Kinin B1 Receptor Enhances the Oxidative Stress in a Rat Model of Insulin Resistance: Outcome in Hypertension,Allodynia and Metabolic Complications

Background

Kinin B₁ receptor (B₁R) is induced by the oxidative stress in models of diabetes mellitus. This study aims at determining whether B₁R activation could perpetuate the oxidative stress which leads to diabetic complications.

Methods and Findings

Young Sprague-Dawley rats were fed with 10% D-Glucose or tap water (controls) for 8–12 weeks. A selective B₁R 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 B₁R expression, aortic superoxide anion (O₂ ^•−) 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 O₂ ^•−, NADPH oxidase activity, MnSOD and catalase expression. All these abnormalities including B₁R overexpression (spinal cord, aorta, liver and gastrocnemius muscle) were normalized by the prolonged treatment with SSR240612. The production of O₂ ^•− in the aorta of glucose-fed rats was also measured in the presence and absence of inhibitors (10–100 µM) of NADPH oxidase (apocynin), xanthine oxidase (allopurinol) or nitric oxide synthase (L-NAME) with and without SarD-Phe⁸]des-Arg⁹-BK (20 µM; B₁R agonist). Data show that the greater aortic O₂ ^•− production induced by the B₁R agonist was blocked only by apocynin.

Conclusions

Activation of kinin B₁R increased O₂ ^•− through the activation of NADPH oxidase in the vasculature. Prolonged blockade of B₁R restored cardiovascular, sensory and metabolic abnormalities by reducing oxidative stress and B₁R gene expression in this model.