Interplay between the kinin B1receptor and inducible nitric oxide synthase in insulin resistance

Background and Purpose Kinins are vasoactive and pro‐inflammatory peptides whose biological effects are mediated by two GPCRs, named B 1 and B 2 receptors. While the B 2 receptor plays a protective role in the cardiovascular system via the activation of endothelial NOS, the B 1 receptor is associated with vascular inflammation, insulin resistance and diabetic complications. Because the B 1 receptor is a potent activator of the inducible form of NOS (iNOS), this study has addressed the role of iNOS in the deleterious effects of B 1 receptors in insulin resistance. Experimental Approach Male Sprague–Dawley rats (50–75 g) had free access to a drinking solution containing 10% d ‐glucose or tap water (control) for 9 weeks. During the last week, a selective iNOS inhibitor (1400W, 1 mg·kg −1 twice daily) or its vehicle was administered s.c. Key Results Prolonged glucose treatment caused insulin resistance and several hallmarks of type 2 diabetes. Whereas the treatment with 1400W had no impact on the elevated systolic blood pressure and leptin levels in glucose‐fed rats, it significantly reversed or attenuated hyperglycaemia, hyperinsulinaemia, insulin resistance (HOMA index), body weight gain, peroxynitrite formation (nitrotyrosine expression) and the up‐regulation of biomarkers of inflammation (B 1 receptor, carboxypeptidase M, iNOS and IL‐1β) in renal cortex and aorta and to some extent in the liver. Conclusions and Implications Pharmacological blockade of iNOS prevents the formation of peroxynitrite, which amplifies the pro‐inflammatory effects of B 1 receptors through a positive feedback mechanism. Hence, targeting iNOS can prevent the deleterious effects of B 1 receptors in insulin resistance and peripheral inflammation.