Published online before print February 19, 2004, doi: 10.1161/01.STR.0000119753.05670.F1
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(Stroke. 2004;35:964.)
© 2004 American Heart Association, Inc.
Original Contributions |
Potassium Channel Dysfunction in Cerebral Arteries of Insulin-Resistant Rats Is Mediated by Reactive Oxygen Species
From the Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC (B.E., S.A.S., J.A.S., A.W.M., D.W.B.), and Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary (B.E.).
Correspondence to Benedek Erdös, MD, Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC 27157-1083. E-mail berdos{at}wfubmc.edu
Background and Purpose— Insulin resistance (IR) increases the risk of stroke in humans. One possible underlying factor is cerebrovascular dysfunction resulting from altered K+ channel function. Thus, the goal of this study was to examine K+ channel–mediated relaxation in IR cerebral arteries.
Methods— Experiments were performed on pressurized isolated middle cerebral arteries (MCAs) from fructose-fed IR and control rats.
Results— Dilator responses to iloprost, which are BKCa channel mediated, were reduced in the IR compared with control arteries (19±2% versus 33±2% at 10-6 mol/L). Similarly, relaxation to the KATP opener pinacidil was diminished in the IR MCAs (17±2%) compared with controls (38±2% at 10-5 mol/L). IR also reduced the KATP channel–dependent component in calcitonin gene-related peptide–induced dilation; however, the magnitude of the relaxation remained unchanged in IR because of a nonspecified K+ channel–mediated compensatory mechanism. In contrast, Kir channel–mediated relaxation elicited by increases in extracellular [K+] (4 to 12 mmol/L) was similar in the control and IR arteries. Blockade of the Kir and Kv channels with Ba2+ and 4-aminopyridine, respectively, constricted the MCAs in both experimental groups with no significant difference. Pretreatment of arteries with superoxide dismutase (200 U/mL) plus catalase (150 U/mL) restored the dilatory responses to iloprost and pinacidil in the IR arteries. Immunoblots showed that the expressions of the pore-forming subunits of the examined K+ channels are not altered by IR.
Conclusions— IR induces a type-specific K+ channel dysfunction mediated by reactive oxygen species. The alteration of KATP and BKCa channel–dependent vascular responses may be responsible for the increased risk of cerebrovascular events in IR.
Key Words: diabetes mellitus • insulin resistance • middle cerebral artery • potassium channels • oxidative stress • rats
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