Why is nisoldipine a specific agent in ischemic left ventricular dysfunction?

Abstract

Nisoldipine is a dihydropyridine calcium entry blocker that inhibits contraction of vascular smooth muscle with a potency that is 2-3 times greater than its impact on myocardial contractility. In isolated human coronary arteries, tonic contractions induced by serotonin are inhibited by nisoldipine with a potency 10 times greater than that in internal mammary arteries and 1,000 times greater than that in electrically driven myocardium. In contrast, nifedipine had little effect and verapamil and diltiazem had none. In this article an hypothesis is reviewed that relates vascular smooth muscle selectivity to membrane potential sensitivity. Nisoldipine's effect on calcium channel binding and blocking is enhanced by the degree of depolarization of the cell membrane. Verapamil and diltiazem are not membrane-potential sensitive. Vascular smooth muscle cells are more depolarized than myocardial cells, and human coronary arteries have a particularly small membrane potential. Thus, the potency of nisoldipine in these organs parallels the degree of membrane depolarization. This may then suggest ischemia selectivity, since membrane depolarization occurs in ischemic tissue. Nisoldipine might therefore have a potent negative inotropic effect and an enhanced vasodilator action in ischemic myocardium, yet leave normoxic regions functionally intact. Some experimental evidence is discussed.