Angiotensin Ⅱ Induced Insulin Resist-ance In Adrenomedullin Knockout Mice

Objective Hypertension and insulin resistance are closely related. The possible causative mechanism might be an oxidative stress, Adrenomedullin, a vasodilatory peptide, is now revealed as an intrinsic antioxidant agent. In the present study, to reveal the involvement of oxidative stress in hypertension and insulin resistance, we administered angioten-sin II to adrenomedullin knockout mice and examined blood pressure changes and insulin resistance. Angiotensin n can stimulate the production of reactive oxygen species both in vitro and in vivo. The adrenomedullin knockout heterozygous mouse has almost as half concentration of adrenomedullin in plasma and organ as those in wild type, hence with lower antioxidant capacity.Methods Angiotensin â…¡ was administered intraperitonealy by osmotic minipump at a dose of 640ng. kg-1min-1 for 4 weeks. Systolic blood pressure was measured by the tail cuff method. Glucose uptake in soleus muscle with the stimulation of insulin was taken as the criteria of insulin resistance. 8-Iso-Prostaglandin F2. (Isoprostane) was measured by immunoassay. The real time oxidative stress in the muscle was measured by electronic spin resonance spintrap method. In order to clarify the relationship of oxidative stress with insulin resistance, Hydroxy-TEMPOL, an ROS scavenger, was administered at a dose of 10mmol/L in drinking water simultaneously with angiotensin n loading.Results Systolic blood pressure was significantly elevated both in adrenomedullin knockout heterozygous group and wild group by angiotensin â…¡ loading to the same extent. Angiotensin â…¡ more attenuated insulin sensitivity in adrenomedullin knockout mice than in wild type, which was measured by 2-deoxyglucose uptake to soleus muscle. And 4-hy-droxy-2,2, 6, 6-tetramethyl-piperidine-N-oxyl , a superoxide scavenger mimetic reversed the insulin resistance. Angiotensin H induced higher urinary excretion of isoprostane, a marker for oxidative stress. Moreover, the local production of oxidative stress in mice muscle measured by electronic spin resonance showed the significant higher level in adrenomedullin knockout heterozygous angiotensin â…¡ group compared with the wild angiotensin n group.Conclusions The results presented suggest that insulin resistance was induced independently by blood pressure but by oxidative stress in vivo and adrenomedullin can be a protective peptide in insulin resistance via its intrinsic antioxidant effect.