bluuebunny/crossref_metadata_2025 huggingface dataset:
Synergism between the canine left and right hemidiaphragms
Authors: De Troyer André , Cappello Matteo , Meurant Nathalie , Scillia Pierre
Published: March 2015

Expansion of the lung during inspiration results from the coordinated contraction of the diaphragm and several groups of rib cage muscles, and we have previously shown that the changes in intrathoracic pressure generated by the latter are essentially additive. In the present studies, we have assessed the interaction between the right and left hemidiaphragms in anesthetized dogs by comparing the changes in airway opening pressure (ΔPao) obtained during simultaneous stimulation of the two phrenic nerves (measured ΔPao) to the sum of the ΔPao values produced by their separate stimulation (predicted ΔPao). The measured ΔPao was invariably greater than the predicted ΔPao, and the ratio between these two values increased gradually as the stimulation frequency was increased; the ratio was 1.10 ± 0.01 ( P < 0.05) for a frequency of 10 Hz, whereas for a frequency of 50 Hz it amounted to 1.49 ± 0.05 ( P < 0.001). This interaction remained unchanged after the rib cage was stiffened and its compliance was made linear, thus indicating that the load against which the diaphragm works is not a major determinant. However, radiographic measurements showed that stimulation of one phrenic nerve extends the inactive hemidiaphragm toward the sagittal midplane and reduces the caudal displacement of the central portion of the diaphragmatic dome. As a result, the volume swept by the contracting hemidiaphragm is smaller than the volume it displaces when the contralateral hemidiaphragm also contracts. These observations indicate that 1) the left and right hemidiaphragms have a synergistic, rather than additive, interaction on the lung; 2) this synergism operates already during quiet breathing and increases in magnitude when respiratory drive is greater; and 3) this synergism is primarily related to the configuration of the muscle.
Endurance training induces muscle-specific changes in mitochondrial function in skinned muscle fibers
Authors: Burelle Yan , Hochachka Peter W.
Published: March 2015

The present study was conducted to investigate the potential role of changes in the apparent Kmfor ADP and in the functional coupling of the creatine (Cr) kinase (CK) system (CK efficiency) in explaining the tighter integration of ATP supply and demand after exercise training. Mitochondrial function was assessed in saponin-skinned fibers from the soleus and the deep red portion of the medial gastrocnemius isolated from trained (T; treadmill running, 5 days/wk, 4 wk) and control (C) female Sprague-Dawley rats. In the soleus, V˙maxin the presence of 1 mM ADP was increased by 21% after training (5.9 ± 0.2 vs. 4.7 ± 0.4 nmol O2· min−1· mg dry wt−1, P < 0.05). This was accompanied by no change in the Kmfor ADP measured in the absence of Cr (146 ± 9 vs. 149 ± 13 μM in T and C, respectively) and in its presence (50 ± 4 vs. 48 ± 6 μM in T and C, respectively) and in CK efficiency [ Km(+Cr)/ Km(−Cr)]. In contrast, in the red gastrocnemius, training decreased, by 35%, the apparent Kmfor ADP in the absence (83 ± 5 vs. 129 ± 9 μM, P < 0.01) of Cr, without affecting V˙max(6.2 ± 0.4 vs. 6.7 ± 0.3 nmol O2· min−1· mg dry wt−1in T and C, respectively) and CK efficiency. These results thus suggest that training induces muscle-specific adaptations of mitochondrial function and that a change in the intrinsic sensitivity of mitochondria to ADP could at least partly explain the tighter integration of ATP and demand commonly observed after training.
EPR spectroscopic detection of free radical outflow from an isolated muscle bed in exercising humans
Authors: Bailey Damian M. , Davies Bruce , Young Ian S. , Jackson Malcolm J. , Davison Gareth W. , Isaacson Roger , Richardson Russell S.
Published: March 2015

There is no direct evidence to support the contention that contracting skeletal muscle and/or associated vasculature generates free radicals in exercising humans. The unique combination of isolated quadriceps exercise and the measurement of femoral arterial and venous free radical concentrations with the use of electron paramagnetic resonance (EPR) spectroscopy enabled this assumption to be tested in seven healthy men. Application of ex vivo spin trapping using α-phenyl- tert-butylnitrone (PBN) resulted in the detection of oxygen- or carbon-centered free radicals ( a N = 1.38 ± 0.01 mT and a [Formula: see text] = 0.17 ±0.01 mT, where a N and a [Formula: see text] are the nitrogen and β-hydrogen coupling constants, respectively) with consistently higher EPR signal intensities of the PBN spin adduct observed in the venous compared with the arterial circulation ( P < 0.05). Incremental exercise further increased the venoarterial intensity difference [85 ± 58 arbitrary units (AU) at 24 ± 6% maximal work rate (WRmax) vs. 387 ± 214 AU at 69 ± 7% WRmax; P < 0.05]. When combined with measured changes in femoral venous blood flow (Q˙), this resulted in a net adduct outflow of 130 ± 118 and 1,146 ± 582 AU/min ( P < 0.05), which was positively associated with leg oxygen uptake ( r 2 = 0.47, P < 0.05) andQ˙ ( r 2 = 0.47, P < 0.05). These results provide the first evidence for oxygen- or carbon-centered free radical outflow from an active muscle bed in humans.
IGF-I has no effect on postexercise suppression of the ubiquitin-proteasome system in rat skeletal muscle
Authors: Kee Anthony J. , Taylor Alan J. , Carlsson Anthony R. , Sevette Andre , Smith Ross C. , Thompson Martin W.
Published: March 2015

Both exercise and insulin-like growth factor I (IGF-I) are known to have major hypertrophic effects in skeletal muscle; however, the interactive effect of exogenous IGF-I and exercise on muscle protein turnover or the ubiquitin-proteasome pathway has not been reported. In the present study, we have examined the interaction between endurance exercise training and IGF-I treatment on muscle protein turnover and the ubiquitin-proteasome pathway in the postexercise period. Adult male rats (270–280 g) were randomized to receive 5 consecutive days of progressive treadmill exercise and/or IGF-I treatment (1 mg · kg body wt−1· day−1). Twenty-four hours after the last bout of exercise, the rate of protein breakdown in incubated muscles was significantly reduced compared with that in unexercised rats. This was associated with a significant reduction in the chymotrypsin-like activity of the proteasome and the rate of ubiquitin-proteasome-dependent casein hydrolysis in muscle extracts from exercised compared with unexercised rats. In contrast, the muscle expression of the 20S proteasome subunit β-1, ubiquitin, and the 14-kDa E2 ubiquitin-conjugating enzyme was not altered by exercise or IGF-I treatment 24 h postexercise. Exercise had no effect on the rates of total mixed muscle protein synthesis in incubated muscles 24 h postexercise. IGF-I treatment had no effect on muscle weights or the rates of protein turnover 24 h after endurance exercise. These results suggest that a suppression of the ubiquitin-proteasome proteolytic pathway after endurance exercise may contribute to the acute postexercise net protein gain.
Nonuniform changes in arteriolar myogenic tone within skeletal muscle following hindlimb unweighting
Authors: Heaps Cristine L. , Bowles Douglas K.
Published: March 2015

Hindlimb unweighting (HLU) has been shown to alter myogenic tone distinctly in arterioles isolated from skeletal muscles composed predominantly of fast-twitch (white gastrocnemius) compared with slow-twitch (soleus) fibers. Based on these findings, we hypothesized that HLU would alter myogenic tone differently in arterioles isolated from distinct fiber-type regions within a single skeletal muscle. We further hypothesized that alterations in myogenic tone would be associated with alterations in voltage-gated Ca2+channel current (VGCC) density of arteriolar smooth muscle. After 14 days of HLU or weight bearing (control), first-order arterioles were isolated from both fast-twitch and mixed fiber-type regions of the gastrocnemius muscle, cannulated, and pressurized at 90 cmH2O. Mixed gastrocnemius arterioles of HLU rats demonstrated increased spontaneous tone [43 ± 5% (HLU) vs. 27 ± 4% (control) of possible constriction] and an approximately twofold enhanced myogenic response when exposed to step changes in intraluminal pressure (10–130 cmH2O) compared with control rats. In contrast, fast-twitch gastrocnemius arterioles of HLU rats demonstrated similar levels of spontaneous tone [6 ± 2% (HLU) vs. 6 ± 2% (control)] and myogenic reactivity to control rats. Neither KCl-induced contractile responses (10–50 mM KCl) nor VGCC density was significantly different between mixed gastrocnemius arterioles of HLU and control rats. These results suggest that HLU produces diverse adaptations in myogenic reactivity of arterioles isolated from different fiber-type regions of a single skeletal muscle. Furthermore, alterations in myogenic responses were not attributable to altered VGCC density.
Skin cooling maintains cerebral blood flow velocity and orthostatic tolerance during tilting in heated humans
Authors: Wilson Thad E. , Cui Jian , Zhang Rong , Witkowski Sarah , Crandall Craig G.
Published: March 2015

Orthostatic tolerance is reduced in the heat-stressed human. The purpose of this project was to identify whether skin-surface cooling improves orthostatic tolerance. Nine subjects were exposed to 10 min of 60° head-up tilting in each of four conditions: normothermia (NT-tilt), heat stress (HT-tilt), normothermia plus skin-surface cooling 1 min before and throughout tilting (NT-tiltcool), and heat stress plus skin-surface cooling 1 min before and throughout tilting (HT-tiltcool). Heating and cooling were accomplished by perfusing 46 and 15°C water, respectively, though a tube-lined suit worn by each subject. During HT-tilt, four of nine subjects developed presyncopal symptoms resulting in the termination of the tilt test. In contrast, no subject experienced presyncopal symptoms during NT-tilt, NT-tiltcool, or HT-tiltcool. During the HT-tilt procedure, mean arterial blood pressure (MAP) and cerebral blood flow velocity (CBFV) decreased. However, during HT-tiltcool, MAP, total peripheral resistance, and CBFV were significantly greater relative to HT-tilt (all P< 0.01). No differences were observed in calculated cerebral vascular resistance between the four conditions. These data suggest that skin-surface cooling prevents the fall in CBFV during upright tilting and improves orthostatic tolerance, presumably via maintenance of MAP. Hence, skin-surface cooling may be a potent countermeasure to protect against orthostatic intolerance observed in heat-stressed humans.
Some historical perspectives on thermoregulation
Authors: Cooper K. E.
Published: March 2015

In this paper, selected historical aspects of thermoregulation and fever are presented as background to the application of molecular biology to thermoregulation. Temperature-sensing mechanisms, coordination of thermal information, thermoregulatory circuitry, efferent responses to thermal stimuli, set point mechanisms, and some of the mechanisms and consequences of fever and hyperthermia are highlighted. Neurotransmitters used in thermoregulatory circuits are also discussed. An attempt is made to include information from comparative physiological sources. Possible future avenues of research in the light of recent new technologies are also presented.
Selected Contribution: Effects of spaceflight on immunity in the C57BL/6 mouse. II. Activation, cytokines, erythrocytes, and platelets
Authors: Gridley Daila S. , Nelson Gregory A. , Peters Luanne L. , Kostenuik Paul J. , Bateman Ted A. , Morony Sean , Stodieck Louis S. , Lacey David L. , Simske Steven J. , Pecaut Michael J.
Published: March 2015

This portion of the study quantified the effects of a 12-day space shuttle mission (Space Transport System-108/UF-1) on body and lymphoid organ masses, activation marker expression, cytokine secretion, and erythrocyte and thrombocyte characteristics in C57BL/6 mice. Animals in flight (Flt group) had 10–12% lower body mass compared with ground controls housed either in animal enclosure modules or under standard vivarium conditions ( P < 0.001) and the smallest thymus and spleen masses. Percentages of CD25+lymphocytes, CD3+/CD25+T cells, and NK1.1+/CD25+natural killer cells from Flt mice were higher compared with both controls ( P < 0.05). In contrast, CD71 expression was depressed in the Flt and animal enclosure module control mice compared with vivarium control animals ( P < 0.001). Secretion of interferon-γ, IL-2, and IL-4, but not tumor necrosis factor-α and IL-5, by splenocytes from Flt mice was decreased relative to either one or both ground controls ( P < 0.05). Flt mice also had high red blood cell and thrombocyte counts compared with both sets of controls; low red blood cell volume and distribution width, percentage of reticulocytes, and platelet volume were also noted ( P < 0.05) and were consistent with dehydration. These data indicate that relatively short exposure to the spaceflight environment can induce profound changes that may become significant during long-term space missions.
Muscle inflammatory cells after passive stretches, isometric contractions, and lengthening contractions
Authors: Pizza Francis X. , Koh Timothy J. , McGregor Stephen J. , Brooks Susan V.
Published: March 2015

We tested the hypotheses that lengthening contractions, isometric contractions, and passive stretches increase muscle inflammatory cells (neutrophils and macrophages) and that prior conditioning with lengthening contractions, isometric contractions, or passive stretches reduces neutrophils and macrophages after subsequent lengthening contractions. Extensor digitorum longus muscles in anesthetized mice were subjected in situ to lengthening contractions, isometric contractions, or passive stretches. Six hours or 3 days after a protocol of contractions or passive stretches, neutrophils and macrophages were quantified in muscle cross sections. Three days after isometric contractions or passive stretches, neutrophils were elevated ( P < 0.05) 3.7- and 5.5-fold, respectively, relative to controls. Both macrophages and neutrophils were increased 51.2- and 7.9-fold, respectively, after lengthening contractions. Prior lengthening contractions, isometric contractions, or passive stretches reduced inflammatory cells after lengthening contractions performed 2 wk later. The major finding of this study was that passive stretches and isometric contractions elevated neutrophils without causing overt signs of injury. Because both passive stretches and isometric contractions elevated neutrophils and afforded some protection from contraction-induced muscle injury, neutrophils and/or the related inflammatory events may contribute to the induction of a protective mechanism.
Effects of microgravity elicited by parabolic flight on abdominal aortic pressure and heart rate in rats
Authors: Waki Hidefumi , Shimizu Tsuyoshi , Katahira Kiyoaki , Nagayama Tadanori , Yamasaki Masao , Katsuda Shin-Ichiro
Published: March 2015

Abdominal aortic pressure (AAP), heart rate (HR), and aortic nerve activity (ANA) during parabolic flight were measured by using a telemetry system to clarify the acute effect of microgravity (μG) on hemodynamics in rats. While the animals were conscious, AAP increased up to 119 ± 3 mmHg on exposure to μG compared with the value at 1 G (95 ± 3 mmHg; P < 0.001), whereas AAP decreased immediately on exposure to μG under urethane anesthesia (μG: 72 ± 9 mmHg vs. 1 G: 78 ± 8 mmHg; P < 0.05). HR also increased during μG in conscious animals (μG: 349 ± 12 beats/min vs. 1 G: 324+9 beats/min; P < 0.01), although no change was observed under anesthesia. ANA, which was measured under anesthesia, decreased in response to acute μG exposure (μG: 33 ± 7 counts/s vs. 1 G: 49 ± 5 counts/s; P < 0.01). These results suggest that μG essentially induces a decrease of arterial pressure; however, emotional stress and body movements affect the responses of arterial pressure and HR during exposure to acute μG.
Dietary nucleotides prevent decrease in cellular immunity in ground-based microgravity analog
Authors: Yamauchi Keiko , Hales Nathan W. , Robinson Sandra M. , Niehoff Michael L. , Ramesh Vani , Pellis Neal R. , Kulkarni Anil D.
Published: March 2015

Microgravity and stress of spaceflights result in immune dysfunction. The role of nutrition, especially nucleotide supplementation, has become an area of intensive research and significant interest in immunomodulation for maintenance of cellular immune responses. The studies presented here evaluate the plausibility of administering nucleotides to obviate immune dysfunction in an Earth-based in vivo analog of microgravity as studied in anti-orthostatic tail suspension (AOS) of mice. Mice were divided into three housing groups: group, isolation, and AOS. Mice were fed either control chow diet (CD), or RNA-, adenine-, or uracil-supplemented CD for the 1-wk duration of the experiments. In AOS mice, supplemental nucleotides significantly increased in vivo lymph node proliferation and ex vivo lymphoproliferation response to alloantigen and mitogens, respectively, and interleukin-2 and interferon-γ production. A lower corticosterone level was observed in uracil-supplemented CD compared with CD. These results suggest that exogenous nucleotide supplementation, especially uracil, of normal diet is beneficial in the maintenance and restoration of the immune response during the microgravity analog conditions.
Saccharomyces cerevisiae gene expression changes during rotating wall vessel suspension culture
Authors: Johanson Kelly , Allen Patricia L. , Lewis Fawn , Cubano Luis A. , Hyman Linda E. , Hammond Timothy G.
Published: March 2015

This study utilizes Saccharomyces cerevisiae to study genetic responses to suspension culture. The suspension culture system used in this study is the high-aspect-ratio vessel, one type of the rotating wall vessel, that provides a high rate of gas exchange necessary for rapidly dividing cells. Cells were grown in the high-aspect-ratio vessel, and DNA microarray and metabolic analyses were used to determine the resulting changes in yeast gene expression. A significant number of genes were found to be up- or downregulated by at least twofold as a result of rotational growth. By using Gibbs promoter alignment, clusters of genes were examined for promoter elements mediating these genetic changes. Candidate binding motifs similar to the Rap1p binding site and the stress-responsive element were identified in the promoter regions of differentially regulated genes. This study shows that, as in higher order organisms, S. cerevisiae changes gene expression in response to rotational culture and also provides clues for investigations into the signaling pathways involved in gravitational response.
Three-dimensional mapping of smooth muscle in the distal conducting airways of mouse, rabbit, and monkey
Authors: Smiley-Jewell S. M. , Tran M. U. , Weir A. J. , Johnson Z. A. , Van Winkle L. S. , Plopper C. G.
Published: March 2015

Airway smooth muscle remodeling is implicated in a number of constrictive pulmonary diseases such as asthma and may include changes in smooth muscle orientation and abundance. Both factors were compared in the normal distal bronchioles of the mouse, rabbit, and rhesus monkey (respiratory bronchioles included). Airway smooth muscle was measured by using a three-dimensional approach employing confocal microscopy and whole-mount cytochemistry with fluorochrome-conjugated phalloidin, a probe for polymerized actin. Smooth muscle orientation had a wide range of angles along the airway, but the distribution was conserved among species and among distal airway generations. At the bifurcation of proximal bronchioles, smooth muscle was nearly parallel to the longitudinal axis of the airway. Smooth muscle abundance was significantly different between species (abundance was less in the monkey compared with the mouse and rabbit), and there was a trend for abundance to decrease with each more distal airway generation. This study defines the normal distribution of smooth muscle in three test species and provides a basis for future comparisons with the diseased state.
Intersubunit disulfide bridge is not required for the protective role of SP-B against lung inflammation
Authors: Ikegami Machiko , Takabatake Noriaki , Weaver Timothy E.
Published: March 2015

Surfactant protein B (SP-B) is known to promote surfactant phospholipid film formation and reduce surface tension. Native SP-B is a homodimer in which subunit association is stabilized via covalent linkage through cysteine 48. We hypothesized that loss of the intersubunit bridge would alter SP-B function and lead to increased inflammation in response to challenge by hyperoxia or endotoxin. Transgenic mice in which SP-B cysteine 48 was mutated to serine were generated and crossed into the SP-B(−/−) background. Wild-type mice and transgenic mice carrying a single copy (SP-Bmon+) or two copies (SP-Bmon++) of the transgene were exposed to 95% O2for 3 days or intratracheally injected with 10 μg of endotoxin. Interleukin-1β, major intrinsic protein 2, and interleukin-6 in lung homogenates after 3 days of hyperoxia were significantly higher ( P < 0.001) in SP-Bmon+mice than SP-Bmon++or wild-type mice. At 16 h after endotoxin injection, cytokines in lung tissues were higher in SP-Bmon+mice compared with wild-type mice ( P < 0.05). Consistent with prolonged recovery in SP-Bmon+mice, the percentage of apoptotic cells in alveolar lavage was significantly lower in SP-Bmon+mice than in SP-Bmon++and wild-type mice. Overall, increased inflammation in SP-Bmon+mice was corrected to a large extent by increased gene dosage, indicating that formation of the intersubunit disulfide bridge is not critical for SP-B function.
Cardiovascular responses to apneic facial immersion during altered cardiac filling
Authors: Journeay W. Shane , Reardon Francis D. , Kenny Glen P.
Published: March 2015

The hypothesis that reduced cardiac filling, as a result of lower body negative pressure (LBNP) and postexercise hypotension (PEH), would attenuate the reflex changes to heart rate (HR), skin blood flow (SkBF), and mean arterial pressure (MAP) normally induced by facial immersion was tested. The purpose of this study was to investigate the cardiovascular control mechanisms associated with apneic facial immersion during different cardiovascular challenges. Six subjects randomly performed 30-s apneic facial immersions in 6.0 ± 1.2°C water under the following conditions: 1) −20 mmHg LBNP, 2) +40 mmHg lower body positive pressure (LBPP), 3) during a period of PEH, and 4) normal resting (control). Measurements included SkBF at one acral (distal phalanx of the thumb) and one nonacral region of skin (ventral forearm), HR, and MAP. Facial immersion reduced HR and SkBF at both sites and increased MAP under all conditions ( P < 0.05). Reduced cardiac filling during LBNP and PEH significantly attenuated the absolute HR nadir observed during the control immersion ( P < 0.05). The LBPP condition did not result in a lower HR nadir than control but did result in a nadir significantly lower than that of the LBNP and PEH conditions ( P < 0.05). No differences were observed in either SkBF or MAP between conditions; however, the magnitude of SkBF reduction was greater at the acral site than at the nonacral site for all conditions ( P < 0.05). These results suggest that the cardiac parasympathetic response during facial immersion can be attenuated when cardiac filling is compromised.
Changes in force-velocity properties of trachealis due to oscillatory strains
Authors: Wang Lu , Paré Peter D. , Seow Chun Y.
Published: March 2015

The physically dynamic environment of the lung constantly modulates the mechanical properties of airway smooth muscle. In vitro experiments have shown that contractility of the muscle is compromised by oscillatory strains, perhaps through disruption of cross-bridge interaction and organization of the contractile filaments. To understand the mechanism by which oscillation affects contractility, functional changes of the muscle in terms of force-velocity relationship were assessed before and after imposition of length oscillation in both relaxed and activated states. The oscillation protocol was designed to reduce isometric force by 15–20%, followed by measurement of force-velocity properties. Maximal velocity and power changed by +8 and −14%, respectively, after oscillation applied in the relaxed state and changed by −15 and −25%, respectively, after oscillation applied during contraction. A simple model of reduced activation could not account for the results; neither could the results be explained satisfactorily by the current cross-bridge theory of contraction. The results, however, could be explained if the possibility of reorganization of the contractile filaments due to oscillatory strains was considered.
Muscle creatine uptake and creatine transporter expression in response to creatine supplementation and depletion
Authors: Brault Jeffrey J. , Abraham Kirk A. , Terjung Ronald L.
Published: March 2015

The total creatine pool size [Crtotal; creatine (Cr) + phosphocreatine (PCr)] is crucial for optimal energy utilization in skeletal muscle, especially at the onset of exercise and during intense contractions. The Crtotallikely is controlled by long-term modulation of Cr uptake via the sodium-dependent Cr transporter (CrT). To test this hypothesis, adult male Sprague-Dawley rats were fed 1% Cr, their muscle Crtotalwas reduced by ∼85% [1% β-guanidinoproprionic acid (β-GPA)], or their muscle Crtotalwas repleted (1% Cr after β-GPA depletion). Cr uptake was assessed by skeletal muscle14C-Cr accumulation to Cr and PCr by using hindlimb perfusion, and CrT protein content was assessed by Western blot. Cr uptake rate decreased with dietary Cr supplementation in the white gastrocnemius (WG; 45%) only. Depletion of muscle Crtotalto ∼15% of normal increased Cr uptake in the soleus (21%) and red gastrocnemius (22%), corresponding to 70–150% increases in muscle CrT content. In contrast, the inherently lower Cr uptake rate in the WG was unchanged with depletion of muscle Crtotaleven though CrT band density was increased by 230%. Thus there was no direct relationship between apparent muscle CrT abundance and Cr uptake rates. However, Cr uptake rates scaled inversely with decreases in muscle Crtotalin the high-oxidative muscle types but not in the WG. This implies that factors controlling Cr uptake are different among fiber types. These observations may help explain the influence of initial muscle Crtotal, time dependency, and variations in muscle Crtotalaccumulation during Cr supplementation.
Dissociation between skeletal muscle microvascular Po2and hypoxia-induced microvascular inflammation
Authors: Shah Sidharth , Allen Julie , Wood John G. , Gonzalez Norberto C.
Published: March 2015

Systemic hypoxia (SHx) produces microvascular inflammation in mesenteric, cremasteric, and pial microcirculations. In anesthetized rats, SHx lowers arterial blood pressure (MABP), which may alter microvascular blood flow and microvascular Po2(PmO2) and influence SHx-induced leukocyte-endothelial adherence (LEA). These experiments attempted to determine the individual contributions of the decreases in PmO2, venular blood flow and shear rate, and MABP to the hypoxia-induced increase in LEA. Cremaster microcirculation of anesthetized rats was visualized by intravital microscopy. PmO2was measured by a phosphorescence-quenching method. SHx [inspired Po2of 70 Torr for 10 min, MABP of 65 ± 3 mmHg, arterial Po2(PaO2) of 33 ± 1 Torr] and cremaster ischemia (MABP of 111 ± 7 mmHg, PaO2of 86 ± 3 Torr) produced similar PmO2: 7 ± 2 and 6 ± 2 Torr, respectively. However, LEA increased only in SHx (1.9 ± 0.9 vs. 11.2 ± 1.1 leukocytes/100 μm, control vs. SHx, P < 0.05). Phentolamine-induced hypotension (MABP of 55 ± 4 mmHg) in normoxia lowered PmO2to 26 ± 6 Torr but did not increase LEA. Cremaster equilibration with 95% N2-5% CO2during air breathing (PaO2of 80 ± 1 Torr) lowered PmO2to 6 ± 1 Torr but did not increase LEA. On the other hand, when cremaster PmO2was maintained at 60–70 Torr during SHx (PaO2of 35 ± 1 Torr), LEA increased from 2.1 ± 1.1 to 11.1 ± 1.5 leukocytes/100 μm ( P < 0.05). The results show a dissociation between PmO2and LEA and support the idea that SHx results in the release of a mediator responsible for the inflammatory response.
Respiratory muscle dynamics and control during exercise with externally imposed expiratory flow limitation
Authors: Aliverti Andrea , Iandelli Iacopo , Duranti Roberto , Cala Stephen J. , Kayser Bengt , Kelly Susan , Misuri Gianni , Pedotti Antonio , Scano Giorgio , Sliwinski Pawel , Yan Sheng , Macklem Peter T.
Published: March 2015

To determine how decreasing velocity of shortening (U) of expiratory muscles affects breathing during exercise, six normal men performed incremental exercise with externally imposed expiratory flow limitation (EFLe) at ∼1 l/s. We measured volumes of chest wall, lung- and diaphragm-apposed rib cage (Vrc,p and Vrc,a, respectively), and abdomen (Vab) by optoelectronic plethysmography; esophageal, gastric, and transdiaphragmatic pressures (Pdi); and end-tidal CO2concentration. From these, we calculated velocity of shortening and power (W˙) of diaphragm, rib cage, and abdominal muscles (di, rcm, ab, respectively). EFLe forced a decrease in Uab, which increased Pab and which lasted well into inspiration. This imposed a load, overcome by preinspiratory diaphragm contraction. Udi and inspiratory Urcm increased, reducing their ability to generate pressure. Pdi, Prcm, andW˙ab increased, indicating an increased central drive to all muscle groups secondary to hypercapnia, which developed in all subjects. These results suggest a vicious cycle in which EFLe decreases Uab, increasing Pab and exacerbating the hypercapnia, which increases central drive increasing Pab even more, leading to further CO2 retention, and so forth.
Invited Review: Biophysical properties of sodium channels in lung alveolar epithelial cells
Authors: Matalon Sadis , Lazrak Ahmed , Jain Lucky , Eaton Douglas C.
Published: March 2015

Amiloride-sensitive sodium channels in the lung play an important role in lung fluid balance. Particularly in the alveoli, sodium transport is closely regulated to maintain an appropriate fluid layer on the surface of the alveoli. Alveolar type II cells appear to play an important role in this sodium transport, with the role of alveolar type I cells being less clear. In alveolar type II cells, there are a variety of different amiloride-sensitive, sodium-permeable channels. This significant diversity appears to play a role in both normal lung physiology and in pathological states. In many epithelial tissues, amiloride-sensitive epithelial sodium channels (ENaC) are formed from three subunit proteins, designated α-, β-, and γ-ENaC. At least part of the diversity of sodium-permeable channels in lung arises from the assembling of different combinations of these subunits to form channels with different biophysical properties and different mechanisms for regulation. This leads to epithelial tissue in the lung, which has enormous flexibility to alter the magnitude and regulation of salt and water transport. In this review, we discuss the biophysical properties and occurrence of these various channels and some of the mechanisms for their regulation.
Forces, Fishes, and Fluids: Hydrodynamic Mechanisms of Aquatic Locomotion
Authors: Lauder George V. , Drucker Eliot G.
Published: March 2015

Understanding how fishes generate external fluid force to swim steadily and maneuver has proven to be difficult because water does not provide a stable platform for force measurement. But new methods in experimental fluid mechanics provide insights into the physiological mechanisms of aquatic force generation and limits to locomotor performance.
Pulmonary Edema and Elevated Left Atrial Pressure: Four Hours and Beyond
Authors: Drake R. E. , Doursout M. F.
Published: March 2015

Cardiogenic pulmonary edema is caused by the increase in left atrial pressure when the left heart fails. The increased pressure causes rapid fluid accumulation within the lung interstitial spaces. However, over the following days to weeks, additional fluid may accumulate due to the deposition of excess lung connective tissue.
Genesis and Control of the Respiratory Rhythm in Adult Mammals
Authors: Hilaire Gérard , Pásaro Rosario
Published: March 2015

The neural mechanisms responsible for respiratory rhythmogenesis in mammals were studied first in vivo in adults and subsequently in vitro in neonates. In vitro data have suggested that the pacemaker neurons are the kernel of the respiratory network. These data are reviewed, and their relevance to adults is discussed.
ATP as a Signaling Molecule: the Exocrine Focus
Authors: Novak Ivana
Published: March 2015

Why and how do cells release ATP? It is not spilled energy. ATP becomes an extracellular regulator. Various cellular responses are initiated by purinergic receptors and signaling processes and are terminated by breakdown of ATP by ectonucleotidases. In epithelia, ATP regulates salt and water transport; other effects may be longer lasting.
Arteriovenous Pairing: a Determinant of Capillary Exchange
Authors: Harris Norman R.
Published: March 2015

Venuloarteriolar signaling helps mediate microvascular function and dysfunction. Mediators produced at venular sites of inflammation appear to constrict arterioles and increase capillary permeability. In contrast, venules beneficially dilate arterioles to enhance capillary flow according to metabolic demand. These mechanisms are altered with cardiovascular risk factors, contributing to microvascular complications.
Vesicle-Mediated Restoration of a Plasmalemmal Barrier in Severed Axons
Authors: Fishman Harvey M. , Bittner George D.
Published: March 2015

Ca2+-induced endocytotic vesicles undergo protein-mediated interactions to restore a selectively permeable barrier and propagated action potentials in severed invertebrate giant axons. Similar barrier-restoration phenomena observed in cultured mammalian cells with transected neurites suggest that cellular/molecular mechanisms that repair plasmalemmal damage are phylogenetically conserved.
Flt3 Ligand: Role in Control of Hematopoietic and Immune Functions of the Bone Marrow
Authors: Wodnar-Filipowicz Aleksandra
Published: March 2015

The concerted action of cytokines secreted locally in the bone marrow controls the maintenance, expansion, and differentiation of hematopoietic stem cells (HSCs), whereas aberrant cytokine signaling contributes to leukemic transformation. Potent effects of flt3 ligand on HSCs and the development of the immune system have generated much interest in the clinical application of this cytokine in stem cell transplantation and cancer immunotherapy.
Quantitative assessment of ground squirrel mRNA levels in multiple stages of hibernation
Authors: Epperson L. Elaine , Martin Sandra L.
Published: March 2015

Hibernators in torpor dramatically reduce their metabolic, respiratory, and heart rates and core body temperature. These extreme physiological conditions are frequently and rapidly reversed during the winter hibernation season via endogenous mechanisms. This phenotype must derive from regulated expression of the hibernator’s genome; to identify its molecular components, a cDNA subtraction was used to enrich for seasonally upregulated mRNAs in liver of golden-mantled ground squirrels. The relative steady-state levels for seven mRNAs identified by this screen, plus five others, were measured and analyzed for seasonal and stage-specific differences using kinetic RT-PCR. Four mRNAs show seasonal upregulation in which all five winter stages differ significantly from and are higher than summer (α2-macroglobulin, apolipoprotein A1, cathepsin H, and thyroxine-binding globulin). One of these mRNAs, α2-macroglobulin, varies during the winter stages with significantly lower levels at late torpor. None of the 12 mRNAs increased during torpor. The implications for these newly recognized upregulated mRNAs for hibernation as well as more global issues of maintaining steady-state levels of mRNA during torpor are discussed.
Use of echocardiography for the phenotypic assessment of genetically altered mice
Authors: Collins Keith A. , Korcarz Claudia E. , Lang Roberto M.
Published: March 2015

Transgenic mice displaying abnormalities in cardiac development and function represent a powerful new tool for understanding molecular mechanisms underlying normal cardiovascular function and the pathophysiological bases of human cardiovascular disease. Complete cardiac evaluation of phenotypic changes in mice requires the ability to noninvasively assess cardiovascular structure and function in a serial manner. However, the small mouse heart beating at rates in excess of 500 beats/min presents unique methodological challenges. Two-dimensional and Doppler echocardiography have been recently used as effective, noninvasive tools for murine imaging, because quality images of cardiac structures and valvular flows can be obtained with newer high-frequency transthoracic transducers. We will discuss the use of echocardiography for the assessment of 1) left ventricular (LV) chamber dimensions and wall thicknesses, 2) LV mass, 3) improved endocardial border delineation using contrast echocardiography, 4) LV contractility using ejection phase indices and load-independent indices, 5) vascular properties, and 6) LV diastolic performance. Evaluation of cardiovascular performance in closed chest mice is feasible in a variety of murine models using Doppler echocardiographic imaging.
Ultrasound biomicroscopy-Doppler in mouse cardiovascular development
Authors: Phoon Colin K. L. , Turnbull Daniel H.
Published: March 2015

The ability to modify the mouse genome has yielded new insights into the genetic control of mammalian cardiovascular development. However, it is far less understood how genetic factors and their consequent structural changes alter cardiovascular function, a void largely due to the lack of effective noninvasive techniques to assess function in the developing mouse cardiovascular system. In this review, we discuss the recent advances in ultrasound biomicroscopy (UBM)-Doppler echocardiography for analyzing cardiovascular function in the embryonic mouse in utero. “Cardiovascular function” encompasses broad aspects of physiology, including systolic and diastolic cardiac function, distribution of blood flow among various embryonic vascular beds, and vascular bed properties (impedance). A wide range of physiological measurements is possible using UBM-Doppler, but it is clear that the limitations of any single measurement warrant a multi-parameter approach to characterizing cardiovascular function. We further discuss the prospects for UBM-Doppler analysis of alternative vertebrate systems increasingly studied in developmental biology. The ability to correlate cardiovascular physiological phenotypes with their corresponding genotypes should lead to the elucidation of mechanisms underlying normal development, as well as embryonic disease and death.
Analysis of isoproterenol-induced changes in parotid gland gene expression
Authors: Ten Hagen Kelly G. , Balys Marlene M. , Tabak Lawrence A. , Melvin James E.
Published: March 2015

Parotid gland acinar cells undergo marked hypertrophy and hyperplasia upon systemic exposure to the β-adrenergic agonist, isoproterenol. This glandular enlargement is accompanied by substantial cellular changes including DNA synthesis, an increase in glandular protein synthesis, and differential changes in RNA transcription. To gain a more detailed understanding of the underlying changes induced by isoproterenol, we have examined the parotid gland gene expression profile of mice up to 24 h post-isoproterenol injection using high-density oligonucleotide arrays. Depending upon the exposure time, between 22 and 48 of the ∼6,500 mouse genes and expressed sequence tags (ESTs) analyzed displayed significant changes in expression patterns. Genes that were previously shown to be repressed (α-amylase) or activated (proline-rich proteins) following isoproterenol exposure were found to be similarly affected in this experiment, validating this technique. This study demonstrates that the oligonucleotide array technology is a useful tool for examining isoproterenol-induced salivary gland gene expression changes. Using this as a starting point, we can begin to dissect the specific pathways involved in mediating isoproterenol action within the parotid gland.
Gene expression profile of aging in human muscle
Authors: Welle Stephen , Brooks Andrew I. , Delehanty Joseph M. , Needler Nancy , Thornton Charles A.
Published: March 2015

Studies of gene expression related to aging of skeletal muscle have included few subjects or a limited number of genes. We conducted the present study to produce more comprehensive gene expression profiles. RNA was extracted from vastus lateralis biopsies obtained from healthy young (21–27 yr old, n = 8) and older men (67–75 yr old, n = 8) and was analyzed with high-density oligonucleotide arrays. Of the ∼44,000 probe sets on the arrays, ∼18,000 yielded adequate signals for statistical analysis. There were ∼700 probe sets for which t-tests or rank sum tests indicated a difference ( P ≤ 0.01) in mean expression between young and old and for which the estimated false discovery rate was <10%. Most of these differences were less than 1.5-fold in magnitude. Genes that encode proteins involved in energy metabolism and mitochondrial protein synthesis were expressed at a lower level in older muscle. Genes encoding metallothioneins, high-mobility-group proteins, heterogeneous nuclear ribonucleoproteins and other RNA binding/processing proteins, and components of the ubiquitin-proteasome proteolytic pathway were expressed at higher levels in older muscle. Expression of numerous genes involved with stress responses, hormone/cytokine/growth factor signaling, control of the cell cycle and apoptosis, and transcriptional regulation appeared to be affected by aging. More transcripts were detected in older muscle, suggesting dedifferentiation, an increased number of splice variants, or increased cellular heterogeneity. We conclude that in human skeletal muscle the expression of many genes tends to increase or decrease between the third and seventh decades. The changes are modest when averaged over all of the cells in the tissue.
Nicotinic receptor gene cluster on rat chromosome 8 in nociceptive and blood pressure hyperresponsiveness
Authors: Khan Imran M. , Singletary Erin , Alemayehu Adamu , Stanislaus Shanaka , Printz Morton P. , Yaksh Tony L. , Taylor Palmer
Published: March 2015

Spontaneously hypertensive rats (SHR) exhibit enhanced pressor, heart rate, and nociceptive responses to spinal nicotinic agonists. This accompanies a paradoxical decrease in spinal nicotinic receptor number in SHR compared with normotensive rats. The congenic strain, SHR-Lx, with an introgressed chromosome 8 segment from the normotensive Brown-Norway-Lx strain (BN-Lx) exhibits reduced blood pressure. This segment contains a gene cluster for three nicotinic receptor subunits expressed in the nervous system. We examined the implication of this gene cluster in the enhanced responsiveness of the SHR. Pressor and nociceptive responses to spinal cytisine, a nicotinic agonist, were diminished in SHR-Lx. Moreover, with repeated administration, these responses desensitized faster in SHR-Lx and progenitor BN-Lx than in progenitor SHR/Ola. This implicates the gene cluster in both cardiovascular and nociceptive responses to spinal nicotinic agonists. Since diminished responsiveness to agonist stimulation is greater than the basal blood pressure differences between the strains and the introgressed rat chromosome maps to a quantitative trait locus in human hypertension, polymorphisms in the three nicotinic receptor genes become candidates for altered central control of blood pressure.
Phenotypic variations oforpkmutation and chromosomal localization of modifiers influencing kidney phenotype
Authors: SOMMARDAHL CARLA , COTTRELL MARILYN , WILKINSON J. ERBY , WOYCHIK RICHARD P. , JOHNSON DABNEY K.
Published: March 2015

The Oak Ridge polycystic kidney ( orpk) mutant mouse model resulted from a transgene insertion into the Tg737 gene and exhibits a pleiotropic syndrome with lesions in the kidney, liver, and pancreas. We found marked differences in the phenotypic expression of the orpk mutation when bred on different genetic backgrounds. In the FVB/N background, the phenotype is very severe for kidney, pancreas, and liver lesions. To evaluate better how genetic background might influence the expressivity of the orpk phenotype, we bred the transgene into the C3HeB/FeJLe (C3H) genetic background. We performed a genome-wide scan using backcross and intercross populations with more than 150 markers to map the chromosomal location of the modifier genes that differ in the FVB/N and C3H genetic backgrounds that affect the severity of kidney disease in the orpk mouse. Low-resolution interval mapping was performed using the Map Manager QTb program, with the interval explaining a significant portion of the variance being the distal end of chromosome 4.
Quantitative trait locus mapping of genes that regulate HDL cholesterol in SM/J and NZB/B1NJ inbred mice
Authors: Pitman Wendy A. , Korstanje Ron , Churchill Gary A. , Nicodeme Edwige , Albers John J. , Cheung Marian C. , Staton Megan A. , Sampson Stephen S. , Harris Stephen , Paigen Beverly
Published: March 2015

To investigate the quantitative trait loci (QTL) regulating plasma cholesterol, the female progeny of an (SM×NZB/ B1NJ)×NZB/B1NJ backcross were fed an atherogenic diet. After 18 wk, plasma total cholesterol and high-density lipoprotein cholesterol (HDL-C) was measured. HDL-C concentrations were greater in NZB than in SM mice. For standard chow-fed mice, QTL were found near D5Mit370 and D18Mit34. For mice fed an atherogenic diet, a QTL was found near D5Mit239. The QTL for chow-fed and atherogenic-fed mice on chromosome 5 seem to be two different loci. We used a multitrait analysis to rule out pleiotropy in favor of a two-QTL hypothesis. Furthermore, the HDL-C in these strains was induced by the high-fat diet. For inducible HDL-C, one significant locus was found near D15Mit39. The gene for an HDL receptor, Srb1, maps close to the HDL-C QTL at D5Mit370, but the concentrations of Srb1 mRNA and SR-B1 protein and the gene sequence of NZB/B1NJ and SM/J did not support Srb1 as a candidate gene. With these QTL, we have identified chromosomal regions that affect lipoprotein profiles in these strains.
Cloning and characterization of bovine cytosolic and mitochondrial PEPCK during transition to lactation
Authors: Agca Cansu , Greenfield Randall B. , Hartwell Jennifer R. , Donkin Shawn S.
Published: March 2015

The cytosolic (C) and mitochondrial (M) forms of phospho enolpyruvate carboxykinase (PEPCK; EC 4.1.1.32 ) are encoded by two different nuclear genes in mouse, human, and chicken. Our objective was to clone the two forms of PEPCK for bovine and determine their expression during the immediate periparturient interval in dairy cows. Bovine PEPCK-C cDNA contains 2,592 nucleotides and contains 84% similarity to the coding sequence of human PEPCK-C cDNA. A 449-nt partial clone of the 3′ end of PEPCK-M is 76% similar to the corresponding sequence of human PEPCK-M. The coding sequence of bovine PEPCK-C and coding sequence of the partial PEPCK-M clone were 58% similar but the similarities in the 3′-untranslated regions were negligible. Northern blot analysis revealed single transcripts of 2.85 and 2.35 kb for PEPCK-C and PEPCK-M, respectively. The transition to lactation did not alter PEPCK-M transcript expression, but expression of PEPCK-C mRNA was transiently increased during early lactation, indicating that enhanced hepatic gluconeogenesis during this period may be tied to enhanced capacity for cytosolic rather than mitochondrial formation of phosphoenolpyruvate.