HYPERCHOLESTEROLEMIA AND ATHEROSCLEROSIS CHANGE VASCULAR REACTIVITY IN RABBITS BY DIFFERENT MECHANISMS

Vasomotor reactivity was assessed in vitro in arterial segments obtained from rabbits with different stages of atherosclerosis. Rabbits were fed a standard chow diet (controls) or a cholesterol-enriched diet to induce hypercholesterolemia and atherosclerosis. A third group received the hydroxymethylglutaryl coenzyme A reductase inhibitor, lovastatin, simultaneously with the cholesterol diet. Contractile responses of thoracic aortas to norepinephrine, serotonin, and potassium-rich solution, as well as endothelium-dependent dilations to acetylcholine, were compared after 2 and 4 months on the respective diet. Additionally, plasma cholesterol levels and the amount of plaques covering the intimal surface (as a percentage of the intimal surface) were determined; transmission electron microscopy of atherosclerotic arteries was also performed. After 2 months, the only difference was an enhancement of contractile responses to serotonin in the cholesterol-fed versus the control group. After 4 months on the diet, contractile responses to serotonin were further enhanced, and norepinephrine- and potassium-induced vasoconstrictions were now also significantly enhanced in cholesterol-fed animals versus controls. Endothelium-dependent vasodilations were simultaneously reduced in cholesterol-fed animals. These alterations were partly prevented in cholesterol-fed and lovastatin-treated animals. Suppression of nitric oxide synthesis in control aortas by N(G)-nitro-L-arginine did not reveal any significant increases in contractile responses. Contractile responses to serotonin were enhanced after 2 months on the diet but before the appearance of intimal plaques, whereas attenuation of endothelium-dependent dilations, as well as the further enhancement of contractile responses to serotonin and to other agonists, were closely correlated with the degree of intimal plaques after 4 months on the diet. The similarity of alterations in vascular reactivity after 4 months on the diet to the effects of isolated low density lipoproteins on vascular tone and the correlation of these changes with the degree of lipid-containing plaques support the hypothesis that lipoprotein accumulation in atherosclerotic arteries contributes to altered vascular reactivity.