Effects of Ca2+ channel antagonists on sinus node: prolongation of late phase 4 depolarization by efonidipine.

Effects of various Ca2+ channel antagonists on the action potential configuration of rabbit sino-atrial node tissue were examined with standard microelectrode techniques. All Ca2+ channel antagonists decreased the maximum rate of phase 0 depolarization (Vmax) and increased the cycle length. The potency order to increase the cycle length was nisoldipine = verapamil > nifedipine = clentiazem > efonidipine > diltiazem. The potency order to decrease Vmax and to shift the threshold potential to a positive direction was the same as that to increase the cycle length, indicating that the major mechanism of negative chronotropism was inhibition of the L-type Ca2+ current. All Ca2+ channel antagonists except efonidipine shifted the maximum diastolic potential to the positive direction, decreased the action potential amplitude and prolonged the action potential duration. The effects of nifedipine were slightly weaker than those of other drugs when compared at equally bradycardiac concentrations. These differences may reflect differences in drug effects on currents other than the L-type Ca2+ current. A characteristic feature of efonidipine was selective suppression of the later phase of pacemaker depolarization with no effect on action potential amplitude and duration. Similar suppression of the later phase was observed with 50 microM Ni2+, which is reported to inhibit the T-type, but not L-type, Ca2+ current. Thus, efonidipine appears to suppress selectively the later phase of pacemaker depolarization through inhibition of both L- and T-type Ca2+ currents, which may be the underlying mechanism for its reported potent negative chronotropic but weak inotropic activity.