Alterations of Vascular Reactivity in Atherosclerosis
Authors: David G. Harrison, Paul C. Freiman, Mark L. Armstrong, Melvin L. Marcus, Donald D. Heistad
Journal: Circulation Research (1987)

We have previously found that vascular relaxation to acetylcholine and thrombin is markedly impaired in vessels from monkeys with diet-induced atherosclerosis.In the present study, we found that both normal and atherosclerotic vessels relaxed completely to the calcium ionophore A23187, which stimulates release of the endothelium-derived relaxing factor by nonreceptor-mediated mechanisms.Atherosclerotic vessels, however, were less sensitive to this agent.The finding that responses to the calcium ionophore were impaired in atherosclerosis suggests that abnormal endothelium-dependent relaxation in atherosclerotic vessels is not related entirely to alterations of thrombin and muscarinic receptors but may also be due to abnormal endothelium-derived relaxing factor production or transfer from the endothelium to the underlying vascular smooth muscle.Neither normal nor atherosclerotic iliac arteries constricted in response to acetylcholine when studied in the nonpreconstricted state.Constriction to acetylcholine in these vessels was not unmasked by removal of the endothelium.Thus, the smooth muscle of iliac vessels from monkeys contains few functioning muscarinic receptors.Impaired relaxation of atherosclerotic vessels to acetylcholine is not due to enhanced muscarinicmediated constriction or to production of an endothelium-derived constricting factor.In vivo studies were performed to determine if a-adrenergic coronary vascular constriction is enhanced in the presence of atherosclerosis.In anesthetized monkeys, myocardial oxygen consumption was increased by two mechanisms, aortic occlusion and phenylephrine infusion.During both aortic occlusion and phenylephrine infusion, decreases in coronary vascular resistance were similar in control and atherosclerotic monkeys.If a-adrenergic coronary constriction was enhanced in atherosclerotic coronary arteries, the decrease in coronary vascular resistance would have been blunted in atherosclerotic monkeys.These data suggest that coronary atherosclerosis is not associated with alterations of aadrenergic constriction.Thus, atherosclerosis impairs endothelial modulation of vascular smooth muscle reactivity in response to both receptor-mediated and nonreceptor-mediated agents.In vivo studies of a-adrenergic mediated coronary constriction did not demonstrate augmented responses in atherosclerotic animals.These in vivo and in vitro studies indicate that dietary-induced atherosclerosis in primates alters vascular responses in a heterogeneous manner.(Circulation Research 1987;61(suppl II):S everal recent observations in both patients and experimental animals have shown that atherosclerotic vessels may exhibit augmented responses to a variety of humoral and pharmacologic agents. 1 " 1 Patients with atherosclerosis are prone to develop coronary spasm in response to ergonovine. 5 Also, patients with coronary atherosclerosis may develop enhanced a-adrenergic coronary constriction during cold pressor stress 6 and during cigarette smoking. 7Vessels from cholesterol-fed rabbits exhibit enhanced constriction to ergonovine in vitro. 4Hind limb vessels in a primate model of atherosclerosis demon-