Long-term cholesterol feeding alters the reactivity of primate coronary microvessels to platelet products

Hypercholesterolemia impairs endothelium-dependent relaxations to several platelet-derived substances in large vessels. The effect of hypercholesterolemia on the response of coronary microvessels to platelet products and thrombin is less well defined. Three groups of cynomolgus monkeys were studied: normal (n = 6), short-term hypercholesterolemic (8-11 weeks, n = 5), and long-term hypercholesterolemic (18-80 months, n = 6). Responses of coronary microvessels, 100-200 microns in diameter, to thrombin (0.1-10 units/ml) and the platelet products ADP (1 nM-100 microM), serotonin (1 nM-100 microM), and the thromboxane A2 analogue U46619 were studied using an in vitro microvessel imaging apparatus. Vessels were studied after preconstriction with thromboxane A2 analogue U46619 to evaluate both relaxations and constrictions to each agent. Concentrations of U46619 to attain preconstriction were much lower for the long-term group (16 +/- 19 nM) as compared with the control and short-term hypercholesterolemic groups (689 +/- 48 and 664 +/- 63 nM, respectively, p less than 0.01). Relaxations of long-term hypercholesterolemic vessels to ADP tended to be less than those of either control or short-term hypercholesterolemic vessels. Thrombin, when added to normal or short-term hypercholesterolemic vessels, caused identical relaxations but paradoxically caused constrictions in microvessels of long-term hypercholesterolemic monkeys (55 +/- 17% of KCl contraction, p less than 0.001 vs. other groups). Peak constrictions to serotonin were markedly enhanced in the long-term hypercholesterolemic group (59 +/- 7% of maximal KCl responses) compared with control and short-term hypercholesterolemic responses (28 +/- 8% and 32 +/- 5%, respectively, both p less than 0.05 vs. long-term hypercholesterolemia.(ABSTRACT TRUNCATED AT 250 WORDS)