Submitted on December 11, 2007
Accepted on February 14, 2008
Effect of Chronic Endothelin Receptor Antagonism on Cerebrovascular Function in Type 2 Diabetes
Alex K Harris1, Mostafa M. Elgebaly1, Weiguo Li2, Kamakshi Sachidanandam1, and Adviye Ergul3*
1 Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, Georgia, United States
2 Physiology, Medical College of Georgia, Augusta, Georgia, United States
3 Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, Georgia, United States; Physiology, Medical College of Georgia, Augusta, Georgia, United States
* To whom correspondence should be addressed. E-mail: aergul{at}mcg.edu.
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 ETA receptors ameliorates while ETB receptor blockade augments vascular dysfunction. GK or control rats were treated with antagonists to either ETA (Atrasentan, 5mg/kg/d) or ETB (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. ETA receptor antagonism caused a rightward shift indicating decreased sensitivity in diabetes while it increased sensitivity to ET-1 in control rats. Endothelium-dependent vasorelaxation was impaired in diabetes. ETA receptor blockade restored relaxation to control values in the GK animals with no significant effect in Wistars and ETB 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 ETA receptors mediate vascular dysfunction, ETB receptors display differential effects. These results underscore the importance of ETA/ETB receptor balance and interactions in cerebrovascular dysfunction in diabetes.
