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Impaired generation of NO and mitochondrial superoxide underlie abnormal diazoxide induced vasodilation in insulin resistance
Author(s) -
Katakam Prasad V.G.,
Snipes James A.,
Busija David W.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1226.14
Subject(s) - diazoxide , apocynin , vasodilation , endocrinology , medicine , chemistry , superoxide , insulin resistance , mitochondrion , nadph oxidase , insulin , oxidative stress , biochemistry , enzyme
Insulin resistance (IR) is a risk factor for cerebrovascular disease. We evaluated responses to diazoxide, a putative mitochondrial K ATP channel opener, in cerebral arteries from Zucker obese rats (ZO) with IR and lean rats (ZL). Diameter changes to diazoxide were determined in the presence and absence of endothelium and inhibitors of eNOS (L‐NAME) and NADPH oxidase (apocynin). Changes in mitochondrial membrane potential (TMRE) and superoxide (HEt) in response to diazoxide were also determined. Diazoxide induced vasodilation was reduced in ZO compared to ZL (‰ maximal dilation: 37±3 in ZL vs. 21±4 in ZO, p<0.05). Vasodilation was reduced by endothelial denudation or L‐NAME but unaffected by apocynin in both groups. Diazoxide induced vasodilation was accompanied by similar TMRE fluorescence changes in both while ‰increase in HEt fluorescence was diminished in ZO (74±19) vs. ZL (180±33, p<0.05). Thus, diazoxide induced vasodilation in cerebral arteries was partly mediated by endothelium and NO. Reduced production of NO and/or mitochondrial superoxide appears to underlie the impaired vasodilation to diazoxide in IR. Support: NIH grants HL‐030260, HL‐065380, HL‐077731.