Chronic endothelin antagonism restores cerebrovascular function in diabetes

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.

Twenty-eight Wistar rats were divided into four experimental groups (n = 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.

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).

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.