bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelin-1 contributes to antigen-induced airway hyperresponsiveness
Authors: Noguchi K. , Ishikawa K. , Yano M. , Ahmed A. , Cortes A. , Abraham W. M.
Published: December 2017

Endothelin A (ETA)-receptors mediate ET-1 contractions of ovine airway smooth muscle. Therefore, the ETA-receptor antagonist, BQ-123, was used to test the hypothesis that ET-1 contributes to antigen-induced airway responses in sheep allergic to Ascaris suum. We first established the protective effect of BQ-123 by demonstrating that BQ-123 given as an aerosol (0.3 or 1.0 mg/kg in 3 ml buffer) or by continuous intravenous infusion (100 micrograms.kg-1.min-1) significantly blocked the bronchoconstriction to aerosolized ET-1 (0.2–200 micrograms/ml). To determine whether ET-1 contributed to antigen-induced airway responses, BQ-123 was given either as an intravenous infusion (100 micrograms.kg-1.min-1) beginning 30 min before and continuing for 8 h after antigen challenge or as an aerosol (1 mg/kg in 3 ml buffer) 30 min before and 4, 8, and 24 h after antigen challenge. Neither treatment with intravenous infusion nor aerosolized BQ-123 blocked the immediate antigen-induced bronchoconstriction, but both treatments significantly reduced the late response (approximately 50%). The treatments with aerosolized BQ-123 also blocked the antigen-induced airway hyperresponsiveness to inhaled carbachol seen 24 h after challenge. Subsequently, we found that sheep developed airway hyperresponsiveness to inhaled carbachol at 4 and 24 h after ET-1 challenge, an effect that was blocked by aerosolized BQ-123. We conclude that in allergic sheep 1) aerosolized ET-1 causes bronchoconstriction, in part, by stimulation of ETA-receptors, 2) ET-1 is released in the airways after antigen challenge, and 3) this peptide contributes to the severity of the allergic responses, probably by increasing airway smooth muscle responsiveness.
Augmented mesenteric and renal vasoconstriction during exercise in senescent Fischer 344 rats
Authors: Kregel K. C.
Published: December 2017

The purpose of this study was to test the hypothesis that vasoconstriction in the mesenteric and renal circulations is greater at both submaximal and maximal exercise intensities with advancing age. Arterial blood pressure, heart rate, and mesenteric, renal, and iliac (hindlimb) artery blood flow velocities were measured before and during graded treadmill exercise in mature (12 mo) and senescent (24 mo) male Fischer 344 rats. During treadmill running at mild, moderate, and maximal exercise intensities (approximately 45, 70, and 100% of maximal oxygen uptake), the increases in arterial pressure were similar in the mature and senescent animals, whereas heart rate rose less in the older group (P < 0.05). Mesenteric and renal flow velocities declined and vascular resistances increased from resting levels in both groups in response to graded exercise; however, the magnitudes of the increases in both mesenteric and renal vascular resistance were significantly augmented in the older rats at the moderate and maximal workloads. Hindlimb blood flow velocity increased and resistance declined from resting levels at each exercise intensity in both groups. In contrast to the visceral and renal adjustments, the magnitudes of the changes in both hindlimb flow and resistance were similar for the two age groups at all exercise intensities. These findings support the hypothesis that mesenteric and renal vasoconstriction is augmented in senescent Fischer 344 rats during exercise at moderate and maximal intensities but not at mild workloads. Despite these regional differences, the maintenance of arterial pressure is not altered at either submaximal or maximal exercise intensities with advancing age.
Beat-by-beat forearm blood flow with Doppler ultrasound and strain-gauge plethysmography
Authors: Tschakovsky M. E. , Shoemaker J. K. , Hughson R. L.
Published: December 2017

Simultaneous Doppler ultrasound estimates of brachial artery mean blood velocity (MBV) and venous occlusion strain-gauge plethysmography measures of forearm blood flow (FBF) were performed to determine the beat-by-beat relationship between the two methods and provide a method for flow calibration of Doppler MBV estimates. Such a calibration of Doppler MBV eliminates the need for knowledge of vessel cross-sectional area and angle of insonation while allowing for the quantification of limb blood flow. Six healthy subjects (5 men and 1 woman) performed 40 s of isometric forearm contraction at 35% maximal voluntary contraction with arterial inflow occluded. This resulted in elevated blood flow on relaxation and cuff deflation, and simultaneous beat-by-beat Doppler MBV and strain-gauge FBF measurements were then made over a period of 2–3 min as flow gradually decreased to resting levels. The r2 values for the fitted regression lines over a wide range of flows ranged from 0.87 to 0.98, and the mean square error terms ranged from 0.88 to 3.07 ml.100 ml-1.min-1. Significant day-to-day variation of the fitted regression parameters within subjects indicated that quantitative estimates of FBF from Doppler MBV require a calibration to be performed for each experiment. The finding of a strong linear relationship between Doppler MBV and venous occlusion strain-gauge plethysmography, as well as the marked beat-by-beat effect of cuff inflation on blood flow, confirms the importance of calibration on the same beats, not on adjacent segments of beats.
Ventilatory stability to CO2 disturbances in wakefulness and quiet sleep
Authors: Modarreszadeh M. , Bruce E. N. , Hamilton H. , Hudgel D. W.
Published: December 2017

Oscillatory ventilatory pattern occurs more frequently in sleep despite the stabilizing factor of sleep-induced reduction in CO2 chemosensitivity. In nine young normal humans, we have tested the hypothesis that, despite a sleep-induced reduction in chemosensitivity, the transient central chemoreceptor-mediated change inspiratory ventilation (VI) caused by a standardized disturbance to chemoreflex ventilatory control is similar in quiet sleep and wakefulness. The equivalent VI response to a single-breath hyperoxic hypercapnic stimulus (i.e., inhaling a single breath of 0.01 liter of CO2 in O2--a direct measure of “closed-loop” dynamic response) was determined using pseudorandom binary CO2 stimulation and the prediction-error method of transfer function estimation. From these data, the response of VI to a single-breath increase of 1 Torr in end-tidal PCO2 was also derived, from which “dynamic” central chemosensitivity was calculated. Despite a 43% reduction in dynamic central chemosensitivity, the peak and the area under the closed-loop VI response are similar in wakefulness and quiet sleep, whereas sleep increases the duration of the response by 48%. Thus hyperoxic ventilatory stability is not reduced in quiet sleep relative to wakefulness. We propose that changes in dynamics of pulmonary gas exchange in sleep substantially offset the decreased chemosensitivity, thereby maintaining the gains and time constants of the central chemoreceptor-mediated component of the closed-loop ventilatory control system similar to those during wakefulness.
Endothelin-1 potentiates leukotoxin-induced edematous lung injury
Authors: Ishizaki T. , Shigemori K. , Nakai T. , Miyabo S. , Hayakawa M. , Ozawa T. , Voelkel N. F. , Chang S. W.
Published: December 2017

We tested the hypothesis that leukotoxin (Lx), a cytochrome P-450-dependent linoleate product of leukocytes, can stimulate the release of endothelin-1 (ET-1) from the lung and further that exogenous ET-1 synergizes with Lx to produce edematous lung injury. In isolated rat lungs perfused with Earle's balanced salt solution, Lx (10 mumol) alone caused lung edema and increased the perfusate and lung tissue ET-1 levels. The combination of ET-1 (5 nM) and Lx (5 mumol), at concentrations that by themselves did not increase wet lung weight, significantly increased wet lung weight, wet-to-dry lung weight ratio, as well as the lung effluent lactate dehydrogenase activity. Pretreatment with BQ-123 (5 x 10(-6) M), an endothelin A receptor antagonist that significantly attenuated the ET-1 (5 nM)-induced increase in pulmonary arterial pressure (Ppa) and pulmonary capillary pressure (Ppc), suppressed the edematous lung injury generated by the combination of ET-1 and Lx, suggesting that the edema-enhancing effect of ET-1 in Lx-treated lungs occurred through endothelin A receptor-dependent elevation of Ppa and Ppc. Elevation of the pulmonary venous pressure in Lx-treated lungs (13.5 cmH2O) mimicked the effect of ET-1 on Ppa and Ppc and produced a degree of lung edema that was comparable to that after combined ET-1 + Lx treatment but without increase in the perfusate lactate dehydrogenase. These data support the idea that ET-1 and Lx promote lung edema in a synergistic fashion.
Secretory leukoprotease inhibitor attenuates lung injury induced by continuous air embolization into sheep
Authors: Gossage J. R. , Perkett E. A. , Davidson J. M. , Starcher B. C. , Carmichael D. , Brigham K. L. , Meyrick B.
Published: December 2017

Continuous air embolization (CAE) into the pulmonary arterial circulation of sheep results in functional and structural changes of chronic pulmonary hypertension. Release of elastin peptides into lung lymph during CAE and attenuation of CAE-induced pulmonary hypertension by neutrophil depletion suggest that neutrophil elastase may contribute to these changes. To investigate this notion, we treated awake sheep with a potent neutrophil elastase inhibitor, recombinant secretory leukoprotease inhibitor (SLPI) (100 mg/day by aerosol), during 12 days of CAE (CAE+SLPI; n = 7). Controls included sheep receiving CAE + vehicle (VEH) (n = 6), VEH alone (n = 3), and SLPI alone (n = 3). SLPI significantly attenuated the CAE-induced increases in lung lymph flow (day 8; 2.3 +/- 0.5 vs. 5.6 +/- 1.7 ml/15 min), protein clearance (day 8; 1.36 +/- 0.32 vs. 3.08 +/- 0.84 ml/15 min), and elastin peptide concentration (day 8; 243 +/- 41 vs. 398 +/- 44 ng/ml). SLPI delayed the onset of sustained pulmonary hypertension from day 8 to day 12. Both CAE groups showed similar structural changes in the pulmonary arteries. SLPI was well tolerated in control sheep and did not affect hemodynamics or structure. We conclude that serine proteases may contribute to the early initiation of chronic pulmonary hypertension but do not play a striking role in its eventual development.
Changes in diaphragm muscle collagen gene expression after acute unilateral denervation
Authors: Gosselin L. E. , Sieck G. C. , Aleff R. A. , Martinez D. A. , Vailas A. C.
Published: December 2017

The purpose of the present study was to examine the effects of acute (3 days) unilateral diaphragm denervation (DNV) on 1) levels of alpha 1(I) and alpha 1(III) procollagen mRNA; 2) collagen concentration [hydroxyproline (HYP)]; 3) amount of the nonreducible collagen cross-link hydroxylysylpyridinoline (HP); and 4) the passive force-length relationship of the muscle. The levels of alpha 1(I) and alpha 1(III) procollagen mRNA, HYP concentration, and amount of HP were measured in muscle segments from the midcostal region of DNV and intact (INT) hemidiaphragms of adult male Fischer 344 rats (250–300 g). The in vitro passive force-length relationship of DNV and INT hemidiaphragm was determined by lengthening and shortening the diaphragm muscle segments from 85 to 115% of optimal length at a constant velocity (0.6 optimal length/s). Three days after DNV, the level of alpha 1(I) procollagen mRNA was increased over 15-fold in the DNV hemidiaphragm compared with INT (P < 0.05), whereas the level of alpha 1(III) procollagen mRNA was increased by approximately sixfold in the DNV hemidiaphragm compared with INT (P < 0.05). Collagen (HYP) concentration did not differ between groups, averaging 8.7 and 8.9 micrograms/mg dry wt for the DNV and INT hemidiaphragms, respectively. In addition, there was no difference in the amount of the mature nonreducible collagen cross-link HP between the DNV and INT hemidiaphragms (0.66 vs. 0.76 mole HP/mole collagen, respectively). The amount of passive force developed during lengthening did not differ between DNV and INT hemidiaphragms. These data indicate that acute DNV of the hemidiaphragm is associated with an increase in the mRNA level of the two principal fibrillar collagen phenotypes in skeletal muscle. However, despite extensive muscle remodeling, the passive force-length relationship of the DNV hemidiaphragm is unaffected compared with the INT muscle.
Role of the vascular endothelium in O2 extraction during progressive ischemia in canine skeletal muscle
Authors: Curtis S. E. , Vallet B. , Winn M. J. , Caufield J. B. , King C. E. , Chapler C. K. , Cain S. M.
Published: December 2017

O2 extraction during progressive ischemia in canine skeletal muscle, J. Appl. Physiol. 79(4): 1351–1360, 1995.--O2 uptake (VO2) is defended during decreased O2 delivery (QO2) by an increase in the O2 extraction ratio (O2ER, VO2/QO2), presumably by recruitment of capillaries. This study tested the hypothesis that activity of the microvascular endothelium plays a necessary role in achievement of maximal O2ER. We pump perfused the vascularly isolated hindlimbs of 24 anesthetized and paralyzed dogs at progressively lower flows over a 90-min period. In eight dogs, hindlimb vascular endothelium was removed by injection of deoxycholate (DOC) into the perfusing artery before the ischemic challenge. DOC treatment resulted in loss of normal in vivo and in vitro endothelium-dependent dilatory responses to acetylcholine, but endothelium-independent vascular smooth muscle responses were intact. Eight other dogs were pretreated with nitro-L-arginine methyl ester plus indomethacin (L+I group) to block the synthesis of the vasodilators nitric oxide and prostacyclin. L+I and DOC treatment were associated with increases in hindlimb vascular resistance of 168 +/- 17 and 63 +/- 12%, respectively. O2ER at critical QO2 (QO2 at which VO2 begins to decrease) was 81 +/- 2% in eight control dogs, 66 +/- 6% in L+I, and 42 +/- 4% in DOC, indicating a significant O2 extraction defect in the two treatment groups. These data suggest that products of the vascular endothelium play an important role in the matching of O2 supply to demand during supply limitation in skeletal muscle.
Changes in muscle proton transverse relaxation times and acidosis during exercise and recovery
Authors: Cheng H. A. , Robergs R. A. , Letellier J. P. , Caprihan A. , Icenogle M. V. , Haseler L. J.
Published: December 2017

We studied changes in muscle proton (1H) transverse relaxation times (T2) by magnetic resonance imaging during exercise and compared these changes with alterations in muscle metabolism measured by phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Eleven subjects completed two trials of intermittent incremental forearm wrist flexion exercise requiring 30 contractions/min for 5 min, 7 min of recovery between stages, and 5-N load increments/stage. Between stages of the first trial, T2 images of muscle 1H were obtained. Muscle T2 increased from 27.3 +/- 1.1 (SD) ms at rest to 35.8 +/- 3.6 ms after volitional fatigue (P < 0.05), whereas less active wrist extensor muscle T2 remained unchanged (26.8 +/- 0.9 to 28.8 +/- 1.6 ms; P > 0.05). After localizing the predominant muscle recruited from the T2 images, subjects completed an identical trial at least 1 wk later but involving surface coil 31P-MRS of the T2-enhanced muscle to measure the H+ concentration ([H+]). Intramuscular [H+] of T2-enhancing muscle increased from 1.1 +/- 0.1 x 10(-7) M at rest to 4.1 +/- 2.0 x 10(-7) M after volitional fatigue. Both muscle T2 and intramuscular [H+] increased in a bimodal manner, with T2 increasing before muscle [H+] (P < 0.05). The correlation coefficient between the percent change in T2 and muscle [H+] during exercise was +0.74 (range 0.48–0.98; P < 0.05) and +0.47 during recovery. After 12 min of recovery, muscle [H+] decreased to 1.4 +/- 0.3 x 10(-7) M (P < 0.05), and T2 remained close to postexercise values (32.2 +/- 3.1 ms, P > 0.05). The data indicate that 1) the T2 increases during increases in exercise intensity are nonlinear, 2) the T2 increases during exercise are significantly correlated with increases in [H+], and 3) the slow recovery of T2 compared with [H+] indicates that [H+] has a minor contribution to the recovery in T2.
Left ventricular volumes and hemodynamic responses at onset of dynamic exercise with reduced venous return
Authors: Nobrega A. C. , Williamson J. W. , Mitchell J. H.
Published: December 2017

The hemodynamic effects of reducing venous return were assessed beat by beat at the onset of upright dynamic exercise. Mean arterial pressure (MAP), heart rate, and left ventricular end-systolic (ESV) and end-diastolic volumes (EDV; two-dimensional echocardiography) were measured in 10 healthy men during 20-s trials of upright cycling (30 W; 60 rpm). Exercise was performed either with or without venous occlusion of the legs (bilateral thigh cuffs inflated to 100 mmHg) in a random order. Without venous occlusion, MAP and cardiac output (CO) increased, and total peripheral resistance (TPR) decreased (P < 0.05) during the first approximately 10 beats after the onset of exercise. Initially, the CO response was accounted for by a rapid heart rate acceleration and, after approximately 15 cardiac cycles, by an increase in stroke volume, which occurred with a decrease in ESV and no change in EDV. With venous occlusion, EDV decreased and stroke volume did not rise during exercise. Thus the CO response was blunted by venous occlusion and MAP did not increase initially. However, after approximately 13 heart beats, MAP increased with no change in TPR. These findings suggest that compensatory mechanisms can elicit an increase in MAP at the onset of mild upright cycling when the CO response is blunted by reducing venous return.
Control of thermoregulatory sweating is altered by hydration level and exercise intensity
Authors: Montain S. J. , Latzka W. A. , Sawka M. N.
Published: December 2017

The purpose of this study was to examine the thermoregulatory sweating control parameters of threshold temperature and sensitivity to determine whether 1) these variables were altered by hypohydration level and exercise intensity and 2) these alterations, if present, were additive and independent. Nine heat-acclimated men completed a matrix of nine trials: three exercise intensities of 25, 45, and 65% maximal O2 uptake and three hydration levels, i.e., euhydration and hypohydration (Hy) at 3 and 5% of body weight. During each trial, subjects attempted 50 min of treadmill exercise in a warm room (30 degrees C dry bulb, 50% relative humidity) while esophageal temperature and upper arm sweating rate were continuously measured. Hypohydration was achieved by exercise and fluid restriction the day preceding the trials. The following new findings were made: 1) threshold temperature increased in graded manner with hypohydration level (approximately 0.06 degree C/% Hy); 2) sensitivity decreased in a graded manner with hypohydration level (approximately 0.06 units/%Hy); 3) threshold temperature was not altered by exercise intensity; and 4) sensitivity increased from low- to moderate- and high-intensity exercise. We conclude that both hypohydration level and exercise intensity produce independent effects on control of thermoregulatory sweating.
Endurance run increases circulating IL-6 and IL-1ra but downregulates ex vivo TNF-alpha and IL-1 beta production
Authors: Drenth J. P. , Van Uum S. H. , Van Deuren M. , Pesman G. J. , Van der Ven-Jongekrijg J. , Van der Meer J. W.
Published: December 2017

This investigation determined the manner in which the cardiovascular system copes with the dehydration-induced reductions in cardiac output (Q) during prolonged exercise in the heat. On two separate occasions, seven endurance-trained subjects (maximal O2 consumption 4.70 +/- 0.41 l/min) cycled in the heat (35 degrees C) for 2 h, beginning at 62 +/- 2% maximal O2 consumption. During exercise, they randomly received either 0.2 liter of fluid and became dehydrated by 4.9 +/- 0.2% of their body weight [i.e., dehydration trial (DE)] or 3.6 +/- 0.4 liter of fluid and replaced 95% of fluid losses [i.e., euhydration trial (EU)]. During the 10- to 120-min period of EU, Q, mean arterial pressure (MAP), systemic vascular resistance (SVR), cutaneous vascular resistance (CVR), and plasma catecholamines did not change while esophageal temperature stabilized at 38.0 +/- 0.1 degrees C. Conversely, after 120 min of DE, Q and MAP were reduced 18 +/- 3 and 5 +/- 2%, respectively, compared with EU (P < 0.05). This was associated with a significantly higher SVR (17 +/- 6%) and plasma norepinephrine concentration (50 +/- 19%, P < 0.05). In addition, CVR was also significantly higher (126 +/- 16 vs. 102 +/- 6% of 20-min value; P < 0.05) during DE despite a 1.2 +/- 0.1 degrees C greater esophageal temperature (P < 0.05). In conclusion, significant reductions in Q are accompanied by significant increases in SVR and plasma norepinephrine and a slight although significant decline in MAP. The cutaneous circulation participates in this systemic vasoconstriction as indicated by increases in CVR despite significant hyperthermia.
Selective brain cooling in the horse during exercise and environmental heat stress
Authors: McConaghy F. F. , Hales J. R. , Rose R. J. , Hodgson D. R.
Published: December 2017

Five horses were exercised on a treadmill [to central blood temperature (Tcore) approximately 42.5 degrees C]. Three of those horses were heated at rest in a climate room (53 degrees C, 90% relative humidity) (to Tcore approximately 41.5 degrees C). Temperatures were measured in the rectum, hypothalamus (Thyp), cerebrum, and cavernous sinus (Tsinus), on the skin of the head and midside, and Tcore. When Tcore increased above 38.5 degrees C, Thyp remained 0.6 +/- 0.1 degree C (SE) lower during heat exposure and 1 +/- 0.2 degrees C lower during exercise. During heat exposure, Tsinus was 2.2 +/- 0.4 degrees C below Tcore, and during exercise, Tsinus was 5 +/- 0.9 degrees C below Tcore. Upper respiratory tract bypass during exercise in one horse resulted in substantial reductions in Tcore-Thyp to 0.4 +/- 0.3 degrees C and Tcore-Tsinus to 0.9 +/- 0.2 degrees C. Thus the horse, a species without a carotid rete, can selectively cool the brain during exercise or heat exposure; this occurs, at least in part, via cool blood within the cavernous sinus, presumably resulting principally from cooling of venous blood within the upper respiratory tract.
Enhanced hepatic gluconeogenic capacity for selected precursors after endurance training
Authors: Sumida K. D. , Donovan C. M.
Published: December 2017

The effects of endurance training (running 90 min/day, 30 m/min, approximately 10% grade) on hepatic gluconeogenesis were studied in 24-h-fasted rats by using the isolated liver perfusion technique. After isolation, livers were perfused (single pass) for 30 min with Krebs-Henseleit bicarbonate buffer and fresh bovine red blood cells (hematocrit 20–24%) with no added substrate. Alanine (10 mM), dihydroxyacetone (20 mM), or glutamine (10 mM) was then added to the reservoir, and perfusions continued for 60 min. No significant differences were observed in perfusate pH, hematocrit, bile production, or serum alanine aminotransferase effluxing from livers from trained or control animals for any perfusion. Livers from trained animals that were perfused with 10 mM alanine demonstrated significantly higher rates of glucose production compared with livers from control animals (0.51 +/- 0.04 vs. 0.40 +/- 0.02 micromol.min-1.g liver-1, respectively). Elevations of a similar magnitude were observed for rates of [14C]alanine incorporation into [14C]glucose in livers from trained vs. control animals (8,797 +/- 728 vs. 6,962 +/- 649 dpm.min-1.g liver-1, respectively). Significant increases were also observed in hepatic alanine uptake (30%), oxygen consumption (23%), urea release (22%), and 14CO2 production (29%) of livers of endurance-trained animals. In contrast, no significant differences between groups were observed for hepatic glucose output after perfusions with either dihydroxyacetone (1.75 +/- 0.06 micromol.min-1.g liver-1) or glutamine (0.62 +/- 0.04 micromol.min-1.g liver-1). Further, during perfusions with dihydroxyacetone and glutamine, training had no significant impact on precursor uptake, oxygen consumption, or urea output. The current findings indicate a training-induced adaptation for hepatic gluconeogenesis located below the level of the triose phosphates.
Progressive effect of endurance training on VO2 kinetics at the onset of submaximal exercise
Authors: Phillips S. M. , Green H. J. , MacDonald M. J. , Hughson R. L.
Published: December 2017

The rates of increase in O2 uptake (VO2) after step changes in work rate from 25 W to 60% of pretraining peak VO2 (VO2 peak) were measured at various times during an endurance training program (2 h/day at 60% pretraining VO2 peak). Seven untrained males [23 +/- 1 (SE) yr] performed a series of repeated step changes in work rate before training (PRE) and after 4 days (4D), 9 days (9D), and 30 days (30D) of training. VO2 kinetic responses were determined from breath-by-breath data averaged across four repetitions and analyzed using a two-component exponential model. Mean response time (time taken to reach 63% of steady-state VO2) was faster (P < 0.01) than PRE (38.1 +/- 2.6 s) at both 4D (34.9 +/- 2.4 s) and 9D (32.5 +/- 1.8 s) and was faster (P < 0.01) at 30D than at all other times (28.3 +/- 1.0 s). Blood lactate concentrations (after 6 min of cycling) were also lower at 4D and 9D than PRE (P < 0.01) and were lower at 30D than at all other times (P < 0.01). VO2 peak was unchanged from PRE (3.52 +/- 0.20 l/min) at 8D (3.55 +/- 0.20 l/min) but was increased (P < 0.01) at 30D (3.89 +/- 0.18 l/min). Muscle oxidative capacity (maximal citrate synthase activity) was not significantly increased until 30D (P < 0.01). It is concluded that at least part of the acceleration of whole body VO2 kinetics with endurance training is a rapid phenomenon, occurring before changes in VO2 peak and/or muscle oxidative potential.
Relationship between fatty acid delivery and fatty acid oxidation during strenuous exercise
Authors: Romijn J. A. , Coyle E. F. , Sidossis L. S. , Zhang X. J. , Wolfe R. R.
Published: December 2017

To evaluate the extent to which decreased plasma free fatty acid (FFA) concentration contributes to the relatively low rates of fat oxidation during high-intensity exercise, we studied FFA metabolism in six endurance-trained cyclists during 20–30 min of exercise [85% of maximal O2 uptake (VO2max)]. They were studied on two occasions: once during a control trial when plasma FFA concentration is normally low and again when plasma FFA concentration was maintained between 1 and 2 mM by intravenous infusion of lipid (Intralipid) and heparin. During the 20–30 min of exercise, fat and carbohydrate oxidation were measured by indirect calorimetry, and the rates of appearance (Ra) of plasma FFA and glucose were determined by the constant infusion of [6,6–2H2]glucose and [2H2]palmitate. Lipid-heparin infusion did not influence the Ra or rate of disappearance of glucose. During exercise in the control trial, Ra FFA failed to increase above resting levels (11.0 +/- 1.2 and 12.4 +/- 1.7 mumol.kg-1.min-1 for rest and exercise, respectively) and plasma FFA concentration dropped from a resting value of 0.53 +/- 0.08 to 0.29 +/- 0.02 mM. The restoration of plasma FFA concentration resulted in a 27% increase in total fat oxidation (26.7 +/- 2.6 vs. 34.0 +/- 4.4 mumol.kg-1.min-1, P < 0.05) with a concomitant reduction in carbohydrate oxidation, apparently due to a 15% (P < 0.05) reduction in muscle glycogen utilization. However, the elevation of plasma FFA concentration during exercise at 85% VO2max only partially restored fat oxidation compared with the levels observed during exercise at 65% VO2max. These findings indicate that fat oxidation is normally impaired during exercise at 85% VO2max because of the failure of FFA mobilization to increase above resting levels, but this explains only part of the decline in fat oxidation when exercise intensity is increased from 65 to 85% VO2max.
Confocal- and electron-microscopic localization of FITC-albumin in H2O2-induced pulmonary edema
Authors: Pietra G. G. , Johns L. W.
Published: December 2017

Fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA) was used to detect sites of protein leakage in rat lungs perfused for 15-60 min with H2O2 (75, 150, and 300 microM). Leaky vessels were localized by confocal laser microscopy. Endothelial routes of protein leakage were identified by electron microscopy after photo-conversion of FITC-BSA to an osmiophilic diaminobenzidine product. Transport of FITC-BSA into the alveolar interstitium was assessed by immunogold labeling and anti-FITC antibodies. We detected leakage of FITC-BSA through transendothelial gaps in the pulmonary arterial endothelium after 30 min of perfusion with 300 microM H2O2 and after 60 min of perfusion with 150 microM H2O2. Junctional permeability and distribution of ZO-1 protein in the arterial endothelium were unchanged. Microvascular permeability to FITC-BSA was not increased in lungs perfused with H2O2. In lungs perfused with 300 microM H2O2, progressive extravasation of albumin was associated with significant increases in water content and perfusing pressure. We conclude that the pulmonary arterial endothelium is the primary target of circulating H2O2.
Influences of gender on sympathetic nerve responses to static exercise
Authors: Ettinger S. M. , Silber D. H. , Collins B. G. , Gray K. S. , Sutliff G. , Whisler S. K. , McClain J. M. , Smith M. B. , Yang Q. X. , Sinoway L. I.
Published: December 2017

We compared reflex responses to static handgrip at 30% maximal voluntary contraction (MVC) in 26 untrained men (mean age 35 +/- 3 yr) and 23 untrained women (mean age 39 +/- 4 yr). Women demonstrated attenuated increases in blood pressure and muscle sympathetic nerve activity (MSNA; by microneurography) compared with men. This difference was also observed during a period of posthandgrip circulatory arrest. 31P-nuclear magnetic resonance (NMR) spectroscopy studies demonstrated attenuations in the production of diprotonated phosphate and the development of cellular acidosis in women compared with men. Subjects also performed ischemic handgrip to fatigue. During this paradigm, MSNA responses were similar in the two groups, suggesting that freely perfused conditions are necessary for the full expression of the gender effect. Finally, we examined MSNA responses to adductor pollicus exercise in 7 men (26 +/- 1 yr) and 6 women (25 +/- 2 yr). MVC values and times to fatigue were similar in the two groups (MVC: men, 4.3 +/- 0.4 kg; women, 4.0 +/- 0.3 kg; not significant. Time to fatigue: men, 209 +/- 16 s; women, 287 +/- 50 s; not significant). At periods of end exercise and postexercise circulatory arrest, MSNA responses were attenuated in the women compared with the men. We conclude that, during nonischemic static exercise, sympathetic neural outflow is less in women compared with men. This response is due to an attenuated metaboreflex in women. Finally, on the basis of the adductor pollicus experiments, this effect appears independent of muscle mass, workload, and the level of training.
Composition and size of type I, IIA, IID/X, and IIB fibers and citrate synthase activity of rat muscle
Authors: Delp M. D. , Duan C.
Published: December 2017

A population of muscle fibers containing a myosin heavy-chain isoform IId (or 2x) has recently been identified in rat muscle. The purpose of this study was to histochemically determine the relative population and size of muscle fibers composed of type IID/X fibers as well as type I, IIA, and IIB fibers to estimate the absolute mass of the different types of fibers in rat muscle. In addition, muscle citrate synthase activity was measured to determine the relationship between fiber composition and muscle oxidative capacity. Seventy-six muscles or muscle parts from the face, neck, shoulder, arm, trunk, hip, thigh, and leg of three adult (4.5-5 mo of age) male Sprague-Dawley rats were removed, weighed, and frozen for histochemical and biochemical analyses. The data demonstrated that type IIB fibers make up 71% of the total muscle mass, type IID/X fibers 18%, type IIA fibers 5%, and type I fibers 6%. The mean cross-sectional area across all muscles was 5,078 +/- 175 microns 2 for type IIB fibers, 3,078 +/- 105 microns2 for type IID/X fibers, 2,045 +/- 80 microns2 for type IIA fibers, and 1,898 +/- 90 microns2 for type I fibers. Citrate synthase activity, an indicator of muscle mitochondrial content, was most closely related to the population of type IIA fibers and was in the rank order of type IIA = I = IID/X = IIB. NADH-tetrazolium reductase staining intensity also confirmed this order. These data demonstrate that type IID/X fibers make up a significant portion of the adult rat muscle mass and are intermediate to type IIA and IIB fibers in regard to fiber size and oxidative potential.
Intrathecal blockade of both NMDA and non-NMDA receptors attenuates the exercise pressor reflex in cats
Authors: Adreani C. M. , Hill J. M. , Kaufman M. P.
Published: December 2017

In decerebrate unanesthetized cats we tested the hypothesis that glutamatergic-receptor blockade in the lumbosacral spinal cord attenuated the reflex increases in mean arterial pressure, inspired minute ventilation, and renal sympathetic nerve activity (RSNA) evoked by static contraction of the triceps surae muscles. Blockade of N-methyl-D-aspartate (NMDA) receptors by intrathecal injection of DL-2-amino-5-phosphonovaleric acid had no effect on the initial phase of the pressor, ventilatory, and RSNA responses to contraction but did attenuate the secondary phase of these responses. Subsequent blockade of non-NMDA receptors in the lumbosacral spinal cord by intrathecal injection of 6-cyano-7-nitroquinoxaline-2,3-dione attenuated both the initial phase of the pressor, RSNA, and ventilatory responses to contraction and the secondary phase of these responses. In addition, NMDA-receptor blockade had no effect on the pressor or RSNA responses to tendon stretch, whereas non-NMDA-receptor blockade abolished these responses. We confirmed that our results were not related to the order of the antagonists injected by performing a series of experiments in which a non-NMDA-receptor antagonist was injected first. Our findings suggest that non-NMDA receptors mediate the spinal transmission of the initial and secondary phases of the pressor, RSNA, and ventilatory responses to contraction and tendon stretch. Therefore, non-NMDA receptors in the dorsal horn appear to be involved in the spinal processing of input from mechanoreceptors and metaboreceptors. Our findings also suggest that NMDA receptors mediate the spinal transmission of the secondary phase of the pressor, RSNA, and ventilatory responses to contraction but do not mediate the spinal transmission of the responses to tendon stretch. Therefore, NMDA receptors in the dorsal horn appear to be involved in the spinal processing of input from metaboreceptors.
Pulmonary entrapment of sickle cells: the role of regional alveolar hypoxia
Authors: Aldrich T. K. , Dhuper S. K. , Patwa N. S. , Makolo E. , Suzuka S. M. , Najeebi S. A. , Santhanakrishnan S. , Nagel R. L. , Fabry M. E.
Published: December 2017

Pulmonary microvascular occlusion by abnormally adherent and/or nondeformable sickle red blood cells (SS cells) may contribute to the pathogenesis of acute chest syndrome of sickle cell disease. We hypothesized that regional alveolar hypoxia reduces SS cell deformability and, by causing regional vasoconstriction, slows regional perfusion, facilitating endothelial adhesion and mechanical entrapment of cells. In isolated rat lungs perfused at constant average flow with physiological salt solution, we separately ventilated the two lungs: one with 95% O2 and the other with 0, 2.5, 5, or 21% O2. We infused a bolus of 99mTc-labeled SS cells or normal human AA cells along with 113Sn-labeled 15-mu m microspheres as a perfusion marker, then sliced the lungs and counted 99mTc and 113Sn. Weight-normalized perfusion decreased with hypoxia (P < 0.02). Retention of AA cells (perfusion-normalized) averaged approximately 1% in lungs ventilated with 95% O2 and increased only twofold with 0% O2. In contrast, retention of SS cells averaged 3-fold higher than that of AA cells at 95 and 5% O2, 15-fold higher at 2.5% O2, and 25-fold higher at 0% O2 (P < 0.01). Histological examination demonstrated entrapment of individual SS cells in alveolar capillaries of hypoxic but not well-oxygenated lungs. Relief of hypoxia, but not increased perfusate flow, caused prompt efflux of most entrapped cells, which were primarily high-density (high mean corpuscular hemoglobin concentration) cells. Thus substantial retention of SS cells does not occur without hypoxia, but regional hypoxia and/or the resulting vasoconstriction causes extraordinary regional retention of dense SS cells, a phenomenon that appears to be due more to mechanical entrapment of nondeformable cells in capillaries than to endothelial adhesion.
Differential effects of exercise and heat stress on liver HSP70 accumulation with aging
Authors: Kregel K. C. , Moseley P. L.
Published: December 2017

Previous reports have suggested that the heat shock response to passive heating may be blunted by aging. However, during exertional heating, factors in addition to elevated temperature may amplify the degree of stress compared with hyperthermia alone. The purpose of this study was to compare the pattern of accumulation of the highly inducible 72-kDa heat shock protein (HSP72) in liver tissue of mature (12-mo-old) and senescent (24-mo-old) male Fischer 344 rats after either passive or exertional heat stress. A euthermic control group was exposed to an ambient temperature (Ta) of 25 degrees C for 4.5 h. A passive heating (heat) group was exposed to an Ta of 42 degrees C until colonic temperature (Tco) reached 41 degrees C. An exertional heating (exercise) group performed intermittent moderate-intensity treadmill exercise (similar absolute intensities for the two age groups) at an Ta of 32 degrees C until Tco reached 41 degrees C. Heating rates were similar in the heat and exercise groups (approximately 0.08 degrees C/min). Rats in both the heat and exercise groups were maintained at a Tco of 41 degrees C for an additional 30 min and subsequently returned to an Ta of 25 degrees C for 3 h. Liver HSP72 accumulation was increased in mature rats after both the heat (+192% vs. control) and exercise (+292%) protocols. In contrast, the senescent rats demonstrated no significant increase in inducible HSP70 with heating but a large increase with exercise (+232%; P < 0.01 compared with control and heat groups). These data suggest that the blunted heat shock protein response to heating observed with aging is not a result of the inability to produce inducible HSP72 because older rats had an robust response to exertional hyperthermia.
Endurance exercise training decreases capillary basement membrane width in older nondiabetic and diabetic adults
Authors: Williamson J. R. , Hoffmann P. L. , Kohrt W. M. , Spina R. J. , Coggan A. R. , Holloszy O.
Published: December 2017

The objectives of these studies were to 1) evaluate the relationships among age, glucose intolerance, and skeletal muscle capillary basement membrane (CBM) width (CBMW) and 2) determine the effects of exercise training on CBMW by comparing values of young (28 +/- 4 yr) and older (63 +/- 7 yr) athletes with those of age-matched sedentary control subjects and by measuring CBMW in older men and women before and after a 9-mo endurance-exercise training program. CBMW was measured in tissue samples obtained from the gastrocnemius muscle. CBMW in sedentary 64 +/- 3-yr-old subjects was 25% thicker than in sedentary 24 +/- 3-yr-old subjects. CBMW was similar in young and older athletes and was thinner than the CBMW of age-matched sedentary control subjects. There were no differences in CBMW among older sedentary individuals with normal or impaired glucose tolerance or mild non-insulin-dependent diabetes mellitus. Nine months of endurance exercise training reduced CBMW in older men and women by 30-40%, to widths that were not different from those of the young subjects; this response was independent of glucose tolerance status. These findings suggest that habitual exercise prevents the thickening of the skeletal muscle CBM that is characteristic of advancing age. Moreover, the thickening of the CBM appears to be readily reversed as a result of exercise training, even in older individuals.
Effect of marathon run on serum IGF-I and IGF-binding protein 1 and 3 levels
Authors: Koistinen H. , Koistinen R. , Selenius L. , Ylikorkala Q. , Seppala M.
Published: December 2017

Acute physical exercise increases growth hormone (GH) secretion, and GH regulates the expression of insulin-like growth factor I (IGF-I) and IGF-binding protein (IGFBP) 3. IGFBP-1 is a local modulator of IGF activity with rapid dynamic regulation that is downregulated by insulin. The IGF system mediates the metabolic actions of GH, and possibly it regulates glucose metabolism. We hypothesize that strenuous exercise causes changes in the IGF system. We studied the effects of the marathon run on the circulating levels of IGF-I, IGFBP-1, IGFBP-3, and insulin in 23 participants. Immediately after the run, the most striking change was an 11.6-fold median increase in serum IGFBP-1 level (from 63.7 +/- 50.5 to 736 +/- 408 micrograms/l; P < 0.001). Because the insulin level remained unchanged, the elevation of serum IGFBP-1 level cannot be explained by changes in insulin. One day after the run, the IGFBP-1 level had returned to baseline. The physiological role of this increment could be the inhibition of hypoglycemic effects of IGF-I and/or regulation of glucose availability to the muscles. The changes in IGF-I and IGFBP-3 levels were less dramatic: the IGF-I and IGFBP-3 levels were lower 1 and 3 days after the run. This report provides an important basis for authentic effects of strenuous exercise on the IGF-system.
Myosin heavy chain of immature soleus muscle grafts adapts to hyperthyroidism more than to physical activity
Authors: Devor S. T. , White T. P.
Published: December 2017

The interaction of hyperthyroidism and the elements of physical activity on early regeneration of muscle grafts was investigated. Soleus muscle grafts were studied 15 days after graft operations in eu- and hyperthyroid rats. Hypotheses were tested regarding the adaptation of the myosin heavy chain (MHC) profile of grafts and nongrafted control muscles and whether the effect of hyperthyroidism would predominate over the opposing influence of recruitment and mechanical load on MHC of grafts. Denervation and myectomy of synergist muscles were employed to manipulate the elements of physical activity. Denervation decreased the expression of type I MHC, and hyperthyroidism furthered the shift toward a “fast” isoform profile. For example, in denervated grafts, type IIb was undetected in euthyroid rats and accounted for 31% of MHC in hyperthyroid rats. Compared with control muscles, grafts in the denervated and innervated-normal load groups demonstrated greater plasticity because the adaptive response of MHC to thyroid status was more pronounced. Hyperthyroidism predominated over the opposing influence of the elements of physical activity on the regulation of MHC expression in innervated plus overload grafts. For example, type I MHC was 86% of MHC profile of innervated plus overload grafts in euthyroid rats and was only 49% in hyperthyroid rats. In conclusion, a heightened plasticity for grafts was evidenced in denervated and innervated tissues, and the regulation of MHC by thyroid hormone predominated over that due to the elements of physical activity.
Detection of two clusters of mechanical properties of smooth muscle along the airway tree
Authors: Ma X. , Li W. , Stephens N. L.
Published: December 2017

Heterogeneity of function of airway smooth muscle along the airways may be of great importance in regulating regional ventilation and in the pathogenesis of asthma. To investigate the distribution of mechanical properties of airway smooth muscle along the airway, muscle strips free of cartilage and epithelium from the trachea down to bronchial generation 6 were studied by employing electrical field stimulation. Results showed that smooth muscle mechanical performance decreased progressively down the airway tree. Cluster analysis further indicated that smooth muscle from these airways could be divided into two groups: 1) an extrapulmonary group, which contains muscle from the trachea and bronchial generations 1 and 2 and is characterized by higher maximum shortening capacity and zero-load velocity of shortening (V0) in early shortening, the expected decrease of V0 values (the so-called latch phase) in the later phase of shortening, and lower sensitivity to stimulation; and 2) an intrapulmonary group, which contains bronchi from generations 3-6 and has a lower maximum shortening capacity and V0 in early shortening but higher sensitivity to stimulation. The relatively lower mechanical performance of intrapulmonary bronchial smooth muscle may represent a safety device that prevents excessive smooth muscle shortening in vivo.
Treadmill exercise training and estradiol increase plasma ACTH and prolactin after novel footshock
Authors: White-Welkley J. E. , Warren G. L. , Bunnell B. N. , Mougey E. H. , Meyerhoff J. L. , Dishman R. K.
Published: December 2017

We examined whether rats that were treadmill exercise trained (Tr) or chronically immobilized (CI) had similar responses by the hypothalamic-pituitary-adrenal (HPA) cortical axis to acute stress and whether the HPA responses interacted with the hypothalamic-pituitary-gonadal (HPG) axis. After 6 wk (1 h/day, 6 days/wk) of Tr or CI, plasma concentrations of adrenocorticotropic hormone ([ACTH]), [prolactin], and [corticosterone] were measured after familiar (treadmill running or immobilization) or novel (footshock) stress. Ovariectomized Sprague-Dawley females (n = 72) were implanted with capsules containing estradiol benzoate (E2) and randomly assigned in a 2-group (E2 vs. no E2) x 3 treatment (Tr vs. CI vs. sedentary) x 4 acute stressor [footshock vs. treadmill running (Run) vs. immobilization (Im) vs. no stress] x 3 recovery time (1 vs. 15 vs. 30 min) mixed-model analysis of variance. E2 capsules were removed from one-half of the animals 48 h before the first stressor session. After 10 min of acute stress, blood was drawn from a jugular catheter at 1, 15, and 30 min of recovery. [ACTH] and [prolactin] after footshock were higher in Tr rats with E2 compared with CI and sedentary rats without E2; recovery levels for sedentary animals were higher after Run compared with Im. The elevation in [corticosterone] from minute 1 to 15 of recovery was higher after the familiar Run and Im conditions. Our findings are consistent with an increased responsiveness of the HPA axis to novel footshock after treadmill exercise training that is additionally modulated by the HPG axis.