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

Glibenclamide (GLI) enhances insulin release for Type II diabetes patients by inhibiting pancreatic ATP‐sensitive K + (K ATP ) channels. However, systemic K ATP channel inhibition decreases maximal aerobic capacity (V̇O 2 max) during treadmill running in rats; where V̇O 2 max is determined by cardiac output (Q̇) and O 2 utilization within contracting skeletal muscle (arterial‐venous O 2 difference). In vitro studies demonstrate that K ATP channels enhance isolated cardiomyocyte and vascular smooth muscle relaxation. In vivo studies show that GLI induces vasoconstriction, decreases blood flow, and impairs O 2 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) K ATP channel function in vivo is unknown. PURPOSE To determine the role of K ATP channels in establishing cardiac function (see below), maximal aerobic capacity (V̇O 2 max) and sustaining submaximal exercise tolerance (CS). We hypothesized that acute K ATP channel inhibition via GLI would decrease V̇O 2 max and CS, but not decrease cardiac function. METHODS Ten 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. V̇O 2 max and CS tests utilized a motorized treadmill at a 5% incline. V̇O 2 max was measured via plexiglass metabolic chamber connected to an O 2 analyzer with increasing treadmill speed (5–10 m min −1 ) every minute until V̇O 2 plateaued with increases in treadmill speed. Multiple (i.e., ≥5) constant speed runs to exhaustion were used to resolve CS and D′. RESULTS At 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 V̇O 2 max or CS (p>0.05 for both). GLI significantly reduced V̇O 2 max (69 ± 2 vs 72 ± 1 mL O 2 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). CONCLUSIONS Consistent with our hypothesis, K ATP channels are vital in establishing maximal aerobic capacity (GLI decreased V̇O 2 max ~4%) and exercise tolerance (GLI decreased CS ~12%). Therefore, we speculate that HR regulation via K ATP channel activity is overridden during exercise. These data support that vascular K ATP channel function is important for matching O 2 delivery to O 2 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 Information HL108328 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .