Inducible Nitric Oxide Synthase Is Involved in Endothelial Dysfunction of Mesenteric Small Arteries from Hypothyroid Rats

• Published in: Endocrinology (Philadelphia) 2009-02, Vol.150 (2), p.1033-1042
• Main Authors: Virdis, Agostino, Colucci, Rocchina, Fornai, Matteo, Polini, Antonio, Daghini, Elena, Duranti, Emiliano, Ghisu, Narcisa, Versari, Daniele, Dardano, Angela, Blandizzi, Corrado, Taddei, Stefano, Del Tacca, Mario, Monzani, Fabio
• Format: Article
• Language: English
• Subjects: Adenine; Aging; Allopurinol - pharmacology; Animal models; Animals; Arteries; Ascorbic Acid - pharmacology; Availability; Biological and medical sciences; Endothelium; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiopathology; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Hormones; Hypothyroidism; Hypothyroidism - chemically induced; Hypothyroidism - metabolism; Hypothyroidism - pathology; Hypothyroidism - physiopathology; Inhibitors; Male; Mesenteric Arteries - metabolism; Mesenteric Arteries - physiopathology; Methimazole; NAD(P)H oxidase; NADPH Oxidases - antagonists & inhibitors; NADPH Oxidases - physiology; NADPH-diaphorase; NG-Nitroarginine Methyl Ester - pharmacology; Nicotinamide; Nicotinamide adenine dinucleotide; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; Nitric Oxide Synthase Type II - physiology; Nitric-oxide synthase; Oxidants; Oxidizing agents; Rats; Rats, Wistar; Superoxide; Superoxides - metabolism; Thyroid; Thyroid gland; Thyroid hormones; Thyroid-stimulating hormone; Thyroxine; Thyroxine - pharmacology; Vasodilation - drug effects; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2008-1112

The time-dependent effects of mild hypothyroidism on endothelial function were assessed in rat mesenteric arteries. Male Wistar rats were treated with methimazole (MMI; 0.003%) or placebo up to 16 wk. Endothelial function of mesenteric small arteries was assessed by pressurized myograph. MMI-treated animals displayed a decrease in serum thyroid hormones, an increment of plasma TSH and inflammatory cytokines, and a blunted vascular relaxation to acetylcholine, as compared with controls. Endothelial dysfunction resulted from a reduced nitric oxide (NO) availability caused by oxidative excess. Vascular-inducible NO synthase (iNOS) expression was up-regulated. S-methylisothiourea (an iNOS inhibitor) normalized endothelium-dependent relaxations and restored NO availability in arteries from 8-wk MMI-animals and partly ameliorated these alterations in 16-wk MMI rats. Similar results were obtained when MMI-induced hypothyroidism was prevented by T4 replacement. Among controls, an impaired NO availability, secondary to oxidative excess, occurred at 16 wk, and it was less pronounced than in age-matched MMI animals. Both endothelial dysfunction and oxidant excess secondary to aging were prevented by apocynin (nicotinamide adenine dinucleotide phosphate oxidase inhibitor). Mesenteric superoxide production was reduced by S-methylisothiourea and T4 replacement in MMI animals and abolished by apocynin in controls (dihydroethidium staining). MMI-induced mild hypothyroidism is associated with endothelial dysfunction caused by a reduced NO availability, secondary to oxidative excess. It is suggested that in this animal model, characterized by TSH elevation and low-grade inflammation, an increased expression and function of iNOS, resulting in superoxide generation, accounts for an impaired NO availability. In methimazole-induced mild hypothyroid rats, low-grade inflammation and an increased inducible nitric oxide synthase enhance vascular oxidative stress generation, leading to reduced nitric oxide availability.