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 atherogenesis in animal models and to prevent the development of early angiographic lesions in human coronary arteries. Endothelial dysfunction is an early event in the pathogenesis of cardiovascular disease. We investigated whether nifedipine could improve endothelial function in hypercholesterolemia, independently of changes in blood pressure or plasma lipids.


METHODS
First, we compared in vivo forearm vascular responses to the endothelium-dependent 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 controls. 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 nifedipine on endothelial function. We investigated the effects of nifedipine on both NO production by recombinant endothelial NO synthase (eNOS) and endothelial cells, using 3H-arginine conversion, as well as on superoxide generation by endothelial cell lysates, using lucigenin enhanced chemiluminescence.


RESULTS
In hypercholesterolemia 5-HT-induced vasodilation was impaired (47 +/- 9% increase in forearm bloodflow vs. 99 +/- 8% in controls). Treatment with nifedipine completely restored 5-HT-induced vasodilation (113 +/- 13%), whereas it did not influence basal forearm vasomotion or SNP-induced vasodilation. Nifedipine did not alter forearm vascular responses in control subjects 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 endothelial 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 experiments that this effect is due to reduced NO degradation.
Verhaar
M C
MC
Department of Nephrology and Hypertension, University Hospital, Utrecht, Netherlands.
Honing
M L
ML
van Dam
T
T
Zwart
M
M
Koomans
H A
HA
Kastelein
J J
JJ
Rabelink
T J
TJ
D000328:Adult; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D016022:Case-Control Studies; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009543:Nifedipine / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology
D002121:Calcium Channel Blockers; D011994:Recombinant Proteins; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D012701:Serotonin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D009543:Nifedipine