Attenuation by R 56865, a novel cytoprotective drug, of regional myocardial ischemia- 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 experimental protocols. In the first, R 56865 (0.02-0.16 mg/kg) was administered 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 the same route during ischemia, 5 min after coronary artery ligation. Ischemia-induced ST segment increase and reperfusion-induced ventricular arrhythmias were determined in lead II of the four-limb ECG. Mean carotid arterial pressure and heart rate (HR) were also measured. When given before ischemia, R 56865 dose-dependently prevented ischemia-induced ST segment increase and reperfusion arrhythmias. The antiischemic and antiarrhythmic dose-response curves were superimposable, suggesting a common mechanism of action. R 56865 (0.16 mg/kg) fully attenuated ischemia-induced ST segment shift and ventricular arrhythmias on reperfusion. These protective effects were not associated with systemic hypotension or bradycardia. When high-dose R 56865 (0.16 mg/kg) was given during ischemia, ST segment shift and ventricular arrhythmias on reperfusion were not attenuated. The results strongly suggest that R 56865 affords protection against the deleterious effects of moderate ischemia by mechanisms not associated with an indirect reduction of cardiac work. R 56865 may elicit cardioprotection directly in ischemic tissue.
Verscheure
Y
Y
Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases II, Castres, France.
Pouget
G
G
De Courtois
F
F
Le Grand
B
B
John
G W
GW
D000704:Analysis of Variance; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D052160:Benzothiazoles; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium / Q000166:cytology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D011897:Random Allocation; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D052160:Benzothiazoles; D002121:Calcium Channel Blockers; D010880:Piperidines; D013844:Thiazoles; C054551:R 56865