No abstract

Within skeletal muscle the greatest resistance to oxygen transport is thought to reside across the short distance at the red blood cell-myocyte interface. These structures generate a significant transmural oxygen pressure (PO 2) gradient in mixed fibre-type muscle. r Increasing O 2 flux across the capillary wall during exercise depends on: (i) the transmural O 2 pressure gradient, which is maintained in mixed-fibre muscle, and/or (ii) elevating diffusing properties between microvascular and interstitial compartments resulting, in part, from microvascular haemodynamics and red blood cell distribution. r We evaluated the PO 2 within the microvascular and interstitial spaces of muscles spanning the slow-to fast-twitch fibre and high-to low-oxidative capacity spectrums, at rest and during contractions, to assess the magnitude of transcapillary PO 2 gradients in rats. r Our findings demonstrate that, across the metabolic rest-contraction transition, the transcapillary pressure gradient for O 2 flux is: (i) maintained in all muscle types, and (ii) the lowest in contracting highly oxidative fast-twitch muscle.

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.

This is the first study, to our knowledge, demonstrating that mechanical ventilation, with low and high positive end-expiratory pressure (PEEP), increases vascular resistance and reduces total and regional diaphragm perfusion. The rapid reduction in diaphragm perfusion and increased vascular resistance may initiate a cascade of events that predispose the diaphragm to vascular and thus contractile dysfunction with prolonged mechanical ventilation.

During mechanical ventilation (MV), supplemental oxygen (O2) is commonly administered to critically ill patients to combat hypoxemia.Previous studies demonstrate that hyperoxia exacerbates MV-induced diaphragm oxidative stress and contractile dysfunction. Whereas normoxic MV (i.e. 21% O2) diminishes diaphragm perfusion and O2 delivery, the effect of MV with 100% O2 is unknown. We hypothesized that MV with 100% O2 would decrease diaphragmatic blood flow and O2 delivery to a greater extent than MV alone. Female Sprague-Dawley rats (~6 mo) were divided into two groups: 1) MV + 100% O2 followed by MV + 21% O2 (n = 9) or 2) MV + 21% O2 followed by MV + 100% O2 (n = 10). Diaphragmatic blood flow and vascular resistance were determined, via fluorescent microspheres, during spontaneous breathing (SB), MV + 100% O2 and MV + 21% O2. Compared to SB, total diaphragm vascular resistance was increased, and blood flow was decreased with both MV + 100% O2 and MV + 21% O2 (P <0.05). Medial costal diaphragmatic blood flow was lower with MV + 100% O2 (26 ± 6 ml/min/100g) versus MV + 21% O2 (51 ± 15 ml/min/100g; P < 0.05). The addition of 100% O2 during normoxic MV exacerbated the MV-induced reductions in medial costal diaphragm perfusion (23 ± 7 versus 51 ± 15 ml/min/100g; P < 0.05) and O2 delivery (3.4 ± 0.2 versus 6.4 ± 0.3 ml O2/min/100g; P < 0.05). These data demonstrate that supplemental 100% O2 during MV increases diaphragm vascular resistance and diminishes perfusion and O2 delivery to a greater degree than normoxic MV, and may accelerate MV-induced vascular dysfunction.