ATP‐sensitive K+ Channel Inhibition via Glibenclamide Impairs Maximal Aerobic Capacity and Critical Speed of Healthy Rats without Compromising Cardiac Function

Abstract

Glibenclamide (GLI) enhances insulin release for Type II diabetes patients by inhibiting pancreatic ATP‐sensitive K+ (KATP) channels. However, systemic KATP channel inhibition decreases maximal aerobic capacity (V̇O2max) during treadmill running in rats; where V̇O2max is determined by cardiac output (Q̇) and O2 utilization within contracting skeletal muscle (arterial‐venous O2 difference). In vitro studies demonstrate that KATP channels enhance isolated cardiomyocyte and vascular smooth muscle relaxation. In vivo studies show that GLI induces vasoconstriction, decreases blood flow, and impairs O2 delivery‐utilization matching in contracting skeletal muscle. Whether high‐intensity exercise tolerance (i.e. the speed‐duration relationship with critical speed, CS, and distance covered above CS, D′) is dependent upon cardiac and/or peripheral (i.e., vascular) KATP channel function in vivo is unknown.PURPOSETo determine the role of KATP channels in establishing cardiac function (see below), maximal aerobic capacity (V̇O2max) and sustaining submaximal exercise tolerance (CS). We hypothesized that acute KATP channel inhibition via GLI would decrease V̇O2max and CS, but not decrease cardiac function.METHODSTen adult female Sprague‐Dawley rats were assessed during the proestrus cycle in randomized order with and without GLI. GLI (10 mg kg−1 in DMSO i.p.) was administered 30–60 min prior to resting Doppler echocardiography and exercise tests. Doppler echocardiography measured Q̇, heart rate (HR), stroke volume (SV), ejection fraction (EF), fractional shortening (FS) and rates of left ventricular contraction and relaxation. V̇O2max and CS tests utilized a motorized treadmill at a 5% incline. V̇O2max was measured via plexiglass metabolic chamber connected to an O2 analyzer with increasing treadmill speed (5–10 m min−1) every minute until V̇O2 plateaued with increases in treadmill speed. Multiple (i.e., ≥5) constant speed runs to exhaustion were used to resolve CS and D′.RESULTSAt rest GLI did not alter SV, EF, FS, nor rates of left ventricular contraction and relaxation compared to control (p>0.05 for all). However, GLI did reduce HR (321 ± 8 vs 300 ± 7 b min−1) and V̇ (217 ± 23 vs 192 ± 13 mL min−1; p<0.05 for both). Despite HR and Q̇ reductions at rest, neither were significantly correlated with decreases in V̇O2max or CS (p>0.05 for both). GLI significantly reduced V̇O2max (69 ± 2 vs 72 ± 1 mL O2 kg−1 min−1), CS (32 ± 1 vs 36 ± 1 m min−1; n=8), and D′ (100 ± 6 vs 86 ± 8 m; n=7) compared to control (all p<0.05).CONCLUSIONSConsistent with our hypothesis, KATP channels are vital in establishing maximal aerobic capacity (GLI decreased V̇O2max ~4%) and exercise tolerance (GLI decreased CS ~12%). Therefore, we speculate that HR regulation via KATP channel activity is overridden during exercise. These data support that vascular KATP channel function is important for matching O2 delivery to O2 requirements within skeletal muscles and this plays a pivotal role in determining exercise tolerance. Thus GLI treatment may potentiate the exercise intolerance of diabetic and other cardiovascular disease patients.Support or Funding InformationHL108328This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.