Chronic endothelin antagonism restores cerebrovascular function in diabetes

OBJECTIVE: Diabetes profoundly alters vascular function and is a risk factor for cerebrovascular disease. Diabetes increases myogenic tone and decreases responsiveness to adenosine triphosphatase (ATP)-sensitive K+ (K-ATP) channel openers and endothelium-dependent vasodilators. The mechanism(s) by which diabetes impairs cerebrovascular function remain obscure. In the present study, the effects of the potent vasoactive peptide endothelin-1 on myogenic tone and endothelium-dependent and potassium channel-mediated vasodilation in middle cerebral arteries from diabetic and nondiabetic rats were investigated. METHODS: Twenty-eight Wistar rats were divided into four experimental groups (n = I 7 per group): control (C), control treated with bosentan (an endothelin A/B receptor antagonist) (CB), diabetic (D), and diabetic bosentan-treated (DB). Diabetes was induced with streptozotocin (D and DB groups), after which chronic bosentan treatment was initiated (CB and DB groups). Middle cerebral arteries were mounted in a pressure, myograph, and myogenic responses were recorded. In addition, endothelium-dependent and -independent responses and the effects of the K-ATP channel opener pinacidil were examined. RESULTS: Cerebral arteries from the diabetic and nondiabetic rats constricted, in response to graded pressure increases. Maximum myogenic responses (percent constriction at 60 mm Hg) were significantly greater in the D group (38 +/- 3% versus 25 +/- 3% in C; P < 0.02). The enhanced myogenic tone in the D group was completely prevented by bosentan treatment (DB, 23 +/- 5% versus D; P < 0.003) without an effect on the CB group. In addition, bosentan treatment improved endothelium-dependent vasomotion and improved K-ATP-mediated vasodilation in the DB group (P < 0.001). CONCLUSION: These data describe, for the first time, the interaction between endothelin-1, myogenic tone, and endothelial function in diabetes. Chronic endothelin antagonism restores cerebrovascular function in this model of diabetes and has global implications for the management of cerebrovascular disease in diabetes.