Late dual endothelin receptor blockade with bosentan restores impaired cerebrovascular function in diabetes
Abstract
AIMS: Up-regulation of the endothelin (ET) system in type-2 diabetes increases contraction and decreases relaxation in basilar artery. We showed that 1) ET-receptor antagonism prevents diabetes-mediated cerebrovascular dysfunction; and 2) glycemic control prevents activation of the ET-system in diabetes. Here, our goal is to determine whether and to what extent glycemic control or ET-receptor antagonism reverses established cerebrovascular dysfunction in diabetes.
MAIN METHODS: Non-obese type-2 diabetic Goto-Kakizaki rats were administered either vehicle, metformin (300 mg/kg/day) or dual ET-receptor antagonist bosentan (100mg/kg) for 4-weeks starting at 18-weeks after established cerebrovascular dysfunction (n=5-6/group). Control group included vehicle-treated aged-matched Wistar rats. Blood glucose and pressure were monitored weekly. At termination, basilar arteries were collected and cumulative dose-response curves to ET-1 (0.1-500 nM), 5-HT (1-1000 nM) and acetylcholine (Ach, 0.1 nM-5 μM) were studied by wire myograph. Middle cerebral artery (MCA) myogenic reactivity and tone were measured using pressurized arteriograph.
KEY FINDINGS: There was no difference in ET-1 and 5-HT-mediated constrictions. Endothelium-dependent relaxation was impaired in diabetes. Bosentan improved sensitivity to Ach as well as the maximum relaxation. Myogenic-tone is decreased over the course of the disease. Both treatments improved the ability of MCAs to develop tone at 80 mm Hg and only…
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