Cardiovascular action of a cardioselective Ca(2+)channel blocker AH-1058 in conscious dogs assessed by telemetry.
AH-1058, 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-propenyl]piperidine hydrochloride, is a novel Ca(2+)channel blocker exerting cardioselective action in isolated or anesthetized canine heart preparations. To clarify the cardiac and hemodynamic action of AH-1058 in conscious dogs, we assessed the effects of the drug on the hemodynamic parameters continuously recorded by telemetry in conscious unrestrained beagle dogs, and its cardiovascular effects were compared with those of verapamil, disopyramide and atenolol. Oral administration of AH-1058 (0.15, 0.3 and 0.6 mg/kg) reduced the systolic blood pressure and maximal upstroke velocity of the left ventricular pressure (LVdP/dt(max)), increased heart rate and prolonged the QA interval in a dose-dependent manner whereas the drug did not affect diastolic blood pressure. Verapamil at 10 mg/kg reduced systolic and diastolic blood pressure with little effect on heart rate, LVdP/dt(max) and QA interval. Disopyramide at 20 mg/kg increased systolic and diastolic blood pressure, decreased LVdP/dt(max) and prolonged the QA interval with little changes in heart rate. Atenolol at 10 mg/kg decreased LVdP/dt(max) and prolonged the QA interval with little changes in systolic blood pressure, diastolic blood pressure and heart rate. The time course of the cardiohemodynamic action of AH-1058 was longer than those of the other drugs. These results suggest that AH-1058 is a long-acting cardiodepressive drug, and its hemodynamic profile is obviously different from that of disopyramide and atenolol. This unique cardiovascular profile may be beneficial for the treatment of certain pathological processes in which selective inhibition of the ventricular Ca(2+)channels would be the target of drug therapy.
Takahara
A
A
Pharmaceutical Research Laboratories, Ajinomoto Co., Inc., 1-1 Suzuki, Kawasaki, 210-8681, Kawasaki, Japan
Dohmoto
H
H
Yoshimoto
R
R
Sugiyama
A
A
Hashimoto
K
K
D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects*; D003243:Consciousness; D004206:Disopyramide / Q000494:pharmacology; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity; D013686:Telemetry; D017725:Ventricular Pressure / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology
D001643:Bridged Bicyclo Compounds; D002121:Calcium Channel Blockers; D010880:Piperidines; D001262:Atenolol; D014700:Verapamil; D004206:Disopyramide; C119283:AH 1058