Dual mode of action of dihydropyridine calcium antagonists: a role for nitric oxide.

Dihydropyridine calcium antagonists have been used for many years in the treatment of angina pectoris and hypertension. According to the common view, their mechanism of action is based on an inhibition of the smooth muscle L-type calcium current, thus decreasing intracellular calcium concentration and inducing smooth muscular relaxation. However, in recent years evidence has accumulated that besides the smooth muscle effects of these agents, their effect on the endothelium must also to be taken into account. It was shown that dihydropyridines can induce the release of nitric oxide (NO) from the vascular endothelium of various vessels and in different species. This was first shown by Günther and colleagues by assaying the methaemoglobin formation in the presence of intact endothelium (in porcine coronary arteries) with and without treatment with nitrendipine. These findings were later confirmed by direct measurement of NO or of nitrite production. In addition, in several preparations, including micro- and macrovasculature, the sensitivity of the vasorelaxing effect of the dihydropyridines to inhibitors of NO-synthase, such as L-N(G)-nitroarginine (LNNA) or L-N-nitro-arginine-methyl-ester (L-NAME), has been shown. With these studies it became evident that the NO-releasing effect was not unique to nitrendipine but was a group phenomenon shared by the dihydropyridines and several nondihydropyridine calcium antagonists. In addition to their action on vascular endothelium, NO release by nifedipine has also been detected in platelets. There are also studies showing long term effects of calcium antagonists involving NO release. Regarding the underlying mechanism of NO release, nitrendipine was shown, not to decrease but to increase intracellular Ca2+ in cultured endothelial cells. This increase was sensitive to both Ca2+-free extracellular superfusion and to gadolinium, a lanthanide known to inhibit shear-stress activated cation channels. This increase in intracellular calcium can activate endothelial NO-synthase, thus inducing the release of NO. These findings on a dual mode of action, i.e. the direct relaxing effect by inhibition of the smooth muscle L-type calcium current and indirect relaxing effect by release of NO from vascular endothelium may help to understand the beneficial antihypertensive effects of the dihydropyridine calcium antagonists and the preferential effect of certain drugs in certain vascular regions (resistance versus conductive vessels). In addition, NO release from both vascular endothelium and platelets may contribute to the antiatherosclerotic and antithrombotic effects described for certain dihydropyridines.