SR 33589, a new amiodarone-like antiarrhythmic agent: electrophysiological effects in anesthetized dogs.
We compared the electrophysiological effects of a new amiodarone-like agent, SR 33589, with those of amiodarone. Mongrel dogs were anesthetized with chloralose, and electrodes were implanted in right atrium and ventricle for electrical stimulation and regional ECG measurement. Sinus cycle length (CL), AH interval, Wenckebach CL (WCL), atrial, atrioventricular node, and ventricular effective refractory periods (AERP, AVNERP, VERP), and parameters calculated from surface ECG were measured. SR 33589 was administered intravenously (i.v.) at 1, 2.5, or 5 mg/kg followed 60 min later by a second similar dose. The same protocol was followed with amiodarone 5 mg/kg, which reduced heart rate (HR) by 19% (p < 0.05), increased WCL by 31% (p < 0.01), AH interval by 14% (p < 0.05) and AERP, AVNERP, and VERP by 13% (p < 0.05), 19% (p < 0.05), and 11% (p < 0.01) respectively. No effect was observed on HV or PQ intervals. A second administration of 5 mg/kg changed these indexes further. SR 33589 (2.5 mg/kg) reduced HR by 21% (p < 0.001), increased WCL by 44% (p < 0.001), AH interval by 24% (p < 0.01), and AERP, AVNERP, and VERP by 17% (p < 0.001), 63% (p < 0.01), and 15% (p < 0.01) respectively, with an 18% increase in PQ interval (p < 0.05) but no significant effect on HV interval. Higher doses (5 mg/kg) and/or administration of a second dose both resulted in greater changes. Both amiodarone and SR 33589 prolonged VERP more at longer CL than at shorter CL, but the degree of reduction at shorter CL was less with SR 33589 than with amiodarone. Results suggest that acute administration of SR 33589 results in electrophysiological actions similar to those produced by amiodarone.
Manning
A
A
Department of Pharmacology, Sanofi Research Centre, Sanofi Pharma, Brussels, Belgium.
Thisse
V
V
Hodeige
D
D
Richard
J
J
Heyndrickx
J P
JP
Chatelain
P
P
D000638:Amiodarone / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D000077764:Dronedarone; D004558:Electric Stimulation; D004562:Electrocardiography / Q000187:drug effects*; D004567:Electrodes, Implanted; D004594:Electrophysiology; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D001572:Benzofurans; D000077764:Dronedarone; D000638:Amiodarone