Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 4th communication: influence on experimentally induced ventricular arrhythmia in dogs.
Influence of 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]- 1,2,5,6,-tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013) and vesnarinone (CAS 81840-15-5) on the arrhythmia experimentally induced by three different methods was investigated in dogs. In digitalis-induced arrhythmia, SCH00013 (3 mg/kg i.v.) showed a tendency to improve the arrhythmia with a decrease in the arrhythmic ratio and an increase in the conducted beats (CB), though these changes did not reach a significant level; it decreased significantly the blood pressure (BP) with no change in the total heart rate (THR) and atrial rate (AR). Vesnarinone (3 mg/kg i.v.) did not affect these parameters except for BP that was decreased significantly. In two-stage coronary ligation-induced arrhythmia, SCH00013 (1 and 3 mg/kg i.v.) did not change the arrhythmic ratio, CB, AR and BP, while the THR being slightly decreased; the arrhythmic ratio showed a tendency to decrease with SCH00013 when examined at 24 h after coronary ligation. Vesnarinone (3 mg/kg i.v.) did not affect these parameters at 24 and 48 h after ligation. In epinephrine (adrenaline)-induced arrhythmia, both SCH00013 and vesnarinone showed exacerbation of arrhythmia. SCH00013 at 1 mg/kg i.v. did not elicit ventricular fibrillation (VF) in five dogs examined, but at 3 mg/kg i.v. it elicited VF in two of three dogs. Vesnarinone at 1 mg/kg i.v. induced VF in all of three dogs examined. Incidence of VF induced by optical isomers of SCH00013 was not significantly different from each other: both isomers elicited VF in two of six dogs at 1 mg/kg i.v. and at 3 mg/kg i.v. each of them induced VF in two dogs examined. The present results indicate that SCH00013 is a cardiotonic agent that is equivalent to or less arrhythmogenic than vesnarinone in animal models of arrhythmia, such as adrenaline- and digitalis-induced arrhythmia and the two-stage coronary ligation-induced arrhythmia. Optical isomers of SCH00013 were essentially equieffective in eliciting exacerbation of adrenaline-induced arrhythmia in the dog.
Yoshimura
A
A
Research Laboratory, Zenyaku Kogyo Co. Ltd., Tokyo, Japan.
Yoshioka
K
K
Hino
M
M
Sugawara
H
H
Sakato
M
M
Endoh
M
M
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D002120:Calcium Channel Agonists / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D003331:Coronary Vessels / Q000502:physiology; D004071:Digitalis Glycosides; D004095:Dihydropyridines / Q000627:therapeutic use*; D004285:Dogs; D004837:Epinephrine; D005260:Female; D006352:Heart Ventricles / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D011719:Pyrazines; D011724:Pyridazines / Q000627:therapeutic use*; D011804:Quinolines / Q000494:pharmacology; D013237:Stereoisomerism; D014662:Vasoconstrictor Agents; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control
D000889:Anti-Arrhythmia Agents; D002120:Calcium Channel Agonists; D002316:Cardiotonic Agents; D004071:Digitalis Glycosides; D004095:Dihydropyridines; D011719:Pyrazines; D011724:Pyridazines; D011804:Quinolines; C115124:Sch 00013; D014662:Vasoconstrictor Agents; C041667:vesnarinone; D004837:Epinephrine