Vascular ATP-sensitive K + channels support maximal aerobic capacity and critical speed via convective and diffusive O 2 transport

Oral sulphonylureas, widely prescribed for diabetes, inhibit pancreatic ATP-sensitive K (K ) channels to increase insulin release. However, K channels are also located within vascular (endothelium and smooth muscle) and muscle (cardiac and skeletal) tissue. We evaluated left ventricular function at rest, maximal aerobic capacity ( O max) and submaximal exercise tolerance (i.e. speed-duration relationship) during treadmill running in rats, before and after systemic K channel inhibition via glibenclamide. Glibenclamide impaired critical speed proportionally more than O max but did not alter resting cardiac output. Vascular K channel function (topical glibenclamide superfused onto hindlimb skeletal muscle) resolved a decreased blood flow and interstitial PO during twitch contractions reflecting impaired O delivery-to-utilization matching. Our findings demonstrate that systemic K channel inhibition reduces O max and critical speed during treadmill running in rats due, in part, to impaired convective and diffusive O delivery, and thus O , especially within fast-twitch oxidative skeletal muscle. Vascular ATP-sensitive K (K ) channels support skeletal muscle blood flow and microvascular oxygen delivery-to-utilization matching during exercise. However, oral sulphonylurea treatment for diabetes inhibits pancreatic K channels to enhance insulin release. Herein we tested the hypotheses that: i) systemic K channel inhibition via glibenclamide (GLI; 10 mg kg i.p.) would decrease cardiac output at rest (echocardiography), maximal aerobic capacity ( O max) and the speed-duration relationship (i.e. lower critical speed (CS)) during treadmill running; and ii) local K channel inhibition (5 mg kg GLI superfusion) would decrease blood flow (15 µm microspheres), interstitial space oxygen pressures (PO is; phosphorescence quenching) and convective and diffusive O transport ( O and DO , respectively; Fick Principle and Law of Diffusion) in contracting fast-twitch oxidative mixed gastrocnemius muscle (MG: 9% type I+IIa fibres). At rest, GLI slowed left ventricular relaxation (2.11 ± 0.59 vs. 1.70 ± 0.23 cm s ) and decreased heart rate (321 ± 23 vs. 304 ± 22 bpm, both P < 0.05) while cardiac output remained unaltered (219 ± 64 vs. 197 ± 39 ml min , P > 0.05). During exercise, GLI reduced O max (71.5 ± 3.1 vs. 67.9 ± 4.8 ml kg min ) and CS (35.9 ± 2.4 vs. 31.9 ± 3.1 m min , both P < 0.05). Local K channel inhibition decreased MG blood flow (52 ± 25 vs. 34 ± 13 ml min 100 g tissue )