Enhanced endothelium-dependent vasodilatation by dual endothelin receptor blockade in individuals with insulin resistance

Insulin resistance is associated with endothelial dysfunction and increased production of the pro-inflammatory vasoconstrictor peptide endothelin-1 (ET-1). The aim of this study was to test the hypothesis that blockade of ET receptors results in enhanced endothelium-dependent vasodilatation (EDV) in individuals with insulin resistance. Twelve individuals with insulin resistance without any history of diabetes or cardiovascular disease and 8 age-matched controls with high insulin sensitivity, as determined by hyperinsulinemic-euglycemic clamp, were investigated on 2 separate occasions using forearm venous Occlusion plethysmography. Endothelium-dependent and endothelium-independent vasodilatation was determined before and after selective ETA and dual ETA/ETB receptor blockade. A 60 minute intraarterial infusion of the ETA receptor antagonist BQ123 (10 nmol/min) combined with the ETB receptor antagonist BQ788 (5 nmol/min) evoked a significant increase in acetylcholine-mediated EDV (P < 0.01) in individuals with insulin resistance. The endothelium-independent vasodilator response to nitroprusside was not changed by dual ETA/ETB receptor blockade. Dual ETA/ETB receptor blockade did not affect the response to acetylcholine or nitroprusside in the insulin-sensitive group. Selective ETA receptor blockade did not evoke any changes in endothelium-dependent or endothelium-independent vasodilatation in either group. This study demonstrates that dual ETA/ETB receptor blockade, but not selective ETA blockade, enhances EDV in subjects with insulin resistance, suggesting that ET-1 is involved in the regulation of endothelial function in individuals with insulin resistance.