Interplay between the kinin B1 receptor and inducible nitric oxide synthase in insulin resistance

Background and PurposeKinins 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 ApproachMale Sprague-Dawley rats (50-75g) had free access to a drinking solution containing 10% d-glucose or tap water (control) for 9weeks. During the last week, a selective iNOS inhibitor (1400W, 1mgkg(-1) twice daily) or its vehicle was administered s.c. Key ResultsProlonged 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-1) in renal cortex and aorta and to some extent in the liver. Conclusions and ImplicationsPharmacological 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.