bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel rabbit model of variably compensated complete heart block
Authors: Suto Fumiaki , Cahill Sean A. , Wilson Gregory J. , Hamilton Robert M. , Greenwald Ilana , Gross Gil J.
Published: March 2015

Complete heart block (CHB) provides a useful substrate for study of bradycardia-dependent ventricular arrhythmias and cardiac function. Existing CHB animal models are limited by surgical recovery time and reliance on intrinsic escape rhythms. We describe a novel closed-chest rabbit model of CHB involving transcatheter radiofrequency (RF) atrioventricular (AV) node ablation and ventricular rate control with chronic transvenous pacing. Permanent CHB was achieved in 34 of 38 attempts overall. Procedural mortality due to cardiac tamponade ( n = 2), airway complications ( n = 2), and unknown causes ( n = 5) occurred in nine animals. Survivors with CHB ( n = 28) were maintained for ≤22 days, during which there were three late deaths related to infection ( n = 1) or respiratory distress ( n = 2). None of the survivors with CHB showed recovery of AV conduction or pacemaker capture loss during chronic ventricular pacing at about one-half normal sinus rates, and 25 animals surviving to death showed no overt signs of hemodynamic compromise such as lethargy, poor feeding, or respiratory distress. This approach provides a reproducible nonsurgical CHB model with adjustable ventricular rate control.
Blood flow distribution within the airway wall
Authors: Wagner Elizabeth M. , Brown Robert H.
Published: March 2015

Altered perfusion of the bronchial mucosal plexus relative to the adventitial plexus may contribute to geometric changes in the airway wall and lumen. We studied bronchial perfusion distribution in sheep by using fluorescent microspheres at baseline and during intrabronchial artery challenge with methacholine chloride (MCh; n = 7). Additionally, we measured airway resistance (Raw) during MCh with control or increased perfusion ( n = 9). Raw with MCh was significantly greater for high than control flow. Microspheres in histological sections lodged predominantly in the mucosa (60%), and this was not altered by MCh. However, more microspheres lodged in airways >1-mm in diameter during MCh and increased perfusion than MCh and control flow. In airways ≤1 mm in diameter, fewer microspheres lodged during control than increased flow. If the number of microspheres represents regional agonist access to airway smooth muscle, then the differences observed in Raw can be explained by the distribution of agonist. During challenge, there was greater MCh delivery to larger airways during increased flow and less delivery to smaller airways during control flow. The results demonstrate the effects of axial perfusion distribution on Raw.
Effects of age on human muscle torque, velocity, and power in two muscle groups
Authors: Lanza I. R. , Towse T. F. , Caldwell G. E. , Wigmore D. M. , Kent-Braun J. A.
Published: March 2015

The purpose of this study was to test the hypotheses that, under isovelocity conditions, older compared with young humans would 1) be slower to reach target velocity and 2) exhibit a downward shift in the torque-velocity and power-velocity relationships in the ankle dorsiflexor and knee extensor muscles. We studied 12 young (26 ± 5 yr, 6 men/6 women) and 12 older (72 ± 6 yr, 6 men/6 women) healthy adults during maximal voluntary concentric contractions at preset target velocities (dorsiflexion: 0–240°/s; knee extension: 0–400°/s) using an isokinetic dynamometer. The time to target velocity was longer in older subjects in the dorsiflexors and knee extensors (both P ≤ 0.02). Averaged across all velocities, older subjects produced ∼26% less concentric torque and power in the dorsiflexors ( P < 0.01) and ∼32% less in the knee extensors ( P < 0.01). The downward shift in the torque-velocity relationship persisted even when torque was expressed relative to each subject's maximum. In the knee extensors only, the age-related decrement in power increased with increasing velocities, suggesting that this muscle group may be more susceptible to age-related losses of function than the dorsiflexor muscles are. In support of our hypotheses, these results demonstrate an age-related impairment in the dynamic performance of two functionally distinct muscle groups in healthy older adults. With age, the impairment of dynamic performance appears to exceed the loss of isometric performance, particularly in the knee extensor muscles.
Effect of acute hypoxia on glomus cellEmand ψmas measured by fluorescence imaging
Authors: Roy Arijit , Li Jinqing , Al-Mehdi Abu-Bakr , Mokashi Anil , Lahiri Sukhamay
Published: March 2015

We have reinvestigated the hypothesis of the relative importance of glomus cell plasma and mitochondrial membrane potentials ( Emand ψm, respectively) in acute hypoxia by a noninvasive fluorescence microimaging technique using the voltage-sensitive dyes bis-oxonol and JC-1, respectively. Short-term (24 h)-cultured rat glomus cells and cultured PC-12 cells were used for the study. Glomus cell Emdepolarization was indirectly confirmed by an increase in bis-oxonol (an anionic probe) fluorescence due to a graded increase in extracellular K+. Fluorescence responses of glomus cell Emto acute hypoxia (∼10 Torr Po2) indicated depolarization in 20%, no response in 45%, and hyperpolarization in 35% of the cells tested, whereas all PC-12 cells consistently depolarized in response to hypoxia. Furthermore, glomus cell Emhyperpolarization was confirmed with high CO (∼500 Torr). Glomus cell ψmdepolarization was indirectly assessed by a decrease in JC-1 (a cationic probe) fluorescence. Accordingly, 1 μM carbonyl cyanide p-trifluoromethoxyphenylhydrazone (an uncoupler of oxidative phosphorylation), high CO (a metabolic inhibitor), and acute hypoxia (∼10 Torr Po2) consistently depolarized the mitochondria in all glomus cells tested. Likewise, all PC-12 cell mitochondria depolarized in response to FCCP and hypoxia. Thus, although bis-oxonol could not show glomus cell depolarization consistently, JC-1 monitored glomus cell mitochondrial depolarization as an inevitable phenomenon in hypoxia. Overall, these responses supported our “metabomembrane hypothesis” of chemoreception.
QDR 4500A DXA overestimates fat-free mass compared with criterion methods
Authors: Tylavsky Frances , Lohman Timothy , Blunt Barbara A. , Schoeller Dale A. , Fuerst Thomas , Cauley Jane A. , Nevitt Michael C. , Visser Marjolein , Harris Tamara B.
Published: March 2015

This study evaluated the accuracy with which the dual-energy X-ray absorptiometer (Hologic QDR 4500A) measured fat-free mass (FFM), fat mass (FM), and hydration of FFM. In a study of 58 men and women (ages 70–79 yr), the QDR 4500A was found to provide a systematically higher estimate of FFM and lower estimate of FM than a four-component model of body composition. A correction factor from this study was developed and applied to two other samples ( n = 13 and 37). We found mean corrected levels of FFM and FM to be equivalent to that obtained by the four-component model or total body water. In addition, the hydration of the corrected FFM was closer to the established hydration level in adult samples and that obtained from the four-component model. These findings suggest that the current calibration of the fan-beam system of the Hologic QDR 4500A provides an overestimate of FFM and underestimate of FM compared with reference methods.
Activation of mast cells by systemic hypoxia, but not by local hypoxia, mediates increased leukocyte-endothelial adherence in cremaster venules
Authors: Dix Randy , Orth Teresa , Allen Julie , Wood John G. , Gonzalez Norberto C.
Published: March 2015

Systemic hypoxia, produced by lowering inspired Po2, induces a rapid inflammation in several microcirculations, including cremaster muscle. Mast cell activation is a necessary element of this response. Selective reduction of cremaster microvascular Po2(PmO2) with normal systemic arterial Po2(PaO2; cremaster hypoxia/systemic normoxia), however, does not elicit increased leukocyte-endothelial adherence (LEA) in cremaster venules. This could be due to a short time of leukocyte exposure to the hypoxic cremaster environment. Conversely, LEA increases when PaO2is lowered, while cremaster PmO2remains high (cremaster normoxia/systemic hypoxia). An alternative explanation of these results is that a mediator released from a central site during systemic hypoxia initiates the inflammatory cascade. We hypothesized that if this is the case, cremaster mast cells would be activated during cremaster normoxia/systemic hypoxia, but not during cremaster hypoxia/systemic normoxia. The microcirculation of rat cremaster muscles was visualized by using intravital microscopy. Cremaster PmO2was measured with a phosphorescence quenching method. Cremaster hypoxia/systemic normoxia (PmO27 ± 1 Torr, PaO287 ± 2 Torr) did not increase LEA; however, topical application of the mast cell activator compound 48/80 under these conditions did increase LEA. The effect of compound 48/80 on LEA was blocked by topical cromolyn, a mast cell stabilizer. LEA increased during cremaster normoxia/systemic hypoxia, (PmO264 ± 5 Torr, PaO233 ± 2 Torr); this increase was blocked by topical cromolyn. The results suggest that mast cell stimulation occurs only when PaO2is reduced, independent of cremaster PmO2, and support the idea of a mediator that is released during systemic hypoxia and initiates the inflammatory cascade.
Structural and functional differences of the carotid body between DBA/2J and A/J strains of mice
Authors: Yamaguchi Shigeki , Balbir Alexander , Schofield Brian , Coram Judith , Tankersley Clarke G. , Fitzgerald Robert S. , O'Donnell Christopher P. , Shirahata Machiko
Published: March 2015

In a previous study, DBA/2J and A/J inbred mice showed extremely different hypoxic ventilatory responses, suggesting variations in their carotid bodies. We have assessed the morphological and functional differences of the carotid bodies in these mice. Histological examination revealed a clearly delineated carotid body only in the DBA/2J mice. Many typical glomus cells and glomeruli appeared in the DBA/2J but not in the A/J mice. The size of the carotid body in the DBA/2J and A/J mice was 6.3 ± 0.5 × 106and 1.5 ± 0.3 × 106μm3, respectively. The area immunostained for tyrosine hydroxylase, an estimation of the glomus cell quantity, was four times larger in the DBA/2J mice than in the A/J mice. The individual data points in the DBA/2J mice segregated from those in the A/J mice. ACh increased intracellular Ca2+in most clusters (81%) of cultured carotid body cells from the DBA/2J mice, but only in 18% of clusters in the A/J mice. These data suggest that genetic determinants account for the strain differences in the structure and function of the carotid body.
Acetazolamide reduces exercise capacity and increases leg fatigue under hypoxic conditions
Authors: Garske Luke A. , Brown Michael G. , Morrison Stephen C.
Published: March 2015

Acetazolamide (Acz) is used at altitude to prevent acute mountain sickness, but its effect on exercise capacity under hypoxic conditions is uncertain. Nine healthy men completed this double-blind, randomized, crossover study. All subjects underwent incremental exercise to exhaustion with an inspired O2 fraction of 0.13, hypoxic ventilatory responses, and hypercapnic ventilatory responses after Acz (500 mg twice daily for 5 doses) and placebo. Maximum power of 203 ± 38 (SD) W on Acz was less than the placebo value of 225 ± 40 W ( P < 0.01). At peak exercise, arterialized capillary pH was lower and Po 2 higher on Acz ( P < 0.01). Ventilation was 118.6 ± 20.0 l/min at the maximal power on Acz and 102.4 ± 20.7 l/min at the same power on placebo ( P < 0.02), and Borg score for leg fatigue was increased on Acz ( P < 0.02), with no difference in Borg score for dyspnea. Hypercapnic ventilatory response on Acz was greater ( P < 0.02), whereas hypoxic ventilatory response was unchanged. During hypoxic exercise, Acz reduced exercise capacity associated with increased perception of leg fatigue. Despite increased ventilation, dyspnea was not increased.
Modeling the energetics of 100-m running by using speed curves of world champions
Authors: Arsac Laurent M. , Locatelli Elio
Published: March 2015

The present study aims to assess energy demand and supply in 100-m sprint running. A mathematical model was used in which supply has two components, aerobic and anaerobic, and demand has three components, energy required to move forward (C), energy required to overcome air resistance (Caero), and energy required to change kinetic energy (Ckin). Supply and demand were equated by using assumed efficiency of converting metabolic to external work. The mathematical model uses instantaneous velocities registered by the 1997 International Association of Athletics Federations world champions at 100 m in men and women. Supply and demand components obtained in the male champion were (in J/kg) aerobic 30 (5%), anaerobic 607 (95%), C 400 (63%), Caero 83 (13%), Ckin 154 (24%). Comparatively, a model that uses the average velocity of the male and female 100-m champions overestimates Ckin by 37 and 44%, respectively, and underestimates Caero by 14%. We argued that such a model is not appropriate because Ckin and Caero are nonlinear functions of velocity. Neither height nor body mass seems to have any advantage in the energetics of sprint running.
Effects of exercise and thermal stress on caffeine pharmacokinetics in men and eumenorrheic women
Authors: McLean C. , Graham T. E.
Published: March 2015

The influence of gender, exercise, and thermal stress on caffeine pharmacokinetics is unclear. We hypothesized that these factors would not have an effect on the metabolism of caffeine. Eight women participated in four 8-h trials and six men participated in two 8-h trials after the ingestion of 6 mg/kg caffeine. The women performed two resting trials (1 in the follicular phase and 1 in the luteal phase of the menstrual cycle) and two exercise trials (90 min of cycling exercise at 65% of maximal O2 uptake, 1 h after caffeine ingestion) in the follicular phase (1 without and 1 with an additional thermal stress). The men performed one exercise and one resting trial. Menstrual cycle, gender, and exercise, with or without an additional thermal stress, had no effect on the pharmacokinetic measurements or urine caffeine. There was a trend for higher plasma caffeine and lower plasma paraxanthine concentrations in the women. These results confirm that gender, exercise, and thermal stress have no effect on caffeine pharmacokinetics in men and women.
Selected Contribution: Hyperthermia-induced intestinal permeability and the role of oxidative and nitrosative stress
Authors: Lambert G. P. , Gisolfi C. V. , Berg D. J. , Moseley P. L. , Oberley L. W. , Kregel K. C.
Published: March 2015

The purpose of this study was to characterize intestinal permeability changes over a range of physiologically relevant body temperatures in vivo and in vitro. Initially, FITC-dextran (4,000 Da), a large fluorescent molecule, was loaded into the small intestine of anesthetized rats. The rats were then maintained at ∼37°C or heated over 90 min to a core body temperature of ∼41, ∼41.5, or ∼42.5°C. Permeability was greater in the 42.5°C group compared with the 37, 41, or 41.5°C groups. Histological analysis revealed intestinal epithelial damage in heated groups. Everted intestinal sacs were then used to further characterize hyperthermia-induced intestinal permeability and to study the potential role of oxidative and nitrosative stress. Increased permeability to 4,000-Da FITC-dextran in both small intestinal and colonic sacs was observed at a temperature of 41.5–42°C compared with 37°C, along with widespread intestinal epithelial damage. Administration of antioxidant enzyme mimics or a nitric oxide synthase inhibitor did not reduce permeability due to heat stress, and tissue concentrations of a lipid peroxidation product were not altered by heat stress, suggesting that oxidative and nitrosative stress were not likely mediators of this phenomenon in vitro. In conclusion, hyperthermia produced increased permeability and marked intestinal epithelial damage both in vivo and in vitro, suggesting that thermal disruption of epithelial membranes contributes to the intestinal barrier dysfunction manifested with heat stress.
Prolonged head-down tilt exposure reduces maximal cutaneous vasodilator and sweating capacity in humans
Authors: Crandall C. G. , Shibasaki M. , Wilson T. E. , Cui J. , Levine B. D.
Published: March 2015

Cutaneous vasodilation and sweat rate are reduced during a thermal challenge after simulated and actual microgravity exposure. The effects of microgravity exposure on cutaneous vasodilator capacity and on sweat gland function are unknown. The purpose of this study was to test the hypothesis that simulated microgravity exposure, using the 6° head-down tilt (HDT) bed rest model, reduces maximal forearm cutaneous vascular conductance (FVC) and sweat gland function and that exercise during HDT preserves these responses. To test these hypotheses, 20 subjects were exposed to 14 days of strict HDT bed rest. Twelve of those subjects exercised (supine cycle ergometry) at 75% of pre-bed rest heart rate maximum for 90 min/day throughout HDT bed rest. Before and after HDT bed rest, maximal FVC was measured, via plethysmography, by heating the entire forearm to 42°C for 45 min. Sweat gland function was assessed by administering 1 × 10−6 to 2 M acetylcholine (9 doses) via intradermal microdialysis while simultaneously monitoring sweat rate over the microdialysis membranes. In the nonexercise group, maximal FVC and maximal stimulated sweat rate were significantly reduced after HDT bed rest. In contrast, these responses were unchanged in the exercise group. These data suggest that 14 days of simulated microgravity exposure, using the HDT bed rest model, reduces cutaneous vasodilator and sweating capacity, whereas aerobic exercise training during HDT bed rest preserves these responses.
Chronic hypoxia increases MCA contractile response to U-46619 by reducing NO production and/or activity
Authors: Sillau A. Hugo , McCullough Robert E. , Dyckes Rebecca , White Margueritte M. , Moore Lorna G.
Published: March 2015

Chronic hypoxia alters contractile sensitivity of isolated arteries to α-adrenergic stimulation and other agonists. However, most studies have been performed in thoracic aortas or other large vessels making little contribution to vascular resistance in their respective circulations. To determine the effect of chronic hypoxia on the vasoconstrictor response in a small, resistance-sized vessel, we studied second and third generation middle cerebral arteries (MCA; ∼75-μm internal diameter before mounting). MCA were isolated from normoxic (inspired oxygen = 125 Torr) and hypoxic (8 wk at 3,960 m; inspired oxygen = 90 Torr) guinea pigs, and their vasoconstrictor responses were determined to the thromboxane mimetic U-46619 by using dual-pipette video microscopy. Arteries from hypoxic animals had greater contractile sensitivity to U-46619 compared with those of the normoxic animals (−log EC50 = 7.86 ± 0.11 vs. 7.62 ± 0.06, respectively, P < 0.05). Addition of the nitric oxide (NO) inhibitor nitro-l-arginine (200 μM) to the vessel bath eliminated the differences in contractile sensitivity between the MCA from the normoxic and chronically hypoxic groups. Supplementation with l-arginine in the drinking water sufficient to raise plasma l-arginine levels 41% reduced MCA contractile sensitivity to U-46619 in the normoxic group (−log EC50 = 7.22 ± 0.31, P < 0.05 compared with the nonsupplemented normoxic group) but not in the chronically hypoxic group. These results show that chronic hypoxia increases the sensitivity of the MCA to the vasoconstrictor U-46619, likely because of a reduction in NO production and/or activity.
Limb venous compliance in patients with idiopathic orthostatic intolerance and postural tachycardia
Authors: Freeman Roy , Lirofonis Vasilios , Farquhar William B. , Risk Marcelo
Published: March 2015

Venous denervation and increased venous pooling may contribute to symptoms of orthostatic intolerance. We examined venous compliance in the calf and forearm in 11 orthostatic-intolerant patients and 15 age-matched controls over a range of pressures, during basal conditions and sympathetic excitation. Occlusion cuffs placed around the upper arm and thigh were inflated to 60 mmHg and deflated to 10 mmHg over 1 min. Limb volume was measured continuously with a mercury-in-Silastic strain gauge. Compliance was calculated as the numerical derivative of the pressure-volume curve. The pressure-volume relationship in the upper and lower extremities in the basal and sympathetically activated state was significantly lower in the orthostatic-intolerant patients (all P < 0.05). Sympathoexcitation lowered the pressure-volume relationship in the lower extremity in patients ( P < 0.001) and controls ( P < 0.01). Venous compliance was significantly less in patients in the lower extremity in the basal state over a range of pressures ( P < 0.05). Venous compliance was less in patients compared with controls in the upper ( P < 0.005) and lower extremities ( P < 0.01) in the sympathetically activated state, but there were no differences at individual pressure levels. Sympathetic activation did not change venous compliance in the upper and lower extremity in patients and controls. Patients with orthostatic intolerance have reduced venous compliance in the lower extremity. Reduced compliance may limit the dynamic response to orthostatic change and thereby contribute to symptoms of orthostatic intolerance in this population group.
Regular aerobic exercise and the age-related increase in carotid artery intima-media thickness in healthy men
Authors: Tanaka Hirofumi , Seals Douglas R. , Monahan Kevin D. , Clevenger Christopher M. , DeSouza Christopher A. , Dinenno Frank A.
Published: March 2015

Carotid artery intima-media thickness (IMT), an independent risk factor for stroke, increases with age. Habitual exercise is associated with a lower prevalence of stroke, but it is unclear whether this protective effect could be mediated through a favorable influence on carotid IMT. We examined this possibility using both cross-sectional and intervention approaches. First, 137 healthy men (age 18–77 yr) who were either sedentary or endurance trained were studied. In both groups, carotid IMT and IMT-to-lumen ratio were progressively higher with age ( P < 0.05). There were no significant differences in measures of carotid IMT between sedentary and endurance-trained men at any age. Carotid systolic blood pressure increased progressively with age and was related to carotid IMT ( r = 0.63, P < 0.01). Second, 18 healthy sedentary subjects (54 ± 2 yr) were studied before and after 3 mo of endurance training. Carotid IMT, IMT/lumen ratio, and carotid systolic blood pressure did not change with exercise intervention. Our results do not support the hypothesis that regular aerobic exercise exerts its protective effect against stroke by attenuating the age-related increase in carotid IMT. This lack of effect on carotid IMT may be due to the apparent inability of habitual exercise to prevent or reduce the age-associated elevation in carotid distending pressure.
Upregulation of uncoupling proteins by oral administration of capsiate, a nonpungent capsaicin analog
Authors: Masuda Yoriko , Haramizu Satoshi , Oki Kasumi , Ohnuki Koichiro , Watanabe Tatsuo , Yazawa Susumu , Kawada Teruo , Hashizume Shu-ichi , Fushiki Tohru
Published: March 2015

Capsiate is a nonpungent capsaicin analog, a recently identified principle of the nonpungent red pepper cultivar CH-19 Sweet. In the present study, we report that 2-wk treatment of capsiate increased metabolic rate and promoted fat oxidation at rest, suggesting that capsiate may prevent obesity. To explain these effects, at least in part, we examined uncoupling proteins (UCPs) and thyroid hormones. UCPs and thyroid hormones play important roles in energy expenditure, the maintenance of body weight, and thermoregulation. Two-week treatment of capsiate increased the levels of UCP1 protein and mRNA in brown adipose tissue and UCP2 mRNA in white adipose tissue. This dose of capsiate did not change serum triiodothyronine or thyroxine levels. A single dose of capsiate temporarily raised both UCP1 mRNA in brown adipose tissue and UCP3 mRNA in skeletal muscle. These results suggest that UCP1 and UCP2 may contribute to the promotion of energy metabolism by capsiate, but that thyroid hormones do not.
Invited Review: The crossed phrenic phenomenon: a model for plasticity in the respiratory pathways following spinal cord injury
Authors: Goshgarian Harry G.
Published: March 2015

Hemisection of the cervical spinal cord rostral to the level of the phrenic nucleus interrupts descending bulbospinal respiratory pathways, which results in a paralysis of the ipsilateral hemidiaphragm. In several mammalian species, functional recovery of the paretic hemidiaphragm can be achieved by transecting the contralateral phrenic nerve. The recovery of the paralyzed hemidiaphragm has been termed the “crossed phrenic phenomenon.” The physiological basis for the crossed phrenic phenomenon is as follows: asphyxia induced by spinal hemisection and contralateral phrenicotomy increases central respiratory drive, which activates a latent crossed respiratory pathway. The uninjured, initially latent pathway mediates the hemidiaphragm recovery by descending into the spinal cord contralateral to the hemisection and then crossing the midline of the spinal cord before terminating on phrenic motoneurons ipsilateral and caudal to the hemisection. The purpose of this study is to review work conducted on the crossed phrenic phenomenon and to review closely related studies focusing particularly on the plasticity associated with the response. Because the review deals with recovery of respiratory muscles paralyzed by spinal cord injury, the clinical relevance of the reviewed studies is highlighted.
Denervation-induced changes in myosin heavy chain expression in the rat diaphragm muscle
Authors: Geiger Paige C. , Bailey Jeffrey P. , Zhan Wen-Zhi , Mantilla Carlos B. , Sieck Gary C.
Published: March 2015

Unilateral denervation (Dnv) of the rat diaphragm muscle (Diam) markedly alters expression of myosin heavy chain (MHC) isoforms. After 2 wk of DiamDnv, MHC content per half-sarcomere decreases in fibers expressing MHC2Xand MHC2B. We hypothesized that changes in MHC protein expression parallel changes in MHC mRNA expression. Relative MHC isoform mRNA levels were determined by Northern analysis after 1, 3, 7, and 14 days of Dnv of the rat Diam. MHC protein expression was determined by SDS-PAGE. Changes in MHC isoform protein and mRNA expression were not concurrent. Expression of MHCSlowand MHC2XmRNA isoforms decreased dramatically by 3 days of Dnv, whereas that of MHC2Aand MHC2Bdid not change. Expression of all MHC protein isoforms decreased by 3 days of Dnv. We observed a differential effect of rat DiamDnv on MHC isoform protein and mRNA expression. The time course of the changes in MHC isoform mRNA and protein expression suggests a predominant effect of altered protein turnover rates on MHC protein expression instead of altered transcription after Dnv.
N-acetylcysteine infusion alters blood redox status but not time to fatigue during intense exercise in humans
Authors: Medved I. , Brown M. J. , Bjorksten A. R. , Leppik J. A. , Sostaric S. , McKenna M. J.
Published: March 2015

Infusion of the antioxidant N-acetylcysteine (NAC) reduces fatigability in electrically evoked human muscle contraction, but due to reported adverse reactions, no studies have investigated NAC infusion effects during voluntary exercise in humans. We investigated whether a modified NAC-infusion protocol (125 mg · kg−1· h−1for 15 min, then 25 mg · kg−1· h−1) altered blood redox status and enhanced performance during intense, intermittent exercise. Eight untrained men participated in a counterbalanced, double-blind, crossover study in which they received NAC or saline (control) before and during cycling exercise, which comprised three 45-s bouts and a fourth bout that continued to fatigue, at 130% peak oxygen consumption. Arterialized venous blood was analyzed for glutathione status, hematology, and plasma electrolytes. NAC infusion induced no severe adverse reactions. Exercise decreased the reduced glutathione ( P < 0.005) and increased oxidized glutathione concentrations ( P < 0.005); NAC attenuated both effects ( P < 0.05). NAC increased the rise in plasma K+concentration-to-work ratio ( P < 0.05), indicating impaired K+regulation, although time to fatigue was unchanged (NAC 102 ± 45 s; saline 107 ± 53 s). Thus NAC infusion altered blood redox status during intense, intermittent exercise but did not attenuate fatigue.
A comparison of voluntary and electrically induced contractions by interleaved 1H- and 31P-NMRS in humans
Authors: Vanderthommen M. , Duteil S. , Wary C. , Raynaud J. S. , Leroy-Willig A. , Crielaard J. M. , Carlier P. G.
Published: March 2015

Skeletal muscle voluntary contractions (VC) and electrical stimulations (ES) were compared in eight healthy men. High-energy phosphates and myoglobin oxygenation were simultaneously monitored in the quadriceps by interleaved1H- and 31P-NMR spectroscopy. For the VC protocol, subjects performed five or six bouts of 5 min with a workload increment of 10% of maximal voluntary torque (MVT) at each step. The ES protocol consisted of a 13-min exercise with a load corresponding to 10% MVT. For both protocols, exercise consisted of 6-s isometric contractions and 6-s rest cycles. For an identical mechanical level (10% MVT), ES induced larger changes than VC in the Pi-to-phosphocreatine ratio [1.38 ± 1.14 (ES) vs. 0.13 ± 0.04 (VC)], pH [6.69 ± 0.11 (ES) vs. 7.04 ± 0.07 (VC)] and myoglobin desaturation [43 ± 15.9 (ES) vs. 6.1 ± 4.6% (VC)]. ES activated the muscle facing the NMR coil to a greater extent than did VCs when evaluated under identical technical conditions. This metabolic pattern can be interpreted in terms of specific temporal and spatial muscle cell recruitment. Furthermore, at identical levels of energy charge, the muscle was more acidotic and cytoplasm appeared more oxygenated during ES than during VC. These results are in accordance with a preferential recruitment of type II fibers and a relative muscle hyperperfusion during ES.
Measurement of nasal patency in anesthetized and conscious dogs
Authors: Koss Michael C. , Yu Yongxin , Hey John A. , McLeod Robbie L.
Published: March 2015

Experiments were undertaken to characterize a noninvasive chronic, model of nasal congestion in which nasal patency is measured using acoustic rhinometry. Compound 48/80 was administered intranasally to elicit nasal congestion in five beagle dogs either by syringe (0.5 ml) in thiopental sodium-anesthetized animals or as a mist (0.25 ml) in the same animals in the conscious state. Effects of mast cell degranulation on nasal cavity volume as well as on minimal cross-sectional area ( A min) and intranasal distance to A min ( D min) were studied. Compound 48/80 caused a dose-related decrease in nasal cavity volume and A min together with a variable increase in D min. Maximal responses were seen at 90–120 min. Compound 48/80 was less effective in producing nasal congestion in conscious animals, which also had significantly larger basal nasal cavity volumes. These results demonstrate the utility of using acoustic rhinometry to measure parameters of nasal patency in dogs and suggest that this model may prove useful in studies of the actions of decongestant drugs.
MLR stimulation and exercise pressor reflex activate different renal sympathetic fibers in decerebrate cats
Authors: Hayes Shawn G. , Kaufman Marc P.
Published: March 2015

Although mesencephalic locomotor region (MLR) stimulation and the exercise pressor reflex have been shown to increase whole nerve renal sympathetic activity, it is not known whether these mechanisms converge onto the same population of renal sympathetic postganglionic efferents. In decerebrate cats, we examined the responses of single renal sympathetic postganglionic efferents to stimulation of the MLR and the exercise pressor reflex (i.e., static contraction of the triceps surae muscles). We found that, in most instances (24 of 28 fibers), either MLR stimulation or the muscle reflex, but not both, increased the discharge of renal postganglionic sympathetic efferents. In addition, we found that renal sympathetic efferents that responded to static contraction while the muscles were freely perfused responded more vigorously to static contraction during circulatory arrest. Moreover, stretch of the calcaneal (Achilles) tendon stimulated the same renal sympathetic efferents as did static contraction. These findings suggest that MLR stimulation and the exercise pressor reflex do not converge onto the same renal sympathetic postganglionic efferents.
Physiology of sulfide in the rat colon: use of bismuth to assess colonic sulfide production
Authors: Levitt Michael D. , Springfield John , Furne Julie , Koenig Thomas , Suarez Fabrizis L.
Published: March 2015

Colonic bacteria produce hydrogen sulfide, a toxic compound postulated to play a pathogenetic role in ulcerative colitis. Colonic sulfide exposure has previously been assessed via measurements of fecal sulfide concentration. However, we found that <1% of fecal sulfide of rats was free, the remainder being bound in soluble and insoluble complexes. Thus fecal sulfide concentrations may reflect sulfide binding capacity rather than the toxic potential of feces. We utilized bismuth subnitrate to quantitate intracolonic sulfide release based on observations that bismuth 1) avidly binds sulfide; 2) quantitatively releases bound sulfide when acidified; and 3) does not influence fecal sulfide production by fecal homogenates. Rats ingesting bismuth subnitrate excreted 350 ± 18 μmol/day of fecal sulfide compared with 9 ± 1 μmol/day in control rats. Thus the colon normally absorbs ∼340 μmol of sulfide daily, a quantity that would produce local and systemic injury if not efficiently detoxified by the colonic mucosa. Studies utilizing bismuth should help to clarify the factors influencing sulfide production in the human colon.
Brain activation by central command during actual and imagined handgrip under hypnosis
Authors: Williamson J. W. , McColl R. , Mathews D. , Mitchell J. H. , Raven P. B. , Morgan W. P.
Published: March 2015

The purpose was to compare patterns of brain activation during imagined handgrip exercise and identify cerebral cortical structures participating in “central” cardiovascular regulation. Subjects screened for hypnotizability, five with higher (HH) and four with lower hypnotizability (LH) scores, were tested under two conditions involving 3 min of 1) static handgrip exercise (HG) at 30% of maximal voluntary contraction (MVC) and 2) imagined HG (I-HG) at 30% MVC. Force (kg), forearm integrated electromyography, rating of perceived exertion, heart rate (HR), mean blood pressure (MBP), and differences in regional cerebral blood flow distributions were compared using an ANOVA. During HG, both groups showed similar increases in HR (+13 ± 5 beats/min) and MBP (+17 ± 3 mmHg) after 3 min. However, during I-HG, only the HH group showed increases in HR (+10 ± 2 beats/min; P < 0.05) and MBP (+12 ± 2 mmHg; P < 0.05). There were no significant increases or differences in force or integrated electromyographic activity between groups during I-HG. The rating of perceived exertion was significantly increased for the HH group during I-HG, but not for the LH group. In comparison of regional cerebral blood flow, the LH showed significantly lower activity in the anterior cingulate (−6 ± 2%) and insular cortexes (−9 ± 4%) during I-HG. These findings suggest that cardiovascular responses elicited during imagined exercise involve central activation of insular and anterior cingulate cortexes, independent of muscle afferent feedback; these structures appear to have key roles in the central modulation of cardiovascular responses.
Development of sex differences in the rabbit masseter muscle is not restricted to a critical period
Authors: English Arthur W. , Schwartz Gail
Published: March 2015

The proportions of muscle fibers of different phenotype in the adult rabbit masseter differ greatly in different sexes. These sex differences are not apparent in young adults, but arise under the influence of testosterone in the males. We examined whether this switch occurred during a critical period of postnatal development. Testosterone was administered to young adults 1, 2, or 4 mo after castration, and also to adult females. Samples of masseter muscle were taken at four monthly intervals after the onset of treatment and examined for the expression of different myosin heavy chain (MyHC) isoforms by using a panel of monoclonal antibodies. Despite the length of androgen deprivation, treatment with testosterone produced a marked MyHC isoform switch from α-slow/β to IIa. This male proportion of fibers of different phenotypes persisted well beyond the return of serum testosterone levels to pretreatment levels. Thus brief exposure to testosterone produces a permanent change in the proportions of masseter muscle fibers of different phenotypes, and the capacity for this change is not restricted to a critical period.
Desferrioxamine elevates pulmonary vascular resistance in humans: potential for involvement of HIF-1
Authors: Balanos George M. , Dorrington Keith L. , Robbins Peter A.
Published: March 2015

Hypoxia-inducible factor (HIF)-1 is stabilized by hypoxia and iron chelation. We hypothesized that HIF-1 might be involved in pulmonary vascular regulation and that infusion of desferrioxamine over 8 h would consequently mimic hypoxia and elevate pulmonary vascular resistance. In study A, we characterized the pulmonary vascular response to 4 h of isocapnic hypoxia; in study B, we measured the pulmonary vascular response to 8 h of desferrioxamine infusion. For study A, 11 volunteers undertook two protocols: 1) 4 h of isocapnic hypoxia (end-tidal Po2= 50 Torr), followed by 2 h of recovery with isocapnic euoxia (end-tidal Po2= 100 Torr), and 2) 6 h of air breathing (control). For study B, nine volunteers undertook two protocols while breathing air: 1) continuous infusion of desferrioxamine (4 g/70 kg) over 8 h and 2) continuous infusion of saline over 8 h (control). In both studies, pulmonary vascular resistance was assessed at 0.5- to 1-h intervals by Doppler echocardiography via the maximum pressure gradient during systole across the tricuspid valve. Results show a progressive rise in pressure gradient over the first 3–4 h with both isocapnic hypoxia ( P < 0.001) and desferrioxamine infusion ( P < 0.005) to increases of ∼16 and 4 Torr, respectively. These results support a role for HIF-regulated gene activation in human hypoxic pulmonary vasoconstriction.
Combined creatine and protein supplementation in conjunction with resistance training promotes muscle GLUT-4 content and glucose tolerance in humans
Authors: Derave Wim , Eijnde Bert O. , Verbessem Patricia , Ramaekers Monique , Van Leemputte Mark , Richter Erik A. , Hespel Peter
Published: March 2015

The present study was undertaken to explore the effects of creatine and creatine plus protein supplementation on GLUT-4 and glycogen content of human skeletal muscle. This was investigated in muscles undergoing a decrease (immobilization) and subsequent increase (resistance training) in activity level, compared with muscles with unaltered activity pattern. A double-blind, placebo-controlled trial was performed by 33 young healthy subjects. The subjects′ right legs were immobilized with a cast for 2 wk, followed by a 6-wk resistance training program for the right knee extensor muscles. The participants were supplemented throughout the study with either placebo (Pl group) or creatine (Cr group) or with creatine during immobilization and creatine plus protein during retraining (Cr+P group). Needle biopsies were bilaterally taken from the vastus lateralis. GLUT-4 protein expression was reduced by the immobilization in all groups ( P < 0.05). During retraining, GLUT-4 content increased ( P < 0.05) in both Cr (+24%) and Cr+P (+33%), which resulted in higher posttraining GLUT-4 expression compared with Pl ( P < 0.05). Compared with Pl, muscle glycogen content was higher ( P < 0.05) in the trained leg in both Cr and Cr+P. Supplements had no effect on GLUT-4 expression or glycogen content in contralateral control legs. Area under the glucose curve during the oral glucose tolerance test was decreased from 232 ± 23 mmol · l−1 · min−1at baseline to 170 ± 23 mmol · l−1 · min−1 at the end of the retraining period in Cr+P ( P < 0.05), but it did not change in Cr or Pl. We conclude that creatine intake stimulates GLUT-4 and glycogen content in human muscle only when combined with changes in habitual activity level. Furthermore, combined protein and creatine supplementation improved oral glucose tolerance, which is supposedly unrelated to the changes in muscle GLUT-4 expression.
Estrogen attenuates the cardiovascular and ventilatory responses to central command in cats
Authors: Hayes Shawn G. , Moya Del Pino Nicolas B. , Kaufman Marc P.
Published: March 2015

Static exercise is well known to increase heart rate, arterial blood pressure, and ventilation. These increases appear to be less in women than in men, a difference that has been attributed to an effect of estrogen on neuronal function. In decerebrate male cats, we examined the effect of estrogen (17β-estradiol; 0.001, 0.01, 0.1, and 1.0 μg/kg iv) on the cardiovascular and ventilatory responses to central command and the exercise pressor reflex, the two neural mechanisms responsible for evoking the autonomic and ventilatory responses to exercise. We found that 17β-estradiol, in each of the three doses tested, attenuated the pressor, cardioaccelerator, and phrenic nerve responses to electrical stimulation of the mesencephalic locomotor region (i.e., central command). In contrast, none of the doses of 17β-estradiol had any effect on the pressor, cardioaccelerator, and ventilatory responses to static contraction or stretch of the triceps surae muscles. We conclude that, in decerebrate male cats, estrogen injected intravenously attenuates cardiovascular and ventilatory responses to central command but has no effect on responses to the exercise pressor reflex.
Invited Review: Cytokine regulation of fever: studies using gene knockout mice
Authors: Leon Lisa R.
Published: March 2015

Fever is defined as a regulated rise in body temperature. The regulation of this phenomenon is accomplished by the actions of two types of endogenous cytokines, some functioning as pyrogens and others as antipyretics. Previous data obtained with the use of traditional pharmacological techniques, such as the injection of neutralizing antibodies, implicate interleukin (IL)-1 and IL-6 as endogenous pyrogens or inducers of fever. In almost all instances in which the endogenous actions of IL-1 or IL-6 are antagonized, fevers are attenuated. Other cytokines, such as tumor necrosis factor-α (TNF-α) and IL-10, are thought to act as endogenous antipyretics or inhibitors of fever. In several studies, the inhibition of TNF action has enhanced fever. Recently, mice genetically engineered to lack cytokines or their receptors in all tissues of the body have been used to examine the regulation of IL-1, IL-6, TNF, and IL-10 on fever. Data obtained with these mice shed new light on our understanding of cytokine interactions in fever and, in some instances, contradict data obtained with pharmacological methods. This review summarizes the responses of cytokine and cytokine receptor knockout mice to fevers induced by lipopolysaccharide, turpentine, and sepsis.
Delay of muscle vasodilation to changes in work rate (treadmill grade) during locomotion
Authors: Sheriff Don D. , Zidon Terese M.
Published: March 2015

Previous studies examining the delay to the onset of vasodilation have primarily focused on the onset of exercise, a setting complicated by the fact that the muscle pump and the vasodilator systems are both activated, making it difficult to attribute changes in blood flow to one or both. The goal here was to determine the delay to the onset of vasodilation after changes in work rate imposed by changes in treadmill grade (work intensity) during locomotion at a steady speed. The rationale was that constant speed would help ensure constant muscle pump activity (contraction frequency) such that vasodilator responses could be examined in isolation. Seven Sprague-Dawley rats underwent three trials each in which treadmill incline was suddenly (∼1 s) elevated from −10° to +10°. The delay to the onset of vasodilation averaged 5.0 ± 1.8 s, and this delay was not altered by inhibition of nitric oxide synthase. Similar or longer delays were seen during sinusoidal exercise. Thus there is a significant delay before the onset of vasodilation after an increase in work intensity (muscle force) during locomotory exercise at constant speed.
Accuracy of noninvasive estimates of respiratory muscle effort during spontaneous breathing in restrictive diseases
Authors: García-Río Francisco , Pino José M. , Ruiz Angeles , Díaz Salvador , Prados Concepción , Villamor José
Published: March 2015

Mean inspiratory pressure (Pi), estimated from the occlusion pressure at the mouth and the inspiratory time, is useful as a noninvasive estimate of respiratory muscle effort during spontaneous breathing in normal subjects and patients with chronic obstructive pulmonary disease. The aim of this study was to compare the Pi with respect to mean esophageal pressure (Pes) in patients with restrictive disorders. Eleven healthy volunteers, 12 patients with chest wall disease, 14 patients with usual interstitial pneumonia, and 17 patients with neuromuscular diseases were studied. Pi, Pes, and mean transdiaphragmatic pressure were simultaneously measured. Tension-time indexes of diaphragm (TTdi) and inspiratory muscles (TTmu) were also determined. In neuromuscular patients, significant correlations were found between Pi and Pes, Pi and transdiaphragmatic pressure, and TTmuand TTdi. A moderate agreement between Pi and Pes and between TTmuand TTdiwas found. No significant correlation between these parameters was found in the other patient groups. These findings suggest that Pi is a good surrogate for the invasive measurement of respiratory muscle effort during spontaneous breathing in neuromuscular patients.
Role played by purinergic receptors on muscle afferents in evoking the exercise pressor reflex
Authors: Hanna Ramy L. , Kaufman Marc P.
Published: March 2015

The exercise pressor reflex is believed to be evoked, in part, by multiple metabolic stimuli that are generated when blood supply to exercising muscles is inadequate to meet metabolic demand. Recently, ATP, which is a P2 receptor agonist, has been suggested to be one of the metabolic stimuli evoking this reflex. We therefore tested the hypothesis that blockade of P2 receptors within contracting skeletal muscle attenuated the exercise pressor reflex in decerebrate cats. We found that popliteal arterial injection of pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS; 10 mg/kg), a P2 receptor antagonist, attenuated the pressor response to static contraction of the triceps surae muscles. Specifically, the pressor response to contraction before PPADS averaged 36 ± 3 mmHg, whereas afterward it averaged 14 ± 3 mmHg ( P < 0.001; n = 19). In addition, PPADS attenuated the pressor response to postcontraction circulatory occlusion ( P < 0.01; n = 11). In contrast, popliteal arterial injection of CGS-15943 (250 μg/kg), a P1 receptor antagonist, had no effect on the pressor response to static contraction of the triceps surae muscles. In addition, popliteal arterial injection of PPADS but not CGS-15943 attenuated the pressor response to stretch of the calcaneal (Achilles) tendon. We conclude that P2 receptors on the endings of thin fiber muscle afferents play a role in evoking both the metabolic and mechanoreceptor components of the exercise pressor reflex.