Effect of Chronic Endothelin Receptor Antagonism on Cerebrovascular Function in Type 2 Diabetes

Diabetes increases the risk of stroke and contributes to poor clinical outcomes in this patient population. Myogenic tone of the cerebral vasculature, including basilar arteries, plays a key role in controlling cerebral blood flow. Increased myogenic tone is ameliorated with ET receptor antagonism in Type 1 diabetes. However, the role of ET-1 and its receptors in cerebrovascular dysfunction in Type-2 diabetes, a common comorbidity in stroke patients, remains poorly elucidated. Therefore, we hypothesized that 1) cerebrovascular dysfunction occurs in the Goto-Kakizaki (GK) model of Type-2 diabetes, and 2) pharmacological antagonism of ET A receptors ameliorates while ET B receptor blockade augments vascular dysfunction. GK or control rats were treated with antagonists to either ET A (Atrasentan, 5mg/kg/d) or ET B (A-192621, 15 or 30 mg/kg/d) receptors for four weeks and vascular function of basilar arteries was assessed using a wire myograph. GK rats exhibited increased sensitivity to ET-1. ET A receptor antagonism caused a rightward shift indicating decreased sensitivity in diabetes while it increased sensitivity to ET-1 in control rats. Endothelium-dependent relaxation was impaired in diabetes. ET A receptor blockade restored relaxation to control values in the GK animals with no significant effect in Wistars and ET B blockade with 30 mg/kg/d A-192621 caused paradoxical constriction in diabetes. These studies demonstrate that cerebrovascular dysfunction occurs and may contribute to altered regulation of myogenic tone and cerebral blood flow in diabetes. While ET A receptors mediate vascular dysfunction, ET B receptors display differential effects. These results underscore the importance of ET A /ET B receptor balance and interactions in cerebrovascular dysfunction in diabetes.