Suppression of reperfusion‐induced arrhythmias with combined administration of 5‐HT₂ and thromboxane A₂ antagonists

Abstract

3BX1 The effects of the 5-HT2 antagonist, ICI 170,809 and the thromboxane A2 antagonist, ICI 192,605, given alone and in combination (n = 12 per group), were examined in anaesthetized rats. Haemodynamics and arrhythmias induced by permanent coronary artery occlusion or by reperfusion after 5 min of ischaemia were monitored. 2 In a study on reperfusion-induced arrhythmias, the only significant effect of ICI 170,809 (1 mg kg', i.v.) was a reduction in the number of ventricular premature beats (VPBs). ICI 192,605 (1 mg kg-' min-1, iv.) did not alter reperfusion-induced arrhythmias. However, in combination, when compared with controls, these drugs caused significant reductions in the incidence of ventricular tachycardia (VT), 100% to 58%; ventricular fibrillation (VF), 92% to 33%; and the mortality due to sustained VF, 67% to 17%. There was also a significant reduction in the number of VPBs following reperfusion. 3 In a second study with lower doses of drugs, ICI 170,809 (0.3 mg kg-1) and ICI 192,605 (0.3 mg kg-' min-') had no significant effects on reperfusion-induced arrhythmias either alone or in combination. 4 A third study examined the effects of the higher doses of the drugs on ischaemia-induced arrhythmias. Neither drug alone, nor in combination, altered the incidence of ischaemia-induced VT, VF, the mortality, or the number of VPBs. 5 These results indicate that, in contrast to the administration of either drug alone, combined administration of a 5-HT2 antagonist and a thromboxane A2 antagonist caused marked suppression of reperfusion-induced but not ischaemia-induced arrhythmias.

Effects and interaction, of cariporide and preconditioning on cardiac arrhythmias and infarction in rat in vivo

“…Experiments were terminated or excluded from the final data analysis, if any of the following occurred ( Shaw & Coker, 1996 ): arrhythmias prior to coronary artery occlusion; mean arterial pressure less than 60 mmHg prior to drug or vehicle administration and atrioventricular block during the first 5 min of ischaemia (probably caused by ligature occluding the septal branch of the left coronary artery). Seventy‐eight rats were entered in this study.…”

Combined administration of 5‐HT2 and thromboxane A2 antagonists: effects on platelet aggregation and isolated cardiac muscle

“…Platelet aggregation was measured by the impedance method in heparin‐treated whole blood obtained from anaesthetized rats which had received the drugs under investigation. Two separate studies were performed investigating either the higher or lower doses of the drugs that were used previously in the studies on reperfusion‐induced arrhythmias (Shaw & Coker, 1996a). The high dose drug study was performed in the Department of Pharmacology and Therapeutics at the University of Liverpool, with a single channel Chronolog Whole Blood Aggregometer on loan from Labmedics (Stockport).…”

“…Rats were anaesthetized and the trachea, a carotid artery and a femoral vein were cannulated in preparation for ECG and blood pressure monitoring as described previously for studies on ischaemia‐induced and reperfusion‐induced arrhythmias (Barnes & Coker, 1995; Shaw & Coker, 1996a). A left thoracotomy was carried out and the rat ventilated as before.…”

“…Previously, it has been shown that combined administration of a 5‐hydroxytryptamine 2 (5‐HT 2 ) antagonist and a thromboxane A 2 antagonist reduced reperfusion‐induced arrhythmias, but not ischaemia‐induced arrhythmias, in anaesthetized rat models of coronary artery occlusion and reperfusion (Shaw & Coker, 1996a). It was only when both drugs, the 5‐HT 2 antagonist ICI 170,809 and the thromboxane A 2 antagonist ICI 192,605, were given together that there was marked suppression of reperfusion‐induced ventricular tachycardia and ventricular fibrillation.…”

Inhibitory Effects of Pre-ischemic and Post-ischemic Treatment With FR 168888, a Na+/H+ Exchange Inhibitor, on Reperfusion-Induced Ventricular Arrhythmias in Anesthetized Rat

“…Experiments were terminated or excluded from the final data analysis, if any of the following occurred (13,18): arrhythmias prior to coronary artery occlusion; mean arterial pressure less than 60 mmHg prior to drug or vehicle administration and atrioventricular block during the first 5 min of ischemia (probably caused by ligature occluding the septal branch of the left coronary artery). Eighty-nine rats were used in this study.…”