History of calcium antagonists.

The discovery of Ca++ antagonism as a new principle of action of coronary drugs reaches back to 1964, when we reported that two new compounds, later given the generic names verapamil (Iproveratril) and prenylamine, mimicked the cardiac effects of simple Ca++ withdrawal in that they diminished Ca++-dependent high energy phosphate utilization, contractile force, and oxygen requirement of the beating heart without impairing the Na+-dependent action potential parameters. Since these effects, clearly distinguishable from beta-receptor blockade, could promptly be neutralized with elevated Ca++, beta-adrenergic catecholamines, or cardiac glycosides, measures that restored the Ca++ supply to the contractile system, we introduced in 1969 the term Ca++ antagonist as a novel drug designation. In an extensive search for other Ca++ antagonists, a considerable number of substances that also met these criteria were identified in our laboratory, i.e., D 600, nifedipine, niludipine, nimodipine, perhexiline, fendiline, terodiline. In 1975 Japanese pharmacologists contributed diltiazem to this group. According to our studies, all specific Ca++ antagonists interfere with the uptake of labelled Ca++ into the myocardium and prevent myocardial necrotization arising from deleterious intracellular Ca++ overload; they also block excitation-contraction coupling of vascular smooth muscle, and in this manner, lower Ca++-dependent coronary vascular tone and neutralize all types of experimental coronary spasms. According to our voltage-clamp studies, these antagonists basically act as specific inhibitors of the slow transsarcolemmal Ca++ influx but do not (or only slightly) affect the fast Na+ current that initiates normal myocardial excitation. However, Ca++ antagonists can counteract SA and AV nodal automaticity, AV conduction, and ectopic impulse discharge because, in these cases, Ca++ ions necessarily act as transmembrane electric charge carriers.