Electropharmacology of Ro 22-9194, a new antiarrhythmic agent.
1. Ro 22-9194 (> or = 10 microM) caused a concentration-dependent decrease in the maximum upstroke velocity (Vmax) and shortening of action potential duration in guinea-pig ventricular cells. 2. The Vmax inhibition by Ro 22-9194 was enhanced in a use-dependent manner. A time constant for Vmax recovery from the use-dependent block was 9.3 sec. Conditioning depolarizing clamp experiments in ventricular cells indicated that Ro 22-9194 may block sodium channels, mainly during the activated state. 3. Ro 22-9194 > or = 30 microM inhibited calcium inward current (Ica) of the ventricular cells. 4. In dogs in vivo Ro 22-9194 (0.1-3 mg/kg, IV) caused a dose-dependent prolongation of atrioventricular conduction time with greater prolongation of His-ventricular (HV) than atrio-His (AH) intervals. Ro 22-9194 had a potent inhibitory action against various types of model arrhythmias. 5. Ro 22-9194 may exert its antiarrhythmic activity primarily by a use-dependent sodium channel block. From the onset and offset kinetics of the use-dependent block, it belongs to the intermediate kinetic Class I drugs. From the state-dependence of the channel block, it belongs to activated channel blockers.
Kodama
I
I
Department of Circulation, Nagoya University, Japan.
Maruyama
K
K
Suzuki
R
R
Honjo
H
H
Toyama
J
J
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004285:Dogs; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D007473:Ion Channels; D011725:Pyridines; C066993:Ro 22-9194