Abstract
Mitochondria affect cerebrovascular tone by activation of mitochondrial ATP‐sensitive K+ channels (mitoKATP). Insulin resistance (IR) causes mitochondrial dysfunction, therefore, we evaluated the effects of diazoxide, a mitoKATP activator, on cerebral arteries of Zucker obese (ZO) rats and lean (ZL) controls. Diameter studies showed reduced vasodilation to diazoxide in ZO compared to ZL. Endothelial denudation reduced vasodilation to diazoxide in all arteries implicating endothelial mitoKATP. Inhibition of nitric oxide synthase (NOS) reduced vasodilation in intact arteries from ZL but not ZO, indicating diminished NO effects. Paradoxically, NOS inhibition in endothelium denuded arteries enhanced vasodilation in ZO implying the expression and uncoupling of NOS in vascular smooth muscle (VSM). Inhibition of cyclooxygenase (COX) enhanced vasodilation in intact arteries from ZL but not ZO. In contrast, endothelial denudation enhanced vasodilation in ZO but not ZL. Thus, ZO arteries exhibit enhanced production of both vasoconstrictor and vasodilator prostanoids. Fluorescence studies of rat cerebral microvascular endothelial cells showed enhanced NO production in response to diazoxide and also confirmed reduced NO generation in ZO arteries. Thus, endothelial mitochondrial dysfunction in ZO arteries results in the impairment of NOS and COX activity. Support: NIH HL077731, HL030260, HL 065380.
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