Nifedipine improves endothelial function in hypercholesterolemia, independently of an effect on blood pressure or plasma lipids

Objective: Dihydropyridine calcium antagonists have been shown to retard at herogenesis in animal models and to prevent the development of early angiog raphic lesions in human coronary arteries. Endothelial dysfunction is an ea rly event in the pathogenesis of cardiovascular disease. We investigated wh ether nifedipine could improve endothelial function in hypercholesterolemia , independently of changes in blood pressure or plasma lipids. Methods: Fir st, we compared in vivo forearm vascular responses to the endothelium-depen dent and independent vasodilators serotonin (5-HT) and sodium nitroprusside (SNP) in 11 patients with familial hypercholesterolemia before and after 6 -weeks treatment with nifedipine GITS (60 mg, OD) and in 12 matched control s. In a subgroup of six control subjects forearm vascular function was also assessed before and after 6-weeks nifedipine GITS treatment. In vitro, we subsequently explored possible mechanisms underlying the effect of nifedipi ne on endothelial function. We investigated the effects of nifedipine on bo th NO production by recombinant endothelial NO synthase (eNOS) and endothel ial cells, using H-3-arginine conversion, as well as on superoxide generati on by endothelial cell lysates, using lucigenin enhanced chemiluminescence. Results: In hypercholesterolemia 5-HT-induced vasodilation was impaired (4 7+/-9% increase in forearm bloodflow vs. 99+/-8% in controls). Treatment wi th nifedipine completely restored 5-HT-induced vasodilation (113+/-13%), wh ereas it did not influence basal forearm vasomotion or SNP-induced vasodila tion. Nifedipine did not alter forearm vascular responses in control subjec ts and did not alter blood pressure or plasma lipids. In vitro, we found no direct effect of nifedipine on NO production by recombinant eNOS or endoth elial cells. However, we did observe a reduction in endothelial superoxide generation. Conclusions: Our data show that nifedipine improves endothelial function in hypercholesterolemia. It is suggested from our in vitro experi ments that this effect is due to reduced NO degradation. (C) 1999 Elsevier Science B.V. All rights reserved.