Effect of chronic endothelin receptor antagonism on cerebrovascular function in type 2 diabetes

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Abstract
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 endothelin-1 (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 ETAreceptors ameliorates, while ETBreceptor blockade augments vascular dysfunction. GK or control rats were treated with antagonists to either ETA(atrasentan, 5 mg·kg−1·day−1) or ETB(A-192621, 15 or 30 mg·kg−1·day−1) receptors for 4 wk and vascular function of basilar arteries was assessed using a wire myograph. GK rats exhibited increased sensitivity to ET-1. ETAreceptor 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. ETAreceptor blockade restored relaxation to control values in the GK animals with no significant effect in Wistar rats and ETBblockade with 30 mg·kg−1·day−1A-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 ETAreceptors mediate vascular dysfunction, ETBreceptors display differential effects. These results underscore the importance of ETA/ETBreceptor balance and interactions in cerebrovascular dysfunction in diabetes.