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

Oral sulphonylureas, widely prescribed for diabetes, inhibit pancreatic ATP-sensitive K⁺ (K_ATP ) channels to increase insulin release. However, K_ATP 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 ( $$ O₂ max) and submaximal exercise tolerance (i.e. speed-duration relationship) during treadmill running in rats, before and after systemic K_ATP channel inhibition via glibenclamide. Glibenclamide impaired critical speed proportionally more than $$ O₂ max but did not alter resting cardiac output. Vascular K_ATP channel function (topical glibenclamide superfused onto hindlimb skeletal muscle) resolved a decreased blood flow and interstitial PO₂ during twitch contractions reflecting impaired O₂ delivery-to-utilization matching. Our findings demonstrate that systemic K_ATP channel inhibition reduces $$ O₂ max and critical speed during treadmill running in rats due, in part, to impaired convective and diffusive O₂ delivery, and thus $$ O₂ , especially within fast-twitch oxidative skeletal muscle.

Vascular ATP-sensitive K⁺ (K_ATP ) channels support skeletal muscle blood flow and microvascular oxygen delivery-to-utilization matching during exercise. However, oral sulphonylurea treatment for diabetes inhibits pancreatic K_ATP channels to enhance insulin release. Herein we tested the hypotheses that: i) systemic K_ATP channel inhibition via glibenclamide (GLI; 10 mg kg^-1 i.p.) would decrease cardiac output at rest (echocardiography), maximal aerobic capacity ( $$ O₂ max) and the speed-duration relationship (i.e. lower critical speed (CS)) during treadmill running; and ii) local K_ATP channel inhibition (5 mg kg^-1 GLI superfusion) would decrease blood flow (15 µm microspheres), interstitial space oxygen pressures (PO₂ is; phosphorescence quenching) and convective and diffusive O₂ transport ( $$ O₂ and DO₂ , 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^-1 ) 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^-1 , P > 0.05). During exercise, GLI reduced $$ O₂ max (71.5 ± 3.1 vs. 67.9 ± 4.8 ml kg^-1 min^-1 ) and CS (35.9 ± 2.4 vs. 31.9 ± 3.1 m min^-1 , both P < 0.05). Local K_ATP channel inhibition decreased MG blood flow (52 ± 25 vs. 34 ± 13 ml min^-1 100 g tissue^-1 ) and PO₂ is_nadir (5.9 ± 0.9 vs. 4.7 ± 1.1 mmHg) during twitch contractions. Furthermore, MG $$ O₂ was reduced via impaired $$ O₂ and DO₂ (P < 0.05 for each). Collectively, these data support that vascular K_ATP channels help sustain submaximal exercise tolerance in healthy rats. For patients taking sulfonylureas, K_ATP channel inhibition may exacerbate exercise intolerance.