Cerebrovascular dysfunction in Zucker obese rats is mediated by oxidative stress and protein kinase C.
Insulin resistance (IR) impairs vascular function in the peripheral and coronary circulations, but its effects on cerebral arteries are virtually unexplored. We examined the vascular responses of the basilar artery (BA) and its side branches through a cranial window in Zucker lean (ZL) and IR Zucker obese (ZO) rats. Nitric oxide (NO) and K+ channel-mediated dilator responses, elicited by acetylcholine, iloprost, cromakalim, and elevated [K+], were greatly diminished in the ZO rats compared with ZL rats. In contrast, sodium nitroprusside induced similar relaxations in the two experimental groups. Expressions of the K+ channel pore-forming subunits were not affected by IR, while endothelial NO synthase was upregulated in the ZO arteries compared with ZL arteries. Protein kinase C (PKC) activity and production of superoxide anion were increased in the cerebral arteries of ZO rats, and pretreatment with superoxide dismutase restored all examined dilator responses. In contrast, application of PKC inhibitors improved only receptor-linked NO-mediated relaxation, but not K+ channel-dependent responses. Thus, IR induces in ZO rats cerebrovascular dysfunction, which is mediated by oxidative stress and partly by PKC activation. The revealed impairment of NO and K+ channel-dependent dilator responses may be responsible for the increased risk of cerebrovascular events and neurodegenerative disorders in IR.
Erdös
Benedek
B
Department of Physiology and Pharmacology, Wake Forest University Health Science, Medical Center Boulevard, Winston-Salem, NC 27157-1083, USA. berdos@wfubmc.edu
Snipes
James A
JA
Miller
Allison W
AW
Busija
David W
DW
D000818:Animals; D002560:Cerebrovascular Circulation; D004789:Enzyme Activation; D007333:Insulin Resistance; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D018384:Oxidative Stress; D015221:Potassium Channels / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000378:metabolism; D014664:Vasodilation
D015221:Potassium Channels; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D011493:Protein Kinase C