SR 33589, a new amiodarone-like agent: effect on ischemia- and reperfusion-induced arrhythmias in anesthetized rats.
We have assessed the ability of the new amiodarone-like antiarrhythmic agent, SR 33589, to reduce the incidence of ischemia- and reperfusion-induced arrhythmias, in comparison to amiodarone, D-sotalol, and lignocaine. Rats were anesthetized, artificially ventilated, and the thorax opened by a left thoracotomy. Ischemia was induced by left coronary artery ligation, and reperfusion was achieved (after a 5-min period of ischemia) in a separate group of rats by removing the ligature. Agents were given intravenously 5 min before occlusion or orally 4 h before study. During a 20-min period of ischemia, SR 33589 reduced significantly the incidence of ventricular fibrillation (VF) from 80 to 30% (p < 0.05) at 3 mg/kg i.v. and eliminated VF and mortality at 10 mg/kg i.v. In contrast, amiodarone at 10 mg/kg i.v. reduced significantly only the incidence of mortality during ischemia (from 60 to 0%, p < 0.01), while having no significant effect on 3 mg/kg i.v. On reperfusion (after a 5-min period of ischemia), SR 33589 reduced significantly the incidence of mortality (from 90 to 20%, p < 0.01) at 1 mg/kg and eliminated VF and mortality when administered at 3 and 10 mg/kg. Against both ischemia- and reperfusion-induced arrhythmias, approximately 20% of animals showed AV block at the highest dose of SR 33589 tested. This was not observed with lower doses. Amiodarone (10 mg/kg i.v.) eliminated completely reperfusion-induced VF and mortality while having no significant effect at 1 and 3 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)
Manning
A S
AS
Department of Pharmacology, Sanofi Research, Sanofi-Pharma, Brussels, Belgium.
Bruyninckx
C
C
Ramboux
J
J
Chatelain
P
P
D000284:Administration, Oral; D000638:Amiodarone / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000077764:Dronedarone; D004562:Electrocardiography / Q000187:drug effects; D006327:Heart Block / Q000188:drug therapy; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D008012:Lidocaine / Q000627:therapeutic use; D015428:Myocardial Reperfusion Injury / Q000150:complications*; D011897:Random Allocation; D051381:Rats; D013015:Sotalol / Q000627:therapeutic use; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000401:mortality
D000889:Anti-Arrhythmia Agents; D001572:Benzofurans; D008012:Lidocaine; D013015:Sotalol; D000077764:Dronedarone; D000638:Amiodarone