Sex And Fiber-type Differences: Vascular ATP-sensitive K + (K ATP ) Channels Support Critical Speed And Interstitial PO 2

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Glibenclamide (GLI), prescribed to Type II diabetes patients, enhances insulin release by inhibiting pancreatic KATP channels. KATP channels support maximal aerobic capacity (V̇O2max) and blood flow during treadmill running in male rats. Whether high-intensity exercise tolerance (i.e. critical speed, CS) and muscle O2 delivery-utilization matching (interstitial PO2, PO2is) is impaired, and whether sex differences exist in KATP function, are unknown. PURPOSE We hypothesized that systemic inhibition of KATP channels via GLI would decrease V̇O2max and CS, while local inhibition would decrease contracting PO2is and blood flow within fast-twitch oxidative (mixed gastrocnemius (MG)) and slow-twitch oxidative (soleus (SOL)) muscles with females (F and F+OVX) expressing the greatest reduction. METHODS: Male (n=12), female (n=10, proestrus) and ovariectomized female (F+OVX; n=12) Sprague-Dawley rats with and without GLI (10 mg kg-1 in DMSO i.p.). V̇O2max and CS were assessed using state-of-the art techniques on a motorized treadmill. 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 contractions and blood flow by fluorescent-labeled microspheres (15 μm). RESULTS: GLI decreased V̇O2max in female (71.5 ± 1.0 vs 67.9 ± 1.5) and F+OVX (76.8 ± 1.4 vs 74.4 ± 1.4; p<0.05 for both) but not males (81.5 ± 2.0 vs 80.8 ± 2.0 mL O2 min-1 kg-1; p>0.05). CS was reduced equivalently in all groups (8-11%; p<0.05). GLI reduced MG blood flow (female: 49 ± 9 vs 34 ± 5; male: 50 ± 5 vs 35 ± 4) and PO2is (female: 7.3 ± 0.5 vs 6.1 ± 0.5; male: 8.9 ± 1.1 vs 7.2 ± 0.5), but not SOL, of female and male rats (p<0.05). Conversely, in F+OVX, PO2is was reduced in the SOL (14.5 ± 1.5 vs 10.2 ± 1.1; p<0.05), but not MG. CONCLUSION: These data support the role of vascular KATP channels in exercise tolerance (i.e. CS) by matching O2 delivery-utilization with ovariectomy shifting KATP channel effects from fast- to slow-twitch muscles. Supported by NIH Grants: HL108328 and F31HL145981