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- I 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, p of ETA receptors mediates oxidative stress whereas ETB receptors display opposing effects. Plasma total antioxidant status (TAS) and 8-isoprostane (8-iso PGF(2 alpha)) 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 PGF(2 alpha) (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. (C) 2007 Elsevier Inc. All rights reserved.