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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Impaired mitochondria-dependent vasodilation in cerebral arteries of Zucker obese rats with insulin resistance

¹Department of Physiology and Pharmacology and ²Wake Forest Institute of Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina; and ³Department of Physiology, Faculty of Medicine, University of Szeged, Szeged, Hungary

Submitted 5 August 2008 ; accepted in final form 4 November 2008

Mitochondria affect cerebrovascular tone by activation of mitochondrial ATP-sensitive K⁺ (K_ATP) channels and generation of reactive oxygen species (ROS). Insulin resistance accompanying obesity causes mitochondrial dysfunction, but the consequences on the cerebral circulation have not been fully identified. We evaluated the mitochondrial effects of diazoxide, a putative mitochondrial K_ATP channel activator, on cerebral arteries of Zucker obese (ZO) rats with insulin resistance and lean (ZL) controls. Diameter measurements showed diminished diazoxide-induced vasodilation in ZO compared with ZL rats. Maximal relaxation was 38 ± 3% in ZL vs. 21 ± 4% in ZO rats (P < 0.05). Iberiotoxin, a Ca²⁺-activated K⁺ channel inhibitor, or manganese(III) tetrakis(4-benzoic acid)porphyrin chloride, an SOD mimetic, or endothelial denudation diminished vasodilation to diazoxide, implicating Ca²⁺-activated K⁺ channels, ROS, and endothelial factors in vasodilation. Inhibition of nitric oxide synthase (NOS) in ZL rats diminished diazoxide-induced vasodilation in intact arteries, but vasodilation was unaffected in endothelium-denuded arteries. In contrast, NOS inhibition in ZO rats enhanced vasodilation in endothelium-denuded arteries, but intact arteries were unaffected, suggesting that activity of endothelial NOS was abolished, whereas factors derived from nonendothelial NOS promoted vasoconstriction. Fluorescence microscopy showed decreased mitochondrial depolarization, ROS production, and nitric oxide generation in response to diazoxide in ZO arteries. Protein and mRNA measurements revealed increased expression of endothelial NOS and SODs in ZO arteries. Thus, cerebrovascular dilation to mitochondria-derived factors involves integration of endothelial and smooth muscle mechanisms. Furthermore, mitochondria-mediated vasodilation was diminished in ZO rats due to impaired mitochondrial K_ATP channel activation, diminished mitochondrial ROS generation, increased ROS scavenging, and abnormal NOS activity.

diazoxide; depolarization; mitochondrial ATP-sensitive potassium channels; Zucker obese rats