Impaired mitochondria-dependent vasodilation in cerebral arteries of Zucker obese rats with insulin resistance.
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.
Katakam
Prasad V G
PV
Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA. pkatakam@wfubmc.edu
Domoki
Ferenc
F
Snipes
James A
JA
Busija
Anna R
AR
Jarajapu
Yagna P R
YP
Busija
David W
DW
D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D009574:Nitro Compounds / Q000494:pharmacology; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D009574:Nitro Compounds; D010455:Peptides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D011422:Propionates; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; C117780:mitochondrial K(ATP) channel; D009569:Nitric Oxide; C064719:iberiotoxin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D013482:Superoxide Dismutase; D013385:Succinate Dehydrogenase; D003981:Diazoxide; C015392:3-nitropropionic acid; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin