bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensory modalities conveyed in the hindlimb somatic afferent input to nucleus tractus solitarius
Authors: Toney Glenn M. , Mifflin Steven W.
Published: December 2017

To determine the somatic sensory modalities conveyed by hindlimb somatic afferent inputs, the discharge of neurons in the nucleus tractus solitarius was recorded in anesthetized rats after electrical stimulation of either the contralateral sciatic nerve or L6 spinal nerve, which innervates the hindlimb. The discharge of seven of eight cells was increased ( P < 0.05) by capsaicin injected into the arterial supply of the hindlimb. Discharge was unaltered in 19 neurons tested for sensitivity to nonnoxious (40°C) and noxious (47°C) heating of the hindlimb skin. In contrast, lightly stroking the skin elicited discharge in 2 of 14 cells, whereas noxious pinching increased activity in 4 other cells. Rhythmic (1- to 3-s) muscle contraction (MC) increased ( P < 0.05) discharge in >60% of neurons tested (11 of 18). Static (10- to 30-s) MC significantly ( P < 0.05) increased discharge in four cells, two of which were also responsive to rhythmic MC. Rhythmic and sustained muscle stretch increased discharge ( P < 0.05) in three of eight neurons tested. These data indicate that nucleus tractus solitarius neurons receive input from low- and high-threshold cutaneous mechanoreceptors, respond to capsaicin delivered into the hindlimb arterial supply, lack thermal sensitivity, and respond to activation of mechanosensitive as well as metabosensitive endings in skeletal muscle.
Effects of respiratory muscle work on exercise performance
Authors: Harms Craig A. , Wetter Thomas J. , St. Croix Claudette M. , Pegelow David F. , Dempsey Jerome A.
Published: December 2017

The normal respiratory muscle effort at maximal exercise requires a significant fraction of cardiac output and causes leg blood flow to fall. We questioned whether the high levels of respiratory muscle work experienced in heavy exercise would affect performance. Seven male cyclists [maximal O2 consumption (V˙o 2) 63 ± 5 ml · kg−1 · min−1] each completed 11 randomized trials on a cycle ergometer at a workload requiring 90% maximal V˙o 2. Respiratory muscle work was either decreased (unloading), increased (loading), or unchanged (control). Time to exhaustion was increased with unloading in 76% of the trials by an average of 1.3 ± 0.4 min or 14 ± 5% and decreased with loading in 83% of the trials by an average of 1.0 ± 0.6 min or 15 ± 3% compared with control ( P < 0.05). Respiratory muscle unloading during exercise reduced V˙o 2, caused hyperventilation, and reduced the rate of change in perceptions of respiratory and limb discomfort throughout the duration of exercise. These findings demonstrate that the work of breathing normally incurred during sustained, heavy-intensity exercise (90%V˙o 2) has a significant influence on exercise performance. We speculate that this effect of the normal respiratory muscle load on performance in trained male cyclists is due to the associated reduction in leg blood flow, which enhances both the onset of leg fatigue and the intensity with which both leg and respiratory muscle efforts are perceived.
Mechanical dissociation of bronchi from parenchyma in the immature piglet lung
Authors: Mansell Anthony L. , McAteer Allison L. , Oldmixon Eben H.
Published: December 2017

Previous studies of isolated piglet lungs suggested that local distending forces around bronchi might be relatively weak before postnatal growth and maturation. The present study used tantalum bronchograms to compare pressure-diameter relationships of bronchi in situ and after excision from the parenchyma in immature (3- to 7-day-old) and mature (3-mo-old) piglets. The mature group reproduced behavior that is well established in mature lungs from other species; i.e., bronchial diameters maintained a constant relationship to the parenchyma as the lungs were deflated from maximum to minimum volume. In sharp contrast, diameters failed to change until the immature lungs were deflated to <5 cmH2O transpulmonary pressure. Total percent change in bronchial diameter was then only 24% in the immature lungs compared with 47% in the mature lungs ( P < 0.002). Total elastances of mature generation 3–8 bronchi did not change when they were excised from the parenchyma. However, in the same generations of immature bronchi, total elastances were lower after than before (1.06 vs. 1.60 cmH2O/%, P < 0.05) excision from the parenchyma. Elastances of the excised immature and mature bronchi were then the same (1.06 vs. 1.03 cmH2O/%, not significant). Because elastic moduli of the lung parenchyma are also similar in the two age groups, it was concluded that local features of airway-parenchyma coupling limited the generation of local parenchymal recoil around bronchi in the immature lungs.
Evaluation of a new body composition phantom for quality control and cross-calibration of DXA devices
Authors: Diessel E. , Fuerst T. , Njeh C. F. , Tylavsky F. , Cauley J. , Dockrell M. , Genant H. K.
Published: December 2017

This study evaluated a new body composition phantom and its use for quality control and cross-calibration of dual-energy X-ray absorptiometry (DXA) instruments for measurements of body composition. We imaged the variable composition phantom (Lunar, Madison, WI) on eight different DXA devices. Deviations of up to 7% fat were observed when we compared the percent fat values measured by the different devices with the nominal values provided by the manufacturer. Absolute precision error of percent fat measurements for the phantom ranged from 0.6 to 0.8%. The phantom's percent fat values were also compared with whole body composition measurements from 130 female and male volunteers. The phantom detected differences in percent fat values that were similar to those found by comparing in vivo measurements with values from different DXA scanner models from the same manufacturer. When comparing different models of scanners from different manufacturers, such as the Hologic QDR-4500 and the Lunar DPX-IQ, the phantom showed a different relationship than was seen for patients. Therefore, corrections or comparisons based on the phantom data alone would be incorrect. In conclusion, the Lunar variable composition phantom is capable of accurately measuring the fat calibration of DXA devices and may be suitable for cross-sectional cross-calibration between scanners from the same manufacturer; however, for comparison of DXA scanners from different manufacturers, in vivo cross-calibration is still the only accurate method. The phantom may be used in longitudinal quality control to verify an instrument's temporal stability.
Muscle afferent activity modulates bioassayable growth hormone in human plasma
Authors: McCall G. E . , Grindeland R . E . , Roy R. R. , Edgerton V. R.
Published: December 2017

Immunoassayable and bioassayable growth hormone responses to vibration-induced activation of muscle spindle afferents of the soleus (Sol) or tibialis anterior (TA) muscles were studied in 10 men. Subjects were supine while a 10-min vibration stimulus (100 Hz; 1.5-mm amplitude) was applied to the muscle, with each of the muscles tested on separate days. Blood samples were collected before, during, immediately after, and after 5 and 10 min of vibration. Plasma growth hormone concentrations were determined by radioimmunoassay (IGH) for all sampling periods and by bioassay (BGH; measurement of tibial epiphysial cartilage growth in hypophysectomized rats) for samples obtained before and immediately after vibration. Plasma IGH concentrations were similar at all time points during the Sol or TA experiments. After 10 min of muscle vibration, mean plasma BGH was elevated 94% [1,216 ± 148 (SD) to 2,362 ± 487 μg/l; P = 0.0001] for TA and decreased 22% (1,358 ± 155 to 1,058 ± 311 μg/l; P = 0.09) for Sol. These data demonstrate that activation of TA muscle spindle afferents increases circulating BGH but not IGH. The absence of a similar vibration-induced BGH response for the Sol indicates a differential regulation of BGH release by these two predominantly slow muscles, perhaps related to their respective flexor and extensor functions. These data indicate that a muscle afferent-pituitary axis modulates the release of BGH, but not IGH, from the pituitary in humans and that this axis is muscle specific, similar to that observed in rats.
Modulation of respiratory motor output by cerebellar deep nuclei in the rat
Authors: Xu Fadi , Frazier Donald T.
Published: December 2017

The present study was undertaken to determine what roles the various cerebellar deep nuclei (CDN) play in modulation of respiration, especially during chemical challenges. Experiments were carried out in 12 anesthetized, tracheotomized, paralyzed, and ventilated rats. The integrated phrenic nerve activity (∫PN) was recorded as an index of respiratory motor output. A stimulating electrode was sequentially placed into the fastigial nucleus (FN), the interposed nucleus, and the lateral nucleus. Only stimulation of the FN significantly altered respiration, primarily via increasing respiratory frequency associated with a pressor response. The evoked respiratory responses persisted after blocking the pressor response via pretreatment with phenoxybenzamine or use of transient stimulation (<2 s) but were abolished by microinjection of kainic acid into the FN. To test the involvement of FN neurons in respiratory chemoreflexes, ventilation with hypercapnic gases mixture and intravenous injection of sodium cyanide were applied before and after CDN lesions induced by kainic acid. CDN lesions did not significantly alter eupneic breathing, but FN lesions attenuated the respiratory response to hypercapnia and sodium cyanide. We conclude that, with respect to the CDN in the rat, FN neurons uniquely modulate respiration independent of cardiovascular effects and facilitate respiratory responses mediated by activation of CO2 and O2 receptors.
No evidence for long-term facilitation after episodic hypoxia in spontaneously breathing, anesthetized rats
Authors: Janssen Patrick L. , Fregosi Ralph F.
Published: December 2017

Repeated electrical or hypoxic stimulation of peripheral chemoreceptors has been shown to cause a persistent poststimulus increase in respiratory motoneuron activity, termed long-term facilitation (LTF). LTF after episodic hypoxia has been demonstrated most consistently in anesthetized, vagotomized, paralyzed, artificially ventilated rats. Evidence for LTF in spontaneously breathing animals and humans after episodic hypoxia is equivocal and may have been influenced by the awake state of the subjects in these studies. The present study was designed to test the hypothesis that LTF is evoked in respiratory-related tongue muscle and inspiratory pump muscle activities after episodic hypoxia in 10 spontaneously breathing, anesthetized, vagotomized rats. The animals were exposed to three (5-min) episodes of isocapnic hypoxia, separated by 5 min of hyperoxia (50% inspired oxygen). Genioglossus, hyoglossus, and inspiratory intercostal EMG activities, along with respiratory-related tongue movements and esophageal pressure, were recorded before, during, and for 60 min after the end of episodic isocapnic hypoxia. We found no evidence for LTF in tongue muscle (genioglossus, hyoglossus) or inspiratory pump muscle (inspiratory intercostal) activities after episodic hypoxia. Rather, the primary poststimulus effect of episodic hypoxia was diminished respiratory frequency, which contributed to a reduction in ventilatory drive.
Hyperosmolality dilates rat skeletal muscle arterioles: role of endothelial KATP channels and daily exercise
Authors: Massett Michael P. , Koller Akos , Kaley Gabor
Published: December 2017

The purpose of this study was to investigate the mechanism underlying arteriolar responses to hyperosmolality and to determine the effects of daily exercise on this response. Dilator responses were measured in isolated, cannulated, and pressurized skeletal muscle arterioles. Osmolality was increased from ∼290 to 330 mosmol/kgH2O by adding glucose, sucrose, or mannitol to the superfusion solution. All three compounds elicited similar changes in vessel diameter, suggesting that this response was due to changes in osmolality. Responses to glucose were abolished by endothelium removal but were not altered in endothelium-intact vessels by superfusion with the nitric oxide synthase inhibitor N ω-nitro-l-arginine or the cyclooxygenase inhibitor indomethacin. In endothelium-intact arterioles, responses to glucose superfusion with the ATP-sensitive potassium (KATP) channel inhibitor glibenclamide; however, intraluminal perfusion with glibenclamide nearly abolished the responses to glucose and mannitol. Intraluminal administration of glucose elicited a significantly greater dilation than extraluminal glucose. The response to intraluminal glucose was also inhibited by intraluminal glibenclamide. Four weeks of daily exercise did not significantly alter the responses to hyperosmolality in gracilis or soleus muscle arterioles. These data demonstrate that physiological increases in intraluminal osmolality dilate rat skeletal muscle arterioles via activation of endothelial KATP channels; however, this endothelium-dependent response is not augmented by daily exercise.
Pro- and macroglycogenolysis during repeated exercise: roles of glycogen content and phosphorylase activation
Authors: Shearer J. , Marchand I. , Tarnopolsky M. A. , Dyck D. J. , Graham T. E.
Published: December 2017

This study examined the relationship between preexercise muscle glycogen content and glycogen utilization in two physiological pools, pro- (PG) and macroglycogen (MG). Male subjects ( n = 6) completed an exercise and dietary protocol before the experiment that resulted in one leg with high glycogen (HL) and one with low glycogen (LL). Preexercise PG levels were 312 ± 29 and 208 ± 31 glucosyl units/kg dry wt (dw) ( P ≤ 0.05) in the HL and LL, respectively, and the corresponding values for MG were 125 ± 37 and 89 ± 43 mmol glucosyl units/kg dw ( P ≤ 0.05). Subjects then performed two 90-s exercise bouts at 130% maximal oxygen uptake separated by a 10-min rest period. Biopsies were obtained at rest and after each exercise bout. Preexercise glycogen concentration was correlated to net glycogenolysis for both PG and MG for bout 1 and bouts 1 and 2 ( r ≤ 0.60). In bout 1, there was no difference in the rate of PG or MG catabolism between HL and LL despite a 26% increase ( P ≤ 0.05) in glycogen phosphorylase transformation ( phos a %) in the HL. In the second bout, more PG was catabolized in the HL vs. LL (38 ± 9 vs. 9 ± 6 mmol glucosyl units · kg dw−1 · min−1) ( P ≤ 0.05) with no difference between legs in phos a %. phos a% was increased in HL vs. LL but does not necessarily increase glycogenolysis in either PG or MG. Despite both legs performing the same exercise and having identical metabolic demands, the HL catabolized 2.3 ( P ≤ 0.05) times more PG and 1.5 ( P ≤ 0.05) times more MG vs. LL in bouts 1 and 2, indicating that preexercise glycogen concentration is a regulator of glycogenolysis.
Cerebrovascular reactivity and hypercapnic respiratory drive in diabetic autonomic neuropathy
Authors: Tantucci Claudio , Bottini Paolo , Fiorani Claudio , Dottorini Marco L. , Santeusanio Fausto , Provinciali Leandro , Sorbini Carlo Augusto , Casucci Giovanni
Published: December 2017

Because abnormalities in cerebrovascular reactivity (CVR) in subjects with long-term diabetes could partly be ascribed to autonomic neuropathy and related to central chemosensitivity, CVR and the respiratory drive output during progressive hypercapnia were studied in 15 diabetic patients without (DAN−) and 30 with autonomic neuropathy (DAN+), of whom 15 had postural hypotension (PH) (DAN+PH+) and 15 did not (DAN+PH−), and in 15 control (C) subjects. During CO2 rebreathing, changes in occlusion pressure and minute ventilation were assessed, and seven subjects in each group had simultaneous measurements of the middle cerebral artery mean blood velocity (MCAV) by transcranial Doppler. The respiratory output to CO2 was greater in DAN+PH+ than in DAN+PH− and DAN− ( P < 0.01), whereas a reduced chemosensitivity was found in DAN+PH− ( P < 0.05 vs. C). MCAV increased linearly with the end-tidal Pco 2 (Pet CO2 ) in DAN+PH− but less than in C and DAN− ( P < 0.01). In contrast, DAN+PH+ showed an exponential increment in MCAV with Pet CO2 mainly >55 Torr. Thus CVR was lower in DAN+ than in C at Pet CO2 <55 Torr ( P < 0.01), whereas it was greater in DAN+PH+ than in DAN+PH− ( P < 0.01) and DAN− ( P < 0.05) at Pet CO2 >55 Torr. CVR and occlusion pressure during hypercapnia were correlated only in DAN+ ( r = 0.91, P < 0.001). We conclude that, in diabetic patients with autonomic neuropathy, CVR to CO2 is reduced or increased according to the severity of dysautonomy and intensity of stimulus and appears to modulate the hypercapnic respiratory drive.
MRI study of pharyngeal airway changes during stimulation of the hypoglossal nerve branches in rats
Authors: Brennick Michael J. , Trouard Theodore P. , Gmitro Arthur F. , Fregosi Ralph F. ,   (With the Technical Assistance of Jennifer C. Reeder)
Published: December 2017

The medial branch (Med) of the hypoglossal nerve innervates the tongue protrudor muscles, whereas the lateral branch (Lat) innervates tongue retractor muscles. Our previous finding that pharyngeal airflow increased during either selective Med stimulation or whole hypoglossal nerve (WHL) stimulation (coactivation of protrudor and retractor muscles) led us to examine how WHL, Med, or Lat stimulation affected tongue movements and nasopharyngeal (NP) and oropharyngeal (OP) airway volume. Electrical stimulation of either WHL, Med, or Lat nerves was performed in anesthetized, tracheotomized rats while magnetic resonance images of the NP and OP were acquired (slice thickness 0.5 mm, in-plane resolution 0.25 mm). NP and OP volume was greater during WHL and Med stimulation vs. no stimulation ( P < 0.05). Ventral tongue depression (measured in the midsagittal images) and OP volume were greater during Med stimulation than during WHL stimulation ( P < 0.05). Lat stimulation did not alter NP volume ( P = 0.39). Our finding that either WHL or Med stimulation dilates the NP and OP airways sheds new light on the control of pharyngeal airway caliber by extrinsic tongue muscles and may lead to new treatments for patients with obstructive sleep apnea.
Biventricular cardiac dysfunction after acute massive pulmonary embolism in the rat
Authors: Sullivan D. Matthew , Watts John A. , Kline Jeffrey A.
Published: December 2017

Cardiac dysfunction has been documented in vivo after acute massive pulmonary embolism (AMPE). The present study tests whether intrinsic ventricular dysfunction occurs in rat hearts isolated after AMPE. AMPE was induced in spontaneously breathing ketamine-xylazine-anesthetized rats by thrombus infusion until mean arterial blood pressure (MAP) was ∼40% of basal measurement. A hypotensive control group underwent controlled blood withdrawal to produce MAP ∼40% of basal levels. Shams underwent identical surgical and anesthesia preparation but without pulmonary embolization. Hearts were perfused in isovolumetric mode, and simultaneous right ventricular (RV) and left ventricular (LV) pressures were measured. AMPE caused arterial hypotension with hypoxemia (Po 2 = 50 ± 14 Torr), acidemia (pH = 7.26 ± 0.11), and high lactate concentration (6.9 ± 1.7 mM). Starling curves from both ventricles demonstrated that AMPE significantly reduced ex vivo systolic contractile function in the RV ( P = 0.031) and LV ( P = 0.008) compared with both the hypotensive control and sham hearts. AMPE did not alter coronary flow or compliance in either ventricle. Soluble tumor necrosis factor-α decreased in the RV ( P = 0.043) and LV ( P = 0.005) tissue. These data support the hypothesis that AMPE produces intrinsic biventricular dysfunction and suggest that arterial hypotension is not the principal mechanism of this dysfunction.
Stiffness of peripheral airway folding membrane in rabbits
Authors: Lambert Rodney K. , Paré Peter D. , Okazawa Mitsushi
Published: December 2017

We have observed that small, membranous bronchioles from rabbits, in which the smooth muscle is not activated, experience a critical elastic buckling involving the whole airway wall during deflation of the lung. This implies that, at some point during the deflation, the airway wall goes from being in a state of tension to a state of compression. At the transition, there is neither net tension nor net compression in the wall, and the transmural pressure difference must, therefore, be zero. Thus at this point, the pressure difference across the muscle that results from the passive stress in the muscle is just balanced by the pressure difference across the folded mucosal membrane. We estimated the muscle stress, and hence the pressure across the muscle, from published data on rabbit trachealis (Opazo-Saez A and Paré PD, J Appl Physiol 77: 1638–1643, 1994) and equated this to the pressure across the folded membrane. By using a theoretical prediction of this pressure (Lambert RK, Codd SL, Alley MR, and Pack RJ, J Appl Physiol 77: 1206–1216, 1994), together with the results of our morphometric measurements on these airways, we estimated that the flexural rigidity of the folding membrane in peripheral rabbit airways is of the order of 10−12 Pa · m3. This value implies that, in these airways, membrane folding provides significant resistance to airway smooth muscle shortening.
Similar effects of cooling and fatigue on eccentric and concentric force-velocity relationships in human muscle
Authors: De Ruiter C. J. , De Haan A.
Published: December 2017

The purpose of this study was to investigate the effects of muscle temperature and fatigue during stretch (eccentric) and shortening (concentric) contractions of the maximally electrically activated human adductor pollicis muscle. After immersion of the lower arm in water baths of four different temperatures, the calculated muscle temperatures were 36.8, 31.6, 26.6, and 22.3°C. Normalized (isometric force = 100%) eccentric force increased with stretch velocity to maximal values of 136.4 ± 1.6 and 162.1 ± 2.0% at 36.8 and 22.3°C, respectively. After repetitive ischemic concentric contractions, fatigue was less at the lower temperatures, and at all temperatures the loss of eccentric force was smaller than the loss of isometric and concentric force. Consequently, normalized eccentric forces increased during fatigue to 159.7 ± 4.6 and 185.7 ± 7.3% at 36.8 and 22.3°C, respectively. Maximal normalized eccentric force increased exponentially ( r 2 = 0.95) when V max was reduced by cooling and/or fatiguing contractions. This may indicate that a reduction in cross-bridge cycling rate could underlie the significant increases in normalized eccentric force found with cooling and fatigue.
Long-term effect of low energy laser irradiation on infarction and reperfusion injury in the rat heart
Authors: Yaakobi Tali , Shoshany Yariv , Levkovitz Sara , Rubin Ofer , Ben Haim Shlomo A. , Oron Uri
Published: December 2017

Low-energy laser irradiation (LELI) has been found to modulate biological processes. The present study investigated the effect of LELI on infarct size after chronic myocardial infarction (MI) and ischemia-reperfusion injury in rats. The left anterior descending (LAD) coronary artery was ligated in 83 rats to create MI or ischemia-reperfusion injury. The hearts of the laser-irradiated (LI) rats received irradiation after LAD coronary artery occlusion and 3 days post-MI. At 14, 21, and 45 days post-LAD coronary artery permanent occlusion, infarct sizes (percentage of left ventricular volume) in the non-laser-irradiated (NLI) rats were 52 ± 12 (SD), 47 ± 11, and 34 ± 7%, respectively, whereas in the LI rats they were significantly lower, being 20 ± 8, 15 ± 6, and 10 ± 4%, respectively. Left ventricular dilatation (LVD) in the chronic infarcted rats was significantly reduced (50–60%) in LI compared with NLI rats. LVD in the ischemia-reperfusion-injured LI rats was significantly reduced to a value that did not differ from intact normal noninfarcted rats. Laser irradiation caused a significant 2.2-fold elevation in the content of inducible heat shock proteins (specifically HSP70i) and 3.1-fold elevation in newly formed blood vessels in the heart compared with NLI rats. It is concluded that LELI caused a profound reduction in infarct size and LVD in the rat heart after chronic MI and caused complete reduction of LVD in ischemic-reperfused heart. This phenomenon may be partially explained by the cardioprotective effect of the HSP70i and enhanced angiogenesis in the myocardium after laser irradiation.
Smooth muscle relaxation and local hydraulic impedance properties of the aorta
Authors: Cholley Bernard P. , Lang Roberto M. , Korcarz Claudia E. , Shroff Sanjeev G.
Published: December 2017

Smooth muscle relaxation is expected to yield beneficial effects on hydraulic impedance properties of large vessels. We investigated the effects of intravenous diltiazem infusion on aortic wall stiffness and local hydraulic impedance properties. In seven anesthetized, closed-chest dogs, instantaneous cross-sectional area and pressure of the descending thoracic aorta were measured using transesophageal echocardiography combined with acoustic quantification and a micromanometer, respectively. Data were acquired during a vena caval balloon inflation, both at the control condition and with diltiazem infusion. At the operating point, diltiazem reduced blood pressure in all dogs but did not alter aortic dimensions or wall stiffness. Over the observed pressure range, aortic area-pressure relationships were linear. Whereas diltiazem affected the slope of this relationship variably (no change in 3 dogs, increase in 1 dog, decrease in 3 dogs), the zero-pressure area intercept was significantly increased in every case such that higher area was observed at any given pressure. When comparisons were made at a common level of wall stress, wall stiffness was either increased or unchanged during diltiazem infusion. In contrast, diltiazem decreased wall stiffness in every case when comparisons were made at a common level of aortic midwall radius. Aortic characteristic impedance and pulse wave velocity, components of left ventricular hydraulic load that are determined by aortic elastic and geometric properties, were affected variably. A comparison of wall stiffness at matched wall stress appears inappropriate for assessing changes in smooth muscle tone. Because of the competing effects of changes in vessel diameter and wall stiffness, smooth muscle relaxation is not necessarily accompanied by the expected beneficial changes in local aortic hydraulic impedance. These results can be reconciled by recognizing that components other than vascular smooth muscle (e.g., elastin, collagen) contribute to aortic wall stiffness.
Invited Review: Intermittent hypoxia and respiratory plasticity
Authors: Mitchell Gordon S. , Baker Tracy L. , Nanda Steven A. , Fuller David D. , Zabka Andrea G. , Hodgeman Brad A. , Bavis Ryan W. , Mack Kenneth J. , Olson E. B.
Published: December 2017

Intermittent hypoxia elicits long-term facilitation (LTF), a persistent augmentation (hours) of respiratory motor output. Considerable recent progress has been made toward an understanding of the mechanisms and manifestations of this potentially important model of respiratory plasticity. LTF is elicited by intermittent but not sustained hypoxia, indicating profound pattern sensitivity in its underlying mechanism. During intermittent hypoxia, episodic spinal serotonin receptor activation initiates cell signaling events, increasing spinal protein synthesis. One associated protein is brain-derived neurotrophic factor, a neurotrophin implicated in several forms of synaptic plasticity. Our working hypothesis is that increased brain-derived neurotrophic factor enhances glutamatergic synaptic currents in phrenic motoneurons, increasing their responsiveness to bulbospinal inspiratory inputs. LTF is heterogeneous among respiratory outputs, differs among experimental preparations, and is influenced by age, gender, and genetics. Furthermore, LTF is enhanced following chronic intermittent hypoxia, indicating a degree of metaplasticity. Although the physiological relevance of LTF remains unclear, it may reflect a general mechanism whereby intermittent serotonin receptor activation elicits respiratory plasticity, adapting system performance to the ever-changing requirements of life.
pH heterogeneity in tibial anterior muscle during isometric activity studied by31P-NMR spectroscopy
Authors: Houtman C. J. , Heerschap A. , Zwarts M. J. , Stegeman D. F.
Published: December 2017

The occurrence of pH heterogeneity in human tibial anterior muscle during sustained isometric exercise is demonstrated by applying 31P-nuclear magnetic resonance (NMR) spectroscopy in a study of seven healthy subjects. Exercise was performed at 30 and 60% of maximal voluntary contraction (MVC) until fatigue. The NMR spectra, as localized by a surface coil and improved by proton irradiation, were obtained at a high time resolution (16 s). They revealed the simultaneous presence of two pH pools during most experiments. Maximum difference in the two pH levels during exercise was 0.40 ± 0.07 (30% MVC, n = 7) and 0.41 ± 0.03 (60% MVC, n = 3). Complementary two-dimensional 31P spectroscopic imaging experiments in one subject supported the supposition that the distinct pH pools reflect the metabolic status of the main muscle fiber types. The relative size of the Pipeak in the spectrum attributed to the type II fiber pool increases with decreasing pH levels. This phenomenon is discussed in the context of the size principle stating that the smaller (type I) motor units are recruited first.
Further analysis of transcytosis of free polypeptides and polypeptide-coated nanobeads in rabbit nasal mucosa
Authors: Cremaschi Dario , Dossena Silvia , Porta Cristina , Rossi Vilma , Pinza Mario
Published: December 2017

In rabbit nasal mucosa, free polypeptides and polypeptide-coated nanospheres are actively absorbed by the M cells present in specialized areas of the epithelium. Because polypeptide-coated nanosphere transport was abolished in the presence of free polypeptides, free polypeptides and polypeptide-coated nanospheres are shown here to compete. Fluxes of polypeptide-coated nanospheres with 356, 490, and 548 nm diameters have been compared. BSA-coated beads were poorly transported, at the same rate, when bead diameters were 356 or 490 nm [net flux of ∼2–2.5 × 106 nanospheres (nan) · cm−2 · h−1]; however, their net transport largely increased toward a value of 25 × 106nan · cm−2 · h−1 at a diameter of 548 nm. Insulin-coated beads displayed a net flux that was significantly higher than BSA-coated beads but equally were transported at the same rate (net flux of ∼8.0 × 106nan · cm−2 · h−1) at diameters of 356 or 490 nm; once again, their net flux significantly increased toward a value of 25 × 106nan · cm−2 · h−1, if the bead diameter was 548 nm. Insulin plus anti-insulin IgG-coated 490-nm-diameter beads displayed a very high net flux, although not yet saturating (∼60 × 106nan · cm−2 · h−1); however, a significantly lower saturated net flux (once again ∼25 × 106nan · cm−2 · h−1) was shown with 548-nm-diameter beads. In conclusion, 1) in the range of 356–490 nm diameter, net transport was independent of bead diameter and, conversely, largely dependent on the coating polypeptides, and 2) at 548 nm diameter, nanospheres tended to be transferred at similar rates independently of coating kind and the maximal net transport capacity of the mucosa was reduced. The suspension viscosity largely increased with 548-nm polypeptide-coated nanospheres; this fact is hypothetically proposed to be the cause of these events.
Physiological consequences of oxygen-dependent chloride binding to hemoglobin
Authors: Prange H. D. , Shoemaker J. L. , Westen E. A. , Horstkotte D. G. , Pinshow B.
Published: December 2017

The Po2-dependent binding of chloride to Hb decreases the Cl−concentration of the red blood cell (RBC) intracellular fluid in venous blood to ∼1–3 mmol/l less than that in arterial blood. This change is physiologically important because 1) Cl−is a negative heterotropic allosteric effector of Hb that competes for binding sites with 2,3-bisphosphoglycerate and CO2and decreases oxyhemoglobin affinity in several species; 2) it may help reconcile several longstanding problems with measured values of the Donnan ratios for Cl−, HCO[Formula: see text], and H+across the RBC membrane that are used to calculate total CO2carriage, ion flux rates, and membrane potentials; 3) it is a factor in the change in the dissociation constant for the combined nonvolatile weak acids of Hb associated with the Haldane effect; and 4) it diminishes the decrease in strong ion difference in the RBC intracellular fluid that would otherwise occur from the chloride shift and prevent the known increase of HCO[Formula: see text] concentration in that compartment.
α-Actin: disposition, quantities, and estimated effects on lung recoil and compliance
Authors: Oldmixon E. H. , Carlsson K. , Kuhn C. , Butler J. P. , Hoppin F. G.
Published: December 2017

We have investigated the basis and implications of pneumoconstriction by measuring disposition and quantities of α-smooth muscle actin in rat and guinea pig lungs and modeling its effects on lung recoil and compliance. A robust marker of contractility, α-smooth muscle actin appears in smooth muscle or myofibroblast-like cells in pleura, airways, blood vessels, and alveolar ductal tissues. In each site, we measured its transected area by immunofluorescent staining and frequency-modulated scanning confocal microscopy. We incorporated these data in a model of the parenchyma consisting of an extensive elastic network with embedded contractile structures. We conclude that contraction at any one of these sites alone can decrease parenchymal compliance by 20–30% during tidal breathing. This is due mostly to the stiffness of activated contractile elements undergoing passive cycling; constant muscle tension would have little effect. The magnitude of the effect corresponds with known responses of the lung to hypocapnia, consistent with a homeostatic function in which gas exchange is defended by redistributing ventilation away from overventilated units.
Invited Review: Significance of spatial and temporal heterogeneity of calcium transients in smooth muscle
Authors: Pabelick Christina M. , Sieck Gary C. , Prakash Y. S.
Published: December 2017

The multiplicity of mechanisms involved in regulation of intracellular Ca2+concentration ([Ca2+]i) in smooth muscle results in both intra- and intercellular heterogeneities in [Ca2+]i. Heterogeneity in [Ca2+]iregulation is reflected by the presence of spontaneous, localized [Ca2+]itransients (Ca2+sparks) representing Ca2+release through ryanodine receptor (RyR) channels. Ca2+sparks display variable spatial Ca2+distributions with every occurrence within and across cellular regions. Individual sparks are often grouped, and fusion of sparks produces large local elevations in [Ca2+]ithat occasionally trigger propagating [Ca2+]iwaves. Ca2+sparks may modulate membrane potential and thus smooth muscle contractility. Sparks may also be the target of other regulatory factors in smooth muscle. Agonists induce propagating [Ca2+]ioscillations that originate from foci with high spark incidence and also represent Ca2+release through RyR channels. With increasing agonist concentration, the peak of regional [Ca2+]ioscillations remains relatively constant, whereas both frequency and propagation velocity increase. In contrast, the global cellular response appears as a concentration-dependent increase in peak as well as mean cellular [Ca2+]i, representing a spatial and temporal integration of the oscillations. The significance of agonist-induced [Ca2+]ioscillations lies in the establishment of a global [Ca2+]ilevel for slower Ca2+-dependent physiological processes.
Selected Contribution: Airway caliber in healthy and asthmatic subjects: effects of bronchial challenge and deep inspirations
Authors: Jensen Andrew , Atileh Haytham , Suki Bela , Ingenito Edward P. , Lutchen Kenneth R.
Published: December 2017

In 9 healthy and 14 asthmatic subjects before and after a standard bronchial challenge and a modified [deep inspiration (DI), inhibited] bronchial challenge and after albuterol, we tracked airway caliber by synthesizing a method to measure airway resistance (Raw; i.e., lung resistance at 8 Hz) in real time. We determined the minimum Raw achievable during a DI to total lung capacity and the subsequent dynamics of Raw after exhalation and resumption of tidal breathing. Results showed that even after a bronchial challenge healthy subjects can dilate airways maximally, and the dilation caused by a single DI takes several breaths to return to baseline. In contrast, at baseline, asthmatic subjects cannot maximally dilate their airways, and this worsens considerably postconstriction. Moreover, after a DI, the dilation that does occur in airway caliber in asthmatic subjects constricts back to baseline much faster (often after a single breath). After albuterol, asthmatic subjects could dilate airways much closer to levels of those of healthy subjects. These data suggest that the asthmatic smooth muscle resides in a stiffer biological state compared with the stimulated healthy smooth muscle, and inhibiting a DI in healthy subjects cannot mimic this.
Selected Contribution: Effect of volatile anesthetics on cADP-ribose-induced Ca2+release system
Authors: Chini Eduardo N.
Published: December 2017

Volatile anesthetics have multiple actions on intracellular Ca2+homeostasis, including activation of the ryanodine channel (RyR) and sensitization of this channel to agonists such as caffeine and ryanodine. Recently it has been described that the nucleotide cADP-ribose (cADPR) is the endogenous regulator of the RyR in many mammalian cells, and cADPR has been proposed to be a second messenger in many signaling pathways. I investigated the effect of volatile anesthetics on the cADPR signaling system, using sea urchin egg homogenates as a model of intracellular Ca2+stores. Ca2+uptake and release were monitored in sea urchin egg homogenates by using the fluo-3 fluorescence technique. Activity of the ADP-ribosyl cyclase was monitored by using a fluorometric method using nicotinamide guanine dinucleotide as a substrate. Halothane in concentrations up to 800 μM did not induce Ca2+release by itself in sea urchin egg homogenates. However, halothane potentiates the Ca2+release mediated by agonists of the ryanodine channel, such as ryanodine. Furthermore, other volatile anesthetics such as isoflurane and sevoflurane had no effect. Halothane also potentiated the activation of the ryanodine channel mediated by the endogenous nucleotide cADPR. The half-maximal concentration for cADPR-induced Ca2+release was decreased about three times by addition of 800 μM halothane. The reverse was also true: addition of subthreshold concentrations of cADPR sensitized the homogenates to halothane. In contrast, all the volatile anesthetics used had no effect on the activity of the enzyme that synthesizes cADPR. I propose that the complex effect of volatile anesthetics on intracellular Ca2+homeostasis may involve modulation of the cADPR signaling system.
Selected Contribution: Effects of ischemia-reperfusion on vascular contractility and α1-adrenergic-receptor signaling in the rat tail artery
Authors: Seasholtz Tammy M. , Cai Guoping , Wang Hoau-Yan , Friedman Eitan
Published: December 2017

To determine the effects of ischemia-reperfusion (I/R) on α1-adrenergic-receptor (α1-AR) functions, α1-AR-mediated contraction, inositol phosphate (IP) accumulation, and α1-AR-G protein coupling were examined in the tail arteries of anesthetized rats after 60 min of ischemia and 60 min of reperfusion. The contractile response to norepinephrine (NE) was significantly increased after I/R, whereas the contractile response to KCl remained unchanged. This was accompanied by a 69% increase in NE-stimulated IP accumulation. Furthermore, receptor-stimulated coupling of α1a-AR to Gαq/11proteins was increased, whereas the coupling of α1b-AR or α1d-AR to their G proteins was not altered by I/R. These changes in vascular α1-AR function occurred without concurrent alteration in expression levels of membrane α1-AR subtypes or in the associated G proteins. These data demonstrate that I/R increases α1a-AR-Gq/11protein coupling and α1-AR-stimulated IP accumulation in the tail artery. The alterations in α1-AR signaling are associated with and may underlie the enhanced contractile response of the tail artery to adrenergic stimulation after I/R.
Severity of contraction-induced injury is affected by velocity only during stretches of large strain
Authors: Brooks Susan V. , Faulkner John A.
Published: December 2017

Our purpose was to investigate the effect of velocity of stretch on contraction-induced injury to whole skeletal muscles. Single stretches provide an effective method for studying factors that initiate contraction-induced injury. We tested the null hypothesis that the severity of injury is not dependent on the velocity of the stretch. From the plateau of maximum isometric contractions, extensor digitorum longus muscles of mice were administered single stretches in situ of 30–50% strain relative to muscle fiber length ( L f) at rates of 1–16 L f/s. The magnitude of injury was represented by the isometric force deficit 1–10 min after the stretch. Although the null hypothesis was not supported because the force deficit was affected by velocity ( r 2= 0.09), the effect was relatively weak and was not significant except at the largest strain. Velocity had no effect on peak or average force or work input, factors established to have significant relationships with the force deficit. Velocity may play a minor role in contraction-induced injury, but its importance is negligible relative to that of strain.
Improved analysis of brachial artery ultrasound using a novel edge-detection software system
Authors: Woodman R. J. , Playford D. A. , Watts G. F. , Cheetham C. , Reed C. , Taylor R. R. , Puddey I. B. , Beilin L. J. , Burke V. , Mori T. A. , Green D.
Published: December 2017

Brachial artery ultrasound is commonly employed for noninvasive assessment of endothelial function. However, analysis is observer dependent and susceptible to errors. We describe studies on a computerized edge-detection and wall-tracking software program to allow more accurate and reproducible measurement. In study 1, three purpose-built Perspex phantom arteries, 3.00, 4.00, and 6.00 mm in diameter, were measured with the software. There was a mean bias of 11 μm ( P < 0.001 at each level) between known and measured values; the mean resolving power of the software was estimated as 8.3 μm. In study 2, the mean intraobserver coefficient of variation of repeated measures of flow-mediated dilation (FMD) using the software (6.7%) was significantly lower than that for traditional manual measurements using the intima-lumen interfaces (24.8%, P < 0.05) and intima-media interfaces (32.5%, P < 0.05). In study 3, 24 healthy volunteers underwent repeat testing twice within 1 wk; the coefficients of variation for between-visit reproducibility of FMD and response to glyceryl trinitrate using the software were 14.7 and 17.6%, respectively. Assuming 80% power and an α of 0.05, eight subjects with matched controls would be required, in a parallel designed study, to detect an absolute 2.5% change in FMD. In summary, we have developed a semiautomated computerized vascular ultrasound analysis system that will improve the power of clinical intervention studies to detect small changes in arterial diameter.
Elevating dietary salt exacerbates hyperpnea-induced airway obstruction in guinea pigs
Authors: Mickleborough Timothy D. , Gotshall Robert W. , Rhodes Jann , Tucker Alan , Cordain Loren
Published: December 2017

Previous studies have indicated that increased dietary salt consumption worsens postexercise pulmonary function in humans with exercise-induced asthma (EIA). It has been suggested that EIA and hyperpnea-induced airway obstruction (HIAO) in guinea pigs (an animal model of EIA) are mediated by similar mechanisms. Therefore, the purpose of this study was to determine whether altering dietary salt consumption also exacerbated HIAO in guinea pigs. Furthermore, the potential pathway of action of dietary salt was investigated by blocking leukotriene (LT) production during HIAO in guinea pigs. Thirty-two male Hartley strain guinea pigs were split into two groups. One group ( n = 16) of animals ingested a normal-salt diet (NSD) for 2 wk; the other group ( n = 16) ingested a high-salt diet (HSD) for 2 wk. Thereafter, animals were anesthetized, cannulated, tracheotomized, and mechanically ventilated during a baseline period and during two dry gas hyperpnea challenges. After the first challenge, the animals were administered either saline or nordihydroguaiaretic acid, a LT inhibitor. Bladder urine was analyzed for electrolyte concentrations and urinary LTE4. The HSD elicited higher airway inspiratory pressures (Ptr) than the NSD ( P < 0.001) postchallenge. However, after infusion of the LT inhibitor and a second hyperpnea challenge, HIAO was blocked in both diet groups ( P < 0.001). Nonetheless, the HSD group continued to demonstrate slightly higher Ptr than the NSD group ( P < 0.05). Urinary LTE4 excretion significantly increased in the HSD group compared with the NSD group within treatment groups. This study has demonstrated that dietary salt loading exacerbated the development of HIAO in guinea pigs and that LT release was involved in HIAO and may be moderated by changes in dietary salt loading.
Homeokinesis and short-term variability of human airway caliber
Authors: Que Cheng-Li , Kenyon C. M. , Olivenstein R. , Macklem Peter T. , Maksym Geoffrey N.
Published: December 2017

We hypothesized that short-term variation in airway caliber could be quantified by frequency distributions of respiratory impedance (Zrs) measured at high frequency. We measured Zrs at 6 Hz by forced oscillations during quiet breathing for 15 min in 10 seated asthmatic patients and 6 normal subjects in upright and supine positions before and after methacholine (MCh). We plotted frequency distributions of Zrs and calculated means, skewness, kurtosis, and significance of differences between normal and log-normal frequency distributions. The data were close to, but usually significantly different from, a log-normal frequency distribution. Mean lnZrs in upright and supine positions was significantly less in normal subjects than in asthmatic patients, but not after MCh and MCh in the supine position. The lnZrs SD (a measure of variation), in the upright position and after MCh was significantly less in normal subjects than in asthmatic patients, but not in normal subjects in the supine position and after MCh in the supine position. We conclude that 1) the configuration of the normal tracheobronchial tree is continuously changing and that this change is exaggerated in asthma, 2) in normal lungs, control of airway caliber is homeokinetic, maintaining variation within acceptable limits, 3) normal airway smooth muscle (ASM) when activated and unloaded closely mimics asthmatic ASM, 4) in asthma, generalized airway narrowing results primarily from ASM activation, whereas ASM unloading by increasing shortening velocity allows faster caliber fluctuations, 5) activation moves ASM farther from thermodynamic equilibrium, and 6) asthma may be a low-entropy disease exhibiting not only generalized airway narrowing but also an increased appearance of statistically unlikely airway configurations.