Potassium channel dysfunction in cerebral arteries of insulin-resistant rats is mediated by reactive oxygen species.

Abstract

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. Experiments were performed on pressurized isolated middle cerebral arteries (MCAs) from fructose-fed IR and control rats. Dilator responses to iloprost, which are BK(Ca) 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 K(ATP) opener pinacidil was diminished in the IR MCAs (17+/-2%) compared with controls (38+/-2% at 10(-5) mol/L). IR also reduced the K(ATP) 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, K(ir) 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 K(ir) and K(v) 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. IR induces a type-specific K+ channel dysfunction mediated by reactive oxygen species. The alteration of K(ATP) and BK(Ca) channel-dependent vascular responses may be responsible for the increased risk of cerebrovascular events in IR.