ATTENUATION BY R-56865, A NOVEL CYTOPROTECTIVE DRUG, OF REGIONAL MYOCARDIAL ISCHEMIA-INDUCED AND REPERFUSION-INDUCED ELECTROCARDIOGRAPHIC DISTURBANCES IN ANESTHETIZED RABBITS

We investigated the antiischemic and antiarrhythmic effects of R 56865 in pentobarbital-anesthetized, open-chest rabbits subjected to 10 min regional myocardial ischemia and 20 min reperfusion, using two experi mental protocols. In the first, R 56865 (0.02-0.16 mg/kg) was administ ered as a bolus intravenous (i.v.) injection 5 min before ligation of a branch of the left circumflex coronary artery (LCX); in the second, the drug, at the highest dose studied (0.16 mg/kg), was injected by th e same route during ischemia, 5 min after coronary artery ligation. Is chemia-induced ST segment increase and reperfusion-induced ventricular arrhythmias were determined in lead II of the four-limb ECG. Mean car otid arterial pressure and heart rate (HR) were also measured. When gi ven before ischemia, R 56865 dose-dependently prevented ischemia-induc ed ST segment increase and reperfusion arrhythmias. The antiischemic a nd antiarrhythmic dose-response curves were superimposable, suggesting a common mechanism of action. R 56865 (0.16 mg/kg) fully attenuated i schemia-induced ST segment shift and ventricular arrhythmias on reperf usion. These protective effects were not associated with systemic hypo tension or bradycardia. When high-dose R 56865 (0.16 mg/kg) was given during ischemia, ST segment shift and ventricular arrhythmias on reper fusion were not attenuated. The results strongly suggest that R 56865 affords protection against the deleterious effects of moderate ischemi a by mechanisms not associated with an indirect reduction of cardiac w ork. R 56865 may elicit cardioprotection directly in ischemic tissue.