Fiber‐Type Effects of KATP Channel Inhibition via Glibenclamide on the Recovery of Interstitial PO2 Following Muscle Contractions in Rats

Abstract

KATP channels allow influx of potassium (K+) which hyperpolarizes cell membranes. Glibenclamide (GLI) is a second‐order sulphonylurea often prescribed to Type II diabetic patients to increase insulin release via the inhibition of pancreatic KATP channels. Unfortunately, in vivo studies demonstrate that GLI impairs vasodilation and O2 delivery‐utilization matching (assessed via interstitial PO2, PO2is) in contracting skeletal muscle. Determination of GLI’s impact on PO2is kinetics (T63; time taken to reach 63% of the final response) across muscles comprised of different fiber types during post‐exercise recovery may provide novel insights into mechanisms of fatigue in patients prescribed this medication, particularly in repeated bouts of activity.PurposeTo test the hypothesis that KATP channel inhibition via GLI will slow PO2is kinetics, thus lengthening recovery time following contractions in rat fast‐(mixed gastrocnemius, MG) and slow‐(soleus, SOL) twitch muscles.MethodsIn twenty Sprague‐Dawley rats (male (n=5), female (n=8) and ovariectomized female (F‐OVX; n=7)), PO2is was determined, before and after GLI superfusion (5 mg kg−1), via phosphorescence quenching (G4). Measurements were taken for 3 min throughout the duration of, and 3 min following, the cessation of electrically‐induced contractions (180 s, 1 Hz, 7V). Blood flow was measured via fluorescent‐labeled microspheres in the last 30 seconds of contractions (15 μm).ResultsIn both muscles, PO2is recovered to its precontracting level in control and GLI conditions within the 3 min measurement window. However, GLI significantly slowed PO2is recovery following contractions in the MG (T63: 87.7 ± 4.6 vs 117.4 ± 7.9 s; p < 0.05), but not in the SOL (73.7 ± 8.8 vs 84.8 ± 11.2 s; p > 0.05). The PO2is value at which T63 occurred was not significantly different between the control and GLI conditions for MG or SOL. During contractions, blood flow was attenuated in the MG following GLI (53 ± 4 vs 39 ± 3 ml/100 g/min; p < 0.05), but not in the SOL (37 ± 4 vs 35 ± 5; p > 0.05).ConclusionThese data highlight the role of KATP channel function in supporting PO2is recovery of fast‐twitch oxidative fiber types due in part to elevated blood flow. These effects of sulphonylurea medication (i.e. GLI) may explain, in part, the early onset of exhaustion in patients performing high‐intensity exercise and/or activities of daily living that recruit fast‐twitch muscles.Support or Funding InformationSupported by NIH Grants: HL108328 (T.I.M and D.C.P) and F31HL145981 (T.D.C)