Comparison of selective versus dual endothelin receptor antagonism on cerebrovascular dysfunction in diabetes

Cerebrovascular tone plays a key role in controlling cerebral blood flow. Our studies have demonstrated that the endothelin system is upregulated in type 2 diabetes leading to increased sensitivity to endothelin-1 and decreased relaxation in basilar artery. While chronic endothelin A receptor blockade restored relaxation, selective endothelin B receptor blockade caused paradoxical constriction in diabetes. Whether this effect was due to activation of endothelin A receptors in the presence of endothelin B receptor blockade or due to the loss of vasculoprotective effects of endothelin B receptors remained unknown. The current study hypothesizes that due to the antagonism of the vasculoprotective endothelin receptor B, dual blockade will not be as effective as selective endothelin receptor A antagonism in improving cerebrovascular dysfunction in type 2 diabetes.

These studies were done in non-obese, type 2 diabetic Goto-Kakizaki rats administered either vehicle, selective endothelin receptor A antagonist Atrasentan (5 mg/kg) or dual endothelin antagonist Bosentan (100 mg/kg) for 4 weeks. At termination, basilar arteries were collected and mounted on a wire myograph and cumulative dose-response curves to endothelin-1 (1-500 nM) and acetylcholine (1 nM-5 μm) were studied.

Basilar artery was highly sensitive to endothelin-1-mediated constriction in diabetic animals. While neither Atrasentan nor Bosentan affected endothelium-dependent vascular relaxation in control animals, both treatments improved the maximum dilatation in diabetes and Atrasentan also improved sensitivity to acetylcholine.

In light of our previous data which showed that endothelin B receptors are vasculoprotective and blockade of this receptor worsens relaxation, current findings suggest that when blocked simultaneously with the endothelin receptor A, the endothelin receptor B antagonism is protective by reducing the hyperreactivity and improving cerebrovascular function in diabetes.