Electrophysiologic and hemodynamic effects of slow-channel blocking drugs

Abstract

T HE last decade has witnessed an intense clinical and experimental investigation of the pharmacologic properties and the therapeutic applications of the class of drugs which now have come to be known as “calcium antagonists, ” “slow-channel inhibitors”, or “calcium influx blockers.“i-3 Although the prototype agent of such compounds, verapamil, has been known since 1 962,4 it is only recently that the concept of the selective slow-channel inhibition has been clearly delineated and has gained widespread recognition.5,6 Such an appreciation has followed closely in the wake of numerous developments which have provided a rational basis for the use of slow-channel inhibitors in a very large and increasing number of cardiocirculatory disorders.‘x7 An important advance was made when it was found that the inward depolarizing current in heart muscle had two components, one having fast kinetics and the other slow, each capable of being blocked selectively by specific antagonists.8-‘0 It was aIso found that certain fibers in the normal heart were dependent almost exclusively on slow-channel potentials.” For example, the selective inhibition of such potentials in the middle of the AV node provided a highly effective and predictable method for terminating reentrant paroxysmal supraventricular tachycardias which utilize anterograde conduction through the AV node as part of the re-entrant circuit.‘2,13 Although not all slow-channel antagonists block AV conduction in this manner, the selective inhibition of the slow-channel in cardiac muscle in general has become the main basis for identifying slow-channel inhibitors.236,‘4 The fact that the transport of calcium through the slowchannel during an action potential is responsible for excitation-contraction coupling in heart muscle, a major consequence of the inhibition of this process is a reduction in myocardial contractility, most clearly evident15*16 in isolated cardiac muscle. However, if such a negative inotropic propensity of this class of agents were not modulated favorably by their associated extracardiac effects, it is unlikely that they could be employed “safely” in clinical therapeutics. It so happens that slow-channel blocking compounds also inhibit calcium movements in smooth muscle;‘7*‘8 in so doing they reduce contraction thereby producing vasodilatation in the peripheral vessels and in the coronary circulation.4”7”9-2’ The peripheral vasodilator effect is of particular significance insofar as it may reflexly increase heart rate, AV conduction, and myocardial contractility while improving ventricular performance indirectly by reducing ventricular afterload. In this atricle, the electrophysiologic and hemodynamic effects of slow-channel blockade are discussed relative to the overall pharmacologic properties of the most significant compounds (Fig. 1). Since the precise delineation of their cardiocirculatory and electrophysiologic actions in intact animals and man is critically dependent on their fundamental effects on isolated cardiac and smooth muscle cells, the role of the slow channel in excitation-contraction coupling in these tissues will first be discussed in brief.