Plasma endothelin levels and vascular responses at different temporal stages of streptozotocin diabetes.

While alterations in the release and action of endothelial derived vasoactive factors such as endothelin- and endothelial derived relaxing factor (EDRF) occur in diabetes mellitus, the nature and direction of these changes is controversial. We examined the role of diabetes duration on endothelin- plasma levels and vasoconstrictor responses to endothelin-1 in aortic rings from streptozotocin-induced diabetic rats. Endothelin-1 plasma levels were attenuated at 2-weeks, but conversely elevated at 14-weeks, after diabetes induction. Similarly, maximal vasoconstriction to endothelin-1 in aorta was exaggerated in 2-week, but attenuated in 14-week diabetic rats. Also, sensitivity of aorta to endothelin-1 was enhanced in the 14-week group. Neither nitric oxide synthase inhibition with nitro-L-arginine-methyl-ester, nor endothelium removal affected alterations in maximal vasoconstriction, but both abolished changes in sensitivity to endothelin-1. Endothelium dependent (acetylcholine-evoked) vasorelaxation responses were attenuated in 14-week, but not 2-week, diabetic rats, while endothelium independent (sodium nitroprusside-evoked) responses remained unchanged. Together, these data indicate a deficiency in EDRF production in the 14-week group. Elevated plasma glucose and attenuated insulin levels were present in both groups, but plasma cholesterol and triglyceride levels were elevated only in 14-week rats. We conclude that differences in the pre-existing duration of diabetes differentially affect both plasma levels and action of endothelin-1. These changes might be linked to coincident diabetes duration dependent changes in EDRF production and plasma lipid levels. Such a shift in the production and action of endothelial derived relaxing and contracting factors might contribute to the characteristic early and late stage cardiovascular complications of diabetes mellitus.