SELECTIVE ENDOTHELIAL DYSFUNCTION IN EARLY ATHEROMA-LIKE LESIONS IN THE RABBIT

Background: The general aim of this study was to use the collar model of atherosclerosis to investigate the extent to which endothelial cell function is impaired at the early stages of lesion development and to determine whether other mechanisms of vascular control at the level of the smooth muscle might be disrupted by the development of these lesions. Methods: Atheroma-like lesions that mimic the events of early human atherosclerosis were induced in rabbits by placing flexible, nonocclusive collars around each common carotid artery. The arterial responsiveness to vasodilator drugs was studied in isolated rings from the arteries both before morphologic changes would be evident (2 days after surgery) and when intimal thickening was evident (7 days after surgery). Results: Relaxation responses to the endothelium-dependent vasodilator acetylcholine were significantly weaker in arterial segments from the center collar (cuffed arteries) than in control segments taken both 2 or 7 days after surgery. In contrast, sodium nitroprusside, an endothelium-independent vasodilator caused no impairment of relaxation. Cuffed and control arterial segments had no difference in relaxation response to two other endothelium-dependent vasodilators, adenosine triphosphate, and the calcium ionophore A23187, at either 2 or 7 days after surgery. High concentrations of acetylcholine elicited contractions in cuffed rings that were denuded of endothelium, but these were not significantly different from those of control rings. Similarly, in rings treated with N-nitro-L-arginine, the contractions of cuffed rings did not differ significantly from those of control rings. Conclusions: The development of atheroma-like lesions results in the specific impairment of acetylcholine-induced relaxation before the intima has thickened, which suggests muscarinic receptor dysfunction. In contrast, vascular smooth muscle relaxation is normal, and some vasoconstrictor mechanisms are enhanced.