Role of the B(2) receptor of bradykinin in insulin sensitivity.
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.
Duka
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I
Hypertension and Atherosclerosis Section of the Department of Medicine, Boston University School of Medicine, MA 02118, USA.
Shenouda
S
S
Johns
C
C
Kintsurashvili
E
E
Gavras
I
I
Gavras
H
H
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D005947:Glucose / Q000493:pharmacokinetics; D015309:Glucose Clamp Technique; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D002216:Captopril; D005947:Glucose