Experimental physiology
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Experimental physiology · Jun 2018
Nerve growth factor-dependent hyperexcitability of capsaicin-sensitive bladder afferent neurones in mice with spinal cord injury.
What is the central question of this study? Nerve growth factor (NGF) is reportedly a mediator inducing urinary bladder dysfunction. Is NGF directly involved in hyperexcitability of capsaicin-sensitive C-fibre bladder afferent pathways after spinal cord injury (SCI)? What is the main finding and its importance? Neutralization of NGF by anti-NGF antibody treatment reversed the SCI-induced increase in the number of action potentials and the reduction in spike thresholds and A-type K+ current density in mouse capsaicin-sensitive bladder afferent neurones. Thus, NGF plays an important and direct role in hyperexcitability of capsaicin-sensitive C-fibre bladder afferent neurones attributable to the reduction in A-type K+ channel activity in SCI. ⋯ Nerve growth factor (NGF) has been implicated as an important mediator in the induction of C-fibre bladder afferent hyperexcitability, which contributes to the emergence of neurogenic lower urinary tract dysfunction after spinal cord injury (SCI). In this study, we determined whether NGF immunoneutralization using an anti-NGF antibody (NGF-Ab) normalizes the SCI-induced changes in electrophysiological properties of capsaicin-sensitive C-fibre bladder afferent neurones in female C57BL/6 mice. The spinal cord was transected at the Th8/Th9 level. Two weeks later, continuous administration of NGF-Ab (10 μg kg-1 h-1 , s.c. for 2 weeks) was started. Bladder afferent neurones were labelled with Fast-Blue (FB), a fluorescent retrograde tracer, injected into the bladder wall 3 weeks after SCI. Four weeks after SCI, freshly dissociated L6-S1 dorsal root ganglion neurones were prepared. Whole-cell patch-clamp recordings were then performed in FB-labelled neurones. After recording action potentials or voltage-gated K+ currents, the sensitivity of each neurone to capsaicin was evaluated. In capsaicin-sensitive FB-labelled neurones, SCI significantly reduced the spike threshold and increased the number of action potentials during membrane depolarization for 800 ms. These SCI-induced changes were reversed by NGF-Ab. Densities of slow-decaying A-type K+ (KA ) and sustained delayed rectifier-type K+ currents were significantly reduced by SCI. The NGF-Ab treatment reversed the SCI-induced reduction in the KA current density. These results indicate that NGF plays an important role in hyperexcitability of mouse capsaicin-sensitive C-fibre bladder afferent neurones attributable to a reduction in KA channel activity. Thus, NGF-targeting therapies could be effective for treatment of afferent hyperexcitability and neurogenic lower urinary tract dysfunction after SCI.
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Experimental physiology · May 2018
The inspired sine-wave technique: A novel method to measure lung volume and ventilatory heterogeneity.
What is the central question of this study? We present a new non-invasive medical technology, the inspired sine-wave technique, which involves inhalation of sinusoidally fluctuating concentrations of a tracer gas. The technique requires only passive patient cooperation and can monitor different cardiorespiratory variables, such as end-expired lung volume, ventilatory heterogeneity and pulmonary blood flow. What is the main finding and its importance? In this article, we demonstrate that the measurements of end-expired lung volume are repeatable and accurate, in comparison to whole-body plethysmography, and the technique is sensitive to the changes in ventilatory heterogeneity associated with advancing age. As such, it has the potential to provide clinically valuable information. ⋯ The inspired sine-wave technique (IST) is a new method that can provide simple, non-invasive cardiopulmonary measurements. Over successive tidal breaths, the concentration of a tracer gas (i.e. nitrous oxide, N2 O) is sinusoidally modulated in inspired air. Using a single-compartment tidal-ventilation lung model, the resulting amplitude/phase of the expired sine wave allows estimation of end-expired lung volume (ELV), pulmonary blood flow and three indices for ventilatory heterogeneity (VH; ELV180 /FRCpleth , ELV180 /FRCpred and ELV60 /ELV180 ). This investigation aimed to determine the repeatability and agreement of ELV with FRCpleth and, as normal ageing results in well-established changes in pulmonary structure and function, whether the IST estimates of ELV and VH are age dependent. Forty-eight healthy never-smoker participants (20-86 years) underwent traditional pulmonary function testing (e.g. spirometry, body plethysmography) and the IST test, which consisted of 4 min of quiet breathing through a face mask while inspired N2 O concentrations were oscillated in a sine-wave pattern with a fixed mean (4%) and amplitude (3%) and a period of either 180 or 60 s. The ELV180 /FRCpleth and ELV180 /FRCpred were age dependent (average decreases of 0.58 and 0.48% year-1 ), suggesting an increase in VH with advancing age. The ELV showed a mean bias of -1.09 litres versus FRCpleth , but when normalized for the effects of age this bias reduced to -0.35 litres. The IST test has potential to provide clinically useful information necessitating further study (e.g. for mechanically ventilated or obstructive lung disease patients), but these findings suggest that the increases in VH with healthy ageing must be taken into account in clinical investigations.
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Experimental physiology · Apr 2018
A vascular mechanism to explain thermally mediated variations in deep-body cooling rates during the immersion of profoundly hyperthermic individuals.
What is the central question of this study? Does the cold-water immersion (14°C) of profoundly hyperthermic individuals induce reductions in cutaneous and limb blood flow of sufficient magnitude to impair heat loss relative to the size of the thermal gradient? What is the main finding and its importance? The temperate-water cooling (26°C) of profoundly hyperthermic individuals was found to be rapid and reproducible. A vascular mechanism accounted for that outcome, with temperature-dependent differences in cutaneous and limb blood flows observed during cooling. Decisions relating to cooling strategies must be based upon deep-body temperature measurements that have response dynamics consistent with the urgency for cooling. ⋯ Physiologically trivial time differences for cooling the intrathoracic viscera of hyperthermic individuals have been reported between cold- and temperate-water immersion treatments. One explanation for that observation is reduced convective heat delivery to the skin during cold immersion, and this study was designed to test both the validity of that observation, and its underlying hypothesis. Eight healthy men participated in four head-out water immersions: two when normothermic, and two after exercise-induced, moderate-to-profound hyperthermia. Two water temperatures were used within each thermal state: temperate (26°C) and cold (14°C). Tissue temperatures were measured at three deep-body sites (oesophagus, auditory canal and rectum) and eight skin surfaces, with cutaneous vascular responses simultaneously evaluated from both forearms (laser-Doppler flowmetry and venous-occlusion plethysmography). During the cold immersion of normothermic individuals, oesophageal temperature decreased relative to baseline (-0.31°C over 20 min; P < 0.05), whilst rectal temperature increased (0.20°C; P < 0.05). When rendered hyperthermic, oesophageal (-0.75°C) and rectal temperatures decreased (-0.05°C) during the transition period (<8.5 min, mostly in air at 22°C), with the former dropping to 37.5°C only 54 s faster when immersed in cold rather than in temperate water (P < 0.05). Minimal cutaneous vasoconstriction occurred during either normothermic immersion, whereas pronounced constriction was evident during both immersions when subjects were hyperthermic, with the colder water eliciting a greater vascular response (P < 0.05). It was concluded that the rapid intrathoracic cooling of asymptomatic, hyperthermic individuals in temperate water was a reproducible phenomenon, with slower than expected cooling in cold water brought about by stronger cutaneous vasoconstriction that reduced convective heat delivery to the periphery.
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Experimental physiology · Apr 2018
Magnesium attenuates endothelin-1-induced vasoreactivity and enhances vasodilatation in mouse pulmonary arteries: Modulation by chronic hypoxic pulmonary hypertension.
What is the central question of this study? The central goal of this study was to elucidate the role of magnesium in the regulation of pulmonary vascular reactivity in relationship to hypoxic pulmonary hypertension. What is the main finding and its importance? We found that magnesium is essential for normal vasoreactivity of the pulmonary artery. Increasing the magnesium concentration attenuates vasoconstriction and improves vasodilatation via release of nitric oxide. Pulmonary hypertension is associated with endothelial dysfunction resulting in the suppression of magnesium modulation of vasodilatation. These results provide evidence that magnesium is important for the modulation of pulmonary vascular function. ⋯ Pulmonary hypertension (PH) is characterized by enhanced vasoreactivity and sustained pulmonary vasoconstriction, arising from aberrant Ca2+ homeostasis in pulmonary arterial (PA) smooth muscle cells. In addition to Ca2+ , magnesium, the most abundant intracellular divalent cation, also plays crucial roles in many cellular processes that regulate cardiovascular function. Recent findings suggest that magnesium regulates vascular functions by altering the vascular responses to vasodilator and vasoactive agonists and affects endothelial function by modulating endothelium-dependent vasodilatation in hypertension. Administration of magnesium also decreased pulmonary arterial pressure and improved cardiac output in animal models of PH. However, the role of magnesium in the regulation of pulmonary vascular function related to PH has not been studied. In this study, we examined the effects of magnesium on endothelin-1 (ET-1)-induced vasoconstriction, ACh-induced vasodilatation and the generation of NO in PAs of normoxic mice and chronic hypoxia (CH)-treated mice. Our data showed that removal of extracellular magnesium suppressed vasoreactivity of PAs to both ET-1 and ACh. A high concentration of magnesium (4.8 mm) inhibited ET-1-induced vasoconstriction in endothelium-intact or endothelium-disrupted PAs of normoxic and CH-treated mice, and enhanced the ACh-induced production of NO in PAs of normoxic mice. Moreover, magnesium enhanced ACh-induced vasodilatation in PAs of normoxic mice, and the enhancement was completely abolished after exposure to CH. Hence, in this study we demonstrated that increasing the magnesium concentration can attenuate the ET-1-induced contractile response and improve vasodilatation via release of NO from the endothelium. We also demonstrated that chronic exposure to hypoxia can cause endothelial dysfunction resulting in suppression of the magnesium-dependent modulation of vasodilatation.
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Experimental physiology · Feb 2018
Premature birth affects the degree of airway dysanapsis and mechanical ventilatory constraints.
What is the central question of this study? Adult survivors of preterm birth without (PRE) and with bronchopulmonary dysplasia (BPD) have airflow obstruction at rest and significant mechanical ventilatory constraints during exercise compared with those born at full term (CON). Do PRE/BPD have smaller airways, indexed via the dysanapsis ratio, than CON? What is the main finding and its importance? The dysanapsis ratio was significantly smaller in BPD and PRE compared with CON, with BPD having the smallest dysanapsis ratio. These data suggest that airflow obstruction in PRE and BPD might be because of smaller airways than CON. ⋯ The DR, using multiple estimates of static recoil pressure, was significantly smaller in PRE and BPD (0.16 ± 0.05 and 0.10 ± 0.03 a.u.) compared with CON (0.22 ± 0.04 a.u.; both P < 0.001) and smallest in BPD (P < 0.001). The DR was significantly correlated with peak expiratory airflow at rest (r = 0.42; P < 0.001) and the extent of expiratory flow limitation during exercise (r = 0.60; P < 0.001). Our findings suggest that PRE/BPD might have anatomically smaller airways than CON, which might help to explain their lower expiratory airflow rate at rest and during exercise and further our understanding of the consequences of preterm birth and neonatal O2 therapy.