Work

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

Year: 2020

Type: article

Abstract: Key points 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 ( O 2 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 O 2 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 PO 2 during twitch contractions reflecting impaired O 2 delivery‐to‐utilization matching. Our findings demonstrate that systemic K ATP channel inhibition reduces O 2 max and critical speed during treadmill running in rats due, in part, to impaired convective and diffusive O 2 delivery, and thus O 2 , especially within fast‐twitch oxidative skeletal muscle. Abstract 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 ( O 2 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 (PO 2 is ; phosphorescence quenching) and convective and diffusive O 2 transport ( O 2 and DO 2 , 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 O 2 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 PO 2 is nadir (5.9 ± 0.9 vs . 4.7 ± 1.1 mmHg) during twitch contractions. Furthermore, MG O 2 was reduced via impaired O 2 and DO 2 ( P < 0.05 for each). Collectively, these da

Source: The Journal of Physiology

DOI: 10.1113/jp280232