Vascular ATP‐sensitive K⁺ channels support maximal aerobic capacity and critical speed via convective and diffusive O₂ transport

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 (trueV̇O2max) 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 trueV̇O2max 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 trueV̇O2max and critical speed during treadmill running in rats due, in part, to impaired convective and diffusive O2 delivery, and thus trueV̇O2, 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 (trueV̇O2max) 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 (PO2is; phosphorescence quenching) and convective and diffusive O2 transport (trueQ̇O2 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 trueV̇O2max (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 PO2isnadir (5.9 ± 0.9 vs. 4.7 ± 1.1 mmHg) during twitch contractions. Furthermore, MG trueV̇O2 was reduced via impaired trueQ̇O2 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.

Regulation of capillary hemodynamics by K ATP channels in resting skeletal muscle

“…Our data are thus in agreement with some, but not all, reports of decreased arteriolar diameter (Hammer et al, 2001;Hodnett et al, 2008;Jackson, 1993;Lu et al, 2013;Murrant & Sarelius, 2002;Saito et al, 1996;Xiang & Hester, 2009) and bulk blood flow (Bank et al, 2000;Colburn, Weber, et al, 2020;Duncker et al, 2001;Farouque & Meredith, 2003a,b;Holdsworth et al, 2015;Vanelli & Hussain, 1994) following K ATP channel inhibition in the resting skeletal muscle. Potential reasons for this discrepancy include species differences, experimental models, GLI doses, K ATP channel density distribution, compensatory vasodilation by redundant pathways, muscle fiber type, and arteriolar size and branch order.…”

“…While there has been no prior evaluation of K ATP channel inhibition on contracting muscle capillary blood flow per se, studies on arteriolar diameter and bulk blood flow have produced contrasting evidence regarding the role of K ATP channels in functional hyperemia (Tykocki et al, 2017). Nonetheless, recent reports from our laboratory indicate that GLI lowers microvascular O 2 partial pressures (PO 2 ) as well as estimated DO 2 m in the contracting spinotrapezius and mixed gastrocnemius muscles (Colburn, Weber, et al, 2020;Holdsworth et al, 2016). Under these circumstances, intramyocyte PO 2 is expected to fall to generate the driving pressure (ΔPO 2 ) and possibly elevate intramyocyte O 2 diffusing capacity by and by further deoxygenating myoglobin as necessary to maintain a given metabolic rate as described by Fick's law of diffusion:…”

“…Superfusion of the spinotrapezius muscle with GLI was employed herein to locally inhibit K ATP channels in vivo. This topical drug delivery method was chosen to prevent the potential confound of alterations in central hemodynamics (e.g., MAP, HR, systemic vascular resistance), myocardial hemodynamics and function (e.g., coronary vascular conductance and O 2 delivery, left ventricular relaxation rate), sympathetic nerve activity, visceral organ blood flow, blood insulin and glucose concentration, among others with systemic drug administration as reported previously (Colburn, Holdsworth, et al, 2020;Colburn, Weber, et al, 2020;Duncker et al, 2001;Farouque & Meredith, 2003a;Holdsworth et al, 2015Holdsworth et al, , 2016Rocha et al, 2020;Thomas et al, 1997). Nonetheless, it is not possible to pinpoint the (4) VO 2 = DO 2 m × ΔPO 2 site of GLI action (e.g., across the vascular network and/ or among distinct cell types) with the current experimental protocol.…”

Sexual dimorphism in vascular ATP‐sensitive K+ channel function supporting interstitial via convective and/or diffusive O2 transport

“…In skeletal muscle, vascular K ATP channels have been implicated in reactive and functional hyperaemia (Banitt et al 1996;Bank et al 2000;Bijlstra et al 1996;Saito et al 1996). During submaximal treadmill running in male rats, vascular K ATP channels mediate increases in muscle blood flow (proportional to oxidative fibre content; K ATP channel inhibition via systemic GLI administration) (Holdsworth et al 2015) leading to enhanced matching of O 2 delivery-to-utilization (P O 2 ) during electrically-induced contractions in mixed and fast-twitch fibre muscles (local GLI) (Holdsworth et al 2016;Colburn et al 2020b) and support exercise tolerance in female rats during treadmill running (i.e. critical speed; systemic GLI) (Colburn et al 2020b).…”

“…During submaximal treadmill running in male rats, vascular K ATP channels mediate increases in muscle blood flow (proportional to oxidative fibre content; K ATP channel inhibition via systemic GLI administration) (Holdsworth et al 2015) leading to enhanced matching of O 2 delivery-to-utilization (P O 2 ) during electrically-induced contractions in mixed and fast-twitch fibre muscles (local GLI) (Holdsworth et al 2016;Colburn et al 2020b) and support exercise tolerance in female rats during treadmill running (i.e. critical speed; systemic GLI) (Colburn et al 2020b). GLI application prior to contractions/exercise significantly reduces functional dilatation of muscle arterioles and maximal aerobic capacity (V O 2 max =Q max × maximal a-vO 2 difference; local/systemic GLI, respectively) (Colburn et al 2020b;Lu et al 2013).…”