Effects of zatebradine and propranolol on canine ischemia and reperfusion-induced arrhythmias.
1,3,4,5-Tetrahydro-7,8-dimethoxy-3[3-[[2-(3, 4-dimethoxyphenyl)-ethyl]methylamino]propyl]-2H-3-benzazepin-2-one -hy drochloride (Zatebradine) is a specific bradycardiac agent, blocking the hyperpolarization-activated pacemaker current (I(f)), and thus has no negative inotropic effect. The purpose of this study was to examine whether zatebradine is effective against ischemia and reperfusion-induced arrhythmias in dogs compared to propranolol. Arrhythmia was induced by ligation of the left anterior descending coronary artery followed by reperfusion. Ischemia-induced biphasic arrhythmias were suppressed in both zatebradine and propranolol groups. During ischemia, fatal ventricular fibrillation occurred in four dogs in the control group, 0 in the zatebradine group, and two dogs in the propranolol group. Of the 31 dogs subjected to reperfusion, mortality rates in the zatebradine, propranolol, and control groups were 56%, 75%, and 86%, respectively, and there were no significant differences. In the heart beating 10 beats/min faster than the predrug heart rate by atrial pacing, both zatebradine and propranolol attenuated ischemia-induced arrhythmias but did not affect reperfusion arrhythmias. Our results suggest that I(f) and/or beta-adrenoceptors rather than the bradycardiac action might be related to the antiarrhythmic effects during ischemia, but that they do not play a role in the generation of the reperfusion-induced ventricular arrhythmias.
Naito
H
H
Department of Pharmacology, Yamanashi Medical University, Tamaho-cho, Nakakoma-gun, Yamanashi, 409-3898, Japan.
Furukawa
Y
Y
Chino
D
D
Yamada
C
C
Hashimoto
K
K
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D001552:Benzazepines / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000503:physiopathology; D011433:Propranolol / Q000627:therapeutic use*
D000319:Adrenergic beta-Antagonists; D001552:Benzazepines; D002316:Cardiotonic Agents; D011433:Propranolol; C043636:zatebradine