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ATP‐sensitive K+ channels (KATP) have been implicated in the regulation of resting vascular smooth muscle membrane potential and tone. However, whether KATP channels modulate skeletal muscle microvascular hemodynamics at the capillary level (the primary site for blood‐myocyte O2 exchange) remains unknown. We tested the hypothesis that KATP channel inhibition would reduce the proportion of capillaries supporting continuous red blood cell (RBC) flow and impair RBC hemodynamics and distribution in perfused capillaries within resting skeletal muscle. RBC flux (fRBC), velocity (VRBC), and capillary tube hematocrit (Hctcap) were assessed via intravital microscopy of the rat spinotrapezius muscle (n = 6) under control (CON) and glibenclamide (GLI; KATP channel antagonist; 10 µM) superfusion conditions. There were no differences in mean arterial pressure (CON:120 ± 5, GLI:124 ± 5 mmHg; p > 0.05) or heart rate (CON:322 ± 32, GLI:337 ± 33 beats/min; p > 0.05) between conditions. The %RBC‐flowing capillaries were not altered between conditions (CON:87 ± 2, GLI:85 ± 1%; p > 0.05). In RBC‐perfused capillaries, GLI reduced fRBC (CON:20.1 ± 1.8, GLI:14.6 ± 1.3 cells/s; p < 0.05) and VRBC (CON:240 ± 17, GLI:182 ± 17 µm/s; p < 0.05) but not Hctcap (CON:0.26 ± 0.01, GLI:0.26 ± 0.01; p > 0.05). The absence of GLI effects on the %RBC‐flowing capillaries and Hctcap indicates preserved muscle O2 diffusing capacity (DO2m). In contrast, GLI lowered both fRBC and VRBC thus impairing perfusive microvascular O2 transport (Q̇m) and lengthening RBC capillary transit times, respectively. Given the interdependence between diffusive and perfusive O2 conductances (i.e., %O2 extraction∝DO2m/Q̇m), such GLI alterations are expected to elevate muscle %O2 extraction to sustain a given metabolic rate. These results support that KATP channels regulate capillary hemodynamics and, therefore, microvascular gas exchange in resting skeletal muscle. [ABSTRACT FROM AUTHOR]

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 NG-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 (LBFAUC)] 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 (LBFAUC: 271±97 mL, P > 0.05) or sPLM (LBFAUC: 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. [ABSTRACT FROM AUTHOR]

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: Exercise in patients with hypertension can be accompanied by an abnormal cardiovascular response that includes attenuated blood flow and an augmented pressor response.Endothelin‐1, a very potent vasoconstrictor, is a key modulator of blood flow and pressure during in health and has been implicated as a potential cause of the dysfunction in hypertension.We assessed the role of endothelin‐1, acting through endothelin A (ETA) receptors, in modulating the central and peripheral cardiovascular responses to exercise in patients with hypertension via local antagonism of these receptors during exercise.ETA receptor antagonism markedly increased leg blood flow, vascular conductance, oxygen delivery, and oxygen consumption during exercise; interestingly, these changes occurred in the presence of reduced leg perfusion pressure, indicating that these augmentations were driven by changes in vascular resistance.These data indicate that ETA receptor antagonism could be a viable therapeutic approach to improve blood flow during exercise in hypertension. Patients with hypertension can exhibit impaired muscle blood flow and exaggerated increases in blood pressure during exercise. While endothelin (ET)‐1 plays a role in regulating blood flow and pressure during exercise in health, little is known about the role of ET‐1 in the cardiovascular response to exercise in hypertension. Therefore, eight volunteers diagnosed with hypertension were studied during exercise with either saline or BQ‐123 (ETA receptor antagonist) infusion following a 2‐week withdrawal of anti‐hypertensive medications. The common femoral artery and vein were catheterized for drug infusion, blood collection and blood pressure measurements, and leg blood flow was measured by Doppler ultrasound. Patients exercised at both absolute (0, 5, 10, 15 W) and relative (40, 60, 80% peak power) intensities. BQ‐123 increased blood flow at rest (79 ± 87 ml/min; P = 0.03) and augmented the exercise‐induced hyperaemia at most intensities (80% saline: Δ3818±1222 vs. BQ‐123: Δ4812±1469 ml/min; P = 0.001). BQ‐123 reduced leg MAP at rest (−8 ± 4 mmHg; P < 0.001) and lower intensities (0–10 W; P < 0.05). Systemic diastolic blood pressure was reduced (0 W, 40%; P < 0.05), but systemic MAP was defended by an increased cardiac output. The exercise pressor response (ΔMAP) did not differ between conditions (80% saline: 25 ± 10, BQ‐123: 30 ± 7 mmHg; P = 0.17). Thus, ET‐1, acting through the ETA receptors, contributes to the control of blood pressure at rest and lower intensity exercise in these patients. Furthermore, the finding that ET‐1 constrains the blood flow response to exercise suggests that ETA receptor antagonism could be a therapeutic approach to improve blood flow during exercise in hypertension. Key points: Exercise in patients with hypertension can be accompanied by an abnormal cardiovascular response that includes attenuated blood flow and an augmented pressor response.Endothelin‐1, a very potent vasoconstrictor, is a key modulator of blood flow and pressure during in health and has been implicated as a potential cause of the dysfunction in hypertension.We assessed the role of endothelin‐1, acting through endothelin A (ETA) receptors, in modulating the central and peripheral cardiovascular responses to exercise in patients with hypertension via local antagonism of these receptors during exercise.ETA receptor antagonism markedly increased leg blood flow, vascular conductance, oxygen delivery, and oxygen consumption during exercise; interestingly, these changes occurred in the presence of reduced leg perfusion pressure, indicating that these augmentations were driven by changes in vascular resistance.These data indicate that ETA receptor antagonism could be a viable therapeutic approach to improve blood flow during exercise in hypertension. [ABSTRACT FROM AUTHOR]

The oxygen partial pressure in the interstitial space (PO2 is) drives O2 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 PO2 is during recovery from contractions remains unknown. We tested the hypothesis that PO2 is would recover to resting values and display considerable on-off asymmetry (fast on-, slow off-kinetics), reflective of asymmetric capillary hemodynamics. Microvascular PO2 (PO2 mv) was also evaluated to test the hypothesis that a significant transcapillary gradient (ΔPO2 = PO2 mv -- PO2 is) would be sustained during recovery. PO2 mv and PO2 is (expressed in mmHg) were determined via phosphorescence quenching in the exposed rat spinotrapezius muscle during and after submaximal twitch contractions (n = 12). PO2 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 PO2 is (18.5 ± 8.1; P > 0.05). PO2 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 ΔPO2 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 PO2 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 ΔPO2 during recovery supports that the microvascular-interstitium interface provides considerable resistance to O2 transport. As dictated by Fick's law (VO2 = DO2 x ΔPO2), modulation of O2 flux (VO2) during recovery must be achieved via corresponding changes in effective diffusing capacity (DO2; mainly capillary red blood cell hemodynamics and distribution) in the face of unaltered ΔPO2. NEW & NOTEWORTHY Capillary blood-myocyte O2 flux (VO2) is determined by effective diffusing capacity (DO2; mainly erythrocyte hemodynamics and distribution) and microvascular-interstitial PO2 gradients (ΔPO2 = PO2 mv -- PO2 is). We show that PO2 is demonstrates on-off asymmetry consistent with PO2 mv and erythrocyte kinetics during metabolic transitions. A substantial transcapillary ΔPO2 was preserved during recovery from contractions, indicative of considerable resistance to O2 diffusion at the microvascular-interstitium interface. This reveals that effective DO2 declines in step with VO2 during recovery, as per Fick's law. [ABSTRACT FROM AUTHOR]

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 O2 delivery-to-utilization ratio (Q̇o2/V̇o2) during contractions; and 2) express greater modulation of Q̇o2/V̇o2 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 Po2 (Po2is, determined by Q̇o2/V̇o2). This was performed under three conditions: control (CON), 300 µM sodium nitroprusside (SNP; NO donor), and 1.5 mM Nω-nitro-l-arginine methyl ester (l-NAME; NOS blockade) superfusion. No sex differences were found for the Po2is 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 ΔPo2 is 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 Po2 is 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 Po2 (Po2is; determined by O2 delivery-to-utilization matching) plays an important role for O2 flux into skeletal muscle. We show that both sexes regulate Po2is 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. [ABSTRACT FROM AUTHOR]

Chronic heart failure (CHF) results in central and peripheral derangements that ultimately reduce skeletal muscle O2 delivery and impair exercise tolerance. Dietary nitrate (NO3−) supplementation improves skeletal muscle vascular function and tolerance to exercise. We tested the hypothesis that NO3− supplementation would elevate exercising skeletal muscle blood flow (BF) and vascular conductance (VC) in CHF rats. Myocardial infarction (MI) was induced (coronary artery ligation) in young adult male rats. After 21 days of recovery, rats randomly received 5 days of NO3−-rich beetroot juice (CHF + BR, n = 10) or a placebo (CHF, n = 10). Mean arterial pressure (carotid artery catheter) and skeletal muscle BF (radiolabeled microspheres) were measured during treadmill exercise (20 m/min, 5% grade). CHF-induced dysfunction, as determined by myocardial infarction size (29 ± 3% and 33 ± 4% in CHF and CHF + BR, respectively) and left ventricular end-diastolic pressure (18 ± 2 and 18 ± 2 mmHg in CHF and CHF + BR, respectively), and exercising mean arterial pressure (131 ± 3 and 128 ± 4 mmHg in CHF and CHF + BR, respectively) were not different (P > 0.05) between groups. Total exercising hindlimb skeletal muscle BF (95 ± 5 and 116 ± 9 ml·min−1·100 g−1 in CHF and CHF + BR, respectively) and VC (0.75 ± 0.05 and 0.90 ± 0.05 ml·min−1·100 g−1·mmHg−1 in CHF and CHF + BR, respectively) were 22% and 20% greater in BR-supplemented rats, respectively (P < 0.05). During exercise, BF in 9 and VC in 10 hindlimb muscles and muscle portions were significantly greater in the CHF + BR group. These results provide strong evidence that dietary NO3− supplementation improves skeletal muscle vascular function during exercise in rats with CHF and, thus, support the use of BR as a novel therapeutic modality for the treatment of CHF. [ABSTRACT FROM AUTHOR]

Schäfer, Hayes, & Dekerle ([3]) are to be congratulated on assimilating the power-duration relationship, constant-power exercise bouts and the assessment of neuromuscular fatigue with creatine supplementation to investigate the association between I W i ' (the curvature constant of the power-duration relationship) and neuromuscular fatigue. The authors report that creatine supplementation increased I W i ' and cycling time to exhaustion, with no overt increase in the magnitude of end-exercise quadriceps fatigue. During cycling exercise, however, many muscle groups contribute to I W i ' (i.e. quadriceps, hamstrings, calves and gluteals), but only one of these muscle groups is assessed in the quadriceps SB pot sb , inherently weakening the relationship between I W i ' and quadriceps SB pot sb . [Extracted from the article]

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]

A letter to the editor is presented in response to the article "Exercise intensity thresholds: identifying the boundaries of sustainable performance" is presented.

Exercising muscle blood flow is reduced in patients with heart failure with a preserved ejection fraction (HFpEF), which may be related to disease-related changes in the ability to overcome sympathetic nervous system (SNS)-mediated vasoconstriction during exercise, (i.e., "functional sympatholysis"). Thus, in 12 patients with HFpEF (69 ± 7 yr) and 11 healthy controls (Con, 69 ± 4 yr), we examined forearm blood flow (FBF), mean arterial pressure (MAP), and forearm vascular conductance (FVC) during rhythmic handgrip exercise (HG) at 30% of maximum voluntary contraction with or without lower-body negative pressure (LBNP, -20 mmHg) to increase SNS activity and elicit peripheral vasoconstriction. SNS-mediated vasoconstrictor responses were determined as LBNP-induced changes (%Δ) in FVC, and the "magnitude of sympatholysis" was calculated as the difference between responses at rest and during exercise. At rest, the LBNP-induced change in FVC was significantly lesser in HFpEF compared with Con (HFpEF: -9.5 ± 5.5 vs. Con: -21.0 ± 8.0%; P < 0.01). During exercise, LBNP-induced %ΔFVC was significantly attenuated in Con compared with rest (HG: -5.8 ± 6.0%; P < 0.05) but not in HFpEF (HG: -9.9 ± 2.5%; P = 0.88). Thus, the magnitude of sympatholysis was lesser in HFpEF compared with Con (HFpEF: 0.4 ± 4.7 vs. Con: -15.2 ± 11.8%; P < 0.01). These data demonstrate a diminished ability to attenuate SNS-mediated vasoconstriction in HFpEF and provide new evidence suggesting impaired functional sympatholysis in this patient group. NEW & NOTEWORTHY Data from the current study suggest that functional sympatholysis, or the ability to adequately attenuate sympathetic nervous system (SNS)-mediated vasoconstriction during exercise, is impaired in patients with heart failure with preserved ejection fraction (HFpEF). These observations extend the current understanding of HFpEF pathophysiology by implicating inadequate functional sympatholysis as an important contributor to reduced exercising muscle blood flow in this patient group.

An exaggerated mean arterial blood pressure (MAP) response to exercise in patients with peripheral artery disease (PAD), likely driven by inflammation and oxidative stress and, perhaps, required to achieve an adequate blood flow response, is well described. However, the blood flow response to exercise in patients with PAD actually remains equivocal. Therefore, eight patients with PAD and eight healthy controls completed 3 min of plantar flexion exercise at both an absolute work rate (WR) (2.7 W, to evaluate blood flow) and a relative intensity (40%WR max , to evaluate MAP). The exercise-induced change in popliteal artery blood flow (BF, Ultrasound Doppler), MAP (Finapress), and vascular conductance (VC) were quantified. In addition, resting markers of inflammation and oxidative stress were measured in plasma and muscle biopsies. Exercise-induced ΔBF, assessed at 2.7 W, was lower in PAD compared with controls (PAD: 251 ± 150 vs. Controls: 545 ± 187 mL/min, P < 0.001), whereas ΔMAP, assessed at 40%WR max , was greater for PAD (PAD: 23 ± 14 vs. Controls: 11 ± 6 mmHg, P = 0.028). The exercise-induced ΔVC was lower for PAD during both the absolute WR (PAD: 1.9 ± 1.6 vs. Controls: 4.7 ± 1.9 mL/min/mmHg) and relative intensity exercise (PAD: 1.9 ± 1.8 vs. Controls: 5.0 ± 2.2 mL/min/mmHg) trials (both, P < 0.01). Inflammatory and oxidative stress markers, including plasma interleukin-6 and muscle protein carbonyls, were elevated in PAD (both, P < 0.05), and significantly correlated with the hemodynamic changes during exercise ( r = -0.57 to -0.78, P < 0.05). Thus, despite an exaggerated ΔMAP response, patients with PAD exhibit an impaired exercise-induced ΔBF and ΔVC, and both inflammation and oxidative stress likely play a role in this attenuated hemodynamic response.

Competing Interests: Conflict of Interest No potential conflict of interest relevant to this article was reported.

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.

Sex differences in the mechanisms underlying cardiovascular pathophysiology of O 2 transport in heart failure (HF) remain to be explored. In HF, nitric oxide (NO) bioavailability is reduced and contributes to deficits in O 2 delivery-to-utilization matching. Females may rely more on NO for cardiovascular control and as such experience greater decrements in HF. We tested the hypotheses that moderate HF induced by myocardial infarction would attenuate the skeletal muscle interstitial Po 2 response to contractions (Po 2is ; determined by O 2 delivery-to-utilization matching) compared with healthy controls and females would express greater dysfunction than male counterparts. Furthermore, we hypothesized that 5 days of dietary nitrate supplementation (Nitrate; 1 mmol·kg -1 ·day -1 ) would raise Po 2is in HF rats. Forty-two Sprague-Dawley rats were randomly assigned to healthy, HF, or HF + Nitrate groups (each n = 14; 7 female/7 male). Spinotrapezius Po 2is was measured via phosphorescence quenching during electrically induced twitch contractions (180 s; 1 Hz). HF reduced resting Po 2is for both sexes compared with healthy controls ( P < 0.01), and females were lower than males (14 ± 1 vs. 17 ± 2 mmHg) ( P < 0.05). In HF both sexes expressed reduced Po 2is amplitudes following the onset of muscle contractions compared with healthy controls (female: -41 ± 7%, male: -26 ± 12%) ( P < 0.01). In HF rats, Nitrate elevated resting Po 2is to values not different from healthy rats and removed the sex difference. Female HF + Nitrate rats expressed greater resting Po 2is and amplitudes compared with female HF ( P < 0.05). In this model of moderate HF, O 2 delivery-to-utilization matching in the interstitial space is diminished in a sex-specific manner and dietary nitrate supplementation may serve to offset this reduction in HF rats with greater effects in females. NEW & NOTEWORTHY Interstitial Po 2 (Po 2is ; indicative of O 2 delivery-to-utilization matching) determines, in part, O 2 flux into skeletal muscle. We show that heart failure (HF) reduces Po 2is at rest and during skeletal muscle contractions in rats and this negative effect is amplified for females. However, elevating NO bioavailability with dietary nitrate supplementation increases resting Po 2is and alters the dynamic response with greater efficacy in female HF rats, particularly at rest and following the onset of muscle contractions.

Blood velocity measured in the middle cerebral artery (MCA V ) increases with finite kinetics during moderate-intensity exercise, and the amplitude and dynamics of the response provide invaluable insights into the controlling mechanisms. The MCA V response after exercise onset is well fit to an exponential model in young individuals but remains to be characterized in their older counterparts. The responsiveness of vasomotor control degrades with advancing age, especially in skeletal muscle. We tested the hypothesis that older subjects would evince a slower and reduced MCA V response to exercise. Twenty-nine healthy young (25 ± 1 yr old) and older (69 ± 1 yr old) adults each performed a rapid transition from rest to moderate-intensity exercise on a recumbent stepper. Resting MCA V was lower in older than young subjects (47 ± 2 vs. 64 ± 3 cm/s, P < 0.001), and amplitude from rest to steady-state exercise was lower in older than young subjects (12 ± 2 vs. 18 ± 3 cm/s, P = 0.04), even after subjects were matched for work rate. As hypothesized, the time constant was significantly longer (slower) in the older than young subjects (51 ± 10 vs. 31 ± 4 s, P = 0.03), driven primarily by older women. Neither age-related differences in fitness, end-tidal CO 2 , nor blood pressure could account for this effect. Thus, MCA V kinetic analyses revealed a marked impairment in the cerebrovascular response to exercise in older individuals. Kinetic analysis offers a novel approach to evaluate the efficacy of therapeutic interventions for improving cerebrovascular function in elderly and patient populations. NEW & NOTEWORTHY Understanding the dynamic cerebrovascular response to exercise has provided insights into sex-related cerebrovascular control mechanisms throughout the aging process. We report novel differences in the kinetics response of cerebrovascular blood velocity after the onset of moderate-intensity exercise. The exponential increase in brain blood flow from rest to exercise revealed that 1) the kinetics profile of the older group was blunted compared with their young counterparts and 2) the older women demonstrated a slowed response.

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.