Atherosclerosis impairs endothelium-dependent vascular relaxation to acetylcholine and thrombin in primates

Abstract

To test the hypothesis that atherosclerosis impairs endothelium-dependent vascular relaxation, we examined the effect of the endothelium-dependent vasodilators acetylcholine and thrombin and the endothelium-independent vasodilator nitroglycerin on iliac arteries from normal cynomolgus monkeys and cynomolgus monkeys with diet-induced atherosclerosis. Rings of iliac artery were suspended in organ chambers at their optimal length for generating tension. After preconstriction with prostaglandin F2α, cumulative concentration-response curves to acetylcholine, thrombin, and nitroglycerin were examined. The presence of endothelium was confirmed in each vessel by scanning electron microscopy. Atherosclerotic vessels showed morpholigic evidence of moderate to severe atherosclerosis. Acetylcholine produced a maximal relaxation of 65 ± 10% in the normal group and 27 ± 10% in atherosclerotic vessels (P < 0.05). Thrombin (10.0 U/ml) produced relaxation of 39 ± 9% in the normal group and 13 ± 7% in atherosclerotic iliac arteries (P < 0.05). Nitroglycerin relaxed both normal and atherosclerotic blood vessels to an equal extent; maximal relaxation was 92 ± 4% in normal vessels and 98 ± 2% in atherosclerotic vessels. To determine if hypercholesterolemia alone produces an abnormality in endothelium-dependent relaxation, we performed two additional studies. First, because veins are exposed to hypercholesterolemia, but do not develop atherosclerosis, we studied relaxation responses to acetylcholine and thrombin in veins from normal monkeys and monkeys with diet-induced atherosclerosis. Veins from normal and atherosclerotic monkeys relaxed to a similar extent upon exposure to the endothelium-dependent vasodilators acetylcholine and thrombin. Second, we studied relaxation responses to acetylcholine, thrombin, and nitroglycerin in left circumflex coronary arteries from normal dogs and dogs fed a hypercholesterolemic diet for 4-5 weeks when serum cholesterol levels were elevated (serum cholesterol 442 ± 14 mg/dl), but before the onset of atherosclerosis. The endothelium-dependent vasodilators acetylcholine and thrombin produced equivalent degrees of relaxation in arteriers removed from normal hypercholesterolemic dogs. These studies demonstrate that atherosclerosis impairs endothelium-dependent relaxation in primate iliac arteries, and that this impairment is not due to a generalized defect in the endothelium caused by hypercholesterolemia, but requires the presence of atherosclerosis.