1. The electrophysiological effects of
bepridil, its quaternary derivative,
CERM 11888 (
methylpyrrolidinium bromide) (both 2.5 mg kg-1 i.v.) and those of
verapamil and
diltiazem (0.2 mg kg-1 i.v.) were studied in closed chest anaesthetized dogs at doses used in clinical studies. 2. The four drugs caused a
bradycardia with the following order of potency:
bepridil greater than
CERM 11888 greater than
diltiazem greater than
verapamil. 3. All the compounds slowed conduction in the AV node, increased the refractory period (RP) and decreased Wenckebach rates with the following order:
verapamil much greater than
diltiazem greater than
bepridil greater than
CERM 11888. 4.
Verapamil and
diltiazem did not affect conduction or the RP in atria while
bepridil weakly slowed the former and markedly increased the latter.
CERM 11888 caused a lengthening of RP but this was a delayed effect. 5. In the ventricle,
bepridil and
CERM 11888 caused a small increase in the QRS and a more pronounced increase in the RP. Both compounds increased QTc but did not modify HV.
Verapamil and
diltiazem had no significant effects at the ventricular level. 6. Our results confirm that the main sites of action of
calcium antagonists are the SA and AV nodes.
Bepridil has a broader spectrum of activity and also acts at the atrial and ventricular levels. A comparison of the effects of
bepridil with those of its quaternary derivative suggests the involvement of an intracellular action in the electrophysiological effects of
bepridil.