Changes in the endothelin-1-induced contraction of aorta in streptozotocin-induced diabetic rats.

Cheong, Hyun Joo; Kim, Eun Jin; Kim, Su Jin; Lee, Sun Hee; Rhim, Byung Yong

Abstract

Vascular diseases are significant complications of diabetes mellitus (DM), and the endothelial cells may play a pivotal role in the development of vascular disease in DM. Endothelin-1 (ET-1) released from endothelium is a potent vasoconstrictor peptide and circulating level of ET-1 is increased in a variety of disease states. The purpose of this study was to determine the changes of responsiveness to ET-1 in DM, and we experimented on the changes in the ET-1-induced contraction, levels of nitrite and lipid peroxidation, and ET-1 immunoreactivity in aorta from streptozotocin-induced DM rats. DM was induced by single injection of streptozotocin (55 mg/kg, i.p.). The immunoreactive ET-1 levels in endothelial layer of thoracic aorta were much higher in DM rats than control rats. Nitrite in tissue homogenate was decreased and plasma nitrite was increased in DM rats. Malondialdehyde (MDA) was significantly increased in DM rats and cGMP was not significantly different between control and DM rats. ET-1 produced concentration-dependent contractile responses that are significantly attenuated in DM rats compared to controls. In the presence of selective ETA receptor antagonist BQ610, the maximum contraction was decreased and the concentration ratios for BQ610 yielded pA2 values of 7.3 (slope, 0.65) in control rats, whereas BQ610 had no antagonistic effect on ET-1-induced contraction in DM rats. However, pretreatment with BQ788, an ETB receptor antagonist, maximum response was decreased and the dose-response curves for ET-1 were shifted to the right in both groups and pA2 values were 7.9 and 7.7 (slope, 1.05 in control and DM rats), respectively. IRL 1620 and sarafotoxin S6c, ETB agonists, induced relaxation in control rats but not in DM rats. These results indicate that endothelial cell dysfunction and enhanced immunoreactivity of ET-1 have been found in DM rat and ET-1-induced contraction was attenuated in DM rat. These attenuated responses might be at least in part caused by the alteration of ETA receptor properties (e.g. desensitization), and partly related with an alteration in intracellular mechanism for contraction to ET-1.