Ca²⁺Channel Antagonists and Agonists

Abstract

Ca²⁺channel antagonists were originally developed as coronary vasodilators. Ca²⁺antagonism, as a new principle of pharmacological action of coronary drugs, was reported by Albert Fleckenstein in 1964 (FLECKENSTEIN 1964). Shortly after that, verapamil, gallopamil (D600), nifedipine, and diltiazem were shown to suppress cardiac E-C coupling in that they abolished contractile force without a major change in the action potential. These drugs were termed Ca²⁺antagonists, because the inhibitory actions of these drugs were antagonized by increasing the extracellular Ca²⁺concentration (FLECKENSTEIN 1983). The vascular smooth muscle E-C coupling also turned out to be susceptible to Ca²⁺antagonism (FLECKENSTEIN 1977). In the 1970s, the voltage-clamp technique made it possible to demonstrate the specific suppression of the voltage-dependent slow Ca²⁺-influx by verapamil, D600, nifedipine, and diltiazem. These studies opened up a new concept of “Ca²⁺antagonism” as a new therapeutic principle in the treatment of cardiovascular diseases such as hypertension, angina pectoris, cerebral, and peripheral vascular disorders. The use of Ca²⁺channel antagonists as a pharmacological tool helped clarify the biophysical and molecular properties of voltage-dependent L-type Ca²⁺channels.