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 (KATPand KCa channels, respectively) in pressurized isolated middle cerebral arteries (MCAs) from fructose-fed insulin-resistant (IR) and control rats. Blockade of KCa 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 KATP channel blocker glibenclamide (10 μM) inhibited relaxation to BK in control MCAs but did not alter dilation in IR arteries. Relaxation to the KATP 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 KATP and KCa channels in isolated MCAs and affects the control of resting vascular tone and the mediation of dilator stimuli.