Effects of acute phosphodiesterase type 5 inhibition on skeletal muscle interstitial PO2 during contractions and recovery.

The oxygen partial pressure within the interstitial space (PO2is; mmHg) provides the driving force for oxygen diffusion into the myocyte thereby supporting oxidative phosphorylation. We tested the hypothesis that potentiation of the nitric oxide pathway with sildenafil (phosphodiesterase type 5 inhibitor) would enhance PO2is during muscle metabolic transitions, thereby slowing PO2is on- and accelerating PO2is off-kinetics. The rat spinotrapezius muscle (n = 17) was exposed for PO2is measurements via phosphorescence quenching under control (CON), low-dose sildenafil (1 mg/kg i.a., SIL1) and high-dose sildenafil (7 mg/kg i.a., SIL7). Data were collected at rest and during submaximal twitch contractions (1 Hz, 4-6 V, 3 min) and recovery (3 min). Mean arterial blood pressure (MAP; mmHg) was reduced with both SIL1 (pre:132 ± 5; post:99 ± 5) and SIL7 (pre:111 ± 6; post:99 ± 4) (p < 0.05). SIL7 elevated resting PO2is (18.4 ± 1.1) relative to both CON (15.7 ± 0.7) and SIL1 (15.2 ± 0.7) (p < 0.05). In addition, SIL7 increased end-recovery PO2is (17.7 ± 1.6) compared to CON (12.8 ± 0.9) and SIL1 (13.4 ± 0.8) (p < 0.05). The overall PO2is response during recovery (i.e., area under the PO2is curve) was greater in SIL7 (4107 ± 444) compared to CON (3493 ± 222) and SIL1 (3114 ± 205 mmHg s) (p < 0.05). Contrary to our hypothesis, there was no impact of acute SIL (1 or 7 mg/kg) on the speed of the PO2is response during contractions or recovery (p > 0.05). However, sildenafil lowered MAP and improved skeletal muscle interstitial oxygenation in healthy rats. Specifically, SIL7 enhanced PO2is at rest and during recovery from submaximal muscle contractions. Potentiation of the nitric oxide pathway with sildenafil enhances microvascular blood-myocyte O2 transport and is expected to improve repeated bouts of contractile activity.

Exertional oscillatory ventilation in subjects without heart failure reporting chronic dyspnoea.

Oscillatory ventilation detected on incremental cardiopulmonary exercise testing might be found in subjects without heart failure reporting exertional dyspnoea despite the best available therapy for their underlying cardiopulmonary disease https://bit.ly/3Tyl7bE.

Exercise training decreases intercostal and transversus abdominis muscle blood flows in heart failure rats during submaximal exercise.

Diaphragm muscle blood flow (BF) and vascular conductance (VC) are elevated with chronic heart failure (HF) during exercise. Exercise training (ExT) elicits beneficial respiratory muscle and pulmonary system adaptations in HF. We hypothesized that diaphragm BF and VC would be lower in HF rats following ExT than their sedentary counterparts (Sed). Respiratory muscle BFs and mean arterial pressure were measured via radiolabeled microspheres and carotid artery catheter, respectively, during submaximal treadmill exercise (20 m/min, 5 % grade). During exercise, no differences were present between HF + ExT and HF + Sed in diaphragm BFs (201 ± 36 vs. 227 ± 44 mL/min/100 g) or VCs (both, p > 0.05). HF + ExT compared to HF + Sed had lower intercostal BF (27 ± 3 vs. 41 ± 5 mL/min/100 g) and VC (0.21 ± 0.02 vs. 0.31 ± 0.04 mL/min/mmHg/100 g) during exercise (both, p < 0.05). Further, HF + ExT compared to HF + Sed had lower transversus abdominis BF (20 ± 1 vs. 35 ± 6 mL/min/100 g) and VC (0.14 ± 0.02 vs. 0.27 ± 0.05 mL/min/mmHg/100 g) during exercise (both, p < 0.05). These data suggest that exercise training lowers the intercostal and transversus abdominis BF responses in HF rats during submaximal treadmill exercise.

Regulation of capillary hemodynamics by KATP channels in resting skeletal muscle.

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 (DO2 m). 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∝DO2 m/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.

Effects of inorganic nitrate supplementation on cardiovascular function and exercise tolerance in heart failure.

Heart failure (HF) results in a myriad of central and peripheral abnormalities that impair the ability to sustain skeletal muscle contractions and, therefore, limit tolerance to exercise. Chief among these abnormalities is the lowered maximal oxygen uptake, which is brought about by reduced cardiac output and exacerbated by O2 delivery-utilization mismatch within the active skeletal muscle. Impaired nitric oxide (NO) bioavailability is considered to play a vital role in the vascular dysfunction of both reduced and preserved ejection fraction HF (HFrEF and HFpEF, respectively), leading to the pursuit of therapies aimed at restoring NO levels in these patient populations. Considering the complementary role of the nitrate-nitrite-NO pathway in the regulation of enzymatic NO signaling, this review explores the potential utility of inorganic nitrate interventions to increase NO bioavailability in the HFrEF and HFpEF patient population. Although many preclinical investigations have suggested that enhanced reduction of nitrite to NO in low Po2 and pH environments may make a nitrate-based therapy especially efficacious in patients with HF, inconsistent results have been found thus far in clinical settings. This brief review provides a summary of the effectiveness (or lack thereof) of inorganic nitrate interventions on exercise tolerance in patients with HFrEF and HFpEF. Focus is also given to practical considerations and current gaps in the literature to facilitate the development of effective nitrate-based interventions to improve exercise tolerance in patients with HF.

Acute effects of leg heat therapy on walking performance and cardiovascular and inflammatory responses to exercise in patients with peripheral artery disease.

Lower-extremity peripheral artery disease (PAD) is associated with increased risk of cardiovascular events and impaired exercise tolerance. We have previously reported that leg heat therapy (HT) applied using liquid-circulating trousers perfused with warm water increases leg blood flow and reduces blood pressure (BP) and the circulating levels of endothelin-1 (ET-1) in patients with symptomatic PAD. In this sham-controlled, randomized, crossover study, sixteen patients with symptomatic PAD (age 65 ± 5.7 years and ankle-brachial index: 0.69 ± 0.1) underwent a single 90-min session of HT or a sham treatment prior to a symptom-limited, graded cardiopulmonary exercise test on the treadmill. The primary outcome was the peak walking time (PWT) during the exercise test. Secondary outcomes included the claudication onset time (COT), resting and exercise BP, calf muscle oxygenation, pulmonary oxygen uptake (V̇O2 ), and plasma levels of ET-1, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Systolic, but not diastolic BP, was significantly lower (~7 mmHg, p < .05) during HT when compared to the sham treatment. There was also a trend for lower SBP throughout the exercise and the recovery period following HT (p = .057). While COT did not differ between treatments (p = .77), PWT tended to increase following HT (CON: 911 ± 69 s, HT: 954 ± 77 s, p = .059). Post-exercise plasma levels of ET-1 were also lower in the HT session (CON: 2.0 ± 0.1, HT: 1.7 ± 0.1, p = .02). Calf muscle oxygenation, V̇O2 , COT, IL-6, and TNF-α did not differ between treatments. A single session of leg HT lowers BP and post-exercise circulating levels of ET-1 and may enhance treadmill walking performance in symptomatic PAD patients.

The effect of dietary nitrate supplementation on the speed-duration relationship in mice with sickle cell disease.

Sickle cell disease (SCD) causes exercise intolerance likely due to impaired skeletal muscle function and low nitric oxide (NO) bioavailability. Dietary nitrate improves hemodynamic and metabolic control during exercise in humans and animals. The purpose of this investigation was to assess the impact of nitrate supplementation on exercise capacity as measured by the running speed to exercise duration relationship [critical speed (CS)]in mice with SCD. We tested the hypothesis that nitrate supplementation via beetroot juice (BR) would attenuate the exercise intolerance observed in mice with SCD. Ten wild-type (WT) and 18 Berkley sickle-cell mice (BERK) received water (WT: n = 10, BERK: n = 10) or nitrate-rich BR (BERK+BR: n = 8, nitrate dose 1 mmol/kg/day) for 5 days. Following the supplementation period, all mice performed 3-5 constant-speed treadmill tests that resulted in exhaustion within 1.5 to 20 min. Time to exhaustion vs. treadmill speed was fit to a hyperbolic model to determine CS. CS was significantly lower in BERK vs. WT and BERK+BR with no significant difference between WT and BERK+BR (WT: 36.6 ± 1.6, BERK: 23.8 ± 1.5, BERK+BR: 31.1 ± 2.1 m/min, P < 0.05). Exercise tolerance, measured via CS, was significantly lower in BERK mice relative to WT. However, BERK mice receiving 5 days of nitrate supplementation exhibited no difference in exercise tolerance when compared with WT. These results support the potential utility of a dietary nitrate intervention to improve functionality in SCD patients.NEW & NOTEWORTHY Sickle cell disease compromises muscle O2 delivery resulting in exercise intolerance. Dietary nitrate supplementation increases skeletal muscle blood flow during exercise and may improve exercise capacity in a mouse model of sickle cell disease. We investigated the effects of dietary nitrate supplementation on exercise tolerance in a mouse model of sickle cell disease using the treadmill speed-duration relationship (critical speed). Mice with sickle cell disease provided with a dietary nitrate supplement had a critical speed not significantly different from healthy wild-type mice.

Systemic NOS inhibition reduces contracting muscle oxygenation more in intact female than male rats.

Females respond to baroreceptor stimulation with enhanced modulation of heart rate (HR) to regulate blood pressure and also express greater reliance on nitric oxide (NO) for vascular control compared to males. Sex differences in muscle oxygenation consequent to central hemodynamic challenge induced by systemic NO synthase (NOS) inhibition are unknown. We tested the hypotheses that systemic NOS inhibition would induce lower contracting skeletal muscle oxygenation in females compared to males. The spinotrapezius of Sprague-Dawley rats (females (♀) = 9, males (♂) = 9) was surgically exposed and contracted by electrical stimulation (180s, 1 Hz, ~6 V) under pentobarbital sodium anesthesia. Oxyphor G4 was injected into the muscle and phosphorescence quenching was used to measure the interstitial PO2 (PO2is, determined by O2 delivery-to-utilization matching) under control (Krebs-Henseleit solution) and after intra-arterial infusion of nitro-l-arginine methyl ester (l-NAME; NOS blockade; 10 mg kg-1). At rest, females showed a greater PO2is increase (ΔPO2is/ΔMAP) and HR (ΔHR/ΔMAP) reduction than males in response to the elevated MAP induced by systemic NOS inhibition (both p < 0.05). Following l-NAME, during the contracting steady-state, females exhibited lower PO2is than males (♂: 17.1 ± 1.4 vs ♀: 10.8 ± 1.4 mmHg, p < 0.05). The rate pressure product was lower in females than males (♂: 482 ± 14 vs ♀: 392 ± 29, p < 0.05) and correlated with the steady-state PO2is (r = 0.66, p < 0.05). These results support that females express greater reductions in HR than males in response to l-NAME-induced elevation of MAP via the baroreceptor reflex and provide new insights on how central hemodynamics affect skeletal muscle oxygenation in a sex-specific manner.

Transcapillary PO2 gradients in contracting muscles across the fibre type and oxidative continuum.

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: In mixed fibre-type skeletal muscle transcapillary PO2 gradients (PO2 mv-PO2 is; 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 PO2 is would be greater than fast-twitch, (ii) muscles with greater oxidative capacity have greater PO2 is than glycolytic counterparts, and (iii) whether PO2 mv-PO2 is at rest is maintained during contractions across all muscle types. PO2 mv and PO2 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. PO2 mv was higher than PO2 is in each muscle (∼6-13 mmHg; P < 0.05). SOL PO2 isarea was greater than in the fast-twitch muscles during contractions (P < 0.05). Oxidative muscles had greater PO2 isnadir (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 PO2 mv-PO2 is at rest decreased during contractions in MG only (∼11 to 7 mmHg; time × (PO2 mv-PO2 is) 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.

ATP-sensitive K+ channel inhibition in rats decreases kidney and skeletal muscle blood flow without increasing sympathetic nerve discharge.

ATP-sensitive K+ (KATP) channels contribute to exercise-induced hyperemia in skeletal muscle either locally by vascular hyperpolarization or by sympathoinhibition and decreased sympathetic vasoconstriction. However, mean arterial pressure (MAP) regulation via baroreceptors and subsequent efferent activity may confound assessment of vascular versus neural KATP channel function. We hypothesized that systemic KATP channel inhibition via glibenclamide (GLI) would increase MAP without increasing sympathetic nerve discharge (SND). Lumbar and renal nerve SND were measured in anesthetized male rats with intact baroreceptors (n = 12) and sinoaortic denervated (SAD; n = 4) counterparts and blood flow (BF) and vascular conductance (VC) assessed in conscious rats (n = 6). GLI increased MAP (p < 0.05) and transiently decreased HR in intact (p < 0.05), but not SAD rats. Renal (-30 %) and lumbar (-40 %) ΔSND decreased in intact but increased in SAD rats (∼40 % and 20 %; p < 0.05). BF and VC decreased in kidneys and total hindlimb skeletal muscle (p < 0.05). Thus, because KATP inhibition decreases SND, GLI-induced reductions in blood flow cannot result from enhanced sympathetic activity.

Skeletal muscle interstitial Po2 kinetics during recovery from contractions.

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 (V̇o2 = Do2 × ΔPo2), modulation of O2 flux (V̇o2) 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 (V̇o2) 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 V̇o2 during recovery, as per Fick's law.

Central and peripheral factors mechanistically linked to exercise intolerance in heart failure with reduced ejection fraction.

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 O2 delivery-to-utilization matching was determined via phosphorescence quenching (interstitial Po2, Po2 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 Po2 is at rest and during contractions (both P < 0.01) but had no effect on white gastrocnemius Po2 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 O2 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 O2 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.

Sexual dimorphism in the control of skeletal muscle interstitial Po2 of heart failure rats: effects of dietary nitrate supplementation.

Sex differences in the mechanisms underlying cardiovascular pathophysiology of O2 transport in heart failure (HF) remain to be explored. In HF, nitric oxide (NO) bioavailability is reduced and contributes to deficits in O2 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 Po2 response to contractions (Po2is; determined by O2 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 Po2is 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 Po2is was measured via phosphorescence quenching during electrically induced twitch contractions (180 s; 1 Hz). HF reduced resting Po2is 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 Po2is 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 Po2is to values not different from healthy rats and removed the sex difference. Female HF + Nitrate rats expressed greater resting Po2is and amplitudes compared with female HF (P < 0.05). In this model of moderate HF, O2 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 Po2 (Po2is; indicative of O2 delivery-to-utilization matching) determines, in part, O2 flux into skeletal muscle. We show that heart failure (HF) reduces Po2is 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 Po2is and alters the dynamic response with greater efficacy in female HF rats, particularly at rest and following the onset of muscle contractions.

Submaximal exercise cardiac output is increased by 4 weeks of sprint interval training in young healthy males with low initial Q̇-V̇O2: Importance of cardiac response phenotype.

Cardiovascular adaptations to exercise, particularly at the individual level, remain poorly understood. Previous group level research suggests the relationship between cardiac output and oxygen consumption ([Formula: see text]-[Formula: see text]) is unaffected by training as submaximal [Formula: see text] is unchanged. We recently identified substantial inter-individual variation in the exercise [Formula: see text]-[Formula: see text] relationship that was correlated to stroke volume (SV) as opposed to arterial oxygen content. Therefore we explored the effects of sprint interval training (SIT) on modulating [Formula: see text]-[Formula: see text] given an individual's specific [Formula: see text]-[Formula: see text] relationship. 22 (21±2 yrs) healthy, recreationally active males participated in a 4-week SIT (8, 20 second sprints; 4x/week, 170% of the work rate at [Formula: see text] peak) study with progressive exercise tests (PET) until exhaustion. Cardiac output ([Formula: see text] L/min; inert gas rebreathe, Finometer Modelflow™), oxygen consumption ([Formula: see text] L/min; breath-by-breath pulmonary gas exchange), quadriceps oxygenation (near infrared spectroscopy) and exercise tolerance (6-20; Borg Scale RPE) were measured throughout PET both before and after training. Data are mean Δ from bsl±SD. Higher [Formula: see text] ([Formula: see text]) and lower [Formula: see text] ([Formula: see text]) responders were identified post hoc (n = 8/group). SIT increased the [Formula: see text]-[Formula: see text] post-training in [Formula: see text] (3.8±0.2 vs. 4.7±0.2; P = 0.02) while [Formula: see text] was unaffected (5.8±0.1 vs. 5.3±0.6; P = 0.5). [Formula: see text] was elevated beyond 80 watts in [Formula: see text] due to a greater increase in SV (all P<0.04). Peak [Formula: see text] (ml/kg/min) was increased in [Formula: see text] (39.7±6.7 vs. 44.5±7.3; P = 0.015) and [Formula: see text] (47.2±4.4 vs. 52.4±6.0; P = 0.009) following SIT, with [Formula: see text] having a greater peak [Formula: see text] both pre (P = 0.02) and post (P = 0.03) training. Quadriceps muscle oxygenation and RPE were not different between groups (all P>0.1). In contrast to [Formula: see text], [Formula: see text] responders are capable of improving submaximal [Formula: see text]-[Formula: see text] in response to SIT via increased SV. However, the increased submaximal exercise [Formula: see text] does not benefit exercising muscle oxygenation.

Skeletal muscle interstitial O2 pressures: bridging the gap between the capillary and myocyte.

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.

Systemic vascular dysfunction is associated with emphysema burden in mild COPD.

BACKGROUND: Cardiovascular diseases play a major role in morbidity and mortality in the earlier stages of COPD. We hypothesized that systemic vascular dysfunction would be present even in patients who are currently considered at "low-risk" for negative cardiovascular outcomes, i.e., those with largely preserved FEV1, few exacerbations and only mild burden of respiratory symptoms (GOLD spirometric grade 1, clinical group A). METHODS: 16 patients (FEV1 = 86 ±â€¯13%) and 16 age- and gender-matched controls underwent measurements of: a) central arterial stiffness by pulse wave velocity, b) brachial flow-mediated dilation and c) forearm muscle oxygenation by near-infrared spectroscopy. Computed tomography quantified emphysema (% of low attenuation areas (LAA)) and airway disease. RESULTS: Patients and controls were well matched for key clinical variables including co-morbidities burden. Thirteen patients presented with more than 5% LAA: emphysema extension was negatively related to transfer factor for carbon monoxide (TLCO) (r = -0.63; p = .01). Compared to controls, patients had higher central arterial stiffness, lower normalized (to shear stress) flow-mediated dilation, delayed time to peak flow-mediated dilation and poorer muscle oxygenation (p < .05). TLCO and emphysema, but not airway disease, were significantly related to each of these functional abnormalities (r values ranging from 0.51 to 0.66; p < .05). CONCLUSION: Systemic vascular dysfunction is present in the earlier stages of COPD, particularly in patients with greater emphysema burden and low TLCO. Regardless FEV1, patients showing those structural and functional abnormalities might be at higher risk of negative events thereby deserving closer follow-up for early detection of cardiovascular disease.

Do interindividual differences in cardiac output during submaximal exercise explain differences in exercising muscle oxygenation and ratings of perceived exertion?

Considerable interindividual differences in the Q˙-V˙O2 relationship during exercise have been documented but implications for submaximal exercise tolerance have not been considered. We tested the hypothesis that these interindividual differences were associated with differences in exercising muscle deoxygenation and ratings of perceived exertion (RPE) across a range of submaximal exercise intensities. A total of 31 (21 ± 3 years) healthy recreationally active males performed an incremental exercise test to exhaustion 24 h following a resting muscle biopsy. Cardiac output (Q˙ L/min; inert gas rebreathe), oxygen uptake (V˙O2 L/min; breath-by-breath pulmonary gas exchange), quadriceps saturation (near infrared spectroscopy) and exercise tolerance (6-20; Borg Scale RPE) were measured. The Q˙-V˙O2 relationship from 40 to 160 W was used to partition individuals post hoc into higher (n = 10; 6.3 ± 0.4) versus lower (n = 10; 3.7 ± 0.4, P < 0.001) responders. The Q˙-V˙O2 difference between responder types was not explained by arterial oxygen content differences (P = 0.5) or peripheral skeletal muscle characteristics (P from 0.1 to 0.8) but was strongly associated with stroke volume (P < 0.05). Despite considerable Q˙-V˙O2 difference between groups, no difference in quadriceps deoxygenation was observed during exercise (all P > 0.4). Lower cardiac responders had greater leg (P = 0.027) and whole body (P = 0.03) RPE only at 185 W, but this represented a higher %peak V˙O2 in lower cardiac responders (87 ± 15% vs. 66 ± 12%, P = 0.005). Substantially lower Q˙-V˙O2 in the lower responder group did not result in altered RPE or exercising muscle deoxygenation. This suggests substantial recruitment of blood flow redistribution in the lower responder group as part of protecting matching of exercising muscle oxygen delivery to demand.

Sex and nitric oxide bioavailability interact to modulate interstitial Po2 in healthy rat skeletal muscle.

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 ΔPo2is 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 Po2is 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.