title: Differential effects of ET(A) and ET(B) receptor antagonism on oxidative stress in type 2 diabetes.
abstract: 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(2alpha)) 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(2alpha) (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.
authors.affiliation: Program in Clinical and Experimental Therapeutics, Medical College of Georgia, Augusta, Georgia, USA.
authors.forename: Mostafa M
authors.initials: MM
authors.lastname: Elgebaly
authors.forename: Vera
authors.initials: V
authors.lastname: Portik-Dobos
authors.forename: Kamakshi
authors.initials: K
authors.lastname: Sachidanandam
authors.forename: David
authors.initials: D
authors.lastname: Rychly
authors.forename: Daniel
authors.initials: D
authors.lastname: Malcom
authors.forename: Maribeth H
authors.initials: MH
authors.lastname: Johnson
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D000077868:Atrasentan; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008638:Mesenteric Arteries; D018384:Oxidative Stress / Q000187:drug effects*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000502:physiology; D044023:Receptor, Endothelin B / Q000502:physiology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: C120508:A 192621; D000975:Antioxidants; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C075750:8-epi-prostaglandin F2alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D015237:Dinoprost; D000077868:Atrasentan