Dihydropyridine Calcium Antagonist‐Induced Modulation of Endothelial Function: A Review

The vasorelaxing properties of calcium antagonists have been well established in both experimental and clinical settings during the past three decades. Fleckenstein et al. (13) first postulated a blockade of calcium channels by verapamil, a calcium antagonist. The first therapeutically useful dihydropyridine (DHP), nifedipine, was synthesized by Bossert and Vater (9), and formed the basis for a novel class of substances with either calcium antagonistic or agonistic properties. Since then, DHPs have been well characterized (16) and so-called second or third generation dihydropyridines with improved properties were developed. These compounds were either less light sensitive, less cardiodepressant, caused less reflex tachycardia, or had a longer duration of action (34). They all bind (10) to the a1 subunit (21) of voltage-operated L-type calcium channels in vascular smooth muscle cells, thereby inhibiting calcium influx and causing vasorelaxation (the major mechanism of their therapeutic action in the treatment of coronary heart disease and hypertension). In 1990 Kojda et al. (27) studied the vascular selectivity of DHPs and found that DHP-induced vasorelaxation can be modulated by vascular endothelium (27). This was surprising since macrovascular endothelial cells do not express L-type calcium channels (1,11), the specific target of DHPs. It is known that endothelium release factors that control vascular relaxation and contraction, thrombogenesis, fibrinolysis, and platelet activation (30). The major endothelial factor is nitric oxide (NO). It was suspected that interference with endothelial function could be at least partly responsible for some of the vascular effects of DHPs. This review focuses on the mechanism of DHP-induced modulation of endothelial NO release.