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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 O2delivery-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 Po2and 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.

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 l -NAME, during the contracting steady-state, females exhibited lower PO2is than males (♂: 17.1 ± 1.4 vs ♀: 10.8 ± 1.4 mmHg, p 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.

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.

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). 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.

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.

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, We show that a single session of leg heat therapy (HT) reduces systolic blood pressure and lowers post‐exercise circulating levels of the potent vasoconstrictor endothelin‐1. Leg HT also tended to improve peak walking time during a graded treadmill test. This practical and well‐tolerated therapy may be a useful adjunctive tool to improve cardiovascular health and restore functional capacity in PAD patients.

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 O(2) 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.

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

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 O2delivery-to-utilization ratio (Q̇o2/V̇o2) during contractions; and 2) express greater modulation of Q̇o2/V̇o2with 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 Po2iskinetics 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 ΔPo2isduring 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 Po2iswas 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 O2delivery-to-utilization matching) plays an important role for O2flux into skeletal muscle. We show that both sexes regulate Po2isat 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.

Nitric oxide (NO) modulates oxygen delivery-utilization matching in resting and contracting skeletal muscle. Recent reports indicate that neuronal NO synthase (nNOS)-mediated vasoregulation during contractions is enhanced with exercise training and impaired with chronic heart failure (HF). Consequently, we tested the hypothesis that selective nNOS inhibition (S-methyl-l-thiocitrulline; SMTC, 2.1 µmol/kg) would produce attenuated reductions in muscle blood flow during moderate/heavy submaximal exercise in sedentary HF rats compared to their healthy counterparts. In addition, SMTC was expected to evoke greater reductions in exercising muscle blood flow in trained compared to sedentary healthy and HF rats. Blood flow during submaximal treadmill running (20 min/m, 5% grade) was determined via radiolabeled microspheres pre- and post-SMTC administration in healthy sedentary (Healthy + Sed, n = 8), healthy exercise trained (Healthy + ExT, n = 8), HF sedentary (HF + Sed, left ventricular end-diastolic pressure (LVEDP) = 12 ± 1 mmHg, n = 8), and HF exercise trained (HF + ExT, LVEDP = 16 ± 2 mmHg, n = 7) rats. nNOS contribution to exercising total hindlimb blood flow (ml/min/100 g) was not increased by training in either healthy or HF groups (Healthy + Sed: 105 ± 11 vs. 108 ± 16; Healthy + ExT: 96 ± 9 vs. 91 ± 7; HF + Sed: 124 ± 6 vs. 110 ± 12; HF + ExT: 107 ± 13 vs. 101 ± 8; control vs. SMTC, respectively; p > .05 for all). Similarly, SMTC did not reduce exercising blood flow in the majority of individual hindlimb muscles in any group (p > .05 for all, except for the semitendinosus and adductor longus in HF + Sed and the adductor longus in HF + ExT; p < .05). Contrary to our hypothesis, we find no support for either upregulation of nNOS function contributing to exercise hyperemia after training or its dysregulation with chronic HF.

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 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 (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). 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

The vascular ATP-sensitive K+ (KATP) channel is a mediator of skeletal muscle microvascular oxygenation (PO2mv) during contractions in health. We tested the hypothesis that KATP channel function is preserved in chronic heart failure (CHF) and therefore its inhibition would reduce PO2mv and exacerbate the time taken to reach the PO2mv steady-state during contractions of the spinotrapezius muscle. Moreover, we hypothesized that subsequent KATP channel activation would oppose the effects of this inhibition. Muscle PO2mv (phosphorescence quenching) was measured during 180 s of 1-Hz twitch contractions (~6 V) under control, glibenclamide (GLI, KATP channel antagonist; 5 mg/kg) and pinacidil (PIN, KATP channel agonist; 5 mg/kg) conditions in 16 male Sprague-Dawley rats with CHF induced via myocardial infarction (coronary artery ligation, left ventricular end-diastolic pressure: 18±1 mmHg). GLI reduced baseline PO2mv (control: 28.3±0.9, GLI: 24.8±1.0 mmHg, p

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 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.

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.

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 P0.1). 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.

To investigate whether the opposite effects of heart failure (HF) and chronic obstructive pulmonary disease (COPD) on exercise ventilatory inefficiency (minute ventilation [(Equation is included in full-text article.)E]-carbon dioxide output [(Equation is included in full-text article.)CO2] relationship) would negatively impact its prognostic relevance.After treatment optimization and an incremental cardiopulmonary exercise test, 30 male patients with HF-COPD (forced expiratory volume in 1 second [FEV1] = 57% ± 17% predicted, ejection fraction = 35% ± 6%) were prospectively followed up during 412 ± 261 days for major cardiac events.Fourteen patients (46%) had a negative outcome. Patients who had an event had lower echocardiographically determined right ventricular fractional area change (RVFAC), greater ventilatory inefficiency (higher (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 nadir), and lower end-tidal CO2 (PETCO2) (all P.05). Multivariate Cox models revealed that (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 nadir36, ΔPETCO2(PEAK-REST)≥2 mm Hg, and PETCO2PEAK≤33 mm Hg added prognostic value to RVFAC≤45%. Kaplan-Meyer analyses showed that although 18% of patients with RVFAC45% had a major cardiac event after 1 year, no patient with RVFAC45% and (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 nadir ≤36 (or PETCO2PEAK33 mm Hg) had a negative event. Conversely, although 69% of patients with RVFAC≤45% had a major cardiac event after 1 year, all patients with RVFAC≤45% and ΔPETCO2(PEAK-REST)≥2 mm Hg had a negative event.Ventilatory inefficiency remains a powerful prognostic marker in HF despite the presence of mechanical ventilatory constraints induced by COPD. If these preliminary findings are confirmed in larger studies, optimal thresholds for outcome prediction are likely greater than those traditionally recommended for HF patients without COPD.

A 56-year-old white woman was referred to the pulmonary clinic for evaluation of unexplained shortness of breath. She enjoyed good health until 3 months prior to this visit when she reported experiencing recurrent episodes of shortness of breath and oppressive retrosternal chest discomfort with radiation to the neck. Episodes lasting 5 to 10 min often occurred at rest and were inconsistently related to physical activity. These symptoms became progressively worse and were often associated with light-headedness and presyncope. Her past medical history was uneventful apart from a prior diagnosis of breast cysts and suspected prolactinoma. Her symptoms escalated to such a level that she was forced to seek urgent medical attention at our institutional ED on two separate occasions in the preceding weeks. These visits precipitated a number of investigations and, eventually, a referral to the pulmonary clinic.

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.

Central cardiorespiratory and gas exchange limitations imposed by chronic obstructive pulmonary disease (COPD) impair ambulatory skeletal muscle oxygenation during whole body exercise. This investigation tested the hypothesis that peripheral factors per se contribute to impaired contracting lower limb muscle oxygenation in COPD patients. Submaximal neuromuscular electrical stimulation (NMES; 30, 40, and 50 mA at 50 Hz) of the quadriceps femoris was employed to evaluate contracting skeletal muscle oxygenation while minimizing the influence of COPD-related central cardiorespiratory constraints. Fractional O-2 extraction was estimated by near-infrared spectroscopy (deoxyhemoglobin/myoglobin concentration; deoxy-[Hb/Mb]), and torque output was measured by isokinetic dynamometry in 15 nonhypoxemic patients with moderate-to-severe COPD (SpO(2) = 94 +/- 2%; FEV1 = 46.4 +/- 10.1%; GOLD II and III) and in 10 age- and gender-matched sedentary controls. COPD patients had lower leg muscle mass than controls (LMM = 8.0 +/- 0.7 kg vs. 8.9 +/- 1.0 kg, respectively; P < 0.05) and produced relatively lower absolute and LMM-normalized torque across the range of NMES intensities (P < 0.05 for all). Despite producing less torque, COPD patients had similar deoxy-[Hb/Mb] amplitudes at 30 and 40 mA (P > 0.05 for both) and higher deoxy-[Hb/Mb] amplitude at 50 mA (P < 0.05). Further analysis indicated that COPD patients required greater fractional O-2 extraction to produce torque (i.e., up arrow Delta deoxy-[Hb/Mb]/torque) relative to controls (P < 0.05 for 40 and 50 mA) and as a function of NMES intensity (P < 0.05 for all). the present data obtained during sub-maximal NMES of small muscle mass indicate that peripheral abnormalities contribute mechanistically to impaired contracting skeletal muscle oxygenation in nonhypoxemic, moderate-to-severe COPD patients. Universidade Federal de São Paulo, Sch Med, Dept Med, Div Resp,Pulm Funct & Clin Exercise Physiol Unit, São Paulo, Brazil Queens Univ, Dept Med, Div Resp & Crit Care Med, Lab Clin Exercise Physiol LACEP, Kingston, ON K7L 2V6, Canada Queens Univ, Dept Med, Div Resp & Crit Care Med, RIU, Kingston, ON K7L 2V6, Canada Universidade Federal de São Paulo, Sch Med, Dept Med, Div Resp,Pulm Funct & Clin Exercise Physiol Unit, São Paulo, Brazil Web of Science

Increased “wasted” ventilation and heightened neural drive explains excess exercise ventilation in CTEPH http://ow.ly/Z4YBc

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 ± 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 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.

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.Oxygen pressure (PO2) gradients across the blood-myocyte interface are required for diffusive O

Chronic heart failure (CHF) impairs nitric oxide (NO)-mediated regulation of skeletal muscle O2 delivery-utilization matching such that microvascular oxygenation falls faster (i.e., speeds PO2 mv kinetics) during increases in metabolic demand. Conversely, exercise training improves (slows) muscle PO2 mv kinetics following contractions onset in healthy young individuals via NO-dependent mechanisms. We tested the hypothesis that exercise training would improve contracting muscle microvascular oxygenation in CHF rats partly via improved NO-mediated function. CHF rats (left ventricular end-diastolic pressure = 17 ± 2 mmHg) were assigned to sedentary (n = 11) or progressive treadmill exercise training (n = 11; 5 days/wk, 6–8 wk, final workload of 60 min/day at 35 m/min; −14% grade downhill running) groups. PO2 mv was measured via phosphorescence quenching in the spinotrapezius muscle at rest and during 1-Hz twitch contractions under control (Krebs-Henseleit solution), sodium nitroprusside (SNP; NO donor; 300 μM), and NG-nitro-l-arginine methyl ester (L-NAME, nonspecific NO synthase blockade; 1.5 mM) superfusion conditions. Exercise-trained CHF rats had greater peak oxygen uptake and spinotrapezius muscle citrate synthase activity than their sedentary counterparts ( p < 0.05 for both). The overall speed of the PO2 mv fall during contractions (mean response time; MRT) was slowed markedly in trained compared with sedentary CHF rats (sedentary: 20.8 ± 1.4, trained: 32.3 ± 3.0 s; p < 0.05), and the effect was not abolished by L-NAME (sedentary: 16.8 ± 1.5, trained: 31.0 ± 3.4 s; p > 0.05). Relative to control, SNP increased MRT in both groups such that trained CHF rats had slower kinetics (sedentary: 43.0 ± 6.8, trained: 55.5 ± 7.8 s; p < 0.05). Improved NO-mediated function is not obligatory for training-induced improvements in skeletal muscle microvascular oxygenation (slowed PO2 mv kinetics) following contractions onset in rats with CHF.

Purpose : Chronic heart failure (CHF) is hallmarked by cardiac and peripheral vasculature dysfunction which has been associated with elevations in tumor necrosis factor-α (TNF-α) and exercise intolerance. The pharmaceutical TNF-α synthesis suppressor pentoxifylline (PTX) reduces plasma [TNF-α] and improves left ventricular (LV) function in CHF rats, but the effects of PTX on skeletal muscle blood flow (BF) and vascular conductance (VC) during exercise are unknown. We tested the hypothesis that PTX would elevate skeletal muscle BF and VC at rest and during submaximal treadmill exercise in CHF rats and improve exercise tolerance and peak O 2 uptake. Methods : CHF rats (coronary artery ligation) received i.p. injections of 30 mg·kg -1 ·day -1 of PTX (CHF+PTX, n=13) or saline (CHF, n=8) for 21 days. BF was measured using radiolabeled microspheres at rest and during exercise (treadmill, 20 m/min -1 , 5% grade). Results : Resting and exercising mean arterial pressures (MAP) were greater in CHF+PTX compared to CHF (i.e., closer to expected healthy values, both p

There is growing evidence that emphysema on thoracic computed tomography (CT) is associated with poor exercise tolerance in COPD patients with only mild-to-moderate airflow obstruction. We hypothesized that an excessive ventilatory response to exercise (ventilatory inefficiency) would underlie these abnormalities. In a prospective study, 19 patients (FEV1 = 82 ± 13%, 12 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1) and 26 controls underwent an incremental exercise test. Ventilatory inefficiency was assessed by the ventilation ([Formula: see text]E)/CO2 output ([Formula: see text]CO2) nadir. Pulmonary blood flow (PBF) in a submaximal test was calculated by inert gas rebreathing. Emphysema was quantified as % of attenuation areas below 950 HU. Patients typically presented with centrilobular emphysema (76.8 ± 10.1% of total emphysema) in the upper lobes (upper/total lung ratio = 0.82 ± 0.04). They had lower peak oxygen uptake ([Formula: see text]O2), higher [Formula: see text]E/[Formula: see text]CO2 nadir, and greater dyspnea scores than controls (p < 0.05). Lower peak [Formula: see text]O2 and worse dyspnea were found in patients with higher [Formula: see text]E/[Formula: see text]CO2 nadirs (≥30). Patients had blunted increases in PBF from rest to iso-[Formula: see text]O2 exercise (p < 0.05). Higher [Formula: see text]E/[Formula: see text]CO2 nadir in COPD was associated with emphysema severity (r = 0.63) which, in turn, was related to reduced lung diffusing capacity (r = -0.72) and blunted changes in PBF from rest to exercise (r = -0.69) (p < 0.01). Ventilation "wasted" in emphysematous areas is associated with impaired exercise ventilatory efficiency in mild-to-moderate COPD. Exercise ventilatory inefficiency links structure (emphysema) and function (DLCO) to a key clinical outcome (poor exercise tolerance) in COPD patients with only modest spirometric abnormalities.

NO3− supplementation via beetroot juice (BR) augments exercising skeletal muscle blood flow subsequent to its reduction to NO2− then NO. We tested the hypothesis that enhanced vascular control following BR would elevate the skeletal muscle O2 delivery/O2 utilization ratio (microvascular PO2, PmvO2) and raise the PmvO2 during the rest-contractions transition. Rats were administered BR (~0.8 mmol/kg/day, n = 10) or water (control, n = 10) for 5 days. PmvO2 was measured during 180 s of electrically induced (1 Hz) twitch spinotrapezius muscle contractions. There were no changes in resting or contracting steady-state PmvO2. However, BR slowed the PmvO2 fall following contractions onset such that time to reach 63% of the initial PmvO2 fall increased (MRT1; control: 16.8 ± 1.9, BR: 24.4 ± 2.7 s, p < 0.05) and there was a slower relative rate of PmvO2 fall (Δ1PmvO2/τ1; control: 1.9 ± 0.3, BR: 1.2 ± 0.2 mmHg/s, p < 0.05). Despite no significant changes in contracting steady state PmvO2, BR supplementation elevated the O2 driving pressure during the crucial rest-contractions transients thereby providing a potential mechanism by which BR supplementation may improve metabolic control.

Neuronal nitric oxide (NO) synthase (nNOS) inhibition with systemically-administered S-methyl-L-thiocitrulline (SMTC) elevates mean arterial pressure (MAP) and reduces rat hindlimb skeletal muscle and renal blood flow. We tested the hypothesis that those SMTC-induced cardiovascular effects resulted, in part, from increased sympathetic nerve discharge (SND). MAP, HR, and lumbar and renal SND (direct nerve recordings) were measured in 9 baroreceptor (sino-aortic)-denervated rats for 20 minutes each following both saline and SMTC (0.56 mg/kg i.v.). SMTC increased MAP (peak Δ MAP: 50±8 mmHg, p0.05). The Δ SND between saline and SMTC conditions for the lumbar and renal nerves were not different from zero (peak Δ SND, lumbar: 2.0±6.8%; renal: 9.7±9.0%, p>0.05 versus zero for both). These data support that SMTC-induced reductions in skeletal muscle and renal blood flow reported previously reflect peripheral nNOS-derived NO vascular control as opposed to increased sympathetic vasoconstriction.

Key points • Neuronal nitric oxide (NO) synthase (nNOS) inhibition does not impact skeletal muscle blood flow or vascular conductance (VC) during low-speed (20 m min−1) treadmill running. • This may be due to the fact that low exercise intensities recruit primarily oxidative muscle and that nNOS-derived NO contributes to vascular control primarily within glycolytic muscle. • Rats ran in the severe-intensity domain at 15% above critical speed (an important glycolytic fast-twitch fibre recruitment boundary in the rat) before and after selective nNOS inhibition with S-methyl-l-thiocitrulline (SMTC). • SMTC reduced blood flow and VC during supra-critical speed treadmill running (52.5 ± 1.3 m min−1) with the greatest proportional reductions observed in glycolytic fast-twitch compared to oxidative slow- and fast-twitch muscle. There were no effects of SMTC on muscle blood flow or VC during low-speed running (20 m min−1). • The present data reveal important fibre-type- and exercise intensity-dependent peripheral vascular effects of nNOS-derived NO during whole-body exercise. Abstract We have recently shown that nitric oxide (NO) derived from neuronal NO synthase (nNOS) does not contribute to the hyperaemic response within rat hindlimb skeletal muscle during low-speed treadmill running. This may be attributed to low exercise intensities recruiting primarily oxidative muscle and that vascular effects of nNOS-derived NO are manifest principally within glycolytic muscle. We tested the hypothesis that selective nNOS inhibition via S-methyl-l-thiocitrulline (SMTC) would reduce rat hindlimb skeletal muscle blood flow and vascular conductance (VC) during high-speed treadmill running above critical speed (asymptote of the hyperbolic speed versus time-to-exhaustion relationship for high-speed running and an important glycolytic fast-twitch fibre recruitment boundary in the rat) principally within glycolytic fast-twitch muscle. Six rats performed three high-speed treadmill runs to exhaustion to determine critical speed. Subsequently, hindlimb skeletal muscle blood flow (radiolabelled microspheres) and VC (blood flow/mean arterial pressure) were determined during supra-critical speed treadmill running (critical speed + 15%, 52.5 ± 1.3 m min−1) before (control) and after selective nNOS inhibition with 0.56 mg kg−1 SMTC. SMTC reduced total hindlimb skeletal muscle blood flow (control: 241 ± 23, SMTC: 204 ± 13 ml min−1 (100 g)−1, P < 0.05) and VC (control: 1.88 ± 0.20, SMTC: 1.48 ± 0.13 ml min−1 (100 g)−1 mmHg−1, P < 0.05) during high-speed running. The relative reductions in blood flow and VC were greater in the highly glycolytic muscles and muscle parts consisting of 100% type IIb+d/x fibres compared to the highly oxidative muscles and muscle parts consisting of ≤35% type IIb+d/x muscle fibres (P < 0.05). These results extend our understanding of vascular control during exercise by identifying fibre-type-selective peripheral vascular effects of nNOS-derived NO during high-speed treadmill running.

The nitric oxide (NO) donor sodium nitroprusside (SNP) may promote cyanide-induced toxicity and systemic and/or local responses approaching maximal vasodilation. The hypotheses were tested that SNP superfusion of the rat spinotrapezius muscle exerts 1) residual impairments in resting and contracting blood flow, oxygen utilization (VO(2)) and microvascular O(2) pressure (PO(2)mv); and 2) marked hypotension and elevation in resting PO(2)mv. Two superfusion protocols were performed: 1) Krebs-Henseleit (control 1), SNP (300 μM; a dose used commonly in superfusion studies) and Krebs-Henseleit (control 2), in this order; 2) 300 and 1200 μM SNP in random order. Spinotrapezius muscle blood flow (radiolabeled microspheres), VO(2) (Fick calculation) and PO(2)mv (phosphorescence quenching) were determined at rest and during electrically-induced (1 Hz) contractions. There were no differences in spinotrapezius blood flow, VO(2) or PO(2)mv at rest and during contractions pre- and post-SNP condition (control 1 and control 2; p0.05 for all). With regard to dosing, SNP produced a graded elevation in resting PO(2)mv (p0.05) with a reduction in mean arterial pressure only at the higher concentration (p0.05). Contrary to our hypotheses, skeletal muscle superfusion with the NO donor SNP (300 μM) improved microvascular oxygenation during the transition from rest to contractions (PO(2)mv kinetics) without precipitating residual impairment of muscle hemodynamic or metabolic control or compromising systemic hemodynamics. These data suggest that SNP superfusion (300 μM) constitutes a valid and important tool for assessing the functional roles of NO in resting and contracting skeletal muscle function without incurring residual alterations consistent with cyanide accumulation and poisoning.

Dietary nitrate (NO(3)(-)) supplementation, via its reduction to nitrite (NO(2)(-)) and subsequent conversion to nitric oxide (NO) and other reactive nitrogen intermediates, reduces blood pressure and the O(2) cost of submaximal exercise in humans. Despite these observations, the effects of dietary NO(3)(-) supplementation on skeletal muscle vascular control during locomotory exercise remain unknown. We tested the hypotheses that dietary NO(3)(-) supplementation via beetroot juice (BR) would reduce mean arterial pressure (MAP) and increase hindlimb muscle blood flow in the exercising rat. Male Sprague-Dawley rats (3-6 months) were administered either NO(3)(-) (via beetroot juice; 1 mmol kg(-1) day(-1), BR n = 8) or untreated (control, n = 11) tap water for 5 days. MAP and hindlimb skeletal muscle blood flow and vascular conductance (radiolabelled microsphere infusions) were measured during submaximal treadmill running (20 m min(-1), 5% grade). BR resulted in significantly lower exercising MAP (control: 137 ± 3, BR: 127 ± 4 mmHg, P < 0.05) and blood [lactate] (control: 2.6 ± 0.3, BR: 1.9 ± 0.2 mm, P < 0.05) compared to control. Total exercising hindlimb skeletal muscle blood flow (control: 108 ± 8, BR: 150 ± 11 ml min(-1) (100 g)(-1), P < 0.05) and vascular conductance (control: 0.78 ± 0.05, BR: 1.16 ± 0.10 ml min(-1) (100 g)(-1) mmHg(-1), P < 0.05) were greater in rats that received BR compared to control. The relative differences in blood flow and vascular conductance for the 28 individual hindlimb muscles and muscle parts correlated positively with their percentage type IIb + d/x muscle fibres (blood flow: r = 0.74, vascular conductance: r = 0.71, P < 0.01 for both). These data support the hypothesis that NO(3)(-) supplementation improves vascular control and elevates skeletal muscle O(2) delivery during exercise predominantly in fast-twitch type II muscles, and provide a potential mechanism by which NO(3)(-) supplementation improves metabolic control.

Heightened oxidative stress is implicated in the progressive impairment of skeletal muscle vascular and mitochondrial function in chronic obstructive pulmonary disease (COPD). Whether accumulation of reactive oxygen species contributes to exercise intolerance in the early stages of COPD is unknown. The purpose of the present study was to determine the effects of oral antioxidant treatment with

Chronic heart failure (CHF) impairs skeletal muscle O 2 transport and utilization leading to restricted physical capacity. Dietary nitrate supplementation has been shown to improve vascular function, reduce the O 2 cost of muscle contraction and enhance exercise tolerance (Tlim) in both healthy and clinical populations (e.g., COPD). We tested the hypothesis that dietary nitrate would improve locomotor muscle O 2 delivery-utilization matching and Tlim in CHF patients. Methods: Nine males with CHF (ejection fraction=33±6%) consumed either nitrate-rich (∼12 mmol nitrate; beetroot juice) or nitrate-depleted beetroot juice (placebo) for 8 days. Mean arterial pressure (MAP), central hemodynamics by impedance cardiography (stroke volume, heart rate and cardiac output), pulmonary oxygen uptake (VO 2 ) and muscle oxygenation by near-infrared spectroscopy were determined at rest and during low- and high-intensity “step” exercise tests. Results: No differences were observed between placebo vs. beetroot juice for resting and exercising MAP, central hemodynamics or muscle oxygenation (p>0.05). The O 2 cost of exercise during both low- (placebo: 0.88±0.19 vs. beetroot juice: 0.94±0.24 l/min) and high-intensity (1.33±0.30 vs. 1.36±0.31 l/min) cycling and Tlim (489±194 vs. 485±173 s) were also unaffected by beetroot juice (p>0.05). Conclusions: Contrary to the hypothesis, 8 days of dietary nitrate supplementation did not enhance skeletal muscle O 2 delivery-utilization matching or exercise tolerance in CHF patients. Whether longer treatment duration and/or higher doses are therapeutically effective in this patient population remains to be determined.

Background: Short bursts of high-intensity interval exercise (HIIE) may prevent critical reductions in mechanical ventilatory reserves leading to greater tolerance (TOL) to exercise in COPD. It remains unclear however why some COPD patients have lower TOL to HIIE than others. Methods: 16 patients (FEV1= 42.0±8.9%) underwent, on different days, a constant load test (∼80% peak) and two HIIE tests (100% peak:30 s) to intolerance (Tlim) or 30 min. High-intensity bouts were interspersed by “0” W (HIIE0) or 40% peak (HIIE40) during 60 s. Results: While no patient sustained the constant load trial for 30 min, all but 2 patients tolerated HIIE0. Seven patients did not tolerate HIIE40 (NON-TOL). Despite similar functional impairment and peak exercise capacity, CO2 output (VCO2) and ventilation (VE) progressively increased across exercise bouts only in NON-TOL (Figure for representative patients)(p

Background: Exercise ventilatory inefficiency (e.g., increased ventilation (VE) / CO 2 output (VCO 2 ) nadir) has been consistently found in moderate-to-severe COPD. It remains unknown a) whether this holds true for patients with largely preserved FEV 1 and, if so, b) whether it would be associated with structural findings suggestive of “wasted” ventilation (i.e., emphysema). Methods: 45 subjects of both genders (19 with COPD) prospectively underwent incremental cardiopulmonary exercise testing. % Emphysema in COPD was established by high resolution CT. Results: The groups were well-matched by age, gender and body dimensions. As shown in the Table , patients presented with lower peak exercise capacity and greater VE/VCO 2 nadir compared to controls (p Peak oxygen uptake and power were inversely related to VE/VCO 2 nadir (r=-0.57 and r=-0.46, respectively; p 2 nadir was strongly related to % emphysema ( Figure ). Conclusion: COPD is associated with poor ventilatory efficiency even in patients with largely preserved FEV 1 . Imaging features of mild emphysema may have functional relevance for these patients under the stress of exercise.

Background: Chronic obstructive pulmonary disease (COPD) is associated with an elevated risk of cardiovascular disease, a finding that might be mechanistically linked to systemic endothelial dysfunction. In fact, coexistent cardiovascular disease is a major cause of disability and death in COPD patients with only mild-to-moderate airflow obstruction. It remains unknown, however, whether these patients may present with systemic endothelial dysfunction. Methods: We measured flow mediated dilation (FMD) of the brachial artery (BA) in 10 COPD patients (7 with FEV 1 > 80% predicted, 6 females) and 13 age- and gender-matched sedentary controls. Results: COPD patients had lower FMD compared to controls (4.0±2.9% vs 5.2±2.6%, P=0.11) which was further amplified when normalized for reactive hyperemia induced shear rate (SR=BA blood velocity/BA diameter) (0.0008±0.0003%/SR vs 0.00155±0.008%/SR, P=0.029). The time to peak FMD diameter was significantly delayed in COPD patients compared to controls (71±23s vs 44±8s, P=0.01). These abnormalities, however, were not associated with severity of airflow obstruction (P>0.05). Conclusion: Impairments in systemic endothelial function precede large reductions in FEV 1 in patients with COPD. These findings might hold clinical implications for cardiovascular risk stratification and early treatment in this patient population.

Background Exercise oscillatory ventilation (EOV) is associated with poor ventilatory efficiency and higher operating lung volumes in heart failure. These abnormalities may be particularly deleterious to dyspnea and exercise tolerance in mechanically-limited patients, e.g. those with coexistent COPD. Methods Ventilatory, gas exchange and sensory responses to incremental exercise were contrasted in 68 heart failure-COPD patients (12 EOV+). EOV was established by standard criteria. Results Compared to EOV−, EOV+ had lower exercise capacity, worse ventilatory inefficiency and higher peak dyspnea scores (p 2 (PcCO 2 ) was higher and end-tidal CO 2 (PETCO 2 ) was lower in EOV+. Thus, greater (i.e., more positive) P(c-ET)CO 2 and dead space/tidal volume values were found in these patients compared to EOV− (p 2 stabilized or increased and dyspnea scores rose sharply. Exercise capacity was closely related to IRV decrements and peak dyspnea in EOV+ (r=−0.78 and 0.84, respectively; p Conclusions Dyspnea and exercise tolerance are negatively influenced by EOV in heart failure patients presenting with COPD as co-morbidity. Pharmacological and non-pharmacological interventions known to decrease EOV might prove particularly valuable to mitigate symptom burden and exercise intolerance in this specific heart failure group.

Systolic heart failure is a common and disabling co-morbidity of chronic obstructive pulmonary disease (COPD) which may increase exercise ventilation due to heightened neural drive and/or impaired pulmonary gas exchange efficiency. The influence of heart failure on exercise ventilation, however, remains poorly characterized in COPD. In a prospective study, 98 patients with moderate to very severe COPD [41 with coexisting heart failure; 'overlap' (left ventricular ejection fraction < 50%)] underwent an incremental cardiopulmonary exercise test (CPET). Compared to COPD, overlap had lower peak exercise capacity despite higher FEV1. Overlap showed lower operating lung volumes, greater ventilatory inefficiency and larger decrements in end-tidal CO2 (PETCO2) (P < 0.05). These results were consistent with those found in FEV1-matched patients. Larger areas under receiver operating characteristic curves to discriminate overlap from COPD were found for ventilation ([Formula: see text]E)-CO2 output [Formula: see text]CO2) intercept, [Formula: see text]E-[Formula: see text]CO2 slope, peak [Formula: see text]E/[Formula: see text]CO2 ratio and peak PETCO2. Multiple logistic regression analysis revealed that [Formula: see text]CO2 intercept ≤ 3.5 L/minute [odds ratios (95% CI) = 7.69 (2.61-22.65), P < 0.001] plus [Formula: see text]E-[Formula: see text]CO2 slope ≥ 34 [2.18 (0.73-6.50), P = 0.14] or peak [Formula: see text]E/[Formula: see text]CO2 ratio ≥ 37 [5.35 (1.96-14.59), P = 0.001] plus peak PETCO2 ≤ 31 mmHg [5.73 (1.42-23.15), P = 0.01] were indicative of overlapping. Heart failure increases the ventilatory response to metabolic demand in COPD. Variables reflecting excessive ventilation might prove useful to assist clinical interpretation of CPET responses in COPD patients presenting heart failure as co-morbidity.