Vascular ATP‐sensitive K+ (KATP) Channels: Sex and Fiber‐type Differences in the Support of Contracting Muscle Blood Flow and Interstitial PO2

Abstract

Glibenclamide (GLI), prescribed to Type II diabetes patients, enhances insulin release by inhibiting pancreatic KATP channels. KATP channels support maximal aerobic capacity (V̇O2max; determined by cardiac output (Q̇) and O2 utilization within contracting skeletal muscle (arterial‐venous O2 difference)) and blood flow during treadmill running in male rats. High‐intensity exercise tolerance (critical speed, CS) is impaired by GLI but is not correlated with reductions in resting cardiac function (Q̇) which highlights the role for peripheral vascular KATP channel function to protect against fatigue. Whether muscle O2 delivery‐utilization matching (interstitial PO2, PO2is) is impaired by GLI in a fiber‐type specific manner, and whether sex differences exist in KATP function, are unknown.PURPOSEWe hypothesized that local inhibition of KATP channels via GLI would decrease PO2is and blood flow within contracting fast‐twitch oxidative (mixed gastrocnemius (MG)) and slow‐twitch oxidative (soleus (SOL)) muscles with females (F) exhibiting the greatest reduction.METHODSMale (n=8), female (n=9, proestrus) and ovariectomized female (F+OVX; n=11) Sprague‐Dawley rats were utilized in these experiments. PO2is was determined, before and after GLI superfusion (5 mg kg−1), via phosphorescence quenching (G4) in the exposed MG and SOL muscles during electrically‐induced twitch contractions (180 s, 7V, 1Hz). Blood flow was assessed via infusion of fluorescent‐labeled microspheres (15 μm) at 180 s of contractions.RESULTSGLI reduced MG blood flow (female: 49 ± 9 vs 34 ± 5; male: 50 ± 5 vs 35 ± 4 ml min−1 100 g−1), nadir PO2is (female: 5.9 ± 0.3 vs 4.7 ± 0.3; male: 6.8 ± 0.7 vs 5.5 ± 0.4) and end‐contraction PO2is (female: 7.3 ± 0.5 vs 6.1 ± 0.5; male: 8.9 ± 1.1 vs 7.2 ± 0.5 mmHg), but did not impact SOL, of female and male rats (p<0.05). Conversely, in F+OVX, PO2is was reduced in the SOL (nadir: 12.5 ± 1.5 vs 8.8 ± 0.9; end‐contraction: 14.5 ± 1.5 vs 10.2 ± 1.1 mmHg; p<0.05), but not MG.CONCLUSIONThese data support the role of vascular KATP channels in supporting muscle O2 delivery and high‐intensity exercise tolerance by matching O2 delivery‐utilization with ovariectomy shifting KATP channel effects from fast‐ to slow‐twitch muscles. Thus GLI treatment in diabetic and other cardiovascular disease patients may potentiate exercise intolerance, especially for post‐menopausal females where compromised slow‐twitch fiber function impairs the ability or willingness to engage in low intensity exercise.Support or Funding InformationSupported by NIH Grants: HL108328 (D.C.P and T.I.M) and F31HL145981 (T.D.C)