Preservation of endothelium-dependent vascular relaxation in cholesterol-fed rabbit by treatment with the calcium blocker PN 200110.

Abstract

SUMMARY. We tested the effects of low doses of a dihydropyridine calcium antagonist, PN 200110, on endothelium-dependent vascular relaxation in rabbits fed a 1% cholesterol diet. The drug was given orally, 1 mg/day, and control rabbits received placebo. Plasma total cholesterol after 10 weeks, was similar in the placebo-and PN 200110-treated groups. The respective values averaged 2140 ± 116 (n = 14; mean ± SEM) and 2012 ± 115 mg/dl (n = 13). In placebo-treated rabbits, sudanophilic aortic lesions covered 52 ± 5% of the intimal surface, and the aortic cholesterol concentration was 72 ± 6 mg/g protein. Corresponding values in aortas from PN 200110-treated rabbits were significantly lower [36 ± 5% (P < 0.03) and 52 ± 3 mg/g protein (P < 0.03)]. Maximal endothelium-dependent cholinergic relaxation of aortic strips in untreated (n = 14) and treated cholesterol-fed rabbits (n = 13) differed significantly (P < 0.01) and averaged 31 ± 4% and 61 ± 7% of the value in normocholesterolemic controls (n = 13). We conclude that cholesterol feeding suppresses endothelium-dependent relaxation evoked by acetylchoUne, and that PN 200110 reduces the severity of atherosclerosis and impairment of endothelium-dependent relaxation. (CircRes 58: 305-309, 1986) RECENT studies indicate that calcium antagonists such as nifedipine (Henry and Bentley, 1981; Panagotopoulios and Nayler, 1984;Willis et al., 1985;Miyazaki et al., 1985), verapamil (Rouleau et al., 1983;Blumlein et al., 1984), nicardipine (Willis et al., 1985), diltiazem (Ginsburg et al., 1983), and flunarizine (Ginsburg et al., 1983) may suppress atherogenesis in cholesterol-fed rabbits. In addition, experiments with arterial smooth muscle cells in culture suggest that calcium antagonists may inhibit cell migration (Nakao et al., 1983), influence the uptake and catabolism of lipoproteins (Stein et al., 1985), and promote the depletion of intracellular cholesteryl ester stores (Etingin and Hajjar, 1985). Anti-atherosclerotic effects of calcium antagonists may be related to those of LaCl 3 and calcium-chelating agents (Kramsch et al., 1981), since these agents are known to inhibit calcium-dependent reactions. Organic or inorganic calcium antagonists and chelating agents appear to exert their antiatherogenic effects without altering circulating lipoproteins, but detailed analyses of circulating lipids and lipoproteins in animals treated with these drugs have not been reported (Henry, 1985).One important question is whether calcium antagonists protect against the effects of hypercholesterolemia by lowering arterial pressure (Henry and Bentley, 1981). Therefore, in this study, we treated cholesterol-fed rabbits with a calcium antagonist in a dosage that exerted no hypotensive effect. In addition, since endothelial injury may play an important role in atherogenesis, we addressed the question whether atherogenesis in cholesterol-fed rabbits is associated with impaired endothelial function. Recent studies have demonstrated that cholinergic relaxation of isolated arteries depends upon ...

Influence of chronic treatment with a nitric oxide donor on fatty streak development and reactivity of the rabbit aorta

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Are calcium ion antagonists effective anti-atherogenic agents?

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