Selective endothelin ETA and dual ETA/ETB receptor blockade improves endothelial function in patients with type 2 diabetes and coronary artery disease

Abstract

Purpose: Endothelin-1 contributes to endothelial dysfunction in patients with atherosclerosis and type 2 diabetes. In healthy arteries the endothelin a (ETA) receptor mediates the main part of the vasoconstriction induced by endothelin-1 while the endothelin b (ETB) receptor mediates vasodilatation. The ETB receptor expression is upregulated in atherosclerosis and may thereby contribute to the vasoconstrictor tone and development of endothelial dysfunction. The aim was to compare the effects of selective ETA and dual ETA/ETB blockade on endothelial function in patients with type 2 diabetes and coronary artery disease. Methods: Twelve patients were included in this cross-over study with blinded evaluation. Forearm blood endothelium-dependent and endothelium-independent vasodilatation was assessed by venous occlusion plethysmography during intra-arterial infusions of serotonin and nitroprusside, respectively, before and after 60 minutes of intra-arterial infusion of either the selective ETA antagonist BQ123 or the combination of BQ123 and the ETB antagonist BQ788. Changes between the two treatments were compared using 2-way analysis of variance. Results: Dual ETA/ETB receptor blockade increased baseline forearm blood flow by 30+14% (P<0.01) whereas selective ETA blockade did not (14+8%). Both selective ETA blockade and dual ETA/ETB blockade significantly improved endothelium-dependent vasodilatation. This improvement did not differ between the two treatments (Figure). There was no change in endothelium-independent vasodilatation. Conclusions: Both selective ETA and dual ETA/ETB improve endothelial function in patients with type 2 diabetes and coronary artery disease. ETB blockade increases basal blood flow but does not additionally improve endothelial function.