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Show ARTERIAL REACTIVITY IN INSULIN RECEPTOR-DEFICIENT MICE : THE SPLANCHNIC AND SKELETAL MUSCLE CIRCULATIONS. D. Wade Daniels, Jeffrey Johnson, Daniel Clegg (University of Utah) and Rhett Crapo (Weber State University) (J. David Symons) College of Health Type 2 diabetes often is preceded by years of insulin resistance. This pre-diabetic phase is characterized by obesity, dyslipidemia, and hypertension. Endothelial dysfunction also exists in pre-diabetic individuals and is a key early factor in the development of atherosclerosis. Determining the mechanism(s) responsible for endothelial dysfunction in pre-diabetic individuals is difficult because other risk factors co-exist. To test the hypothesis that insulin resistance per se contributes to vascular dysfunction, we used mice wherein insulin receptors (IRs) were genetically deleted everywhere but the brain, pancreatic p-cells, and liver. These mice have normal blood glucose that results from a compensatory rise in insulin due to "insensitiv-ity" of the deleted IRs. This is similar to the pre-diabetic human condition. Forty-two week old mice homozygous for knockout of the IR (KO, n=8) were compared with their wild-type littermates (WT, n=8). Body weight (g) and blood glucose (mg/dl) were similar between KO (27±1,119±1) and WT mice (26±1,121±4), respectively. Two mesenteric (-160 u.m, internal diameter) and two iliac (-225 urn, internal diameter) arteries were mounted on arteriographs that were immersed in a chamber filled with physiological saline solution (pH 7.4; 37°C). Each artery was precontracted with the a-1 adrenoreceptor agonist phenylephrine. Once stable, cumulative doses of acetylcholine (ACh) were administered to the vessel bathing medium. ACh causes nitric oxide (NO) release from the innermost layer of the blood vessel called the endothelium. NO then diffuses to the smooth muscle cell layer, activates cyclic GMP, and causes vasorelaxation of the blood vessel. This is called endothelium-dependent vasorelaxation. Percent relaxation from precontraction tension in response to 10"6M ACh was less (p<0.05) in mesenteric (11±2 vs 46±5 %) and iliac (43±9 vs 62±4%) arteries from KO vs WT mice, respectively. Next, sodium nitroprusside (SNP) was administered to precontracted vessels to assess the integrity of the vascular smooth muscle. SNP directly stimulates cyclic GMP in vascular smooth muscle to cause endothelium-independent vasorelaxation. Percent relaxation from precontraction tension to 10"3 M SNP was similar in mesenteric (87±4 vs 93±2%) and iliac (85±6 vs 92±3%) arteries from KO vs WT mice. Our results indicate that insulin resistance per se impairs endothelial but not vascular smooth muscle function. These findings have important implications regarding the pathophysiology of cardiovascular disease in insulin-resistant and type 2 diabetic patients. Faculty S J. David Symons |