In recent years therapy with the calcium entry-blocking drugs nifedipine, verapamil, and diltiazem has made a major impact on the treatment of cardiovascular disease. Although all three of these drugs are approved for the treatment of angina pectoris, some are effective in treating supraventricular tachyarrhythmias and all appear to be effective in the treatment of mild-to-moderate hypertension. Reports of their therapeutic potential, however, are not confined to the cardiovascular system, which reflects the ubiquity of calcium ions as stimulus-effect couplers in a wide variety of organ systems. Although chemically heterogenous, all three drugs produce similar negative inotropic effects in the myocardium and similar relaxant effects in vascular smooth muscle. From a review of the excitation-contraction coupling process in cardiac and smooth muscle it is apparent that 'calcium blockade' could occur at any one of several loci. Our present understanding is that the effect of nifedipine, verapamil, and diltiazem is confined to an inhibitory one on channel-mediated membrane calcium influx. There is, in fact, a close parallel between their ability to decrease slow-channel calcium influx in the myocardium and the negative inotropic action of the drugs. Similarly, in vascular smooth muscle their ability to inhibit voltage- or receptor-mediated calcium influx parallels their vasorelaxant properties. With the use of radiolabeled ligands, particularly of the dihydropyridines (nifedipine, nitrendipine, nicardipine, nisoldipine) it has been shown that the drugs show high-affinity stereospecific binding to vascular smooth muscle channels in the same concentration range as their relaxant properties. In contrast, it was originally thought that myocardial binding was of a lower affinity and correlated poorly with the negative inotropic effect. More recent data, however, have cast some doubt on the validity of these observations. Attempts to define specific drug receptors are incomplete at this time. It appears that the dihydropyridine receptor is a 30-60 K D peptide subunit of the calcium channel. Distinct receptors for verapamil and diltiazem are poorly defined, but appear to be allosterically related to the dihydropyridine receptor. By their interactions with the calcium channel, the calcium entry-blocking drugs modulate excitation-contraction coupling, which produces their negative inotropic and vasorelaxant effects. They also interact with other slow channel-dependent functions in the specialized conducting tissues of the heart to slow the spontaneous sinus rate and decrease atrioventricular conduction. In isolated preparations all of the drugs slow the heart rate, decrease the force of contraction, and produce vascular dilatation. In the intact animal, however, it must be remembered that many of these effects will be influenced by various operational reflexes.
|Original language||English (US)|
|Issue number||6 II SUPPL.|
|State||Published - Dec 1 1987|
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)