Vascular dysfunction of venous bypass conduits is mediated by reactive oxygen species in diabetes: Role of endothelin-1

Diabetes is associated with increased risk for complications following coronary bypass grafting (CABG) surgery. Augmented superoxide (O-center dot(2)radical anion) production plays an important role in diabetic complications by causing vascular dysfunction. The potent vasoconstrictor endothelin-1 (ET-1) is also elevated in diabetes and following CABG; however, the effect of ET-1 on O-center dot(2)radical anion generation and/or vascular dysfunction in bypass conduits remain unknown. Accordingly, this study investigated basal and ET-1-stimulated O-center dot(2)radical anion production in bypass conduits and determined the effect of O-center dot(2)radical anion on conduit reactivity. Saphenous vein specimens were obtained from nondiabetic (n = 24) and diabetic (n = 24) patients undergoing CABG. Dihydroethidium staining and NAD(P)H oxidase activity assays (5380 +/- 940 versus 16,362 +/- 2550 relative light units/mu g) demonstrated increased basal O-center dot(2)radical anion levels in the diabetes group (p < 0.05). Plasma ET-1 levels were associated with elevated basal O-center dot(2)radical anion levels, and treatment of conduits with exogenous ET-1 further increased O-center dot(2)radical anion production and augmented vasoconstriction. Furthermore, vascular relaxation was impaired in the diabetic group (75 versus 40%), which was restored by O-center dot(2)radical anion scavenger superoxide dismutase. These findings suggest that ET-1 causes bypass conduits dysfunction via stimulation of O-center dot(2)radical anion production in diabetes. Novel therapies that attenuate O-center dot(2)radical anion generation in bypass conduits may improve acute and late outcome of CABG in diabetic patients.