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

Prasad V G Katakam, F. Domoki, James A. Snipes, Anna R. Busija, Yagna P R Jarajapu, David W. Busija

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Mitochondria affect cerebrovascular tone by activation of mitochondrial ATP-sensitive K+ (KATP) 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 KATP 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 KATP channel activation, diminished mitochondrial ROS generation, increased ROS scavenging, and abnormal NOS activity.

Original languageEnglish
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume296
Issue number2
DOIs
Publication statusPublished - Feb 2009

Fingerprint

Zucker Rats
Cerebral Arteries
Vasodilation
Diazoxide
Insulin Resistance
Mitochondria
Arteries
Reactive Oxygen Species
Nitric Oxide Synthase
Calcium-Activated Potassium Channels
Nitric Oxide Synthase Type III
Endothelium
Cerebrovascular Circulation
KATP Channels
Vasoconstriction
Fluorescence Microscopy
Smooth Muscle
Chlorides
Dilatation
Nitric Oxide

Keywords

  • Depolarization
  • Diazoxide
  • Mitochondrial ATP-sensitive potassium channels
  • Zucker obese rats

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Impaired mitochondria-dependent vasodilation in cerebral arteries of Zucker obese rats with insulin resistance. / Katakam, Prasad V G; Domoki, F.; Snipes, James A.; Busija, Anna R.; Jarajapu, Yagna P R; Busija, David W.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 296, No. 2, 02.2009.

Research output: Contribution to journalArticle

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abstract = "Mitochondria affect cerebrovascular tone by activation of mitochondrial ATP-sensitive K+ (KATP) 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 KATP 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 KATP channel activation, diminished mitochondrial ROS generation, increased ROS scavenging, and abnormal NOS activity.",
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