Time Course of Endothelial Dysfunction in Experimental Atherosclerosis in the Rabbit

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Abstract
In this study we examined the effect of 4,12 and 16 weeks of hypercholesterolemia, induced by feeding a 0.3% cholesterol enriched diet, on endothelial function in rabbit aorta. Endothelial function was assessed by measuring acetylcholine (ACh) induced endothelium dependent relaxations in isolated aorta and ACh induced release of Endothelium Derived Relaxing Factor (EDRF) from the endothelium. In all groups (4, 12 and 16 weeks) hypercholesterolemia was accompanied by a significant rise of total serum cholesterol and HDL-cholesterol/total cholesterol ratio. The intirnal surface of the total aorta covered by atherosclerotic fatty streaks after 4, 12 and 16 weeks of hypercholesterolemia was 33.8 ± 3.3%, 44.1 ± 5.2% and 55.6 ± 6.1% respectively. After 4 weeks of hypercholesterolemia endothelium dependent relaxations to ACh were augmented while ACh induced EDRF release was not affected. In contrast 12 and 16 weeks of hypercholesterolemia significantly reduced both ACh induced EDRF release and endothelium dependent relaxations. Endothelium independent relaxations to sodium nitroprusside (SNP) were not affected by 4 and 12 weeks of cholesterol (0.3%) feeding but 16 weeks of hypercholesterolemia significantly enhanced vascular sensitivity to SNP. Plotting relative maximal endothelium dependent relaxations versus percent intimal lesions of donor segments or aortas revealed an inverse relationship between endothelial function and the extent of atherosclerosis. The results show that in diet induced experimental atherosclerosis, endothelial dysfunction is a time related process.