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Nifedipine improves endothelial function in hypercholesterolemia, independently of an effect on blood pressure or
M C Verhaar1, M L Honing, T van Dam
1Department of Nephrology and Hypertension, University Hospital, Utrecht, Netherlands.
Insights
Nifedipine improves endothelial function in hypercholesterolemia by reducing nitric oxide degradation, not by altering blood pressure or lipids. This finding suggests a novel therapeutic approach for cardiovascular disease.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Endothelial Biology
Background:
- Endothelial dysfunction is an early indicator of cardiovascular disease.
- Dihydropyridine calcium antagonists show potential in preclinical models of atherosclerosis.
- Hypercholesterolemia is associated with impaired endothelial function.
Purpose of the Study:
- To investigate if nifedipine improves endothelial function in hypercholesterolemia.
- To determine if nifedipine's effects are independent of blood pressure and lipid changes.
- To explore the in vitro mechanisms of nifedipine's action on endothelial function.
Main Methods:
- In vivo forearm vascular responses to vasodilators were assessed in hypercholesterolemic patients and controls before and after nifedipine treatment.
- In vitro studies examined nifedipine's effects on nitric oxide (NO) production and superoxide generation in endothelial cells.
- Serotonin (5-HT) and sodium nitroprusside (SNP) were used as endothelium-dependent and independent vasodilators, respectively.
Main Results:
- Nifedipine treatment restored impaired 5-HT-induced vasodilation in hypercholesterolemic patients.
- Nifedipine did not affect basal vasomotion or SNP-induced vasodilation.
- In vitro, nifedipine reduced endothelial superoxide generation but did not directly affect NO production.
Conclusions:
- Nifedipine effectively improves endothelial function in hypercholesterolemia.
- The mechanism appears to involve reduced nitric oxide degradation, possibly due to decreased superoxide generation.
- Nifedipine offers a potential therapeutic strategy for managing endothelial dysfunction in cardiovascular disease.
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.