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Long-term cholesterol feeding alters the reactivity of primate coronary microvessels to platelet products
J E Quillen1, F W Sellke, M L Armstrong
1University of Iowa Cardiovascular Center, Iowa City.
Insights
Long-term hypercholesterolemia paradoxically causes coronary microvessels to constrict in response to thrombin, unlike in normal or short-term hypercholesterolemic states. This study investigates these altered vascular responses in hypercholesterolemia.
Area of Science:
- Cardiovascular Biology
- Vascular Physiology
- Metabolic Disease Research
Background:
- Hypercholesterolemia is known to impair endothelium-dependent relaxations in large arteries.
- The impact of hypercholesterolemia on coronary microvessel responses to platelet-derived substances and thrombin remains less understood.
Purpose of the Study:
- To investigate the effects of short-term and long-term hypercholesterolemia on coronary microvessel reactivity to platelet products and thrombin.
- To compare the responses of microvessels from normal, short-term, and long-term hypercholesterolemic cynomolgus monkeys.
Main Methods:
- Utilized an in vitro microvessel imaging apparatus to study coronary microvessels (100-200 microns diameter) from three groups of cynomolgus monkeys.
- Assessed responses to thrombin, ADP, serotonin, and U46619 after preconstriction with U46619.
Main Results:
- Long-term hypercholesterolemic vessels required significantly lower U46619 concentrations for preconstriction.
- Relaxations to ADP were diminished in long-term hypercholesterolemic vessels.
- Thrombin induced paradoxical constrictions in long-term hypercholesterolemic microvessels, while causing relaxations in other groups.
- Serotonin-induced constrictions were markedly enhanced in long-term hypercholesterolemic vessels.
Conclusions:
- Long-term hypercholesterolemia alters coronary microvessel reactivity, leading to paradoxical vasoconstriction with thrombin and enhanced responses to serotonin.
- These findings highlight significant functional changes in coronary microvasculature associated with prolonged hypercholesterolemia.
Abstract:
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)