bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperthermia and central fatigue during prolonged exercise in humans
Authors: Nybo Lars , Nielsen Bodil
Published: December 2017

The present study investigated the effects of hyperthermia on the contributions of central and peripheral factors to the development of neuromuscular fatigue. Fourteen men exercised at 60% maximal oxygen consumption on a cycle ergometer in hot (40°C; hyperthermia) and thermoneutral (18°C; control) environments. In hyperthermia, the core temperature increased throughout the exercise period and reached a peak value of 40.0 ± 0.1°C (mean ± SE) at exhaustion after 50 ± 3 min of exercise. In control, core temperature stabilized at ∼38.0 ± 0.1°C, and exercise was maintained for 1 h without exhausting the subjects. Immediately after the cycle trials, subjects performed 2 min of sustained maximal voluntary contraction (MVC) either with the exercised legs (knee extension) or with a “nonexercised” muscle group (handgrip). The degree of voluntary activation during sustained maximal knee extensions was assessed by superimposing electrical stimulation (EL) to nervus femoralis. Voluntary knee extensor force was similar during the first 5 s of contraction in hyperthermia and control. Thereafter, force declined in both trials, but the reduction in maximal voluntary force was more pronounced in the hyperthermic trial, and, from 30 to 120 s, the force was significantly lower in hyperthermia compared with control. Calculation of the voluntary activation percentage (MVC/MVC + EL) revealed that the degree of central activation was significantly lower in hyperthermia (54 ± 7%) compared with control (82 ± 6%). In contrast, total force of the knee extensors (MVC + force from EL) was not different in the two trials. Force development during handgrip contraction followed the same pattern of response as was observed for the knee extensors. In conclusion, these data demonstrate that the ability to generate force during a prolonged MVC is attenuated with hyperthermia, and the impaired performance is associated with a reduction in the voluntary activation percentage.
Downregulation of nitric oxide in the brain of mice during their hypoxic preconditioning
Authors: Lu Guo-Wei , Liu Hong-Yan
Published: December 2017

An animal model of hypoxic preconditioning was produced in mice by repeated exposure to autohypoxic condition. The animals' tolerance times to hypoxia were 1.7, 1.8, 2.1, and 2.3 times longer in runs 2, 3, 4, and 5, respectively, than that in run 1, and their oxygen consumption and heart and respiration rates were progressively and significantly slowed down during the repetitive exposure to hypoxia. l-Arginine concentration, nitric oxide (NO) synthase-positive cells, NO synthase activity, and NO content in the whole brain and the subregions telencephalon, diencephalon, and brain stem were significantly increased during the first exposure and were, instead of continuing to increase, significantly decreased in run 4 after the second and third exposure. Tolerance times under the hypoxic condition were significantly shortened and prolonged when preadministration ofl-arginine and its analog, respectively, was made. These results indicate that NO in the brain is downregulated under condition of hypoxic preconditioning and negatively involved in increased tolerance to hypoxia.
Effects of bright light and melatonin on sleep propensity, temperature, and cardiac activity at night
Authors: Burgess Helen J. , Sletten Tracey , Savic Natasha , Gilbert Saul S. , Dawson Drew
Published: December 2017

Melatonin increases sleepiness, decreases core temperature, and increases peripheral temperature in humans. Melatonin may produce these effects by activating peripheral receptors or altering autonomic activity. The latter hypothesis was investigated in 16 supine subjects. Three conditions were created by using bright light and exogenous melatonin: normal endogenous, suppressed, and pharmacological melatonin levels. Data during wakefulness from 1.5 h before to 2.5 h after each subject's estimated melatonin onset (wake time + 14 h) were analyzed. Respiratory sinus arrhythmia (cardiac parasympathetic activity) and preejection period (cardiac sympathetic activity) did not vary among conditions. Pharmacological melatonin levels significantly decreased systolic blood pressure [5.75 ± 1.65 (SE) mmHg] but did not significantly change heart rate. Suppressed melatonin significantly increased rectal temperature (0.27 ± 0.06°C), decreased foot temperature (1.98 ± 0.70°C), and increased sleep onset latency (5.53 ± 1.87 min). Thus melatonin does not significantly alter cardiac autonomic activity and instead may bind to peripheral receptors in the vasculature and heart. Furthermore, increases in cardiac parasympathetic activity before normal nighttime sleep cannot be attributed to the concomitant increase in endogenous melatonin.
Effect of Rho-kinase inhibition on vasoconstriction in the penile circulation
Authors: Mills Thomas M. , Chitaley Kanchan , Wingard Christopher J. , Lewis Ronald W. , Webb R. Clinton
Published: December 2017

A recent report from this laboratory (Chitaley K, Wingard C, Webb R, Branam H, Stopper V, Lewis R, and Mills T. Nature Medicine 7: 119–122, 2001) showed that inhibition of Rho-kinase increased the erectile response (intracavernosal pressure and mean arterial pressure) by a process that does not require nitric oxide or cGMP. The present study investigated whether vasoconstrictor agents, which are active in the penis, act via the Rho-kinase pathway. Western analysis revealed RhoA and Rho-kinase protein in the penis. Treatment with the selective Rho-kinase inhibitor Y-27632 significantly increased the magnitude of the erectile response. Intracavernous administration of endothelin-1 (ET-1; 50 pmol) or methoxamine (10 μg/kg) reduced the erectile response to autonomic stimulation. If Y-27632 was given before ET-1 or methoxamine, the vasoconstrictor effect was reduced, and intracavernosal pressure and mean arterial pressure remained elevated. However, when given after methoxamine, Y-27632 had a reduced vasodilatory effect, and Y-27632 had no vasodilatory effect when given after ET-1. These findings suggest that ET-1 and methoxamine increase Rho-kinase activity in the cavernous circulation and support the hypothesis that the vasoconstriction that maintains the penis in the nonerect state is mediated, in part, by the Rho-kinase pathway.
Total weak acid concentration and effective dissociation constant of nonvolatile buffers in human plasma
Authors: Constable Peter D.
Published: December 2017

The strong ion approach provides a quantitative physicochemical method for describing the mechanism for an acid-base disturbance. The approach requires species-specific values for the total concentration of plasma nonvolatile buffers (Atot) and the effective dissociation constant for plasma nonvolatile buffers ( Ka), but these values have not been determined for human plasma. Accordingly, the purpose of this study was to calculate accurate Atotand Kavalues using data obtained from in vitro strong ion titration and CO2tonometry. The calculated values for Atot(24.1 mmol/l) and Ka(1.05 × 10−7) were significantly ( P < 0.05) different from the experimentally determined values for horse plasma and differed from the empirically assumed values for human plasma (Atot= 19.0 meq/l and Ka= 3.0 × 10−7). The derivatives of pH with respect to the three independent variables [strong ion difference (SID), Pco2, and Atot] of the strong ion approach were calculated as follows: [Formula: see text] [Formula: see text], [Formula: see text]where S is solubility of CO2in plasma. The derivatives provide a useful method for calculating the effect of independent changes in SID+, Pco2, and Atoton plasma pH. The calculated values for Atotand Kashould facilitate application of the strong ion approach to acid-base disturbances in humans.
Efficacy of nasal strip and furosemide in mitigating EIPH in Thoroughbred horses
Authors: Kindig Casey A. , McDonough Paul , Fenton Gus , Poole David C. , Erickson Howard H.
Published: December 2017

The purpose of this investigation was to study the effects of an equine nasal strip (NS), furosemide (Fur), and a combination of both (NS + Fur) on exercise-induced pulmonary hemorrhage (EIPH) at speeds corresponding to near-maximal effort. Five Thoroughbreds (526 ± 25 kg) were run on a flat treadmill from 7 to 14 m/s in 1 m · s−1· min−1 increments every 2 wk (treatment order randomized) under control (Con), Fur (1 mg/kg iv 4 h prior), NS, or NS + Fur conditions. During each run, pulmonary arterial (Ppa) and esophageal (Pes) pressures were measured. Severity of EIPH was quantified via bronchoalveolar lavage (BAL) 30 min postrun. Furosemide (Fur and NS + Fur trials) reduced peak Ppa ∼7 mmHg compared with Con ( P < 0.05) whereas NS had no effect ( P > 0.05). Maximal Pes swings were not different among groups ( P > 0.05). NS significantly diminished EIPH compared with the Con trial [Con, 55.0 ± 36.2; NS, 30.8 ± 21.8 × 106red blood cells (RBC)/ml BAL fluid; P < 0.05]. Fur reduced EIPH to a greater extent than NS (5.2 ± 3.0 × 106RBC/ml BAL; P < 0.05 vs. Con and NS) with no additional benefit from NS + Fur (8.5 ± 4.2 × 106RBC/ml BAL; P > 0.05 vs. Fur, P < 0.05 vs. Con and NS). In conclusion, although both modalities (NS and Fur) were successful in mitigating EIPH, neither abolished EIPH fully as evaluated via BAL. Fur was more effective than NS in constraining the severity of EIPH. The simultaneous use of both interventions appears to offer no further gain with respect to reducing EIPH.
Selected Contribution: HSP20 phosphorylation in nitroglycerin- and forskolin-induced sustained reductions in swine carotid media tone
Authors: Rembold Christopher M. , O'Connor Matthew , Clarkson Michael , Wardle Robert L. , Murphy Richard A.
Published: December 2017

Cyclic nucleotide-induced relaxation of maximally activated arterial smooth muscle has two phases. 1) The initial relaxation transient is typically characterized by a rapid reduction in force associated with brief reductions in myoplasmic Ca2+ concentration ([Ca2+]i) and myosin regulatory light chain (MRLC) phosphorylation on serine (Ser)-19 (Ser19). 2) The sustained inhibitory response is typically associated with Ser16 phosphorylation of heat shock protein 20 (HSP20) without sustained reductions in [Ca2+]i or MRLC phosphorylation. We investigated whether the extent of Ser16-HSP20 phosphorylation quantitatively correlated with the sustained inhibitory response. With addition of nitroglycerin to histamine-stimulated swine carotid media, the initial relaxation transient was associated with a decrease in MRLC phosphorylation without an increase in Ser16-HSP20 phosphorylation. During the sustained phase of nitroglycerin-induced relaxation and during force redevelopment induced by washout of nitroglycerin in the continued presence of histamine, the level of Ser16-HSP20 phosphorylation, but not MRLC phosphorylation, correlated with inhibition of force. Forskolin, which increases cAMP concentration, also induced a sustained inhibitory response that was associated with increases in Ser16-HSP20 phosphorylation without reductions in MRLC phosphorylation levels. Forskolin increased Ser16-HSP20 phosphorylation to a greater extent and inhibited force more completely than that observed with nitroglycerin. Increases in Ser16-HSP20 phosphorylation correlated with the degree of force inhibition regardless of whether the relaxation was induced by nitroglycerin or forskolin. These data are consistent with the hypothesis that Ser16-HSP20 phosphorylation may be a cyclic nucleotide-dependent, yet MRLC phosphorylation-independent, inhibitor of smooth muscle contractile force.
Postexercise muscle glycogen resynthesis in obese insulin-resistant Zucker rats
Authors: Bruce Clinton R. , Lee Jong Sam , Hawley John A.
Published: December 2017

We determined the effect of an acute bout of swimming (8 × 30 min) followed by either carbohydrate administration (0.5 mg/g glucose ip and ad libitum access to chow; CHO) or fasting (Fast) on postexercise glycogen resynthesis in soleus muscle and liver from female lean (ZL) and obese insulin-resistant (ZO) Zucker rats. Resting soleus muscle glycogen concentration ([glycogen]) was similar between genotypes and was reduced by 73 (ZL) and 63% (ZO) after exercise ( P < 0.05). Liver [glycogen] at rest was greater in ZO than ZL (334 ± 31 vs. 247 ± 16 μmol/g wet wt; P < 0.01) and fell by 44 and 94% after exercise ( P < 0.05). The fractional activity of glycogen synthase (active/total) increased immediately after exercise (from 0.22 ± 0.05 and 0.32 ± 0.04 to 0.63 ± 0.08 vs. 0.57 ± 0.05; P < 0.01 for ZL and ZO rats, respectively) and remained elevated above resting values after 30 min of recovery. During this time, muscle [glycogen] in ZO increased 68% with CHO ( P < 0.05) but did not change in Fast. Muscle [glycogen] was unchanged in ZL from postexercise values after both treatments. After 6 h recovery, GLUT-4 protein concentration was increased above resting levels by a similar extent for both genotypes in both fasted (∼45%) and CHO-supplemented (∼115%) rats. Accordingly, during this time CHO refeeding resulted in supercompensation in both genotypes (68% vs. 44% for ZL and ZO). With CHO, liver [glycogen] was restored to resting levels in ZL but remained at postexercise values for ZO after both treatments. We conclude that the increased glucose availability with carbohydrate refeeding after glycogen-depleting exercise resulted in glycogen supercompensation, even in the face of muscle insulin-resistance.
Caffeine increases endurance and attenuates force sensation during submaximal isometric contractions
Authors: Plaskett C. J. , Cafarelli E.
Published: December 2017

Caffeine has known ergogenic effects, some of which have been observed during submaximal isometric contractions. We used 15 subjects in a randomized, double-blind, repeated-measures experiment to determine caffeine's ergogenic effects on neuromuscular variables that would contribute to increased endurance capacity. Subjects performed repeated submaximal (50% maximal voluntary contraction) isometric contractions of the right quadriceps to the limit of endurance (Tlim) 1 h after oral caffeine administration (6 mg/kg). Time to reach Tlim increased by 17 ± 5.25% ( P < 0.02) after caffeine administration compared with the placebo trial. The changes in contractile properties, motor unit activation, and M-wave amplitude that occurred as the quadriceps reached Tlim could not account for the prolonged performance after caffeine ingestion. In a separate experiment with the same subjects, we used a constant-sensation technique to determine whether caffeine influenced force sensation during 100 s of an isometric contraction of the quadriceps. The results of this experiment showed that caffeine reduced force sensation during the first 10–20 s of the contraction. The rapidity of this effect suggests that caffeine exerts its effects neurally. Based on these data, the caffeine-induced increase in Tlim may have been caused by a willingness to maintain near-maximal activation longer because of alterations in muscle sensory processes.
Exposure to hypoxia produces long-lasting sympathetic activation in humans
Authors: Xie Ailiang , Skatrud James B. , Puleo Dominic S. , Morgan Barbara J.
Published: December 2017

The relative contributions of hypoxia and hypercapnia in causing persistent sympathoexcitation after exposure to the combined stimuli were assessed in nine healthy human subjects during wakefulness. Subjects were exposed to 20 min of isocapnic hypoxia (arterial O2 saturation, 77–87%) and 20 min of normoxic hypercapnia (end-tidal Pco 2, +5.3–8.6 Torr above eupnea) in random order on 2 separate days. The intensities of the chemical stimuli were manipulated in such a way that the two exposures increased sympathetic burst frequency by the same amount (hypoxia: 167 ± 29% of baseline; hypercapnia: 171 ± 23% of baseline). Minute ventilation increased to the same extent during the first 5 min of the exposures (hypoxia: +4.4 ± 1.5 l/min; hypercapnia: +5.8 ± 1.7 l/min) but declined with continued exposure to hypoxia and increased progressively during exposure to hypercapnia. Sympathetic activity returned to baseline soon after cessation of the hypercapnic stimulus. In contrast, sympathetic activity remained above baseline after withdrawal of the hypoxic stimulus, even though blood gases had normalized and ventilation returned to baseline levels. Consequently, during the recovery period, sympathetic burst frequency was higher in the hypoxia vs. the hypercapnia trial (166 ± 21 vs. 104 ± 15% of baseline in the last 5 min of a 20-min recovery period). We conclude that both hypoxia and hypercapnia cause substantial increases in sympathetic outflow to skeletal muscle. Hypercapnia-evoked sympathetic activation is short-lived, whereas hypoxia-induced sympathetic activation outlasts the chemical stimulus.
Enhanced in vivo and in vitro contractile responses to β2-adrenergic receptor stimulation in dogs susceptible to lethal arrhythmias
Authors: Houle Melanie S. , Altschuld Ruth A. , Billman George E.
Published: December 2017

The response to β-adrenergic receptor (β-AR) stimulation was evaluated in both isolated cardiomyocytes (video edge detection) and the intact animal (echocardiography) in dogs either susceptible (S) or resistant (R) to ventricular fibrillation induced by a 2-min coronary occlusion during the last minute of exercise. In the intact animal, velocity of circumferential fiber shortening (Vcf) was evaluated both before ( n = 27, S = 12 and R = 15) and after myocardial infarction. Before infarction, increasing doses of isoproterenol provoked similar contractile and heart rate responses in each group of dogs. Either β1-AR (bisoprolol) or β2-AR (ICI-118551) antagonists reduced the isoproterenol response, with a larger reduction noted after the β1-AR blockade. In contrast, after infarction, isoproterenol induced a significantly larger Vcf and heart rate response in the susceptible animals that was eliminated by β2-AR blockade. The single-cell isotonic shortening response to isoproterenol (100 nM) was also larger in cells obtained from susceptible compared with resistant dogs and was reduced to a greater extent by β2-AR blockade in the susceptible dog myocytes (S, −48%, n= 6; R, −15%, n = 9). When considered together, these data suggest that myocardial infarction provoked an enhanced β2-AR response in susceptible, but not resistant, animals.
Enhanced lung C-fiber responsiveness in sensitized adult guinea pigs exposed to chronic tobacco smoke
Authors: Bergren Dale R.
Published: December 2017

Tobacco smoke (TS) exposure induces bronchoconstriction and increases airway secretions and plasma extravasation in certain sensitive individuals, particularly those with asthma. C-fiber activation also induces these effects. Although the mechanism by which chronic TS exposure induces airway dysfunction is not well understood, TS exposure may enhance C-fiber responsiveness. To investigate the effect of chronic TS exposure on C-fiber responsiveness to capsaicin and bradykinin, especially in atopic individuals, we exposed ovalbumin (OA)-sensitized guinea pigs to TS (5 mg/l air, 30 min/day for 7 days/wk) or to compressed air. Nonsensitized guinea pigs were also exposed to either compressed air or TS. Beginning after 120 days of exposure, C fibers and rapidly adapting receptors (RARs) were challenged with capsaicin and bradykinin. TS exposure enhanced sensory receptor and airway responsiveness to both intravenous capsaicin and bradykinin challenge. C-fiber, RAR, and airway responsiveness to capsaicin challenge was greatest in OA-sensitized guinea pigs exposed to TS. OA alone induced capsaicin hyperresponsiveness at 5 μg. Airway responsiveness to bradykinin was also greatest in OA-sensitized guinea pigs exposed to TS. OA alone enhanced C-fiber responsiveness to bradykinin at 5 and 10 μg. C-fiber activation by either agonist appeared direct, whereas RAR activation appeared indirect. Therefore, a mechanism of airway hyperirritability induced by the combination of OA sensitization and chronic TS exposure may include hyperirritability of lung C fibers.
Strenuous exercise decreases the percentage of type 1 T cells in the circulation
Authors: Steensberg Adam , Toft Anders Dyhr , Bruunsgaard Helle , Sandmand Marie , Halkjær-Kristensen Jens , Pedersen Bente Klarlund
Published: December 2017

Prolonged strenuous exercise is followed by a temporary functional immune impairment. Low numbers of CD4+T helper (Th) and CD8+ T cytotoxic (Tc) cells are found in the circulation. These cells can be divided according to their cytokine profile into type 1 (Th1 and Tc1), which produce interferon-γ and interleukin (IL)-2, and type 2 (Th2 and Tc2) cells, which produce IL-4. The question addressed in the present study was whether exercise affected the relative balance between the circulating levels of these cytokine-producing T cells. Nine male runners performed treadmill running for 2.5 h at 75% of maximal oxygen consumption. The intracellular expression of cytokines was detected following stimulation with ionomycin and phorbol 12-myristate 13-acetate in blood obtained before, during, and after exercise. The percentage of type 1 T cells in the circulation was suppressed at the end of exercise and 2 h after exercise, whereas no changes were found in the percentage of type 2 T cells. Plasma epinephrine correlated negatively with the percentage of circulating CD8+ T cells producing IL-2, whereas peak IL-6 correlated with the percentage of CD8+ IL-4-producing T cells in the circulation. Peak plasma IL-6 correlated with plasma cortisol postrunning. In conclusion, the postexercise decrease in T lymphocyte number is accompanied by a more pronounced decrease in type 1 T cells, which may be linked to high plasma epinephrine. Furthermore, IL-6 may stimulate type 2 T cells, thereby maintaining a relatively unaltered percentage of these cells in the circulation compared with total circulating lymphocyte number.
Effects of hypoxia on alveolar fluid transport capacity in rat lungs
Authors: Sakuma Tsutomu , Hida Mieko , Nambu Yoshihiro , Osanai Kazuhiro , Toga Hirohisa , Takahashi Keiji , Ohya Nobuo , Inoue Masao , Watanabe Yoh
Published: December 2017

There is little information regarding the effect of hypoxia on alveolar fluid clearance capacity. We measured alveolar fluid clearance, lung water volume, plasma catecholamine concentrations, and serum osmolality in rats exposed to 10% oxygen for up to 120 h and explored the mechanisms responsible for the increase in alveolar fluid clearance. The principal results were 1) alveolar fluid clearance did not change for 48 h and then increased between 72 and 120 h of exposure to hypoxia; 2) although nutritional impairment during hypoxia decreased basal alveolar fluid clearance, endogenous norepinephrine increased net alveolar fluid clearance; 3) the changes of lung water volume and serum osmolality were not associated with those of alveolar fluid clearance; 4) an administration of β-adrenergic agonists further increased alveolar fluid clearance; and 5) alveolar fluid clearance returned to normal within 24 h of reoxygenation after hypoxia. In conclusion, alveolar epithelial fluid transport capacity increases in rats exposed to hypoxia. It is likely that a combination of endogenous norepinephrine and nutritional impairment regulates alveolar fluid clearance under hypoxic conditions.
Decreased non-MHC-restricted (CD56+) killer cell cytotoxicity after spaceflight
Authors: Mehta Satish K. , Kaur Indreshpal , Grimm Elizabeth A. , Smid Christine , Feeback Daniel L. , Pierson Duane L.
Published: December 2017

Cytotoxic activity of non-major histocompatibility complex-restricted (CD56+) (NMHC) killer cells and cell surface marker expression of peripheral blood mononuclear cells were determined before and after spaceflight. Ten astronauts (9 men, 1 woman) from two space shuttle missions (9- and 10-day duration) participated in the study. Blood samples were collected 10 days before launch, within 3 h after landing, and 3 days after landing. All peripheral blood mononuclear cell preparations were cryopreserved and analyzed simultaneously in a 4-h cytotoxicity51Cr release assay using K562 target cells. NMHC killer cell lytic activity was normalized per 1,000 CD56+cells. When all 10 subjects were considered as one study group, NMHC killer cell numbers did not change significantly during the three sampling periods, but at landing lytic activity had decreased by ∼40% ( P < 0.05) from preflight values. Nine of ten astronauts had decreased lytic activity immediately after flight. NMHC killer cell cytotoxicity of only three astronauts returned toward preflight values by 3 days after landing. Consistent with decreased NMHC killer cell cytotoxicity, urinary cortisol significantly increased after landing compared with preflight levels. Plasma cortisol and ACTH levels at landing were not significantly different from preflight values. No correlation of changes in NMHC killer cell function or hormone levels with factors such as age, gender, mission, or spaceflight experience was found. After landing, expression of the major lymphocyte surface markers (CD3, CD4, CD8, CD14, CD16, CD56), as determined by flow cytometric analysis, did not show any consistent changes from measurements made before flight.
Comparison of lung protection strategies using conventional and high-frequency oscillatory ventilation
Authors: Imai Yumiko , Nakagawa Satoshi , Ito Yushi , Kawano Toshio , Slutsky Arthur S. , Miyasaka Katsuyuki
Published: December 2017

This study compared pathophysiological and biochemical indexes of acute lung injury in a saline-lavaged rabbit model with different ventilatory strategies: a control group consisting of moderate tidal volume (Vt) (10–12 ml/kg) and low positive end-expiratory pressure (PEEP) (4–5 cmH2O); and three protective groups: 1) low Vt (5–6 ml/kg) high PEEP, 2–3 cmH2O greater than the lower inflection point; 2) low Vt (5–6 ml/kg), high PEEP (8–10 cmH2O); and 3) high-frequency oscillatory ventilation (HFOV). The strategy using PEEP > inflection point resulted in hypotension and barotrauma. HFOV attenuated the decrease in pulmonary compliance, the lung inflammation assessed by polymorphonuclear leukocyte infiltration and tumor necrosis factor-α concentration in the alveolar space, and pathological changes of the small airways and alveoli. Conventional mechanical ventilation using lung protection strategies (low Vt high PEEP) only attenuated the decrease in oxygenation and pulmonary compliance. Therefore, HFOV may be a preferable option as a lung protection strategy.
Invited Review: Cell localization, physiology, and nongenomic actions of estrogen receptors
Authors: Levin Ellis R.
Published: December 2017

The existence of binding proteins for the female sex steroid, 17β-estradiol, has been known for almost 50 years. Presently, two estrogen receptors (ERs), ER-α and ER-β, have been cloned in mammals, and they are expressed in many cell types of metazoans. ERs act primarily as nuclear transcription factors, and this effect is enhanced by ligand binding. Emerging data have identified a separate pool of receptors for this steroid in the plasma membrane, but the mechanisms of action and cellular functions of these proteins are just beginning to be defined. In this review, the known details of the nuclear and plasma membrane ER functions will be discussed. A particular focus will be to define the signaling pathways from the membrane that lead to important cell physiology effects of estrogen. The potential interactions of membrane ER with other local proteins will also be discussed, and the unique but often complementary roles of the receptor pools will be highlighted. These details may be of additional relevance to other steroid receptors, since there is evidence of their existence in the cell membrane.
Selected Contribution: Sex differences in osmotic regulation of AVP and renal sodium handling
Authors: Stachenfeld Nina S. , Splenser Andres E. , Calzone Wendy L. , Taylor Matthew P. , Keefe David L.
Published: December 2017

To determine sex differences in osmoregulation of arginine vasopressin (AVP) and body water, we studied eight men (24 ± 1 yr) and eight women (29 ± 2 yr) during 3% NaCl infusion [hypertonic saline infusion (HSI); 120 min, 0.1 ml · kg body wt−1 · min−1]. Subjects then drank 15 ml/kg body wt over 30 min followed by 60 min of rest. Women were studied in the early follicular (F; 16.1 ± 2.8 pg/ml plasma 17β-estradiol and 0.6 ± 0.1 ng/ml plasma progesterone) and midluteal (L; 80.6 ± 11.4 pg/ml plasma 17β-estradiol and 12.7 ± 0.7 ng/ml plasma progesterone) menstrual phases. Basal plasma osmolality was higher in F (286 ± 1 mosmol/kgH2O) and in men (289 ± 1 mosmol/kgH2O) compared with L (280 ± 1 mosmol/kgH2O, P < 0.05). Neither menstrual phase nor gender affected basal plasma AVP concentration (P[AVP]; 1.7 ± 4, 1.9 ± 0.4, and 2.2 ± 0.5 pg/ml for F, L, and men, respectively). The plasma osmolality threshold for AVP release was lowest in L ( x-intercept, 263 ± 3 mosmol/kgH2O, P < 0.05) compared with F (273 ± 2 mosmol/kgH2O) and men (270 ± 4 mosmol/kgH2O) during HSI. Men had greater P[AVP]-plasma osmolality slopes (i.e., sensitivity) compared with F and L (slopes = 0.14 ± 0.04, 0.09 ± 0.01, and 0.24 ± 0.07 for F, L, and men, respectively, P < 0.05). Despite similar Na+-regulating hormone responses, men excreted less Na+ during HSI (0.7 ± 0.1, 0.7 ± 0.1, and 0.5 ± 0.1 meq/kg body wt for F, L, and men, respectively, P < 0.05). Furthermore, men had greater systolic blood pressure (119 ± 5, 119 ± 5, and 132 ± 3 mmHg for F, L, and men, respectively, P < 0.05) than F and L. Our data indicate greater sensitivity in P[AVP] response to changes in plasma osmolality as the primary difference between men and women during HSI. In men, this greater sensitivity was associated with an increase in systolic blood pressure and pulse pressure during HSI, most likely due to a shift in the pressure-natriuresis curve.
Effect of acute exposure to hypergravity (GX vs. GZ) on dynamic cerebral autoregulation
Authors: Serrador J. M. , Wood S. J. , Picot P. A. , Stein F. , Kassam M. S. , Bondar R. L. , Rupert A. H. , Schlegel T. T.
Published: December 2017

We examined the effects of 30 min of exposure to either +3GX(front-to-back) or +GZ (head-to-foot) centrifugation on cerebrovascular responses to 80° head-up tilt (HUT) in 14 healthy individuals. Both before and after +3 GX or +3 GZ centrifugation, eye-level blood pressure (BPeye), end tidal Pco 2(Pet CO2 ), mean cerebral flow velocity (CFV) in the middle cerebral artery (transcranial Doppler ultrasound), cerebral vascular resistance (CVR), and dynamic cerebral autoregulatory gain (GAIN) were measured with subjects in the supine position and during subsequent 80° HUT for 30 min. Mean BPeyedecreased with HUT in both the GX ( n = 7) and GZ ( n = 7) groups ( P < 0.001), with the decrease being greater after centrifugation only in the GZ group ( P < 0.05). Pet CO2 also decreased with HUT in both groups ( P < 0.01), but the absolute level of decrease was unaffected by centrifugation. CFV decreased during HUT more significantly after centrifugation than before centrifugation in both groups ( P < 0.02). However, these greater decreases were not associated with greater increases in CVR. In the supine position after centrifugation compared with before centrifugation, GAIN increased in both groups ( P < 0.05, suggesting an autoregulatory deficit), with the change being correlated to a measure of otolith function (the linear vestibulo-ocular reflex) in the GX group ( r = 0.76, P < 0.05) but not in the GZ group ( r = 0.24, P = 0.60). However, GAIN was subsequently restored to precentrifugation levels during postcentrifugation HUT (i.e., as BPeye decreased), suggesting that both types of centrifugation resulted in a leftward shift of the cerebral autoregulation curve. We speculate that this leftward shift may have been due to vestibular activation (especially during +GX) or potentially to an adaptation to reduced cerebral perfusion pressure during +GZ.
Comparison of oxygen uptake kinetics during concentric and eccentric cycle exercise
Authors: Perrey S. , Betik A. , Candau R. , Rouillon J. D. , Hughson R. L.
Published: December 2017

O2 uptake (V˙o 2) kinetics and electromyographic (EMG) activity from the vastus medialis, rectus femoris, biceps femoris, and medial gastrocnemius muscles were studied during constant-load concentric and eccentric cycling. Six healthy men performed transitions from baseline to high-intensity eccentric (HE) exercise and to high-intensity (HC), moderate-intensity (MC), and low-intensity (LC) concentric exercise. For HE and HC exercise, absolute work rate was equivalent. For HE and LC exercise,V˙o 2 was equivalent.V˙o 2 data were fit by a two- or three-component exponential model. Surface EMG was recorded during the last 12 s of each minute of exercise to obtain integrated EMG and mean power frequency. Only in the HC exercise didV˙o 2 increase progressively with evidence of a slow component ( phase 3), and only in HC exercise was there evidence of a coincident increase with time in integrated EMG of the vastus medialis and rectus femoris muscles ( P < 0.05) with no change in mean power frequency. The phase 2time constant was slower in HC [24.0 ± 1.7 (SE) s] than in HE (14.7 ± 2.8 s) and LC (16.7 ± 2.2 s) exercise, while it was not different from MC exercise (20.6 ± 2.1 s). These results show that the rate of increase inV˙o 2 at the onset of exercise was not different between HE and LC exercise, where the metabolic demand was similar, but both had significantly faster kinetics forV˙o 2 than HC exercise. TheV˙o 2 slow component might be related to increased muscle activation, which is a function of metabolic demand and not absolute work rate.
Prenatal nicotine affects catecholamine gene expression in newborn rat carotid body and petrosal ganglion
Authors: Gauda Estelle B. , Cooper Reed , Akins Patrice K. , Wu Guimei
Published: December 2017

Nicotine exposure modifies the expression of catecholamine and opioid neurotransmitter systems involved in attenuation of hypoxic chemosensitivity. We used in situ hybridization histochemistry to determine the effect of prenatal and early postnatal nicotine exposure on tyrosine hydroxylase (TH), dopamine β-hydroxylase (DβH), preproenkephalin (PPE), and D2-dopamine receptor mRNA levels in the rat carotid body and petrosal ganglion during postnatal development. In the carotid body, nicotine increased TH mRNA expression in animals at 0 and 3 postnatal days (both, P < 0.05 vs. control) without affecting TH mRNA levels at 6 and 15 days. At 15 postnatal days, DβH mRNA levels were increased in the carotid body of nicotine-exposed animals. Dopamine D2-receptor mRNA levels in the carotid body increased with postnatal age but were unaffected by nicotine exposure. PPE was not expressed in the carotid body at any of the ages studied in control or treated animals. In the petrosal ganglion, nicotine increased the number of ganglion cells expressing TH mRNA in animals at 3 days ( P < 0.01 vs. control). DβH mRNA expression was not induced nor was PPE mRNA expression increased in the petrosal ganglion in treated animals. Prenatal nicotine exposure upregulates mRNAs involved in the synthesis of two inhibitory neuromodulators, dopamine and norepinephrine, in peripheral arterial chemoreceptors, which may contribute to abnormalities in cardiorespiratory control observed in nicotine exposed animals.
Nitric oxide impairs Ca2+activation and slows cross-bridge cycling kinetics in skeletal muscle
Authors: Heunks Leo M. A. , Cody Mark J. , Geiger Paige C. , Dekhuijzen P. N. Richard , Sieck Gary C.
Published: December 2017

The effects of the nitric oxide (NO) donor spermine NONOate (Sp-NO, 1.0 mM) on cross-bridge recruitment and cross-bridge cycling kinetics were studied in permeabilized rabbit psoas muscle fibers. Fibers were activated at various Ca2+concentrations (pCa, negative logarithm of Ca2+concentration), and the pCa at which force was maximal (pCa 4.0) and ∼50% of maximal (pCa505.6) were determined. Fiber stiffness was determined using 1-kHz sinusoidal length perturbations, and the fraction of cross bridges in the force-generating state was estimated by the ratio of stiffness during maximal (pCa 4.0) and submaximal (pCa 5.6) Ca2+activation to stiffness during rigor (at pCa 4.0). Cross-bridge cycling kinetics were evaluated by measuring the rate constant for force redevelopment after quick release (by 15% of optimal fiber length, Lo) and restretch of the fiber to Lo. Exposing fibers to Sp-NO for 10 min reduced force and the fraction of cross bridges in the force-generating state at maximal and submaximal (pCa50) Ca2+activation. However, the effects of Sp-NO were more pronounced during submaximal Ca2+activation. Sp-NO also reduced the rate constant for force redevelopment but only during submaximal Ca2+activation. We conclude that Sp-NO reduces Ca2+sensitivity by decreasing the number of cross bridges in the strongly bound state and also impairs cross-bridge cycling kinetics during submaximal activation.
Effect of weight bearing on recovery from nerve injury in skeletal muscle
Authors: Matsuura Tetsuya , Ikata Takaaki , Takata Shinjiro , Kashiwaguchi Shinji , Niwa Mineo , Sogabe Takayuki , Koga Keiko
Published: December 2017

We examined the effect of weight bearing (WB) on muscle recovery after nerve injury. Rats were housed in individual cages for 2 wk under WB or hindlimb suspension (HS) after being subjected to sciatic nerve compression for 1 wk. Sham operated on rats served as controls (sham group). We used 31P- and19F-nuclear magnetic resonance spectroscopy combined with histochemical, physiological, and biochemical techniques to assess the outcome in the three groups. Creatine kinase-BB (CK-BB) mRNA levels expression, CK activity, and type I fiber density in the WB group were elevated compared with those in the HS group. In addition, sciatic functional index, tetanic tension, energy state, and local circulation dynamics of the WB group were greater than those of the HS group. These results suggested that WB plays an important role in muscle regeneration, inhibits the reduction of CK activity, and facilitates the activation of neural recovery, energy state, and local circulation dynamics.
Microinjection of acetazolamide into the fastigial nucleus augments respiratory output in the rat
Authors: Xu Fadi , Zhang Zhong , Frazier Donald T.
Published: December 2017

The rostral fastigial nucleus (FNr) of the cerebellum facilitates the respiratory response to hypercapnia. We hypothesized that some FNr sites are chemosensitive to focal tissue acidosis and contribute, at least partially, to respiratory modulation. Minute ventilation (V˙e) was recorded in 21 anesthetized and spontaneously breathing rats. Acetazolamide (AZ; 50 μM) was microinjected unilaterally into the FNr while an isocapnic condition was maintained throughout the experiment. AZ (1 or 20 nl) injection into the FNr significantly elevated V˙e (46.0 ± 6.7%; P < 0.05), primarily via an increase in tidal volume (31.7 ± 3.8%; P < 0.05), with little effect on arterial blood pressure. This augmented ventilatory response was initiated at 6.3 ± 0.8 min and reached the peak at 19.7 ± 4.1 min after AZ administration. The same dose of AZ delivered into the interposed and lateral cerebellar nuclei, or vehicle injection into the FNr, failed to elicit detectable cardiorespiratory responses. To determine whether the ventilatory response to AZ injection into the FNr resulted from an increase in respiratory central drive, the minute phrenic nerve activity (MPN) was recorded in seven paralyzed and ventilated rats. Similar to V˙e, MPN was increased by 38.9 ± 8.9% ( P < 0.05) after AZ administration. Our results suggest that elevation of CO2/H+ within the FNr facilitates respiratory output, supporting the presence of ventilatory chemoreception in rat FNr.
Increases in intramuscular pressure raise arterial blood pressure during dynamic exercise
Authors: Gallagher K. M. , Fadel P. J. , Smith S. A. , Norton K. H. , Querry R. G. , Olivencia-Yurvati A. , Raven P. B.
Published: December 2017

This investigation was designed to determine the role of intramuscular pressure-sensitive mechanoreceptors and chemically sensitive metaboreceptors in affecting the blood pressure response to dynamic exercise in humans. Sixteen subjects performed incremental (20 W/min) cycle exercise to fatigue under four conditions: control, exercise with thigh cuff occlusion of 90 Torr (Cuff occlusion), exercise with lower body positive pressure (LBPP) of 45 Torr, and a combination of thigh cuff occlusion and LBPP (combination). Indexes of central command (heart rate, oxygen uptake, ratings of perceived exertion, and electromyographic activity), cardiac output, stroke volume, and total peripheral resistance were not significantly different between the four conditions. Mechanical stimulation during LBPP and combination conditions resulted in significant elevations in intramuscular pressure and mean arterial pressure from control at rest and throughout the incremental exercise protocol ( P < 0.05). Conversely, there existed no significant changes in mean arterial pressure when the metaboreflex was stimulated by cuff occlusion. These findings suggest that under normal conditions the mechanoreflex is tonically active and is the primary mediator of exercise pressor reflex-induced alterations in arterial blood pressure during submaximal dynamic exercise in humans.
Vascular adaptation to microgravity: what have we learned?
Authors: Zhang Li-Fan
Published: December 2017

Findings from recent bed rest and spaceflight human studies have indicated that the inability to adequately elevate the peripheral resistance and the altered autoregulation of cerebral vasculature are important factors in postflight orthostatic intolerance. Animal studies with rat model have revealed that simulated microgravity may induce upward and downward regulations in the structure, function, and innervation of the cerebral and hindquarter vessels. These findings substantiate in general the hypothesis that microgravity-induced redistribution of transmural pressures and flows across and within the arterial vasculature may well initiate differential adaptations of vessels in different anatomic regions. Understanding of the mechanisms involved in vascular adaptation to microgravity is also important for the development of multisystem countermeasures. However, future studies will be required to further ascertain the peripheral effector mechanism of postflight cardiovascular dysfunction.
Myosin cross bridges in skeletal muscles: “rower” molecular motors
Authors: Lecarpentier Y. , Chemla D. , Pourny J. C. , Blanc F.-X. , Coirault C.
Published: December 2017

Different classes of molecular motors, “rowers” and “porters,” have been proposed to describe the chemomechanical transduction of energy. Rowers work in large assemblies and spend a large percentage of time detached from their lattice substrate. Porters behave in the opposite way. We calculated the number of myosin II cross bridges (CB) and the probabilities of attached and detached states in a minimal four-state model in slow (soleus) and fast (diaphragm) mouse skeletal muscles. In both muscles, we found that the probability of CB being detached was ∼98% and the number of working CB was higher than 109/mm2. We concluded that muscular myosin II motors were classified in the category of rowers. Moreover, attachment time was higher than time stroke and time for ADP release. The duration of the transition from detached to attached states represented the rate-limiting step of the overall attached time. Thus diaphragm and soleus myosins belong to subtype 1 rowers.
Left ventricular wave speed
Authors: Wang Jiun-Jr , Parker Kim H. , Tyberg John V.
Published: December 2017

Left ventricular (LV) wave speed (LVWS) was studied experimentally and confirmed in theory. Combining the definition of elastance (E) with the equations for the conservation of mass and momentum shows that LVWS is proportional to the square root of E LA, where L is long-axis length and A is the cross-sectional area, and the density of the blood. (We defined E LA = γ, where γ is compressibility.) We studied nine open chest, anesthetized dogs, three of which were studied during caval constriction when LV end-diastolic pressure was ≤0 mmHg. The hearts were paced at ∼90 beats/min, and LV cross-sectional area was measured by using two pairs of ultrasonic crystals; E was calculated from the LV pressure-area loop. A pulse generator was connected to the LV apex, and LVWS was measured by using two pressure transducers: one near the apex and the other near the base. Their distance was measured roentgenographically and compared with the diameter of a reference ball. LVWS ranged from ∼1 m/s during diastole to ∼10 m/s during systole. The slope of the log c(where c is wave speed) vs. log γ was 0.546, which is in agreement with theory (0.5). When γ ≤ 0, LVWS was ∼1.5 m/s.
Differences between inhaled and intravenous bronchial challenge to detect O3-induced hyperresponsiveness
Authors: Sommer Bettina , Vargas Mario H. , Chavez Jaime , Carbajal Veronica , Segura Patricia , Montaño Luis M.
Published: December 2017

Ozone (O3)-induced airway hyperresponsiveness in laboratory animals is usually demonstrated through dose-response curves with inhaled or intravenous bronchoconstrictor agonists. However, comparability of these two routes has not been well documented. Thus guinea pig airway responsiveness to ACh and histamine was evaluated 16–18 h after O3 (3 parts/million, 1 h) or air exposure by two plethysmographic methods (spontaneously breathing and mechanically ventilated) and by two administration routes (inhalatory or intravenous). We found that O3 caused airway hyperresponsiveness to intravenous, but not to inhaled, agonists, independent of the plethysmographic method used. Suitability of the inhalatory route to detect airway hyperresponsiveness was corroborated with inhaled ACh after an antigen challenge or extending O3exposure to 3 h. Acetylcholinesterase activity was not modified after O3 exposure in lung homogenates and blood samples. Thus inhaled agonists were less effective to reveal the airway hyperresponsiveness after an acute O3 exposure than intravenous ones, at least for the 1-h exposure to 3 parts/million, and this difference seems not to be related to an O3-induced inhibition of the acetylcholinesterase activity.
Androgen-receptor defect abolishes sex differences in nitric oxide and reactivity to vasopressin in rat aorta
Authors: Stallone John N. , Salisbury Ronald L. , Fulton Clifford T.
Published: December 2017

Contractions of rat thoracic aorta to vasopressin (VP) are threefold higher in females (F) than in males (M), primarily because nitric oxide (NO) attenuation of contraction is greater in M. To determine the role of the androgen receptor (AR) in this mechanism, vascular reactivity to VP was examined in thoracic aorta of the testicular-feminized male (Tfm) rat, which has an X-linked, recessive defect in AR function in affected M. Maximal contraction of normal aortas to VP was fourfold higher in F (4,128 ± 291 mg/mg ring wt) than in M (971 ± 133 mg); maximal response of Tfm (3,967 ± 253 mg) was similar to that of normal F. NG-nitro-l-arginine methyl ester increased maximal response to VP threefold in M but had no effect in F or Tfm. In contrast, maximal contraction of normal aortas to phenylephrine was 43% higher in M (4,011 ± 179 mg) than in F (2,809 ± 78 mg); maximal response of Tfm (2,716 ± 126 mg) was similar to that of normal F. NG-nitro-l-arginine methyl ester increased maximal response to phenylephrine by >50% in F and Tfm but had no effect in M. Maximal contractile response to 80 mM KCl did not differ among M, F, or Tfm. Thus androgens and normal vascular AR function are important in the greater NO-mediated attenuation of reactivity to VP in M than in F rat aorta, which may involve specific modulation of endothelial VP signal transduction pathways and NO release by androgens. These data also establish the importance of the Tfm rat as a model to study the effects of androgens on cardiovascular function.