Vascular ATP‐sensitive K+ channels support maximal aerobic capacity and critical speed via convective and diffusive O2 transport. (1st September 2020)

• Record Type: Journal Article
• Authors: Colburn, Trenton D.; Weber, Ramona E.; Hageman, K. Sue; Caldwell, Jacob T.; Schulze, Kiana M.; Ade, Carl J.; Behnke, Brad J.; Poole, David C.; Musch, Timothy I.
• Is Part Of: Journal of physiology. Volume 598:Number 21(2020)
• Page Start: 4843
• Page End: 4858
• Publication Date: 2020-09-01
• Subjects: exercise tolerance -- gastrocnemius -- glibenclamide -- interstitial space oxygen pressure; Physiology -- Periodicals; 612.005
• DOI: 10.1113/JP280232
• Languages: English
• ISSNs: 0022-3751

Abstract

Abstract : Key points: Oral sulphonylureas, widely prescribed for diabetes, inhibit pancreatic ATP‐sensitive K + (KATP ) channels to increase insulin release. However, KATP 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 ( V ̇ O2 max ) and submaximal exercise tolerance (i.e. speed–duration relationship) during treadmill running in rats, before and after systemic KATP channel inhibition via glibenclamide. Glibenclamide impaired critical speed proportionally more than V ̇ O2 max but did not alter resting cardiac output. Vascular KATP 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 KATP channel inhibition reduces V ̇ O2 max and critical speed during treadmill running in rats due, in part, to impaired convective and diffusive O2 delivery, and thus V ̇ O2, especially within fast‐twitch oxidative skeletal muscle. Abstract: Vascular ATP‐sensitive K + (KATP ) channels support skeletal muscle blood flow and microvascular oxygen delivery‐to‐utilization matching during exercise. However, oral sulphonylurea treatment for diabetes inhibits pancreatic KATP channels to enhance insulin release. Herein we tested the hypotheses that: i) systemic KATP channel inhibition via glibenclamide (GLI; 10 mg kg −1 i.p. ) would decrease cardiac output at rest (echocardiography), maximal aerobic capacity ( V ̇ O2 max ) and the speed–duration relationship (i.e. lower critical speed (CS)) during treadmill running; and ii) local KATP 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 ( Q ̇ 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 V ̇ 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 KATP 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 V ̇ O2 was reduced via impaired Q ̇ O2 and DO2 ( P < 0.05 for each). Collectively, these data support that vascular KATP channels help sustain submaximal exercise tolerance in healthy rats. For patients taking sulfonylureas, KATP channel inhibition may exacerbate exercise intolerance. Key points: Oral sulphonylureas, widely prescribed for diabetes, inhibit pancreatic ATP‐sensitive K + (KATP ) channels to increase insulin release. However, KATP 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 ( V ̇ O2 max ) and submaximal exercise tolerance (i.e. speed–duration relationship) during treadmill running in rats, before and after systemic KATP channel inhibition via glibenclamide. Glibenclamide impaired critical speed proportionally more than V ̇ O2 max but did not alter resting cardiac output. Vascular KATP 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 KATP channel inhibition reduces V ̇ O2 max and critical speed during treadmill running in rats due, in part, to impaired convective and diffusive O2 delivery, and thus V ̇ O2, especially within fast‐twitch oxidative skeletal muscle.