Suppression of reperfusion-induced arrhythmias with combined administration of 5-HT2 and thromboxane A2 antagonists.
1. 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-1, i.v.) was a reduction in the number of ventricular premature beats (VPBs). ICI 192,605 (1 mg kg-1 min-1, i.v.) 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-1 min-1) 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.
Shaw
L A
LA
Department of Pharmacology and Therapeutics, University of Liverpool.
Coker
S J
SJ
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control*; D004146:Dioxanes / Q000494:pharmacology / Q000627:therapeutic use*; D004338:Drug Combinations; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*
D004146:Dioxanes; D004338:Drug Combinations; D011804:Quinolines; D012702:Serotonin Antagonists; C057498:ICI 192605; D013928:Thromboxane A2; C060632:ICI 170809