10−7 and 10−6 mol/l. SA3212 at the concentration of < 10−6 mol/l did not result in any significant change in force of contraction. The coronary flow was increased dose-dependently by SA3212, while it was first increased and then reduced in the presence of higher concentration of SD-3211 (> 10−7 mol/l). Hearts of aneasthetized rats were also subjected to regional ischaemia for 7 min and subsequent reperfusion. SD-3211, even at the lowest dose tested (25 mg/kg), had a marked protective effect against the ligation-associated arrhythmias. The highest dosage of SA3212 tested (100 mg/kg) also reduced them. SA3212, even at the lowest dosage (25 mg/kg), resulted in a significant reduction of the incidence of reperfusion-induced ventricular fibrillation, while only the highest dosage of SD-3211 (100 mg/kg) reduced it. As for the protective effect against ligation-associated ventricular premature beats SD-3211 is about seven times as potent as bepridil, and for the reduction in the incidence of reperfusion-induced ventricular fibrillation SA3212 is about fourteen times as potent as bepridil. Significant falls in systolic blood pressure and heart rate were observed at the higher doses of SD-3211 (50 and 100 mg/kg).
Thus, SD-3211 affords substantial protection against ischaemia-induced ventricular antiarrhythmias partly through the negative inotropic and chronotropic effects, and reduction of afterload. The antiarrhythmic action of SA3212 against reperfusion-induced ventricular fibrillation may be partly explained by depression of automaticity together with a reduction of the inward sodium current.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Anastasiou-Nana M, Nanas J, Manlove RL, Anderson JL (1984) Experimental antifibrillatory effects of calcium chanel blockade with diltiazem: Comparison with β-blockade and nitroglycerin. J Cardiovasc Pharmacol 6:780–787
Bernier M, Hearse DJ, Manning AS (1986) Reperfusion-induced arrhythmias and oxygen-derived free radicals: studies with “anti-free radical” interventions and a free radical generating system in the isolated perfused rat heart. Circ Res 58:331–340
Bigger JT (1984) Symposium on flecainide acetate. Am J Cardiol 53:1B-122B
Clark C, Foreman MI, Kane KA, McDonald FM, Parratt JR (1980) Coronary artery ligation in anesthetized rats as a method for the production of experimental dysrhythmias and for the determination of infarct size. J Pharmacol Methods 3:357–368
Clusin WT, Bristow MR, Baim DS, Schroeder JS, Jaillon P, Brett P, Harrison DC (1982) The effects of diltiazem and reduced serum ionized calcium on ischemic ventricular fibrillation in the dog. Circ Res 50:518–526
Coker SJ, Parratt JR, Ledingham IMcA, Zeitlin IJ (1982) Evidence that thromboxane contributes to ventricular fibrillation induced by reperfusion of the ischaemia myocardium. J Mol Cell Cardiol 14:483–485
Corblan R, Verrier RL, Lown BL (1976) Differing mechanisms for ventricular vulnerability during coronary artery occlusion and release. Am Heart J 92:223–230
Corr PB, Sobel BE (1982) Amphiphilic lipid metabolism and ventricular arrhythmias. In: Parratt JR (ed) Early arrhythmias resulting from myocardial ischemia. MacMillian, London, pp 199–218
Corr PB, Witkowski FX (1983) Potential electrophysiologic mechanisms responsible for dysrhythmias associated with reperfusion of ischemic myocardium. Circulation 68 (Suppl 1):16–26
Curtis MJ, MacLeod BA, Walker MJA (1984) Antiarrhythmic actions of verapamil against ischaemia arrhythmias in the rat. Br J Pharmacol 83:373–385
Elharrar V, Gaum WE, Zipes DP (1977) Effect of drugs on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in dogs. Am J Cardiol 39:544–549
Fagbemi O, Kane KA, McDonald FM, Parratt JR, Rothaul AL (1984) The effects of verapamil, prenylamine, flunarizine and cinnarizine on coronary artery occlusion-induced arrhythmias in anaesthetized rats. Br J Pharmacol 83:299–304
Gettes LS (1987) What are the effects of potassium on the electrophysiology of acute ischemia? In: DJ Hearse, AS Manning, MJ Janse (eds) Life threatening arrhythmias during ischemia and infarction. Raven, New York, pp 77–90
Grant AO, Starmer CF, Strauss HC (1984) Antiarrhythmic drug action. Blockade of the inward sodium current. Circ Res 55:427–439
Hauswirth O, Singh BN (1979) Ionic mechanisms in heart muscle in relation to the genesis and the pharmacological control of cardiac arrhythmias. Pharmacol Rev 30:5–63
Hondeghem LM, Katzung BG (1984) Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Annu Rev Pharmacol Toxicol 24: 387–423
Hope FG, Marshall RJ, Winslow E (1983) The effects of nifedipine, tetrodotoxin and bepridil on reperfusion-induced arrhythmias in the rat isolated perfused heart (abstract). Br J Pharmacol 78:33P
Kane KA, Parratt JR, Williams FM (1984) An investigation into the characteristics of reperfusion-induced arrhythmias in the anesthetized rat and their susceptibility to antiarrhythmic agents. Br J Pharmacol 82:349–357
Kaumann AJ, Aramendia P (1968) Prevention of ventricular fibrillation induced by coronary ligation. J Pharmacol Exp Ther 164:326–332
Kimura S, Cameron JS, Kozlovskis PL, Bassett AL, Myerburg RJ (1984) Delayed after depolarizations and triggered activity induced in feline Purkinje fibers by α-adrenergic stimulation in the presence of elevated calcium levels. Circulation 70:1074–1082
Kurien VA, Yates PA, Oliver ME (1971) The role of fatty acids in the production of ventricular arrhythmias after acute coronary artery occlusion. Eur J Clin Invest 1:225–241
Lubbe WF, Daries PS, Opie LH (1978) Ventricular arrhythmias associated with coronary artery occlusion and reperfusion in the isolated perfused rat heart: a model for assessment of antifibrillatory action of antiarrhythmic agents. Cardiovasc Res 12:212–220
Lubbe WF, McLean JA, Nguyen T (1983) Antiarrhythmic actions of nifedipine in acute myocardial ischemia. Am Heart J 105:331–333
Manning AS, Hearse DJ (1984) Reperfusion-induced arrhythmias: mechanisms and prevention. J Mol Cell Cardiol 16:497–518
Manning AS, Coltart DJ, Hearse DJ (1984) Ischemia and reperfusion-induced arrhythmias in the rat: effects of xanthine oxidase inhibition with allopurinol. Circ Res 55:545–548
Miyawaki N, Furuta T, Shigei T, Yamauchi H, Iso T (1990) Electrophysiological properties of SD-3211, a novel type of Ca2+ antagonist, in isolated guinea pig and rabbit hearts. J Cardiovasc Pharmacol (in press)
Most AS, Capone RJ, Mastrofrancesco PA (1976) Free fatty acids and arrhythmias following acute coronary artery occlusion in pigs. Cardiovasc Res 11:198–205
Nakaya H, Millard RW, Lathrop DA, Gaum WE, Kaplan S, Schwartz A (1983) Flow-independent improvement by diltiazem of ischemia-induced conduction delay in porcine hearts. J Am Coll Cardiol 2:474–480
Opie LH, Coetzee WA (1987) Are calcium ions involved in the genesis of early ischemic ventricular arrhythmias? In: Hearse DJ, Manning AS, Janse MJ (eds) Life threatening arryhthmias during ischemia and infarction. Raven, New York, pp 63–75
Opie LH, Thandroyen FT, Muller CA, Hamm CW (1984) Calcium channel antagonists as antiarrhythmic agents: contrasting properties of verapamil and diltiazem versus nifedipine. In: Opie LH (ed) Calcium antagonists and cardiovascular disease. Raven, New York, pp 303–311
Peter T, Fujimoto T, Hamamoto H, Mandel WJ (1983) Comparative study of the effect of slow channel inhibiting agents on ischemia-induced conduction delay as relevant to the genesis of ventricular fibrillation. Am Heart J 106:1023–1028
Podzuweit T, Dalby AJ, Cherry GW, Opie LH (1978) Cyclic AMP levels in ischaemia and non-ischaemia myocardium following coronary artery ligation: relation to ventricular fibrillation. J Mol Cell Cardiol 10:81–84
Selye H, Bajusz E, Grasso S, Mendell P (1960) Simple techniques for the surgical occlusion of coronary vessels in the rat. Angiology 11:398–407
Sheridan DJ, Penkoske PA, Sobel BE, Corr PB (1980) Alpha adrenergic contributions to dysrhythmia during myocardial ischemia and reperfusion in cats. J Clin Invest 65:161–171
Somberg JC, Tepper D (1986) Flecainide: a new antiarrhythmic agent. Am Heart J 112:808–813
Thandroyen FT (1982) Protective action of calcium channel antagonists agents against ventricular fibrillation in the isolated perfused rat heart. J Mol Cell Cardiol 14:21–32
Uematsu T, Vozeh S, Ha H-R, Hof RP, Follath F (1986a) Coronary ligation-reperfusion arrhythmia models in anesthetized rats and isolated perfused rat hearts: concentration-effect relationships of lidocaine. J Pharmacol Methods 16:53–61
Uematsu T, Cook NS, Hof RP, Vozeh S, Follath F (1986b) Effects of the enantiomers of the dihydropyridine derivative 202–791 on contractility, coronary flow and ischemia-related arrhythmias in rat heart. Eur J Pharmacol 123:455–458
Vozeh S, Oti-Amoako K, Uematsu T, Follath F (1987) Antiarrhythmic acitivy of two quinidine metabolites in experimental reperfusion arrhythmia: relative potency and pharmacodynamic interaction with the parent drug. J Pharmacol Exp Ther 243: 297–302
Woodward B, Zakaria MNM (1985) Effects of some free radical scavengers on reperfusion-induced arrhythmias in the isolated rat heart. J Mol Cell Cardiol 17:485–493
Author information
Authors and Affiliations
Additional information
Send offprint requests to M. Fukuchi at the above address
Rights and permissions
About this article
Cite this article
Fukuchi, M., Uematsu, T., Nagashima, S. et al. Antiarrhythmic effects of a benzothiazine derivative (SD-3211) and its stereoisomer (SA3212) in anaesthetized rats and isolated perfused rat hearts compared with bepridil. Naunyn-Schmiedeberg's Arch Pharmacol 341, 557–564 (1990). https://doi.org/10.1007/BF00171737
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00171737