A comparison of the cardiac and vasodilatory effects of some calcium entry blockers in perfused isolated guinea-pig hearts.

The chronotropic, inotropic and coronary vasodilator actions of several calcium entry blockers have been compared in isolated guinea-pig hearts. Following the subdivision of calcium entry blockers as proposed by Spedding (1985), we have studied nifedipine (dihydropyridine) (group I), verapamil (phenylalkylamine) and diltiazem (benzothiazepine) (group II), flunarizine and lidoflazine (both diphenylalkylamines) as well as bepridil (group III). Moreover, the effect of the calcium entry blockers upon the calcium induced inotropic response was assessed. All calcium entry blockers displayed a clear negative inotropic, negative chronotropic and coronary vasodilating effect. The order of potency for the negative inotropic, coronary dilator and negative chronotropic actions of the calcium entry blockers was, for inotropy: nifedipine greater than verapamil greater than flunarizine = bepridil greater than lidoflazine greater than diltiazem, for coronary flow: nifedipine greater than verapamil greater than lidoflazine = flunarizine greater than diltiazem greater than bepridil, for chronotropy: nifedipine greater than verapamil greater than lidoflazine greater than flunarizine greater than diltiazem greater than bepridil. With respect to the cardiac parameters, the diphenylalkylamines were more potent in their action than described previously by other authors. Equi-effective doses with respect to the negative inotropic effect of the calcium entry blockers studied also displayed the same effectiveness upon calcium-induced inotropic responses. This suggests that the negative inotropic effect of the calcium entry blockers investigated is the result of a calcium antagonistic effect without the contribution of other actions of these drugs. However, the different potency orders for the coronary dilator and negative chronotropic actions of the calcium entry blockers and the differences in maximum for coronary dilator effects suggest that other mechanisms (such as calmodulin antagonism, adenosine uptake inhibition and sodium channel blockade), may contribute to these effects.