Antiarrhythmic and cardiohemodynamic effects of a novel Ca(2+) channel blocker, AH-1058, assessed in canine arrhythmia models.
The antiarrhythmic profile and cardiohemodynamic effect of a novel Ca(2+) channel blocker, 4-(5H-Dibenzo[a, d]cyclohepten-5-ylidene)-1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-p ropeny l]piperidine hydrochloride (AH-1058), were analyzed using the epinephrine-, digitalis- and two-stage coronary ligation-induced canine ventricular arrhythmia models. Intravenous administration of AH-1058 (100 microg/kg) effectively suppressed each of the ventricular arrhythmias accompanied by weak hypotensive effects. The results contrast well with those of a typical Ca(2+) channel blocker, verapamil, which suppresses only the epinephrine-induced ventricular arrhythmia with severe hypotension. These results indicate that AH-1058 may possess a more selective inhibitory action on Ca(2+) channels in the heart than on those in the vessels. Furthermore, the antiarrhythmic actions of AH-1058 were slower in onset and longer-lasting, than those in our previous studies using other antiarrhythmic drugs, including Na(+) and Ca(2+) channel blockers. The antiarrhythmic effects of AH-1058 did not correlate with its plasma concentrations when administered either intravenously or orally. These results suggest that AH-1058 can become a long-acting Ca(2+) channel blocker with unique antiarrhythmic properties, and that AH-1058 may be used in certain pathological processes, for which selective inhibition of the cardiac Ca(2+) channels is essential.
Takahara
A
A
Pharmaceutical Research Laboratories, Ajinomoto Co., Inc., 1-1 Suzuki-Cho, Kawasaki-Ku, 210-8681, Kawasaki, Japan. akira_takahara@ajinomoto.com
Sugiyama
A
A
Dohmoto
H
H
Yoshimoto
R
R
Hashimoto
K
K
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D001643:Bridged Bicyclo Compounds / Q000097:blood / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003331:Coronary Vessels / Q000601:surgery; D004070:Digitalis / Q000009:adverse effects; D004195:Disease Models, Animal; D004285:Dogs; D004837:Epinephrine / Q000009:adverse effects; D008026:Ligation; D010880:Piperidines / Q000097:blood / Q000494:pharmacology*; D010946:Plants, Medicinal; D010947:Plants, Toxic
D000889:Anti-Arrhythmia Agents; D001643:Bridged Bicyclo Compounds; D002121:Calcium Channel Blockers; D002317:Cardiovascular Agents; D010880:Piperidines; D004837:Epinephrine; C119283:AH 1058