Differential effects of ET_A and ET_B 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 ET_A receptors mediates oxidative stress whereas ET_B receptors display opposing effects. Plasma total antioxidant status (TAS) and 8-isoprostane (8-iso PGF_2α) 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, ET_A antagonist (atrasentan, 5 mg/kg/day), or ET_B receptor antagonist (A-192621, 15 or 30 mg/kg/day, low and high dose, respectively) for 4 weeks. 8-iso PGF_2α (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 ET_A 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.