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Impaired insulin-induced vasodilation in small coronary arteries of Zucker obese rats is mediated by reactive oxygen species. Am J Physiol Heart Circ Physiol 288: H854 -H860, 2005; doi:10.1152/ajpheart.00715. 2004.-Insulin resistance (IR) and associated hyperinsulinemia are major risk factors for coronary artery disease. Mechanisms linking hyperinsulinemia to coronary vascular dysfunction in IR are unclear. We evaluated insulin-induced vasodilation in isolated small coronary arteries (SCA; ϳ225 m) of Zucker obese (ZO) and control Zucker lean (ZL) rats. Vascular responses to insulin (0.1-100 ng/ml), ACh (10 Ϫ9 -10 Ϫ5 mol/l), and sodium nitroprusside (10 Ϫ8 -10 Ϫ4 mol/l) were assessed in SCA by measurement of intraluminal diameter using videomicroscopy. Insulin-induced dilation was decreased in ZO compared with ZL rats, whereas ACh and sodium nitroprusside elicited similar vasodilations. Pretreatment of arteries with SOD (200 U/ml), a scavenger of reactive oxygen species (ROS), restored the vasorelaxation response to insulin in ZO arteries, whereas ZL arteries were unaffected. Pretreatment of SCA with N-nitro-L-arginine methyl ester (100 mol/l), an inhibitor of endothelial nitric oxide (NO) synthase (eNOS), elicited a vasoconstrictor response to insulin that was greater in ZO than in ZL rats. This vasoconstrictor response was reversed to vasodilation in ZO and ZL rats by cotreatment of the SCA with SOD or apocynin (10 mol/l), a specific inhibitor of vascular NADPH oxidase. Lucigenin-enhanced chemiluminescence showed increased basal ROS levels as well as insulin (330 ng/ml)-stimulated production of ROS in ZO arteries that was sensitive to inhibition by apocynin. Western blot analysis revealed increased eNOS expression in ZO rats, whereas Mn SOD and Cu,Zn SOD expression were similar to ZL rats. Thus IR in ZO rats leads to decreased insulin-induced vasodilation, probably as a result of increased production of ROS by vascular NADPH oxidase, leading to decreased NO bioavailability, despite a compensatory increase in eNOS expression.superoxide; NADPH oxidase; hyperinsulinemia; endothelial nitric oxide synthase INSULIN RESISTANCE (IR) and accompanying hyperinsulinemia have been identified as independent risk factors for hypertension, coronary artery disease, and stroke (7, 39, 46, 48a). Vascular dysfunction in IR and type 2 diabetes [non-insulindependent diabetes mellitus (NIDDM)] has been characterized as a combination of an impaired ability to vasodilate and/or an enhanced sensitivity to vasoconstrictor agonists. Importantly, reactive oxygen species (ROS) and insulin are recognized as two key players in the pathogenesis of vascular dysfunction in IR and NIDDM (4,6,24,27,35,46). 1) ROS decreases the bioavailability of nitric oxide (NO) and impairs vasodilation. ROS, such as superoxide and its reactive nitrogen derivative peroxynitrite, are known vasoconstrictors in many vascular beds (34,36,38,42,51). 2) Insulin exhibits vasodilator and vasoconstrictor actions. Acute vasodilator effects of insulin have been shown to be...

Background and Purpose-Insulin resistance (IR) increases the risk of stroke in humans. One possible underlying factor is cerebrovascular dysfunction resulting from altered K ϩ channel function. Thus, the goal of this study was to examine K ϩ channel-mediated relaxation in IR cerebral arteries. Methods-Experiments were performed on pressurized isolated middle cerebral arteries (MCAs) from fructose-fed IR and control rats. Results-Dilator responses to iloprost, which are BK Ca channel mediated, were reduced in the IR compared with control arteries (19Ϯ2% versus 33Ϯ2% at 10 Ϫ6 mol/L). Similarly, relaxation to the K ATP opener pinacidil was diminished in the IR MCAs (17Ϯ2%) compared with controls (38Ϯ2% at 10 Ϫ5 mol/L). IR also reduced the K ATP channel-dependent component in calcitonin gene-related peptide-induced dilation; however, the magnitude of the relaxation remained unchanged in IR because of a nonspecified K ϩ channel-mediated compensatory mechanism. In contrast, K ir channel-mediated relaxation elicited by increases in extracellular [K ϩ ] (4 to 12 mmol/L) was similar in the control and IR arteries. Blockade of the K ir and K v channels with Ba 2ϩ and 4-aminopyridine, respectively, constricted the MCAs in both experimental groups with no significant difference. Pretreatment of arteries with superoxide dismutase (200 U/mL) plus catalase (150 U/mL) restored the dilatory responses to iloprost and pinacidil in the IR arteries. Immunoblots showed that the expressions of the pore-forming subunits of the examined K ϩ channels are not altered by IR. Conclusions-IR