Relationship among cholesterol, superoxide anion and endothelium-dependent relaxation in diabetic rats.

The purpose of the present study was to investigate the time course of changes in plasma low-density lipoprotein (LDL) cholesterol, tissue lipid peroxidation, the expression of hepatic LDL-receptor mRNA and aortic superoxide dismutase, and the relaxation response to acetylcholine in streptozotocin-induced diabetic rats. Plasma cholesterol and LDL levels were significantly increased in both 4- and 10-week diabetic rats. The tissue malonic dialdehyde content in aortas was increased in 10-week compared to 1- or 4-week diabetic rats. The expression of mRNA for LDL receptor mRNA in the liver showed a decrease in both 4- and 10-week diabetic rats. Hepatic LDL-receptor binding activity decreased significantly in 10-week diabetic rats, and decreased binding activity in diabetic rats was improved by the chronic administration of cholestyramine. The relaxation responses to acetylcholine in helical strips of the aorta precontracted with noradrenaline were significantly decreased in 10-week, but not in 1- or 4-week streptozotocin-induced diabetic rats. The decreased relaxation response to acetylcholine was improved by chronic cholestyramine. Both the expression of Mn-superoxide dismutase mRNA and the activity of superoxide dismutase in the aorta were decreased in 10-week, but not in 4-week diabetic rats. From time-course studies, our data suggest that not only increased LDL cholesterol but also decreased activity of superoxide dismutase are responsible for the decreased relaxation response induced by acetylcholine.