Search

Passive leg movement (PLM) evokes a robust and predominantly nitric oxide (NO)-mediated increase in blood flow that declines with age and disease. Consequently, PLM is becoming increasingly accepted as a sensitive assessment of endothelium-mediated vascular function. However, a substantial PLM-induced hyperemic response is still evoked despite nitric oxide synthase (NOS) inhibition. Therefore, in nine young healthy men (25 ± 4 yr), this investigation aimed to determine whether the combination of two potent endothelium-dependent vasodilators, specifically prostaglandin (PG) and endothelium-derived hyperpolarizing factor (EDHF), account for the remaining hyperemic response to the two variants of PLM, PLM (60 movements) and single PLM (sPLM, 1 movement), when NOS is inhibited. The leg blood flow (LBF, Doppler ultrasound) response to PLM and sPLM following the intra-arterial infusion of N G -monomethyl-l-arginine (l-NMMA), to inhibit NOS, was compared to the combined inhibition of NOS, cyclooxygenase (COX), and cytochrome P -450 (CYP450) by l-NMMA, ketorolac tromethamine (KET), and fluconazole (FLUC), respectively. NOS inhibition attenuated the overall LBF [area under the curve (LBF AUC )] response to both PLM (control: 456 ± 194, l-NMMA: 168 ± 127 mL, P < 0.01) and sPLM (control: 185 ± 171, l-NMMA: 62 ± 31 mL, P = 0.03). The combined inhibition of NOS, COX, and CYP450 (i.e., l-NMMA+KET+FLUC) did not further attenuate the hyperemic responses to PLM (LBF AUC : 271 ± 97 mL, P > 0.05) or sPLM (LBF AUC : 72 ± 45 mL, P > 0.05). Therefore, PG and EDHF do not collectively contribute to the non-NOS-derived NO-mediated, endothelium-dependent hyperemic response to either PLM or sPLM in healthy young men. These findings add to the mounting evidence and understanding of the vasodilatory pathways assessed by the PLM and sPLM vascular function tests. NEW & NOTEWORTHY Passive leg movement (PLM) evokes a highly nitric oxide (NO)-mediated hyperemic response and may provide a novel evaluation of vascular function. The contributions of endothelium-dependent vasodilatory pathways, beyond NO and including prostaglandins and endothelium-derived hyperpolarizing factor, to the PLM-induced hyperemic response to PLM have not been evaluated. With intra-arterial drug infusion, the combined inhibition of nitric oxide synthase (NOS), cyclooxygenase, and cytochrome P -450 (CYP450) pathways did not further diminish the hyperemic response to PLM compared with NOS inhibition alone.

Key Points: 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. 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. 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. 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., Abstract: In mixed fibre-type skeletal muscle transcapillary PO 2 gradients (PO 2 mv-PO 2 is; microvascular and interstitial, respectively) drive O 2 flux across the blood-myocyte interface where the greatest resistance to that O 2 flux resides. We assessed a broad spectrum of fibre-type and oxidative-capacity rat muscles across the rest-to-contraction (1 Hz, 120 s) transient to test the novel hypotheses that: (i) slow-twitch PO 2 is would be greater than fast-twitch, (ii) muscles with greater oxidative capacity have greater PO 2 is than glycolytic counterparts, and (iii) whether PO 2 mv-PO 2 is at rest is maintained during contractions across all muscle types. PO 2 mv and PO 2 is were determined via phosphorescence quenching in soleus (SOL; 91% type I+IIa fibres and CSa: ∼21 μmol min -1 g -1 ), peroneal (PER; 33% and ∼20 μmol min -1 g -1 ), mixed (MG; 9% and ∼26 μmol min -1 g -1 ) and white gastrocnemius (WG; 0% and ∼8 μmol min -1 g -1 ) across the rest-contraction transient. PO 2 mv was higher than PO 2 is in each muscle (∼6-13 mmHg; P < 0.05). SOL PO 2 is area was greater than in the fast-twitch muscles during contractions (P < 0.05). Oxidative muscles had greater PO 2 is nadir (9.4 ± 0.8, 7.4 ± 0.9 and 6.4 ± 0.4; SOL, PER and MG, respectively) than WG (3.0 ± 0.3 mmHg, P < 0.05). The magnitude of PO 2 mv-PO 2 is at rest decreased during contractions in MG only (∼11 to 7 mmHg; time × (PO 2 mv-PO 2 is) interaction, P < 0.05). These data support the hypothesis that, since transcapillary PO 2 gradients during contractions are maintained in all muscle types, increased O 2 flux must occur via enhanced intracapillary diffusing conductance, which is most extreme in highly oxidative fast-twitch muscle., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

The oxygen partial pressure in the interstitial space (Po 2 is ) drives O 2 into the myocyte via diffusion, thus supporting oxidative phosphorylation. Although crucial for metabolic recovery and the capacity to perform repetitive tasks, the time course of skeletal muscle Po 2 is during recovery from contractions remains unknown. We tested the hypothesis that Po 2 is would recover to resting values and display considerable on-off asymmetry (fast on-, slow off-kinetics), reflective of asymmetric capillary hemodynamics. Microvascular Po 2 (Po 2 mv ) was also evaluated to test the hypothesis that a significant transcapillary gradient (ΔPo 2  = Po 2 mv - Po 2 is ) would be sustained during recovery. Po 2 mv and Po 2 is (expressed in mmHg) were determined via phosphorescence quenching in the exposed rat spinotrapezius muscle during and after submaximal twitch contractions ( n = 12). Po 2 is rose exponentially ( P < 0.05) from end-contraction (11.1 ± 5.1), such that the end-recovery value (17.9 ± 7.9) was not different from resting Po 2 is (18.5 ± 8.1; P > 0.05). Po 2 is off-kinetics were slower than on-kinetics (mean response time: 53.1 ± 38.3 versus 18.5 ± 7.3 s; P < 0.05). A significant transcapillary ΔPo 2 observed at end-contraction (16.6 ± 7.4) was maintained throughout recovery (end-recovery: 18.8 ± 9.6; P > 0.05). Consistent with our hypotheses, muscle Po 2 is recovered to resting values with slower off-kinetics compared with the on-transient in line with the on-off asymmetry for capillary hemodynamics. Maintenance of a substantial transcapillary ΔPo 2 during recovery supports that the microvascular-interstitium interface provides considerable resistance to O 2 transport. As dictated by Fick's law (V̇o 2  = Do 2 × ΔPo 2 ), modulation of O 2 flux (V̇o 2 ) during recovery must be achieved via corresponding changes in effective diffusing capacity (Do 2 ; mainly capillary red blood cell hemodynamics and distribution) in the face of unaltered ΔPo 2 . NEW & NOTEWORTHY Capillary blood-myocyte O 2 flux (V̇o 2 ) is determined by effective diffusing capacity (Do 2 ; mainly erythrocyte hemodynamics and distribution) and microvascular-interstitial Po 2 gradients (ΔPo 2  = Po 2 mv - Po 2 is ). We show that Po 2 is demonstrates on-off asymmetry consistent with Po 2 mv and erythrocyte kinetics during metabolic transitions. A substantial transcapillary ΔPo 2 was preserved during recovery from contractions, indicative of considerable resistance to O 2 diffusion at the microvascular-interstitium interface. This reveals that effective Do 2 declines in step with V̇o 2 during recovery, as per Fick's law.

Exercise intolerance is a primary symptom of heart failure (HF); however, the specific contribution of central and peripheral factors to this intolerance is not well described. The hyperbolic relationship between exercise intensity and time to exhaustion (speed-duration relationship) defines exercise tolerance but is underused in HF. We tested the hypotheses that critical speed (CS) would be reduced in HF, resting central functional measurements would correlate with CS, and the greatest HF-induced peripheral dysfunction would occur in more oxidative muscle. Multiple treadmill-constant speed runs to exhaustion were used to quantify CS and D' (distance coverable above CS) in healthy control (Con) and HF rats. Central function was determined via left ventricular (LV) Doppler echocardiography [fractional shortening (FS)] and a micromanometer-tipped catheter [LV end-diastolic pressure (LVEDP)]. Peripheral O 2 delivery-to-utilization matching was determined via phosphorescence quenching (interstitial Po 2 , Po 2 is ) in the soleus and white gastrocnemius during electrically induced twitch contractions (1 Hz, 8V). CS was lower in HF compared with Con (37 ± 1 vs. 44 ± 1 m/min, P < 0.001), but D' was not different (77 ± 8 vs. 69 ± 13 m, P = 0.6). HF reduced FS (23 ± 2 vs. 47 ± 2%, P < 0.001) and increased LVEDP (15 ± 1 vs. 7 ± 1 mmHg, P < 0.001). CS was related to FS ( r  = 0.72, P = 0.045) and LVEDP ( r  = -0.75, P = 0.02) only in HF. HF reduced soleus Po 2 is at rest and during contractions (both P < 0.01) but had no effect on white gastrocnemius Po 2 is ( P > 0.05). We show in HF rats that decrements in central cardiac function relate directly with impaired exercise tolerance (i.e., CS) and that this compromised exercise tolerance is likely due to reduced perfusive and diffusive O 2 delivery to oxidative muscles. NEW & NOTEWORTHY We show that critical speed (CS), which defines the upper boundary of sustainable activity, can be resolved in heart failure (HF) animals and is diminished compared with controls. Central cardiac function is strongly related with CS in the HF animals, but not controls. Skeletal muscle O 2 delivery-to-utilization dysfunction is evident in the more oxidative, but not glycolytic, muscles of HF rats and is explained, in part, by reduced nitric oxide bioavailability.

The oxygen transport pathway from air to mitochondria involves a series of transfer steps within closely integrated systems (pulmonary, cardiovascular, and tissue metabolic). Small and finite O 2 stores in most mammalian species require exquisitely controlled changes in O 2 flux rates to support elevated ATP turnover. This is especially true for the contracting skeletal muscle where O 2 requirements may increase two orders of magnitude above rest. This brief review focuses on the mechanistic bases for increased microvascular blood-myocyte O 2 flux (V̇O 2 ) from rest to contractions. Fick's law dictates that V̇O 2 elevations driven by muscle contractions are produced by commensurate changes in driving force (ie, O 2 pressure gradients; ΔPO 2 ) and/or effective diffusing capacity (DO 2 ). While previous evidence indicates that increased DO 2 helps modulate contracting muscle O 2 flux, up until recently the role of the dynamic ΔPO 2 across the capillary wall was unknown. Recent phosphorescence quenching investigations of both microvascular and novel interstitial PO 2 kinetics in health have resolved an important step in the O 2 cascade between the capillary and myocyte. Specifically, the significant transmural ΔPO 2 at rest was sustained (but not increased) during submaximal contractions. This supports the contention that the blood-myocyte interface provides a substantial effective resistance to O 2 diffusion and underscores that modulations in erythrocyte hemodynamics and distribution (DO 2 ) are crucial to preserve the driving force for O 2 flux across the capillary wall (ΔPO 2 ) during contractions. Investigation of the O 2 transport pathway close to muscle mitochondria is key to identifying disease mechanisms and develop therapeutic approaches to ameliorate dysfunction and exercise intolerance., (© 2018 John Wiley & Sons Ltd.)

Premenopausal women express reduced blood pressure and risk of cardiovascular disease relative to age-matched men. This purportedly relates to elevated estrogen levels increasing nitric oxide synthase (NOS) activity and NO-mediated vasorelaxation. We tested the hypotheses that female rat skeletal muscle would: 1) evince a higher O 2 delivery-to-utilization ratio (Q̇o 2 /V̇o 2 ) during contractions; and 2) express greater modulation of Q̇o 2 /V̇o 2 with changes to NO bioavailability compared with male rats. The spinotrapezius muscle of Sprague-Dawley rats (females = 8, males = 8) was surgically exposed and electrically-stimulated (180 s, 1 Hz, 6 V). OxyphorG4 was injected into the muscle and phosphorescence quenching employed to determine the temporal profile of interstitial Po 2 (Po 2is , determined by Q̇o 2 /V̇o 2 ). This was performed under three conditions: control (CON), 300 µM sodium nitroprusside (SNP; NO donor), and 1.5 mM N ω -nitro-l-arginine methyl ester (l-NAME; NOS blockade) superfusion. No sex differences were found for the Po 2is kinetics parameters in CON or l-NAME ( P > 0.05), but females elicited a lower baseline following SNP (males 42 ± 3 vs. females 36 ± 2 mmHg, P < 0.05). Females had a lower ΔPo 2is during contractions following SNP (males 22 ± 3 vs. females 17 ± 2 mmHg, P < 0.05), but there were no sex differences for the temporal response to contractions ( P > 0.05). The total NO effect (SNP minus l-NAME) on Po 2is was not different between sexes. However, the spread across both conditions was shifted to a lower absolute range for females (reduced SNP baseline and greater reduction following l-NAME). These data support that females have a greater reliance on basal NO bioavailability and males have a greater responsiveness to exogenous NO and less responsiveness to reduced endogenous NO. NEW & NOTEWORTHY Interstitial Po 2 (Po 2is ; determined by O 2 delivery-to-utilization matching) plays an important role for O 2 flux into skeletal muscle. We show that both sexes regulate Po 2is at similar levels at rest and during skeletal muscle contractions. However, modulating NO bioavailability exposes sex differences in this regulation with females potentially having a greater reliance on basal NO bioavailability and males having a greater responsiveness to exogenous NO and less responsiveness to reduced endogenous NO.

Key Points: Oxygen pressure gradients across the microvascular walls are essential for oxygen diffusion from blood to tissue cells. At any given flux, the magnitude of these transmural gradients is proportional to the local resistance. The greatest resistance to oxygen transport into skeletal muscle is considered to reside in the short distance between red blood cells and myocytes. Although crucial to oxygen transport, little is known about transmural pressure gradients within skeletal muscle during contractions. We evaluated oxygen pressures within both the skeletal muscle microvascular and interstitial spaces to determine transmural gradients during the rest-contraction transient in anaesthetized rats. The significant transmural gradient observed at rest was sustained during submaximal muscle contractions. Our findings support that the blood-myocyte interface provides substantial resistance to oxygen diffusion at rest and during contractions and suggest that modulations in microvascular haemodynamics and red blood cell distribution constitute primary mechanisms driving increased transmural oxygen flux with contractions., Abstract: Oxygen pressure (PO2) gradients across the blood-myocyte interface are required for diffusive O 2 transport, thereby supporting oxidative metabolism. The greatest resistance to O 2 flux into skeletal muscle is considered to reside between the erythrocyte surface and adjacent sarcolemma, although this has not been measured during contractions. We tested the hypothesis that O 2 gradients between skeletal muscle microvascular (PO2 mv ) and interstitial (PO2 is ) spaces would be present at rest and maintained or increased during contractions. PO2 mv and PO2 is   were determined via phosphorescence quenching (Oxyphor probes G2 and G4, respectively) in the exposed rat spinotrapezius during the rest-contraction transient (1 Hz, 6 V; n = 8). PO2 mv was higher than PO2 is in all instances from rest (34.9 ± 6.0 versus 15.7 ± 6.4) to contractions (28.4 ± 5.3 versus 10.6 ± 5.2 mmHg, respectively) such that the mean PO2 gradient throughout the transient was 16.9 ± 6.6 mmHg (P < 0.05 for all). No differences in the amplitude of PO2 fall with contractions were observed between the microvasculature and interstitium (10.9 ± 2.3 versus 9.0 ± 3.5 mmHg, respectively; P > 0.05). However, the speed of the PO2 is fall during contractions was slower than that of PO2 mv (time constant: 12.8 ± 4.7 versus 9.0 ± 5.1 s, respectively; P < 0.05). Consistent with our hypothesis, a significant transmural gradient was sustained (but not increased) from rest to contractions. This supports that the blood-myocyte interface is the site of a substantial PO2 gradient driving O 2 diffusion during metabolic transients. Based on Fick's law, elevated O 2 flux with contractions must thus rely primarily on modulations in effective diffusing capacity (mainly erythrocyte haemodynamics and distribution) as the PO2 gradient is not increased., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

The vascular ATP-sensitive K + (K ATP ) channel is a mediator of skeletal muscle microvascular oxygenation (PO 2 mv) during contractions in health. We tested the hypothesis that K ATP channel function is preserved in chronic heart failure (CHF) and therefore its inhibition would reduce PO 2 mv and exacerbate the time taken to reach the PO 2 mv steady-state during contractions of the spinotrapezius muscle. Moreover, we hypothesized that subsequent K ATP channel activation would oppose the effects of this inhibition. Muscle PO 2 mv (phosphorescence quenching) was measured during 180s of 1-Hz twitch contractions (∼6V) under control, glibenclamide (GLI, K ATP channel antagonist; 5mg/kg) and pinacidil (PIN, K ATP channel agonist; 5mg/kg) conditions in 16 male Sprague-Dawley rats with CHF induced via myocardial infarction (coronary artery ligation, left ventricular end-diastolic pressure: 18±1mmHg). GLI reduced baseline PO 2 mv (control: 28.3±0.9, GLI: 24.8±1.0mmHg, p<0.05), lowered mean PO 2 mv (average PO 2 mv during the overall time taken to reach the steady-state; control: 20.6±0.6, GLI: 17.6±0.3mmHg, p<0.05), and slowed the attainment of steady-state PO 2 mv (overall mean response time; control: 66.1±10.2, GLI: 93.6±7.8s, p<0.05). PIN opposed these effects on the baseline PO 2 mv, mean PO 2 mv and time to reach the steady-state PO 2 mv (p<0.05 for all vs. GLI). Inhibition of K ATP channels exacerbates the transient mismatch between muscle O 2 delivery and utilization in CHF rats and this effect is opposed by PIN. These data reveal that the K ATP channel constitutes one of the select few well-preserved mechanisms of skeletal muscle microvascular oxygenation control in CHF., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Key points: 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 (PO2) gradient in mixed fibre‐type muscle.Increasing O2 flux across the capillary wall during exercise depends on: (i) the transmural O2 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.We evaluated the PO2 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 PO2 gradients in rats.Our findings demonstrate that, across the metabolic rest–contraction transition, the transcapillary pressure gradient for O2 flux is: (i) maintained in all muscle types, and (ii) the lowest in contracting highly oxidative fast‐twitch muscle. In mixed fibre‐type skeletal muscle transcapillary PO2 gradients (PO2mv‐PO2is; microvascular and interstitial, respectively) drive O2 flux across the blood–myocyte interface where the greatest resistance to that O2 flux resides. We assessed a broad spectrum of fibre‐type and oxidative‐capacity rat muscles across the rest‐to‐contraction (1 Hz, 120 s) transient to test the novel hypotheses that: (i) slow‐twitch PO2is would be greater than fast‐twitch, (ii) muscles with greater oxidative capacity have greater PO2is than glycolytic counterparts, and (iii) whether PO2mv‐PO2is at rest is maintained during contractions across all muscle types. PO2mv and PO2is were determined via phosphorescence quenching in soleus (SOL; 91% type I+IIa fibres and CSa: ∼21 μmol min‐1 g‐1), peroneal (PER; 33% and ∼20 μmol min‐1 g‐1), mixed (MG; 9% and ∼26 μmol min‐1 g‐1) and white gastrocnemius (WG; 0% and ∼8 μmol min‐1 g‐1) across the rest–contraction transient. PO2mv was higher than PO2is in each muscle (∼6–13 mmHg; P < 0.05). SOL PO2isarea was greater than in the fast‐twitch muscles during contractions (P < 0.05). Oxidative muscles had greater PO2isnadir (9.4 ± 0.8, 7.4 ± 0.9 and 6.4 ± 0.4; SOL, PER and MG, respectively) than WG (3.0 ± 0.3 mmHg, P < 0.05). The magnitude of PO2mv‐PO2is at rest decreased during contractions in MG only (∼11 to 7 mmHg; time × (PO2mv‐PO2is) interaction, P < 0.05). These data support the hypothesis that, since transcapillary PO2 gradients during contractions are maintained in all muscle types, increased O2 flux must occur via enhanced intracapillary diffusing conductance, which is most extreme in highly oxidative fast‐twitch muscle. Key points: 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 (PO2) gradient in mixed fibre‐type muscle.Increasing O2 flux across the capillary wall during exercise depends on: (i) the transmural O2 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.We evaluated the PO2 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 PO2 gradients in rats.Our findings demonstrate that, across the metabolic rest–contraction transition, the transcapillary pressure gradient for O2 flux is: (i) maintained in all muscle types, and (ii) the lowest in contracting highly oxidative fast‐twitch muscle. [ABSTRACT FROM AUTHOR]

Key points: Oxygen pressure gradients across the microvascular walls are essential for oxygen diffusion from blood to tissue cells. At any given flux, the magnitude of these transmural gradients is proportional to the local resistance. The greatest resistance to oxygen transport into skeletal muscle is considered to reside in the short distance between red blood cells and myocytes. Although crucial to oxygen transport, little is known about transmural pressure gradients within skeletal muscle during contractions. We evaluated oxygen pressures within both the skeletal muscle microvascular and interstitial spaces to determine transmural gradients during the rest–contraction transient in anaesthetized rats. The significant transmural gradient observed at rest was sustained during submaximal muscle contractions. Our findings support that the blood–myocyte interface provides substantial resistance to oxygen diffusion at rest and during contractions and suggest that modulations in microvascular haemodynamics and red blood cell distribution constitute primary mechanisms driving increased transmural oxygen flux with contractions. Abstract: Oxygen pressure ( P O 2) gradients across the blood–myocyte interface are required for diffusive O2 transport, thereby supporting oxidative metabolism. The greatest resistance to O2 flux into skeletal muscle is considered to reside between the erythrocyte surface and adjacent sarcolemma, although this has not been measured during contractions. We tested the hypothesis that O2 gradients between skeletal muscle microvascular ( P O 2 mv ) and interstitial ( P O 2 is ) spaces would be present at rest and maintained or increased during contractions. P O 2 mv and P O 2 is   were determined via phosphorescence quenching (Oxyphor probes G2 and G4, respectively) in the exposed rat spinotrapezius during the rest–contraction transient (1 Hz, 6 V; n = 8). P O 2 mv was higher than P O 2 is in all instances from rest (34.9 ± 6.0 versus 15.7 ± 6.4) to contractions (28.4 ± 5.3 versus 10.6 ± 5.2 mmHg, respectively) such that the mean P O 2 gradient throughout the transient was 16.9 ± 6.6 mmHg (P < 0.05 for all). No differences in the amplitude of P O 2 fall with contractions were observed between the microvasculature and interstitium (10.9 ± 2.3 versus 9.0 ± 3.5 mmHg, respectively; P > 0.05). However, the speed of the P O 2 is fall during contractions was slower than that of P O 2 mv (time constant: 12.8 ± 4.7 versus 9.0 ± 5.1 s, respectively; P < 0.05). Consistent with our hypothesis, a significant transmural gradient was sustained (but not increased) from rest to contractions. This supports that the blood–myocyte interface is the site of a substantial P O 2 gradient driving O2 diffusion during metabolic transients. Based on Fick's law, elevated O2 flux with contractions must thus rely primarily on modulations in effective diffusing capacity (mainly erythrocyte haemodynamics and distribution) as the P O 2 gradient is not increased. [ABSTRACT FROM AUTHOR]

The oxygen transport pathway from air to mitochondria involves a series of transfer steps within closely integrated systems (pulmonary, cardiovascular, and tissue metabolic). Small and finite O2 stores in most mammalian species require exquisitely controlled changes in O2 flux rates to support elevated ATP turnover. This is especially true for the contracting skeletal muscle where O2 requirements may increase two orders of magnitude above rest. This brief review focuses on the mechanistic bases for increased microvascular blood‐myocyte O2 flux (V̇O2) from rest to contractions. Fick's law dictates that V̇O2 elevations driven by muscle contractions are produced by commensurate changes in driving force (ie, O2 pressure gradients; ΔPO2) and/or effective diffusing capacity (DO2). While previous evidence indicates that increased DO2 helps modulate contracting muscle O2 flux, up until recently the role of the dynamic ΔPO2 across the capillary wall was unknown. Recent phosphorescence quenching investigations of both microvascular and novel interstitial PO2 kinetics in health have resolved an important step in the O2 cascade between the capillary and myocyte. Specifically, the significant transmural ΔPO2 at rest was sustained (but not increased) during submaximal contractions. This supports the contention that the blood‐myocyte interface provides a substantial effective resistance to O2 diffusion and underscores that modulations in erythrocyte hemodynamics and distribution (DO2) are crucial to preserve the driving force for O2 flux across the capillary wall (ΔPO2) during contractions. Investigation of the O2 transport pathway close to muscle mitochondria is key to identifying disease mechanisms and develop therapeutic approaches to ameliorate dysfunction and exercise intolerance. [ABSTRACT FROM AUTHOR]