Chronic endothelin antagonism restores cerebrovascular function in diabetes
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Published on: May 12, 2026
Aaron S Dumont1, Randall J Dumont, John H McNeill
1Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia 22908, USA. asd2f@virginia.edu
Insights
Diabetes impairs cerebrovascular function by increasing myogenic tone. Blocking endothelin-1 with bosentan restored normal blood vessel function in diabetic rats, suggesting a new treatment approach for diabetic cerebrovascular disease.
Area of Science:
- Vascular Biology
- Endocrinology
- Neuroscience
Background:
- Diabetes mellitus is a significant risk factor for cerebrovascular diseases.
- Diabetic complications include increased myogenic tone and reduced responsiveness to vasodilators in cerebral arteries.
- The precise mechanisms underlying diabetes-induced cerebrovascular dysfunction are not fully understood.
Purpose of the Study:
- To investigate the role of endothelin-1 in diabetes-induced alterations of myogenic tone and vasodilation in rat middle cerebral arteries.
- To examine the therapeutic potential of endothelin receptor antagonism in restoring cerebrovascular function in a diabetic rat model.
Main Methods:
- Middle cerebral arteries from control and streptozotocin-induced diabetic Wistar rats were studied using a pressure myograph.
- Experimental groups included control, control treated with bosentan, diabetic, and diabetic treated with bosentan.
- Myogenic responses, endothelium-dependent vasodilation, and potassium channel-mediated vasodilation were assessed.
Main Results:
- Diabetic rats exhibited significantly enhanced myogenic tone compared to control rats.
- Chronic treatment with bosentan, an endothelin receptor antagonist, completely prevented the enhanced myogenic tone in diabetic rats.
- Bosentan treatment also improved endothelium-dependent vasodilation and K(ATP) channel-mediated vasodilation in diabetic rats.
Conclusions:
- Endothelin-1 plays a critical role in mediating increased myogenic tone and impaired vasodilation in the cerebral arteries of diabetic rats.
- Chronic endothelin receptor antagonism effectively restores cerebrovascular function in this model of diabetes.
- These findings suggest endothelin antagonism as a potential therapeutic strategy for managing cerebrovascular complications 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 = 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.
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