Kinin B1 receptor enhances the oxidative stress in a rat model of insulin resistance: outcome in hypertension, allodynia and metabolic complications.
BACKGROUND
Kinin B(1) receptor (B(1)R) is induced by the oxidative stress in models of diabetes mellitus. This study aims at determining whether B(1)R activation could perpetuate the oxidative stress which leads to diabetic complications.


RESULTS
Young Sprague-Dawley rats were fed with 10% D-Glucose or tap water (controls) for 8-12 weeks. A selective B(1)R antagonist (SSR240612) was administered acutely (3-30 mg/kg) or daily for a period of 7 days (10 mg/kg) and the impact was measured on systolic blood pressure, allodynia, protein and/or mRNA B(1)R expression, aortic superoxide anion (O(2)(*-)) production and expression of superoxide dismutase (MnSOD) and catalase. SSR240612 reduced dose-dependently (3-30 mg/kg) high blood pressure in 12-week glucose-fed rats, but had no effect in controls. Eight-week glucose-fed rats exhibited insulin resistance (HOMA index), hypertension, tactile and cold allodynia and significant increases of plasma levels of glucose and insulin. This was associated with higher aortic levels of O(2)(*-), NADPH oxidase activity, MnSOD and catalase expression. All these abnormalities including B(1)R overexpression (spinal cord, aorta, liver and gastrocnemius muscle) were normalized by the prolonged treatment with SSR240612. The production of O(2)(*-) in the aorta of glucose-fed rats was also measured in the presence and absence of inhibitors (10-100 microM) of NADPH oxidase (apocynin), xanthine oxidase (allopurinol) or nitric oxide synthase (L-NAME) with and without Sar[D-Phe(8)]des-Arg(9)-BK (20 microM; B(1)R agonist). Data show that the greater aortic O(2)(*-) production induced by the B(1)R agonist was blocked only by apocynin.


CONCLUSIONS
Activation of kinin B(1)R increased O(2)(*-) through the activation of NADPH oxidase in the vasculature. Prolonged blockade of B(1)R restored cardiovascular, sensory and metabolic abnormalities by reducing oxidative stress and B(1)R gene expression in this model.
Dias
Jenny Pena
JP
Department of Physiology, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.
Talbot
Sébastien
S
Sénécal
Jacques
J
Carayon
Pierre
P
Couture
Réjean
R
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065169:Bradykinin B1 Receptor Antagonists; D048909:Diabetes Complications / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D004149:Dioxoles / Q000008:administration & dosage; D004195:Disease Models, Animal; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D007333:Insulin Resistance; D007705:Kinins; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
C487113:2-((3-(1,3-benzodioxol-5-yl)-3-(((6-methoxy-2-naphthyl)sulfonyl)amino)propanoyl)amino)-3-(4-((2,6-dimethylpiperidinyl)methyl)phenyl)-N-isopropyl-N-methylpropanamide; D065169:Bradykinin B1 Receptor Antagonists; D004149:Dioxoles; D007705:Kinins; D043783:Receptor, Bradykinin B1; D013449:Sulfonamides; D013482:Superoxide Dismutase; D019255:NADPH Oxidases