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PURPOSE Autonomic control of the heart is balanced by sympathetic and parasympathetic inputs. Excitation of both sympathetic and parasympathetic systems occurs concurrently during certain perturbations such as hypoxia, which stimulate carotid chemoreflex to drive ventilation. It is well established that the chemoreflex becomes sensitized throughout hypoxic exposure; however, whether progressive sensitization alters cardiac autonomic activity remains unknown. We sought to determine the duration of hypoxic exposure at high altitude necessary to unmask cardiac arrhythmias during instances of voluntary apnea. METHODS Measurements of steady-state chemoreflex drive (SS-CD), continuous electrocardiogram (ECG) and SpO2 (pulse oximetry) were collected in 22 participants on 1 day at low altitude (1045 m) and over eight consecutive days at high-altitude (3800 m). SS-CD was quantified as ventilation (L/min) over stimulus index (PETCO2/SpO2). RESULTS Bradycardia during apnea was greater at high altitude compared to low altitude for all days (p 50%) following Day 5 at high altitude. Changes in saturation during apnea and apnea duration did not affect the magnitude of bradycardia during apnea (ANCOVA; saturation, p = 0.15 and apnea duration, p = 0.988). Interestingly, the magnitude of bradycardia was correlated with the incidence of arrhythmia per day (r = 0.8; p = 0.004). CONCLUSION Our findings suggest that persistent hypoxia gradually increases vagal tone with time, indicated by augmented bradycardia during apnea and progressively increased the incidence of arrhythmia at high altitude.

Central sleep apnea (CSA) is universal during ascent to high altitude, with intermittent and transient fluctuations in oxygen saturation, but the consequences on mean sleeping blood oxygenation are unclear. We assessed indices of CSA and mean sleeping peripheral oxygen saturation ([Formula: see text]) during ascent to high altitude using two ascent profiles: rapid ascent and residence at 3,800 m and incremental ascent to 5,160 m. The severity of CSA was not correlated with mean sleeping [Formula: see text] with ascent.

Measuring the retinal microvasculature at high altitude provides a surrogate for cerebral microvasculature, offering potential insight into consequence of cerebral hypoxia in critical illness. This study demonstrates dynamic regulation of the retina during rapid ascent and prolonged exposure to high altitude and is the first to demonstrate sex-specific differences in retinal microvasculature at high altitude. The ability to dynamically assess intact microvasculature contiguous with the brain has widespread research and clinical applications.

Key points We have previously shown that carotid body stimulation by lysophosphatidic acid elicits a reflex stimulation of vagal efferent activity sufficient to cause bronchoconstriction in asthmatic rats. Here, we show that pathophysiological concentrations of asthma-associated prototypical Th2 cytokines also stimulate the carotid bodies. Stimulation of the carotid bodies by these asthmakines involves a PKCe-transient receptor potential vanilloid 1 (TRPV1) signalling mechanism likely dependent on TRPV1 S502 and T704 phosphorylation sites. As the carotid bodies' oxygen sensitivity is independent of PKCe-TRPV1 signalling, systemic blockade of PKCe may provide a novel therapeutic target to reduce allergen-induced asthmatic bronchoconstriction. Consistent with the therapeutic potential of blocking the PKCe-TRPV1 pathway, systemic delivery of a PKCe-blocking peptide suppresses asthmatic respiratory distress in response to allergen and reduces airway hyperresponsiveness to bradykinin. Abstract The autonomic nervous system orchestrates organ-specific, systemic and behavioural responses to inflammation. Recently, we demonstrated a vital role for lysophosphatidic acid in stimulating the primary autonomic oxygen chemoreceptors, the carotid bodies, in parasympathetic-mediated asthmatic airway hyperresponsiveness. However, the cacophony of stimulatory factors and cellular mechanisms of carotid body activation are unknown. Therefore, we set out to determine the intracellular signalling involved in carotid body-mediated sensing of asthmatic blood-borne inflammatory mediators. We employed a range of in vitro and rat in situ preparations, site-directed mutagenesis, patch-clamp, nerve recordings and pharmacological inhibition to assess cellular signalling. We show that the carotid bodies are also sensitive to asthma-associated prototypical Th2 cytokines which elicit sensory nerve excitation. This provides additional asthmatic ligands contributing to the previously established reflex arc resulting in efferent vagal activity and asthmatic bronchoconstriction. This novel sensing role for the carotid body is mediated by a PKCe-dependent stimulation of transient receptor potential vanilloid 1 (TRPV1), likely via TRPV1 phosphorylation at sites T704 and S502. Importantly, carotid body oxygen sensing was unaffected by blocking either PKCe or TRPV1. Further, we demonstrate that systemic PKCe blockade reduces asthmatic respiratory distress in response to allergen and airway hyperresponsiveness. These discoveries support an inflammation-dependent, oxygen-independent function for the carotid body and suggest that targeting PKCe provides a novel therapeutic option to abate allergic airway disease without altering life-saving autonomic hypoxic reflexes.

The murine interleukin-4 treated macrophage (MIL4) exerts anti-inflammatory and pro-healing effects and has been shown to reduce the severity of chemical-induced colitis. Positing M(IL4) transfer as an anti-inflammatory therapy, the possibility of side-effects must be considered. Consequently, bone marrow-derived M(IL4)s were administered via intraperitoneal injection to mice concomitant with Citrobacter rodentium infection (infections colitis), azoxymethane/dextran sodium sulphate (AOM/DSS) treatment [a model of colorectal cancer (CRC)], or ovalbumin sensitization (airway inflammation). The impact of M(IL4) treatment on C. rodentium infectivity, colon histopathology, tumor number and size and tissue-specific inflammation was examined in these models. The anti-colitic effect of the M(IL4)s were confirmed in the di-nitrobenzene sulphonic acid model of colitis and the lumen-to-blood movement of 4kDa FITC-dextran and bacterial translocation to the spleen and liver was also improved by M(IL4) treatment. Analysis of the other models of disease, that represent comorbidities that can occur in human inflammatory bowel disease (IBD), revealed that M(IL4) treatment did not exaggerate the severity of any of the conditions. Rather, there was reduction in the size (but not number) of polyps in the colon of AOM/DSS-mice and reduced infectivity and inflammation in C. rodentium-infected mice in M(IL4)-treated mice. Thus, while any new therapy can have unforeseen side effects, our data confirm and extend the anti-colitic capacity of murine M(IL4)s and indicate that systemic delivery of one million M(IL4)s did not exaggerate disease in models of colonic or airways inflammation or colonic tumorigenesis.

Dongxing Zhao,1,2 Asghar Abbasi,1 Richard Casaburi,1 Alessandra Adami,3 Nicholas B Tiller,1 Wei Yuan,1,4 Christopher Yee,5 Nicholas G Jendzjowsky,1 David M MacDonald,6,7 Ken M Kunisaki,6,7 William W Stringer,1 Janos Porszasz,1 Barry J Make,8 Russell P Bowler,8 Harry B Rossiter1 On behalf of the COPDGene Investigators1Rehabilitation Clinical Trials Center, Division of Respiratory and Critical Care Physiology and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA; 2State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, People’s Republic of China; 3Department of Kinesiology, University of Rhode Island, Kingston, RI, USA; 4Respiratory Medicine Department, Beijing Friendship Hospital Affiliated of Capital Medical University, Beijing, 100050, People’s Republic of China; 5MemorialCare Long Beach Medical Center, Long Beach, CA, USA; 6Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, Minneapolis, MN, USA; 7Minneapolis VA Health Care System, Minneapolis, MN, USA; 8National Jewish Health, Denver, CO, USACorrespondence: Harry B Rossiter Email hrossiter@ucla.eduBackground: Slow heart rate recovery (HRR) after exercise is associated with autonomic dysfunction and increased mortality. What HRR criterion at 1-minute after a 6-minute walk test (6MWT) best defines pulmonary impairment?.Study Design and Methods: A total of 5008 phase 2 COPDGene (NCT00608764) participants with smoking history were included. A total of 2127 had COPD and, of these, 385 were followed-up 5-years later. Lung surgery, transplant, bronchiectasis, atrial fibrillation, heart failure and pacemakers were exclusionary. HR was measured from pulse oximetry at end-walk and after 1-min seated recovery. A receiver operator characteristic (ROC) identified optimal HRR cut-off. Generalized linear regression determined HRR association with spirometry, chest CT, symptoms and exacerbations.Results: HRR after 6MWT (bt/min) was categorized in quintiles: ≤ 5 (23.0% of participants), 6– 10 (20.7%), 11– 15 (18.9%), 16– 22 (18.5%) and ≥ 23 (18.9%). Compared to HRR≤ 5, HRR≥ 11 was associated with (p< 0.001): lower pre-walk HR and 1-min post HR; greater end-walk HR; greater 6MWD; greater FEV1%pred; lower airway wall area and wall thickness. HRR was positively associated with FEV1%pred and negatively associated with airway wall thickness. An optimal HRR ≤ 10 bt/min yielded an area under the ROC curve of 0.62 (95% CI 0.58– 0.66) for identifying FEV1< 30%pred. HRR≥ 11 bt/min was the lowest HRR associated with consistently less impairment in 6MWT, spirometry and CT variables. In COPD, HRR≤ 10 bt/min was associated with (p< 0.001): ≥ 2 exacerbations in the previous year (OR=1.76[1.33– 2.34]); CAT≥ 10 (OR=1.42[1.18– 1.71]); mMRC≥ 2 (OR=1.42[1.19– 1.69]); GOLD 4 (OR=1.98[1.44– 2.73]) and GOLD D (OR=1.51[1.18– 1.95]). HRR≤ 10 bt/min was predicted COPD exacerbations at 5-year follow-up (RR=1.83[1.07– 3.12], P=0.027).Conclusion: HRR≤ 10 bt/min after 6MWT in COPD is associated with more severe expiratory flow limitation, airway wall thickening, worse dyspnoea and quality of life, and future exacerbations, suggesting that an abnormal HRR≤ 10 bt/min after a 6MWT may be used in a comprehensive assessment in COPD for risk of severity, symptoms and future exacerbations.Keywords: autonomic dysfunction, chest computed tomography, COPD exacerbation, exercise, spirometry

Autonomic control of the heart is balanced by sympathetic and parasympathetic inputs. Excitation of both sympathetic and parasympathetic systems occurs concurrently during certain perturbations such as hypoxia, which stimulate carotid chemoreflex to drive ventilation. It is well established that the chemoreflex becomes sensitized throughout hypoxic exposure; however, whether progressive sensitization alters cardiac autonomic activity remains unknown. We sought to determine the duration of hypoxic exposure at high altitude necessary to unmask cardiac arrhythmias during instances of voluntary apnea.Measurements of steady-state chemoreflex drive (SS-CD), continuous electrocardiogram (ECG) and SpOBradycardia during apnea was greater at high altitude compared to low altitude for all days (p 0.001). Cardiac arrhythmias occurred during apnea each day but became most prevalent ( 50%) following Day 5 at high altitude. Changes in saturation during apnea and apnea duration did not affect the magnitude of bradycardia during apnea (ANCOVA; saturation, p = 0.15 and apnea duration, p = 0.988). Interestingly, the magnitude of bradycardia was correlated with the incidence of arrhythmia per day (r = 0.8; p = 0.004).Our findings suggest that persistent hypoxia gradually increases vagal tone with time, indicated by augmented bradycardia during apnea and progressively increased the incidence of arrhythmia at high altitude.

The high metabolic demand of cerebral tissue requires that local perfusion is tightly coupled with local metabolic rate (neurovascular coupling; NVC). During chronic altitude exposure, where individuals are exposed to the antagonistic cerebrovascular effects of hypoxia and hypocapnia, pH is maintained through renal compensation and NVC remains stable. However, the potential independent effect of acute hypocapnia and respiratory alkalosis on NVC remains to be determined. We hypothesized that acute steady‐state hypocapnia via voluntary hyperventilation would attenuate the magnitude of NVC. We recruited 17 healthy participants and insonated the posterior cerebral artery (PCA) with transcranial Doppler ultrasound. NVC was elicited using a standardized strobe light stimulus (6 Hz; 5 × 30 s on/off) where absolute delta responses from baseline (BL) in peak, mean, and total area under the curve (tAUC) were quantified. From a BL end‐tidal (PET)CO2 level of 36.7 ± 3.2 Torr, participants were coached to hyperventilate to reach steady‐state hypocapnic steps of Δ‐5 Torr (31.6 ± 3.9) and Δ‐10 Torr (26.0 ± 4.0; p, We assessed the NVC response to a visual stimulus, under conditions of normocapnia and two steps of hypocapnia via voluntary hyperventilation.

Rapid ascent to high altitude imposes an acute hypoxic and acid-base challenge, with ventilatory and renal acclimatization countering these perturbations. Specifically, ventilatory acclimatization improves oxygenation, but with concomitant hypocapnia and respiratory alkalosis. A compensatory, renally-mediated relative metabolic acidosis follows via bicarbonate elimination, normalizing arterial pH(a). The time-course and magnitude of these integrated acclimatization processes are highly variable between individuals. Using a previously-developed metric of renal reactivity (RR), indexing the change in arterial bicarbonate concentration (∆[HCO3-]a; renal response) over the change in arterial pressure of CO2 (∆PaCO2; renal stimulus), we aimed to characterize changes in RR magnitude following rapid ascent and residence at altitude. Resident lowlanders (n=16) were tested at 1,045 m (Day [D]0) prior to ascent, on D2 within 24-hours of arrival, and D9 during residence at 3,800 m. Radial artery blood draws were obtained to measure acid-base variables: PaCO2, [HCO3-]a and pHa. Compared to D0, PaCO2 and [HCO3-]a were lower on D2 (P0.058) and RR (P=0.056) were not detected. As pHa appeared fully compensated on D2 and RR did not increase significantly from D2 to D9, these data demonstrate renal acid-base compensation within 24-hours at moderate steady-state altitude. Moreover, RR was strongly and inversely correlated with ∆pHa on D2 and D9 (r≤-0.95; P

Rationale Bronchial thermoplasty is a mechanical therapeutic intervention that has been advocated as an effective treatment option for severe asthma. The mechanism is promoted as being related to the attenuation of airway smooth muscle which has been shown to occur in the short-term. However, long-term studies of the effects of bronchial thermoplasty on airway remodeling are few with only limited assessment of airway remodeling indices. Objectives To evaluate the effect of bronchial thermoplasty on (a) airway epithelial and smooth muscle cells in culture, and (b), airway remodeling in patients with severe asthma who have been prescribed bronchial thermoplasty up to 12-months post-treatment. Methods The distribution of heat within the airway by bronchial thermoplasty was assessed in a porcine model. Culture of human airway smooth muscle cells and bronchial epithelial cells evaluated the impact of thermal injury. Histological evaluation and morphometric assessment were performed on bronchial biopsies obtained from severe asthma patients at baseline, 6-weeks, and 12-months following bronchial thermoplasty. Results Bronchial thermoplasty resulted in heterogenous heating of the airway wall. Airway smooth muscle cell cultures sustained thermal injury, whilst bronchial epithelial cells were relatively resistant to heat. Airway smooth muscle and neural bundles were significantly reduced at 6-weeks and 12-months post-treatment. At 6-weeks post treatment, submucosal collagen was reduced, and vessel density increased, with both indices returning to baseline at 12-months. Goblet cell numbers, submucosal gland area and subbasement membrane thickness, were not significantly altered at any timepoint examined. Conclusions Bronchial thermoplasty primarily affects airway smooth muscle and nerves with the effects still present at 12-months post-treatment.

The gut microbiome consists of a multi-kingdom microbial community. Whilst the role of bacteria as causal contributors governing host physiological development is well established, the role of fungi remains to be determined. Here, we use germ-free mice colonized with defined species of bacteria, fungi, or both to differentiate the causal role of fungi on microbiome assembly, immune development, susceptibility to colitis, and airway inflammation. Fungal colonization promotes major shifts in bacterial microbiome ecology, and has an independent effect on innate and adaptive immune development in young mice. While exclusive fungal colonization is insufficient to elicit overt dextran sulfate sodium-induced colitis, bacterial and fungal co-colonization increase colonic inflammation. Ovalbumin-induced airway inflammation reveals that bacterial, but not fungal colonization is necessary to decrease airway inflammation, yet fungi selectively promotes macrophage infiltration in the airway. Together, our findings demonstrate a causal role for fungi in microbial ecology and host immune functionality, and therefore prompt the inclusion of fungi in therapeutic approaches aimed at modulating early life microbiomes., The immunomodulatory role of commensal gut fungi and interactions with bacteria remain unclear. Here, using germ-free mice colonized with defined species of bacteria and fungi, the authors find that fungal colonization induces changes in bacterial microbiome ecology while having an independent effect on innate and adaptive immunity in mice.

Gut microbiomes make major contributions to the physiological and immunological development of the host, but the relative importance of their bacterial and fungal components, and how they interact, remain largely unknown. We applied carefully controlled experiments in gnotobiotic mice colonized with defined communities of bacteria, fungi, or both to differentiate the direct role of fungi on microbiome assembly, host development, and susceptibility to colitis and airway inflammation. Our results revealed that fungal colonization alone was insufficient to promote the intestinal anatomic and physiological changes seen in mice colonized by bacteria, and had limited impact on the fecal metabolome. However, fungal colonization promoted major shifts in bacterial microbiome ecology, and had an independent effect on the innate and adaptive immune development in young mice. Fungi further exacerbated some aspects of the inflammatory effects of the bacterial community during OVA-induced airway inflammation by promoting macrophage infiltration in the airway. Our results demonstrate a dominant ecological and physiological role of bacteria in gut microbiomes, but highlight fungi as an ecological factor shaping the assembly of the bacterial community and a direct capacity to impact immune system and modulate disease susceptibility. These findings demonstrate that studies focused on bacteria alone provide an incomplete portrayal on microbiome ecology and functionality, and prompt for the inclusion of fungi in human microbiome studies.

Airway remodeling is a characteristic feature of asthma and is thought to play an important role in the pathogenesis of airway hyperresponsiveness. Myofibroblasts are key structural cells involved in injury and repair, and there is evidence that dysregulation of their normal function contributes to airway remodeling. Despite the importance of myofibroblasts, a lack of specific cellular markers and inconsistent nomenclature have limited recognition of their key role in airway remodeling. Myofibroblasts are increased several-fold in the airways in asthma, in proportion to the severity of the disease. Myofibroblasts are postulated to be derived from both tissue-resident and bone marrow-derived cells, depending on the stage of injury and the tissue. A small number of studies have demonstrated attenuation of myofibroblast numbers and also reversal of established myofibroblast populations in asthma and other inflammatory processes. In this article, we review what is currently known about the biology of myofibroblasts in the airways in asthma and identify potential targets to reduce or reverse the remodeling process. However, further translational research is required to better understand the mechanistic role of the myofibroblast in asthma.

Introduction.Oscillatory patterns in arterial pressure and blood flow (at ∼0.1 Hz) may protect tissue oxygenation during conditions of reduced cerebral perfusion and/or hypoxia. We hypothesized that inducing oscillations in arterial pressure and cerebral blood flow at 0.1 Hz would protect cerebral blood flow and cerebral tissue oxygen saturation during exposure to a combination of simulated hemorrhage and sustained hypobaric hypoxia.Methods.Eight healthy human subjects (4 male, 4 female; 30.1 ± 7.6 year) participated in two experiments at high altitude (White Mountain, California, USA; altitude, 3800 m) following rapid ascent and 5-7 d of acclimatization: (1) static lower body negative pressure (LBNP, control condition) was used to induce central hypovolemia by reducing chamber pressure to -60 mmHg for 10 min(0 Hz), and; (2) oscillatory LBNP where chamber pressure was reduced to -60 mmHg, then oscillated every 5 s between -30 mmHg and -90 mmHg for 10 min(0.1 Hz). Measurements included arterial pressure, internal carotid artery (ICA) blood flow, middle cerebral artery velocity (MCAv), and cerebral tissue oxygen saturation (ScO2).Results.Forced 0.1 Hz oscillations in mean arterial pressure and mean MCAv were accompanied by a protection of ScO2(0.1 Hz: -0.67% ± 1.0%; 0 Hz: -4.07% ± 2.0%;P = 0.01). However, the 0.1 Hz profile did not protect against reductions in ICA blood flow (0.1 Hz: -32.5% ± 4.5%; 0 Hz: -19.9% ± 8.9%;P = 0.24) or mean MCAv (0.1 Hz: -18.5% ± 3.4%; 0 Hz: -15.3% ± 5.4%;P = 0.16).Conclusions.Induced oscillatory arterial pressure and cerebral blood flow led to protection of ScO2during combined simulated hemorrhage and sustained hypoxia. This protection was not associated with the preservation of cerebral blood flow suggesting preservation of ScO2may be due to mechanisms occurring within the microvasculature.

Key points Physical inactivity increases the risk of cardiovascular disease and may alter sympathetic nervous system control of vascular resistance. Hindlimb unweighting (HU), a rodent model of physical inactivity, has been shown to diminish sympathetic vasoconstrictor responsiveness and reduce NO synthase expression in isolated skeletal muscle blood vessels. Our understanding of the effects of HU on sympathetic vascular regulation in vivo is very limited. The present findings demonstrate that HU did not alter sympathetic vasoconstrictor responsiveness and NO-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle. This study suggests that short-term physical inactivity does not alter in vivo sympathetic vascular control in the skeletal muscle vascular bed at rest and during contraction. Abstract We tested the hypothesis that physical inactivity would increase sympathetic vasoconstrictor responsiveness and diminish NO-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle. Sprague–Dawley rats (n = 33) were randomly assigned to sedentary time control (S) or hindlimb unweighted (HU) groups for 21 days. Following the intervention, rats were anaesthetized and instrumented for measurement of arterial blood pressure and femoral artery blood flow and stimulation of the lumbar sympathetic chain. The percentage change of femoral vascular conductance (%FVC) in response to sympathetic chain stimulation delivered at 2 and 5 Hz was determined at rest and during triceps surae muscle contraction before (control) and after NO synthase blockade with l-NAME (5 mg kg i.v.). Sympathetic vasoconstrictor responsiveness was not different (P > 0.05) in S and HU rats at rest (S, 2 Hz, −26 ± 8% and 5 Hz, −46 ± 12%; and HU, 2 Hz, −29 ± 9% and 5 Hz, −51 ± 10%) and during contraction (S, 2 Hz, −10 ± 7% and 5 Hz, −23 ± 11%; and HU, 2 Hz, −9 ± 5% and 5 Hz, −22 ± 7%). Nitric oxide synthase blockade caused a similar increase (P > 0.05) in sympathetic vasoconstrictor responsiveness in HU and S rats at rest (S, 2 Hz, −41 ± 7% and 5 Hz, −58 ± 8%; and HU, 2 Hz, −43 ± 6% and 5 Hz, −63 ± 8%) and during muscle contraction (S, 2 Hz, −15 ± 6% and 5 Hz, −31 ± 11%; and HU, 2 Hz, −12 ± 5% and 5 Hz, −29 ± 8%). Skeletal muscle NO synthase expression and ACh-mediated vasodilatation were also not different between HU and S rats. These data suggest that HU does not alter sympathetic vasoconstrictor responsiveness and NO-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle.

Key points Sympathetic nervous system activity causes tonic vasoconstriction in resting and contracting skeletal muscle. Nitric oxide (NO) has been shown to inhibit sympathetic vasoconstriction. NO derived from both the neuronal and endothelial isoforms of NO synthase (NOS) has been shown to contribute to the inhibition of sympathetic vasoconstriction. Our laboratory recently demonstrated that exercise training augmented NO-dependent inhibition of sympathetic vasoconstriction. However, the NOS isoform responsible for the increase in NO-mediated inhibition of sympathetic vasoconstriction following exercise training has not been established. The present findings demonstrate that exercise training improves neuronal NOS-mediated inhibition of sympathetic vasoconstriction in contracting skeletal muscle. Abstract We tested the hypothesis that exercise training would increase neuronal nitric oxide synthase (nNOS)-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle. Sprague–Dawley rats (n = 18) were randomized to sedentary or exercise-trained (40 m min−1, 5° grade; 5 days week−1 for 4 weeks) groups. Following completion of sedentary behaviour or exercise training, rats were anaesthetized and instrumented with a brachial artery catheter, femoral artery flow probe and stimulating electrodes on the lumbar sympathetic chain. The percentage change of femoral vascular conductance (%FVC) in response to sympathetic chain stimulations delivered at 2 and 5 Hz was determined at rest and during triceps surae muscle contraction before (control) and after selective nNOS blockade with S-methyl-l-thiocitrulline (SMTC, 0.6 mg kg−1, i.v.) and subsequent non-selective NOS blockade with l-NAME (5 mg kg−1, i.v.; SMTC + l-NAME). At rest, sympathetic vasoconstrictor responsiveness was greater (P 0.05) between exercise trained (2 Hz: −11 ± 4%FVC; 5 Hz: −21 ± 5%FVC) and sedentary rats (2 Hz: −7 ± 6%FVC; 5 Hz: −18 ± 10%FVC) in control conditions. SMTC augmented (P 0.05) in exercise-trained and sedentary rats. These data demonstrate that exercise training augmented nNOS-mediated inhibition of sympathetic vasoconstriction in contracting muscle.

Key points • Postsynaptic α1- and α2-adrenoreceptors produce tonic vasoconstriction in resting and contracting skeletal muscle. • Muscular contraction attenuates sympathetic vasoconstriction (functional sympatholysis). The blunting of sympathetic vasoconstriction during contraction has been mechanistically linked to a reduction in postsynaptic α1- and α2-adrenoreceptor responsiveness and nitric oxide. • We recently demonstrated that exercise training augmented sympathetic vasoconstrictor responsiveness and functional sympatholysis. Whether these vascular adaptations were mediated by changes to postsynaptic adrenoreceptors was not investigated. • The present findings demonstrate that exercise training augmented α2-adrenoreceptor- mediated vasoconstriction in resting and contracting skeletal muscle. • These data indicate that exercise training alters the relative contributions of α-adrenoreceptors to sympathetic vasoconstriction in resting and contracting skeletal muscle and that the regulation of sympathetic vasoconstriction becomes more complex following exercise training. Abstract We hypothesized that exercise training (ET) would alter α2-adrenoreceptor-mediated sympathetic vasoconstriction. Sprague-Dawley rats (n= 30) were randomized to sedentary (S), mild- (M) or heavy-intensity (H) treadmill ET groups (5 days per week for 4 weeks). Following the ET component of the study, rats were anaesthetized, and instrumented for lumbar sympathetic chain stimulation, triceps surae muscle contraction and measurement of femoral vascular conductance (FVC). The percentage change of FVC in response to sympathetic stimulation was determined at rest and during contraction in control, α2 blockade (yohimbine) and combined α2+ nitric oxide (NO) synthase (NOS) blockade (Nω-nitro-l-arginine methyl ester hydrochloride, l-NAME) conditions. ET augmented (P < 0.05) sympathetic vasoconstrictor responses at rest and during contraction. Yohimbine reduced (P < 0.05) the vasoconstrictor response in ET rats at rest (M: 2 Hz: 8 ± 2%, 5 Hz: 9 ± 4%; H: 2 Hz: 14 ± 5%, 5 Hz: 11 ± 6%) and during contraction (M: 2 Hz: 9 ± 2%, 5 Hz: 9 ± 5%; H: 2 Hz: 8 ± 3%, 5 Hz: 6 ± 6%) but did not change the response in S rats. The addition of l-NAME caused a larger increase (P < 0.05) in the vasoconstrictor response in ET than in S rats at rest (2 Hz: S: 8 ± 2%, M: 15 ± 3%, H: 23 ± 7%; 5 Hz: S: 8 ± 5%, M: 15 ± 3%, H: 17 ± 5%) and during contraction (2 Hz: S: 9 ± 3%, M: 18 ± 3%, H: 22 ± 6%; 5 Hz: S: 9 ± 5%, M: 22 ± 4%, H:26 ± 9%). Sympatholysis was greater (P < 0.05) in ET than in S rats. Blockade of α2-adrenoreceptors and NOS reduced (P < 0.05) sympatholysis in ET rats, but had no effect on sympatholysis in S rats. In conclusion, ET increased α2-mediated vasoconstriction at rest and during contraction.

Isoform-specific nitric oxide (NO) synthase (NOS) contributions to NO-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle are incompletely understood. The purpose of the present study was to investigate the role of neuronal NOS (nNOS) in the inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle of healthy rats. We hypothesized that acute pharmacological inhibition of nNOS would augment sympathetic vasoconstriction in resting and contracting skeletal muscle, demonstrating that nNOS is primarily responsible for NO-mediated inhibition of sympathetic vasoconstriction. Sprague-Dawley rats ( n = 13) were anesthetized and instrumented with an indwelling brachial artery catheter, femoral artery flow probe, and lumbar sympathetic chain stimulating electrodes. Triceps surae muscles were stimulated to contract rhythmically at 60% of maximal contractile force. In series 1 ( n = 9), the percent change in femoral vascular conductance (%FVC) in response to sympathetic stimulations delivered at 2 and 5 Hz was determined at rest and during muscle contraction before and after selective nNOS blockade with S-methyl-l-thiocitrulline (SMTC, 0.6 mg/kg iv) and subsequent nonselective NOS blockade with Nω-nitro-l-arginine methyl ester (l-NAME, 5 mg/kg iv). In series 2 ( n = 4), l-NAME was injected first, and then SMTC was injected to determine if the effect of l-NAME on constrictor responses was influenced by selective nNOS inhibition. Sympathetic stimulation decreased FVC at rest (−25 ± 7 and −44 ± 8%FVC at 2 and 5 Hz, respectively) and during contraction (−7 ± 3 and −19 ± 5%FVC at 2 and 5 Hz, respectively). The decrease in FVC in response to sympathetic stimulation was greater in the presence of SMTC at rest (−32 ± 6 and −49 ± 8%FVC at 2 and 5 Hz, respectively) and during contraction (−21 ± 4 and −28 ± 4%FVC at 2 and 5 Hz, respectively). l-NAME further increased ( P < 0.05) the sympathetic vasoconstrictor response at rest (−47 ± 4 and −60 ± 6%FVC at 2 and 5 Hz, respectively) and during muscle contraction (−33 ± 3 and −40 ± 6%FVC at 2 and 5 Hz, respectively). The effect of l-NAME was not altered by the order of nNOS inhibition. These data demonstrate that NO derived from nNOS and endothelial NOS contribute to the inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle.

We hypothesized that acute superoxide (O2−) scavenging would attenuate sympathetic vasoconstrictor responsiveness by augmenting nitric oxide (NO)-mediated inhibition of sympathetic vasoconstriction in exercise-trained rats. Sprague-Dawley rats were randomly assigned to sedentary time control (S; n = 7) or mild- (M: 20 m/min, 5° grade; n = 7) or heavy-intensity (H: 40 m/min, 5° grade; n = 7) exercise training (ET) groups and trained 5 days/wk for 4 wk with matched training volume. Following ET, rats were anesthetized and instrumented for lumbar sympathetic chain stimulation and measurement of femoral vascular conductance. In resting skeletal muscle, the percentage change of femoral vascular conductance in response to continuous (2 Hz) and patterned (20 and 40 Hz) sympathetic stimulation was determined during control conditions, O2− scavenging (TIRON, 1 g·kg−1·h−1 iv) and combined O2− scavenging + nitric oxide synthase blockade ( Nω-nitro-l-arginine methyl ester, 5 mg/kg iv). ET augmented the vasoconstrictor response to sympathetic stimulation in a training intensity-dependent manner ( P < 0.05) (S: 2 Hz: −26 ± 7.1%; 20 Hz: −26.9 ± 7.3%; 40 Hz: −27.7 ± 7.0%; M: 2 Hz: −37.4 ± 8.3%; 20 Hz: −35.9 ± 7.4%; 40 Hz: −38.2 ± 9.4%; H: 2 Hz: −46.9 ± 7.8%; 20 Hz: −48.5 ± 7.2%; 40 Hz: −51.2 ± 7.3%). O2− scavenging did not alter ( P > 0.05) the vasoconstrictor response in S rats (S: 2 Hz: −23.9 ± 7.6%; 20 Hz: −26.1 ± 9.1%; 40 Hz: −27.5 ± 7.2%), whereas the response in ET rats was diminished (M: 2 Hz: −26.3 ± 5.1%; 20 Hz: −28.7 ± 5.3%; 40 Hz: −28.5 ± 5.6%; H: 2 Hz: −35.5 ± 10.3%; 20 Hz: −38.6 ± 6.8%; 40 Hz: −43.9 ± 5.9%, P < 0.05). TIRON + Nω-nitro-l-arginine methyl ester increased vasoconstrictor responsiveness ( P < 0.05) in ET rats (M: 2 Hz: −47.7 ± 9.8%; 20 Hz: −41.2 ± 7.2%; 40 Hz: −50.5 ± 7.9%; H: 2 Hz: −55.8 ± 7.6%; 20 Hz: −55.7 ± 7.8%; 40 Hz: −58.7 ± 6.2%), whereas, in S rats, the response was unchanged (2 Hz: −29.4 ± 8.7%; 20 Hz: −30.0 ± 7.4%; 40 Hz: −35.2 ± 10.3%; P > 0.05). These data indicate that the augmented sympathetic vasoconstrictor responsiveness in ET rats was related to increased oxidative stress and altered nitric oxide-mediated inhibition of vasoconstriction.

We tested the hypothesis that short-term mild- (M) and heavy-intensity (H) exercise training would enhance sympatholysis through a nitric oxide (NO)-dependent mechanism. Sprague-Dawley rats (n = 36) were randomly assigned to sedentary (S) or to M (20 m min(-1) 5% gradient) or H exercise training groups (40 m min(-1) 5% gradient). Rats assigned to M and H groups trained on 5 days week(-1) for 4 weeks, with the volume of training being matched between groups. Rats were anaesthetized and instrumented for stimulation of the lumbar sympathetic chain and the measurement of arterial blood pressure and femoral artery blood flow. The triceps surae muscle group was stimulated to contract rhythmically at 30 and 60% of maximal contractile force (MCF). The percentage change of femoral vascular conductance (%FVC) in response to sympathetic stimulation delivered at 2 and 5 Hz was determined at rest and during contraction at 30 and 60% MCF. The vascular response to sympathetic stimulation was reduced as a function of MCF in all rats (P < 0.05). At 30% MCF, the magnitude of sympatholysis (%FVC rest - contraction; %FVC) was greater in H compared with M and S groups (%FVC at 2 Hz, S, 9 ± 5; M, 11 ± 8; and H, 18 ± 7; and %FVC at 5 Hz, S, 6 ± 6; M, 12 ± 9; and H, 18 ± 7; P < 0.05) and was greater in H and M compared with S at 60% MCF (%FVC at 2 Hz, S, 15 ± 5; M, 25 ± 3; and H, 36 ± 6; and %FVC at 5 Hz, S, 22 ± 6; M, 33 ± 9; and H, 39 ± 9; P < 0.05). Blockade of NO synthase did not alter the magnitude of sympatholysis in S during contraction at 30 or 60% MCF. In contrast, NO synthase inhibition diminished sympatholysis in H at 30% MCF and in M and H at 60% MCF (P < 0.05). The present findings indicate that short-term exercise training augments sympatholysis in a training-intensity-dependent manner and through an NO-dependent mechanism.

Non-interval and interval training progressions were used to determine (i) the mean rate at which treadmill speed could be incremented daily using a non-interval training progression to train rats to run continuously at different intensities and (ii) the number of training days required for rats to run continuously at different exercise intensities with non-interval- and interval-based training progressions to establish methods of progressive overload for rodent exercise training studies. Rats were randomly assigned to mild-intensity (n = 5, 20 m·min–1, 5% grade), moderate-intensity (n = 5, 30 m·min–1, 5% grade), and heavy-intensity non-interval groups (n = 5, 40 m·min–1, 5% grade) or a heavy-intensity interval (n = 5, 40 m·min–1, 5% grade) group and ran 5 days·week–1 for 6 weeks. Non-interval training involved a daily increase of treadmill speed, whereas interval training involved a daily increase of interval time, until the animal could run continuously at a prescribed intensity. In mild-, moderate-, and heavy-intensity non-interval-trained rats, treadmill speed was increased by 0.6 ± 0.7 m·min–1·day–1, 0.6 ± 0.2 m·min–1·day–1, and 0.8 ± 0.1 m·min–1·day–1, respectively. Target training intensity and duration were obtained following 0.4 ± 0.5 days, 17 ± 3 days, and 23 ± 3 training days (p < 0.05) in mild-, moderate-, and heavy-intensity groups, respectively. In contrast, interval-trained rodents required 11 ± 1 training days. These data demonstrate that rodents will tolerate an increase in treadmill speed of ∼0.7 ± 0.1 m·min–1·day–1 and that this progression enables rats to run continuously at moderate and heavy intensities with 3–4 weeks of progressive overload. Interval training significantly reduces the number of training days required to attain a target intensity.

BACKGROUND: Pulmonary rehabilitation (PR) is an effective therapeutic strategy to improve health outcomes in patients with chronic obstructive pulmonary disease (COPD); however, there is insufficient PR capacity to service all COPD patients, thus necessitating creative solutions to increase the availability of PR.OBJECTIVE: To examine the efficacy of PR delivered via Telehealth (Telehealth-PR) compared with PR delivered in person through a standard outpatient hospital-based program (Standard-PR).METHODS: One hundred forty-seven COPD patients participated in an eight-week rural PR program delivered via Telehealth-PR. Data were compared with a parallel group of 262 COPD patients who attended Standard-PR. Education sessions were administered two days per week via Telehealth, and patients exercised at their satellite centre under direct supervision. Standard-PR patients viewed the same education sessions in person and exercised at the main PR site. The primary outcome measure was change in quality of life as evaluated by the St George’s Respiratory Questionnaire (SGRQ). A noninferiority analysis was performed using both intention-to-treat and per-protocol approaches.RESULTS: Both Telehealth-PR and Standard-PR resulted in clinically and statistically significant improvements in SGRQ scores (4.5±0.8% versus 4.1±0.6%; PCONCLUSION: Telehealth-PR was an effective tool for increasing COPD PR services, and demonstrated improvements in quality of life and exercise capacity comparable with Standard-PR.

We developed a multivariate prediction equation for estimating the highest obtainable pulmonary oxygen uptake (VO 2p ) during the 6-minute walk test (6-MWT) in 54 organ transplant recipients: heart/heart-double-lung ( n = 14), kidney/kidney-pancreas ( n = 16), liver ( n = 14), double lung ( n = 8), bone marrow ( n = 2). They were of age, 48 ± 12 years. Participants performed a 6-MWT during which expired gases were collected and analyzed with a portable metabolic system interfaced with a wireless heart rate monitor. The following variables significantly contributed to the model for predicting the highest obtainable 6-MWT VO 2p : 6-MWT distance (m), age (years), gender (male = 0, female = 1), resting heart rate, peak heart rate, weight (kg), and transplant type (kidney/kidney-pancreas = 1, other = 0), where: VO 2p = 1.253 + 0.022 (6-MWT distance) + 0.112 (age) −3.192 (gender) −0.104 (resting heart rate) + 0.127 (peak 6-MWT heart rate) − 0.084 (weight) + 2.116 (transplant type). The explanatory variables in our final model accounted for 78% of the variance in 6-MWT VO 2p . In conclusion, the addition of an easily estimated 6-MWT VO 2p will provide added clinical information of functional capacity following an exercise rehabilitation intervention or during routine follow-up for organ transplant recipients.

We examined peak and reserve cardiovascular function and skeletal muscle oxygenation during unilateral knee extension (ULKE) exercise in five heart transplant recipients (HTR, mean ± SE; age: 53 ± 3 years; years posttransplant: 6 ± 4) and five age- and body mass-matched healthy controls (CON). Pulmonary oxygen uptake (V̇o2p), heart rate (HR), stroke volume (SV), cardiac output (Q̇), and skeletal muscle deoxygenation (HHb) kinetics were assessed during moderate-intensity ULKE exercise. Peak exercise and reserve V̇o2p, Q̇, and systemic arterial-venous oxygen difference (a-vO2diff) were 23–52% lower ( P < 0.05) in HTR. The reduced Q̇ and a-vO2diff reserves were associated with lower HR and HHb reserves, respectively. The phase II V̇o2p time delay was greater (HTR: 38 ± 2 vs. CON: 25 ± 1 s, P < 0.05), while time constants for phase II V̇o2p (HTR: 54 ± 8 vs. CON: 31 ± 3 s), Q̇ (HTR: 66 ± 8 vs. CON: 28 ± 4 s), and HHb (HTR: 27 ± 5 vs. CON: 13 ± 3 s) were significantly slower in HTR. The HR half-time was slower in HTR (113 ± 21 s) vs. CON (21 ± 2 s, P < 0.05); however, no significant difference was found between groups for SV kinetics (HTR: 39 ± 8 s vs. CON 31 ± 6 s). The lower peak V̇o2p and prolonged V̇o2p kinetics in HTR were secondary to impairments in both cardiovascular and skeletal muscle function that result in reduced oxygen delivery and utilization by the active muscles.

Purpose. To examine cardiovascular function and risk profile of postmenopausal women treated with chemoendocrine therapy (CET) for hormone receptor-positive operable breast cancer. Methods. Forty-seven breast cancer patients and 11 age-matched healthy controls were studied. Participants performed a cardiopulmonary exercise test with expired gas analysis and impedance cardiography to assess peak aerobic power (VO(2peak)) and cardiovascular function (stroke volume, cardiac output, cardiac power output, and cardiac reserve). Traditional (i.e., body mass index, lipid profile, and fasting insulin and glucose) and novel (i.e., C-reactive protein, brain natriuretic peptide) cardiovascular risk biochemical factors were also assessed. Results. Breast cancer patients had significantly lower peak exercise stroke volume (68 +/- 9 versus 76 +/- 11 ml/beat), cardiac output (10.4 +/- 1.5 versus 11.7 +/- 2.4 l/minute), cardiac power output (3.0 +/- 0.5 versus 3.5 +/- 0.9 Watts), cardiac power output reserve (1.7 +/- 0.6 versus 2.4 +/- 0.8 Watts), and VO(2peak) (1.3 +/- 0.3 versus 1.6 +/- 0.2 l x min(-1)) than control subjects (p-values < .05). Patients with the greatest impairment in VO(2peak) had the worse cardiovascular risk profile. Exploratory analyses revealed several differences in study outcomes between the 26 patients receiving hormonal therapy with tamoxifen (TAM) and the 21 patients receiving aromatase inhibitor (AI) therapy. Conclusion. Breast cancer patients treated with adjuvant CET have a significantly and markedly lower cardiorespiratory fitness and cardiac functional reserve compared with age- and sex-matched controls. AI therapy may be associated with a more unfavorable cardiovascular risk profile than TAM. Prospective studies are required to further investigate the clinical value of these findings.

The effect that pretransplantation heart failure cause has on pulmonary oxygen uptake (VO2p) kinetics and peak aerobic power (VO2peak) in heart transplant recipients (HTRs) has not been studied. We examined VO2p kinetics and VO2peak in HTRs with previous ischemic heart failure (I-HTRs; n=16, mean age 64+/-6 years) or nonischemic heart failure (NI-HTRs; n=13, mean age 50+/-12 years). HTRs performed an incremental exercise (VO2peak) test and a constant work rate submaximal exercise (VO2p kinetics) test. A monoexponential model was used to determine the phase II VO2p time constant (tau). Phase II VO2p tau was slower in I-HTRs (49+/-10 seconds) than in NI-HTRs (34+/-10 seconds) (p0.001). No significant difference was found between I-HTRs and NI-HTRs for VO2peak (19.0+/-6.4 vs 23.0+/-8.2 ml.kg-1.min-1, respectively), change in heart rate from rest to steady-state exercise (11+/-8 vs 9+/-9 beats.min-1, respectively), or peak exercise heart rate (140+/-22 vs 144+/-22 beats.min-1, respectively). In conclusion, the prolonged phase II VO2p tau in I-HTRs compared with NI-HTRs suggests that the magnitude of alteration in VO2p kinetics after heart transplantation may be dependent on previous heart failure cause.

We tested the hypothesis that exercise training would increase neuronal nitric oxide synthase (nNOS)-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle. Sprague-Dawley rats (n = 18) were randomized to sedentary or exercise-trained (40 m min(-1), 5° grade; 5 days week(-1) for 4 weeks) groups. Following completion of sedentary behaviour or exercise training, rats were anaesthetized and instrumented with a brachial artery catheter, femoral artery flow probe and stimulating electrodes on the lumbar sympathetic chain. The percentage change of femoral vascular conductance (%FVC) in response to sympathetic chain stimulations delivered at 2 and 5 Hz was determined at rest and during triceps surae muscle contraction before (control) and after selective nNOS blockade with S-methyl-l-thiocitrulline (SMTC, 0.6 mg kg(-1), i.v.) and subsequent non-selective NOS blockade with l-NAME (5 mg kg(-1), i.v.; SMTC + l-NAME). At rest, sympathetic vasoconstrictor responsiveness was greater (P 0.05) in exercise-trained compared to sedentary rats in control, SMTC and SMTC + l-NAME conditions. During contraction, the constrictor response was not different (P 0.05) between exercise trained (2 Hz: -11 ± 4%FVC; 5 Hz: -21 ± 5%FVC) and sedentary rats (2 Hz: -7 ± 6%FVC; 5 Hz: -18 ± 10%FVC) in control conditions. SMTC augmented (P 0.05) sympathetic vasoconstriction in sedentary and exercise-trained rats; however, sympathetic vasoconstrictor responsiveness was greater (P 0.05) in exercise-trained (2 Hz: -27 ± 5%FVC; 5 Hz: -39 ± 5%FVC) compared to sedentary (2 Hz: -17 ± 6%FVC; 5 Hz: -27 ± 8%FVC) rats during selective nNOS inhibition. SMTC + l-NAME further augmented (P 0.05) sympathetic vasoconstrictor responsiveness by a similar magnitude (P 0.05) in exercise-trained and sedentary rats. These data demonstrate that exercise training augmented nNOS-mediated inhibition of sympathetic vasoconstriction in contracting muscle.

We hypothesized that hindlimb unloading (HU) would increase sympathetic vasoconstrictor responsiveness and diminish nitric oxide (NO) mediated inhibition of sympathetic vasoconstriction in resting ...