Role of the B 2 Receptor of Bradykinin in Insulin Sensitivity

Abstract

The biological actions of bradykinin (BK) are attributed to its B 2 type receptor (B 2 R), whereas the B 1 R is constitutively absent, inducible by inflammation and toxins. Previous studies in B 2 R gene knockout mice showed that the B 1 R is overexpressed, is further upregulated by hypertensive maneuvers, and assumes some of the hemodynamic functions of the B 2 R. The current experiments were designed to further clarify the metabolic function of the B 2 R and to explore whether the upregulated B 1 R can also assume the metabolic function of the missing B 2 R. One group of B 2 R−/− mice (n=9) and one of B 2 R+/+ controls (n=8) were treated for 3 days with captopril (which produced a similar blood pressure-lowering response in both groups) and studied with the hyperinsulinemic euglycemic clamp. The knockout mice had fasting and steady-state blood glucose levels similar to those of the wild-type mice but a had tendency to higher fasting insulin levels (at 27.8±5.2 versus 18±2.9 mU/L, respectively). However, they had significantly higher steady-state insulin levels (749±127.2 versus 429.1±31.5 mU/L, P <0.05) and a significantly lower glucose uptake rate (31±2.4 versus 41±2.3 mg/kg per minute, P <0.05) and insulin sensitivity index (4.6±0.9 versus 10±0.7 P <0.001). Analysis of B 1 R and B 2 R gene expression by reverse transcription-polymerase chain reaction in cardiac muscle, skeletal muscle, and adipose tissues revealed significantly higher B 1 R mRNA level in the knockouts versus wild-type ( P <0.05) at baseline and a further significant upregulation in mRNA by 1.8- to 3.2-fold ( P <0.05) after insulin infusion. We conclude that absence of B 2 R confers a state of insulin resistance because it results in impaired insulin - dependent glucose transport; this is probably a direct B 2 R effect because, unlike the hemodynamic autacoid-mediated effects, it cannot be assumed by the upregulated B 1 R.