Strategies targeting the NO pathway to counteract extra-pulmonary manifestations of COPD: A systematic review and meta-analysis.

The clinical symptoms of chronic obstructive pulmonary disease (COPD) disease are accompanied by severely debilitating extra-pulmonary manifestations, including vascular dysfunction and hypertension. This systematic review evaluated the current evidence for several therapeutic interventions, targeting the nitric oxide (NO) pathway on hemodynamics and, secondarily, exercise capacity in patients with COPD. A comprehensive search on COPD and NO donors was performed on online databases. Of 934 initially found manuscripts, 27 were included in the review, and 16 in the meta-analysis. The analysis indicated inconsistent effects of dietary nitrate supplementation on exercise tolerance in COPD patients. Dietary nitrate supplementation decreased systolic (-3.7 ± 4.3 mmHg; p = 0.10) and diastolic blood pressure (BP; -2.6 ± 3.2 mmHg; p = 0.05) compared with placebo. When restricted to acute studies, a clinically relevant BP lowering effect of nitrate supplementation during diastole was observed (-4.7 ± 3.2 mmHg; n = 5; p = 0.05). In contrast, inhaled NO (iNO) at doses <20 ppm (+9.2 ± 11.3 mmHg) and 25-40 ppm (-5±2 mmHg) resulted in inconsistent effects on PaO2 (p = 0.48). Data on the effect of iNO on exercise capacity were too limited and inconsistent, but preliminary evidence suggests a possible benefit of iNO on pulmonary vascular resistance during exercise in severe COPD patients. Overall, the effects of acute dietary nitrate supplementation on BP may be of clinical relevance as an adjunct therapy and deserve further investigation in large sample size studies of COPD patients with and without cardiovascular comorbidities. iNO exerted inconsistent physiological effects, with the use of high doses posing safety risks.

On the role of skeletal muscle acidosis and inorganic phosphates as determinants of central and peripheral fatigue: A 31 P-MRS study.

Intramuscular hydrogen ion (H+ ) and inorganic phosphate (Pi) concentrations were dissociated during exercise to challenge their relationships with peripheral and central fatigue in vivo. Ten recreationally active, healthy men (27 ± 5 years; 180 ± 4 cm; 76 ± 10 kg) performed two consecutive intermittent isometric single-leg knee-extensor trials (60 maximal voluntary contractions; 3 s contraction, 2 s relaxation) interspersed with 5 min of rest. Phosphorus magnetic resonance spectroscopy (31 P-MRS) was used to continuously quantify intramuscular [H+ ] and [Pi] during both trials. Using electrical femoral nerve stimulation, quadriceps twitch force (Qtw ) and voluntary activation (VA) were quantified at rest and throughout both trials. Decreases in Qtw and VA from baseline were used to determine peripheral and central fatigue, respectively. Qtw was strongly related to both [H+ ] (ß coefficient: -0.9, P < 0.0001) and [Pi] (-1.1, P < 0.0001) across trials. There was an effect of trial on the relationship between Qtw and [H+ ] (-0.5, P < 0.0001), but not Qtw and [Pi] (0.0, P = 0.976). This suggests that, unlike the unaltered association with [Pi], a given level of peripheral fatigue was associated with a different [H+ ] in Trial 1 vs. Trial 2. VA was related to [H+ ] (-0.3, P < 0.0001), but not [Pi] (-0.2, P = 0.243), across trials and there was no effect of trial (-0.1, P = 0.483). Taken together, these results support intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III/IV muscle afferents in the interstitial space, as a contributor to central fatigue during exercise. KEY POINTS: We investigated the relationship between intramuscular metabolites and neuromuscular function in humans performing two maximal, intermittent, knee-extension trials interspersed with 5 min of rest. Concomitant measurements of intramuscular hydrogen (H+ ) and inorganic phosphate (Pi) concentrations, as well as quadriceps twitch-force (Qtw ) and voluntary activation (VA), were made throughout each trial using phosphorus magnetic resonance spectroscopy (31 P-MRS) and electrical femoral nerve stimulations. Although [Pi] fully recovered prior to the onset of the second trial, [H+ ] did not. Qtw was strongly related to both [H+ ] and [Pi] across both trials. However, the relationship between Qtw and [H+ ] shifted leftward from the first to the second trial, whereas the relationship between Qtw and [Pi] remained unaltered. VA was related to [H+ ], but not [Pi], across both trials. These in vivo findings support the hypotheses of intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III/IV muscle afferents, as a contributor to central fatigue.

Combined anthocyanins and bromelain supplement improves endothelial function and skeletal muscle oxygenation status in adults: a double-blind placebo-controlled randomised crossover clinical trial.

Anthocyanins and bromelain have gained significant attention due to their antioxidative and anti-inflammatory properties. Both have been shown to improve endothelial function, blood pressure (BP) and oxygen utility capacity in humans; however, the combination of these two and the impacts on endothelial function, BP, total antioxidant capacity (TAC) and oxygen utility capacity have not been previously investigated. The purpose of this study was to investigate the impacts of a combined anthocyanins and bromelain supplement (BE) on endothelial function, BP, TAC, oxygen utility capacity and fatigability in healthy adults. Healthy adults (n 18, age 24 (sd 4) years) received BE or placebo in a randomised crossover design. Brachial artery flow-mediated dilation (FMD), BP, TAC, resting heart rate, oxygen utility capacity and fatigability were measured pre- and post-BE and placebo intake. The BE group showed significantly increased FMD, reduced systolic BP and improved oxygen utility capacity compared with the placebo group (P < 0·05). Tissue saturation and oxygenated Hb significantly increased following BE intake, while deoxygenated Hb significantly decreased (P < 0·05) during exercise. Additionally, TAC was significantly increased following BE intake (P < 0·05). There were no significant differences for resting heart rate, diastolic BP or fatigability index. These results suggest that BE intake is an effective nutritional therapy for improving endothelial function, BP, TAC and oxygen utility capacity, which may be beneficial to support vascular health in humans.

Influence of group III/IV muscle afferents on small muscle mass exercise performance: a bioenergetics perspective.

KEY POINTS: This investigation assessed the influence of group III/IV muscle afferents on small muscle mass exercise performance from a skeletal muscle bioenergetics perspective. Group III/IV muscle afferent feedback was attenuated with lumbar intrathecal fentanyl during intermittent isometric single-leg knee-extensor all-out exercise, while 31 P-MRS was used to assess skeletal muscle bioenergetics. Attenuation of group III/IV muscle afferent feedback improved exercise performance during the first minute of exercise, due to an increase in total ATP production with no change in the ATP cost of contraction. However, exercise performance was not altered during the remainder of the protocol, despite a sustained increase in total ATP production, due to an exacerbated ATP cost of contraction. These findings reveal that group III/IV muscle afferents directly limit exercise performance during small muscle mass exercise, but, due to their critical role in maintaining skeletal muscle contractile efficiency, with time, the benefit of attenuating the muscle afferents is negated. ABSTRACT: The direct influence of group III/IV muscle afferents on exercise performance remains equivocal. Therefore, all-out intermittent isometric single-leg knee-extensor exercise and phosphorous magnetic resonance spectroscopy (31 P-MRS) were utilized to provide a high time resolution assessment of exercise performance and skeletal muscle bioenergetics in control conditions (CTRL) and with the attenuation of group III/IV muscle afferent feedback via lumbar intrathecal fentanyl (FENT). In both conditions, seven recreationally active men performed 60 maximal voluntary quadriceps contractions (MVC; 3 s contraction, 2 s relaxation), while knee-extensor force and 31 P-MRS were assessed during each MVC. The cumulative integrated force was significantly greater (8 ± 6%) in FENT than CTRL for the first minute of the all-out protocol, but was not significantly different for the second to fifth minutes. Total ATP production was significantly greater (16 ± 21%) in FENT than CTRL throughout the all-out exercise protocol, due to a significantly greater anaerobic ATP production (11 ± 13%) in FENT than CTRL with no significant difference in oxidative ATP production. The ATP cost of contraction was not significantly different between FENT and CTRL for the first minute of the all-out protocol, but was significantly greater (29 ± 34%) in FENT than in CTRL for the second to fifth minutes. These findings reveal that group III/IV muscle afferents directly limit exercise performance during small muscle mass exercise, but, due to their critical role in maintaining skeletal muscle contractile efficiency, with time, the benefit from muscle afferent attenuation is negated.

Bioenergetics and ATP Synthesis during Exercise: Role of Group III/IV Muscle Afferents.

PURPOSE: The purpose of this study was to investigate the role of the group III/IV muscle afferents in the bioenergetics of exercising skeletal muscle beyond constraining the magnitude of metabolic perturbation. METHODS: Eight healthy men performed intermittent isometric knee-extensor exercise to task failure at ~58% maximal voluntary contraction under control conditions (CTRL) and with lumbar intrathecal fentanyl to attenuate group III/IV leg muscle afferents (FENT). Intramuscular concentrations of phosphocreatine (PCr), inorganic phosphate (Pi), diprotonated phosphate (H2PO4), adenosine triphosphate (ATP), and pH were determined using phosphorous magnetic resonance spectroscopy (P-MRS). RESULTS: The magnitude of metabolic perturbation was significantly greater in FENT compared with CTRL for [Pi] (37.8 ± 16.8 vs 28.6 ± 8.6 mM), [H2PO4] (24.3 ± 12.2 vs 17.9 ± 7.1 mM), and [ATP] (75.8% ± 17.5% vs 81.9% ± 15.8% of baseline), whereas there was no significant difference in [PCr] (4.5 ± 2.4 vs 4.4 ± 2.3 mM) or pH (6.51 ± 0.10 vs 6.54 ± 0.14). The rate of perturbation in [PCr], [Pi], [H2PO4], and pH was significantly faster in FENT compared with CTRL. Oxidative ATP synthesis was not significantly different between conditions. However, anaerobic ATP synthesis, through augmented creatine kinase and glycolysis reactions, was significantly greater in FENT than in CTRL, resulting in a significantly greater ATP cost of contraction (0.049 ± 0.016 vs 0.038 ± 0.010 mM·min·N). CONCLUSION: Group III/IV muscle afferents not only constrain the magnitude of perturbation in intramuscular Pi, H2PO4, and ATP during small muscle mass exercise but also seem to play a role in maintaining efficient skeletal muscle contractile function in men.

Electrostimulation improves muscle perfusion but does not affect either muscle deoxygenation or pulmonary oxygen consumption kinetics during a heavy constant-load exercise.

Electromyostimulation (EMS) is commonly used as part of training programs. However, the exact effects at the muscle level are largely unknown and it has been recently hypothesized that the beneficial effect of EMS could be mediated by an improved muscle perfusion. In the present study, we investigated rates of changes in pulmonary oxygen consumption (VO(2p)) and muscle deoxygenation during a standardized exercise performed after an EMS warm-up session. We aimed at determining whether EMS could modify pulmonary O(2) uptake and muscle deoxygenation as a result of improved oxygen delivery. Nine subjects performed a 6-min heavy constant load cycling exercise bout preceded either by an EMS session (EMS) or under control conditions (CONT). VO(2p) and heart rate (HR) were measured while deoxy-(HHb), oxy-(HbO(2)) and total haemoglobin/myoglobin (Hb(tot)) relative contents were measured using near infrared spectroscopy. EMS significantly increased (P < 0.05) the Hb(tot) resting level illustrating a residual hyperaemia. The EMS priming exercise did not affect either the HHb time constant (17.7 +/- 14.2 s vs. 13.1 +/- 2.3 s under control conditions) or the VO(2p) kinetics (time-constant = 18.2 +/- 5.2 s vs. 15.4 +/- 4.6 s under control conditions). Likewise, the other VO(2p) parameters were unchanged. Our results further indicated that EMS warm-up improved muscle perfusion through a residual hyperaemia. However, neither VO(2p) nor [HHb] kinetics were modified accordingly. These results suggest that improved O(2) delivery by residual hyperaemia induced by EMS does not accelerate the rate of aerobic metabolism during heavy exercise at least in trained subjects.