Inhibition of endothelin-1 receptors improves impaired nitric oxide synthase-dependent dilation of cerebral arterioles in type-1 diabetic rats

Objective: Endothelin-1 has been implicated in the pathogenesis of many cardiovascular-related diseases, including diabetes. The goal of this study was to examine the influence of endothelin-1 receptors (ET_A) in impaired responses of cerebral (pial) arterioles in type-1 diabetic rats. Methods: We measured responses of cerebral arterioles in non-diabetic rats to endothelial nitric oxide synthase (eNOS)-dependent (ADP), neuronal nitric oxide synthase (nNOS)-dependent (N-methyl-d-aspartic acid [NMDA]) and NOS-independent (nitroglycerin) agonists before and during application of BQ-123, an ET _A receptor antagonist. In addition, we harvested brain tissue from non-diabetic and diabetic rats to measure the production of superoxide anion under basal conditions and during inhibition of ET_A receptors. Results: We found that diabetes specifically impaired eNOS- and nNOS-dependent reactivity of cerebral arterioles, but did not alter NOS-independent vasodilation. In addition, while BQ-123 did not alter responses in non-diabetic rats, BQ-123 restored impaired eNOS- and nNOS-dependent vasodilation in diabetic rats. Further, superoxide production was higher in brain tissue from diabetic rats compared with non-diabetic rats under basal conditions and BQ-123 decreased basal production of superoxide in diabetic rats. Conclusion: We suggest that activation of ET_A receptors during type-1 diabetes mellitus plays an important role in impaired eNOS- and nNOS-dependent dilation of cerebral arterioles.