Investigation of the mechanism of negative inotropic activity of some calcium antagonists.

An attempt was made to discriminate between calcium entry blockade and other calcium antagonistic mechanisms involved in the negative inotropic activity of nifedipine, verapamil, diltiazem, flunarizine, lidoflazine, and bepridil in isolated guinea pig hearts. For this purpose, we used the calcium entry promoter Bay K 8644 as a tool to modulate the process of calcium entry at the sarcolemmal level. The calcium ionophore A 23187 was employed to increase intracellular calcium content without interfering with calcium channels. Bay K 8644 interacted with nifedipine, verapamil, and diltiazem; however, only a small inhibitory effect on the negative inotropic responses of flunarizine, lidoflazine, and bepridil was observed. The positive inotropic response of A 23187 was not influenced by nifedipine and was only slightly decreased by verapamil or diltiazem. After addition of flunarizine, lidoflazine, or bepridil, however, the positive inotropic effect of A 23187 was completely abolished. These results suggest that the negative inotropic effects of the calcium entry blockers are not only the result of calcium entry blockade. Apparently, an additional calcium antagonistic effect also plays a role for flunarizine, lidoflazine, and for bepridil and, to a lesser degree, for verapamil and diltiazem.