WHY IS NISOLDIPINE A SPECIFIC AGENT IN ISCHEMIC LEFT-VENTRICULAR DYSFUNCTION

Nisoldipine is a dihydropyridine calcium entry blocker that inhibits c ontraction 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 inhibi ted by nisoldipine with a potency 10 times greater than that in intern al mammary arteries and 1,000 times greater than that in electrically driven myocardium. In contrast, nifedipine had little effect and verap amil 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 bloc king is enhanced by the degree of depolarization of the cell membrane. Verapamil and diltiazem are not membrane-potential sensitive. Vascula r 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 enhanc ed vasodilator action in ischemic myocardium, yet leave normoxic regio ns functionally intact. Some experimental evidence is discussed.