Losartan reverses COX-2-dependent vascular dysfunction in offspring of hyperglycaemic rats

• Published in: Life sciences (1973) 2017-09, Vol.184, p.71-80
• Main Authors: de Queiroz, Diego Barbosa, Ramos-Alves, Fernanda Elizabethe, Santos-Rocha, Juliana, Duarte, Gloria Pinto, Xavier, Fabiano Elias
• Format: Article
• Language: English
• Subjects: Acetylcholine; Angiotensin; Angiotensin II; Angiotensin II - metabolism; Angiotensin II Type 1 Receptor Blockers - administration & dosage; Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Antagonist drugs; Arteries; Blood pressure; Contraction; COX-2 inhibitors; Cyclooxygenase 2 - metabolism; Cyclooxygenase-1; Cyclooxygenase-2; Direct reduction; Endothelial dysfunction; Endothelium; Endothelium, Vascular - drug effects; Endothelium, Vascular - pathology; Female; Fetal programming; Hyperglycaemia; Hyperglycemia; Hyperglycemia - complications; Indomethacin; Isometric; Losartan; Losartan - administration & dosage; Losartan - pharmacology; Male; Mesenteric Arteries - drug effects; Mesenteric Arteries - pathology; Noradrenaline; Norepinephrine; Offspring; Pregnancy; Prostaglandin E2; Prostaglandins; Rats; Rats, Wistar; Rodents; Studies; Superoxide dismutase; Tempol; Vasoconstriction; Vasoconstriction - drug effects; Vasodilation; Vasodilation - drug effects
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2017.07.013

This study examined whether chronic treatment with losartan, an angiotensin II type 1 receptor (AT1R) antagonist, might reverse COX-2-mediated vascular dysfunction in mesenteric resistance arteries (MRA) from offspring of hyperglycaemic rats. Male 12-month-old offspring of hyperglycaemic (O-DR) and normoglycaemic (O-CR) rats were treated with losartan (15mg·kg·day−1) during 2months. Third order MRA of untreated and losartan-treated O-DR and O-CR were mounted in wire myograph for isometric tension measurements. COX-2 expression was analyzed by Western blot; TxA2, PGE2 and PGF2α release was measured using commercial kits. O-DR showed increased blood pressure, impaired acetylcholine-induced vasodilation and increased noradrenaline-induced vasoconstriction than O-CR. All these parameters were normalized by losartan in O-DR. Pre-incubation of MRA with indomethacin (COX-1/2 inhibitor), NS-398 (COX-2 inhibitor) or tempol (superoxide dismutase mimetic) increased relaxation to acetylcholine and reduced contraction to noradrenaline only in O-DR. COX-2 expression, TxA2, PGE2 and PGF2α release were increased in O-DR. In losartan-treated O-DR, NS-398, indomethacin or tempol failed to produce any effect on acetylcholine or noradrenaline responses. Losartan treatment reduced COX-2 expression, TxA2, PGE2 and PGF2α release in O-DR. The present results reveal that chronic losartan administration in O-DR normalizes endothelial function in MRA by correcting the existing COX-2 overexpression and the imbalance between endothelium-derived relaxing and contracting factors. These findings not only support the beneficial effects of AT1 receptor antagonist in O-DR, but also suggest the implication of angiotensin II as a putative mediator of hyperglycemia-programmed vascular dysfunction in rats.