Differential effects of ETA and ETB receptor antagonism on oxidative stress in type 2 diabetes

Endothelin (ET-1) is chronically elevated in diabetes. However, role of ET-1 in increased oxidative stress in type 2 diabetes is less clear. This study tested the hypotheses that: 1) oxidative stress markers are increased and total antioxidant capacity is decreased in diabetes, and 2) activation of ETA receptors mediates oxidative stress whereas ETB receptors display opposing effects. Plasma total antioxidant status (TAS) and 8-isoprostane (8-iso PGF2α) as well as total nitrotyrosine levels in mesenteric resistance vessels were measured in control Wistar and diabetic Goto–Kakizaki (GK) rats (n = 5–10) treated with vehicle, ETA antagonist (atrasentan, 5 mg/kg/day), or ETB receptor antagonist (A-192621, 15 or 30 mg/kg/day, low and high dose, respectively) for 4 weeks. 8-iso PGF2α (pg/ml) levels were significantly higher in low dose A-192621 treatment groups of control and diabetic rats than in atrasentan or high-dose A-192621 treated groups. Protein nitration was increased in diabetes and ETA receptor antagonism prevented this increase. TAS levels were similar in all experimental groups.Thus, ET-1 contributes to oxidative stress in type 2 diabetes and ET receptor antagonism with atrasentan or A-192612 displays differential effects depending on dose and receptor subtype.