Alterations in KATP and KCa channel function in cerebral arteries of insulin-resistant rats

We examined whether insulin resistance alters the function of ATP-dependent and Ca2+-activated K+ channels (K-ATP and K-Ca channels, respectively) in pressurized isolated middle cerebral arteries (MCAs) from fructose-fed insulin-resistant (IR) and control rats. Blockade of K-Ca channels with tetraethylammonium chloride (TEA, 2.5 mM) or iberiotoxin (IBTX, 0.1 muM) increased the spontaneously developed tone in control MCAs by 10.5 +/- 1.3% (n = 10) and 13.3 +/- 2.3% (n = 6), respectively. In the IR arteries, TEA induced similar constrictions (8.0 +/- 1.1%, n = 10), but IBTX constricted the IR arteries by only 3.1 +/- 0.9% (n = 8; P < 0.01). Bradykinin (BK)-induced endothelium-mediated relaxation was reduced in IR MCAs. Maximum relaxation to BK (10(-6) M) was 42 +/- 4% in control (n = 9) and 19 +/- 2% in IR (n = 10; P < 0.01) arteries. Pretreatment with TEA, IBTX, or the K-ATP channel blocker glibenclamide (10 muM) inhibited relaxation to BK in control MCAs but did not alter dilation in IR arteries. Relaxation to the K-ATP channel opener cromakalim. was also diminished in IR MCAs. Maximum relaxation to cromakalim. (10(-5) M) was 48 +/- 3% in control (n = 6) and 19 +/- 2% in IR arteries (n = 6; P < 0.01). These findings demonstrate that insulin resistance alters the function of K-ATP and K-Ca channels in isolated MCAs and affects the control of resting vascular tone and the mediation of dilator stimuli.