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

Abstract

We examined whether insulin resistance alters the function of ATP-dependent and Ca²⁺-activated K⁺ channels (K_ATPand 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 μM) 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 μM) 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.