bluuebunny/crossref_metadata_2025 huggingface dataset:
Transport asymmetry in peritoneal dialysis: application of a serial heteroporous peritoneal membrane model
Authors: Venturoli Daniele , Rippe Bengt
Published: December 2017

The transport of macromolecules during peritoneal dialysis is highly selective when they move from blood to dialysate but nearly completely unselective in the opposite direction. Aiming at describing this asymmetry, we modeled the peritoneal barrier as a series arrangement of two heteroporous membranes. First a three-pore membrane was considered, crossed by small [radius of the small pore ( rs) ≈ 45 Å], large [radius of the large pore ( rL) ≈ 250 Å], and transcellular pores accounting for 90, 8, and 2% to the hydraulic conductance, respectively, and with a corresponding pore area over diffusion distance ( A0/Δ x) set to 50,000 cm. We calculated the second membrane parameters by fitting simultaneously the bidirectional clearance of molecules ranging from sucrose [molecular weight = 360, permeating solute radius ( ae) ≈ 5 Å] to α2-macroglobulin (molecular weight = 820,000, ae≈ 90 Å). The results describe a second two-pore membrane with very large pores ( rL≈ 2,300 Å) accounting for 95% of the hydraulic conductance, minor populations of small ( rs≈ 67 Å) and transcellular pores (3 and 2%, respectively), and an A0/Δ x≈ 65,000 cm. The estimated peritoneal lymph flow is ≈0.3 ml/min. The two membranes can be identified as the capillary endothelium and an extracellular interstitium lumped with the peritoneal mesothelium.
Glomerular laminin isoform transitions: errors in metanephric culture are corrected by grafting
Authors: St. John Patricia L. , Wang Ruixue , Yin Yong , Miner Jeffrey H. , Robert Barry , Abrahamson Dale R.
Published: December 2017

Glomerular basement membrane (GBM) assembly and maturation are marked by the replacement of laminin-1 (containing α1-, β1-, and γ1-chains) with laminin-11 (consisting of α5-, β2-, and γ1-chains). Similarly, the α1- and α2-chains of type IV collagen are replaced by collagen α3-, α4-, and α5(IV)-chains. The cellular origins of these molecules and mechanisms for isoform removal and substitution are unknown. To explore glomerular laminin isoform transitions in vitro, we assessed metanephric organ cultures. Standard culture conditions do not support endothelial cell differentiation, and glomerular structures that form in vitro are avascular. Nevertheless, extensive podocyte development occurs in these cultures, including the formation of foot processes and assembly of a GBM-like matrix. Here, we show that the podocyte-specific markers, glomerular epithelial protein 1 and nephrin, which are normally expressed in capillary loop stage glomeruli in vivo, are also expressed by glomerular figures that form in organ culture. However, the GBM-like segments that form in vitro do not undergo normal laminin isoform switching. Instead, both laminin α1- and α5-chains are present, as is the β1-chain, but not β2. When avascular organ-cultured kidneys are grafted into anterior eye chambers, however, kidney-derived angioblasts establish extensive vasculature by 6 days, and glomeruli are lined by endothelial cells. We evaluated embryonic day 12 ( E12) vascular endothelial growth factor receptor (Flk1) -lacZ kidneys that had first been grown in organ culture for 6–7 days and then grafted into wild-type mice. Correct laminin isoform substitution occurred and correlated with the appearance of endothelial cells expressing Flk1. Our findings indicate that endothelial cells, and/or factors present in the circulation, mediate normal GBM laminin isoform transitions in vivo.
Na+-alanine uptake activates a Cl− conductance in frog renal proximal tubule cells via nonconventional PKC
Authors: Millar I. D. , Robson L.
Published: December 2017

Hyposmotically induced swelling of frog renal proximal tubule cells activates a DIDS-sensitive, outwardly rectifying Cl−conductance via a conventional protein kinase C (PKC). This study examines whether Na+-alanine cotransport similarly activates a DIDS-sensitive Cl− conductance in frog renal proximal tubule cells. On stimulation of Na+-alanine cotransport, the DIDS-sensitive current ( I DIDS-Ala) increased markedly over time. I DIDS-Ala exhibited outward rectification, a Na+/Cl− selectivity ratio of 0.19 ± 0.03, and an anion selectivity sequence Br− = Cl− > I− > gluconate−. Activation of I DIDS-Alawas dependent on ATP hydrolysis and PKC-mediated phosphorylation and was inhibited by hyperosmotic conditions. Activation could be not ascribed to a conventional PKC isoform, as I DIDS-Ala was not affected by removing Ca2+ or by phorbol ester treatment, suggesting a role for a nonconventional PKC isoform, either novel or atypical. We conclude that Na+-alanine cotransport activates a DIDS-sensitive Cl− conductance via a nonconventional PKC isoform. This contrasts with the hyposmotically activated Cl−conductance, which requires conventional PKC activation.
Absence of aquaporin-4 water channels from kidneys of the desert rodentDipodomys merriami merriami
Authors: Huang Yan , Tracy Randall , Walsberg Glenn E. , Makkinje Anthony , Fang Pingke , Brown Dennis , Van Hoek Alfred N.
Published: December 2017

Recently, we found that aquaporin-4 (AQP4) is expressed in the S3 segment of renal proximal tubules of mice but not in rat proximal tubules. Because mice have relatively larger papillae than rats, it was proposed that the renal distribution of AQP4 in various species could be related to their maximum urinary concentrating ability. Therefore, kidneys and other tissues of Merriam's desert kangaroo rat, Dipodomys merriami merriami, which produce extremely concentrated urine (up to 5,000 mosmol/kgH2O), were examined for AQP4 expression and localization. Contrary to our expectation, AQP4 immunostaining was undetectable in any region of the kidney, and the absence of AQP4 protein was confirmed by Western blotting. By freeze fracture electron microscopy, orthogonal arrays of intramembraneous particles (OAPs) were not detectable in plasma membranes of principal cells and proximal tubules. However, AQP4 protein was readily detectable in gastric parietal and brain astroglial cells. Northern blotting failed to detect AQP4 mRNA in kangaroo rat kidneys, whereas both in situ hybridization and RT-PCR experiments did reveal AQP4 mRNA in collecting ducts and proximal tubules of the S3 segment. These results suggest that renal expression of AQP4 in the kangaroo rat kidney is regulated at the transcriptional or translational level, and the absence of AQP4 may be critical for the extreme urinary concentration that occurs in this species.
Maturation of carbonic anhydrase IV expression in rabbit kidney
Authors: Winkler Cornelia A. , Kittelberger Ann M. , Watkins Richard H. , Maniscalco William M. , Schwartz George J.
Published: December 2017

Carbonic anhydrase (CA) IV facilitates renal acidification by catalyzing the dehydration of luminal H2CO3. CA IV is expressed in proximal tubules, medullary collecting ducts, and A-intercalated cells of the mature rabbit kidney (Schwartz GJ, Kittelberger AM, Barnhart DA, and Vijayakumar S. Am J Physiol 278: F894–F904, 2000). In view of the maturation of HCO[Formula: see text] transport in the proximal tubule and collecting duct, the ontogeny of CA IV expression was examined. During the first 2 wk, CA IV mRNA was expressed in maturing cortex and medulla at ∼20% of adult levels. The maturational increase was gradual in cortex over 3–5 wk of age but surged in the medulla, so that mRNA levels appeared higher than those in the adult medulla. In situ hybridization showed very little CA IV mRNA at 5 days, with increases in deep cortex and medullary collecting ducts by 21 days. Expression of CA IV protein in the cortex and medulla was minimal at 3 days of age but then apparent in the juxtamedullary region, A-intercalated cells and medullary collecting ducts by 18 days; there was little labeling of the proximal straight tubules of the medullary rays. Thus CA IV expression may be regulated to accommodate the maturational increase in HCO[Formula: see text] absorption in the proximal tubule. In the medullary collecting duct, there is a more robust maturation of CA IV mRNA and protein, commensurate with the high rate of HCO[Formula: see text] absorption in the neonatal segment.
Effects of filtration rate on the glomerular barrier and clearance of four differently shaped molecules
Authors: Ohlson Maria , Sörensson Jenny , Lindström Karin , Blom Anna M. , Fries Erik , Haraldsson Börje
Published: December 2017

The effect of shape on the transglomerular passage of solutes has not been hitherto systematically studied. We perfused isolated rat kidneys to determine the fractional clearances (θ) at various filtration rates for four molecules of different shapes but with similar Stokes-Einstein radii ( aSE= 34–36 Å). The θ for hyaluronan, bikunin, and Ficoll36 Åwere 66, 16, and 11%, respectively, at a glomerular filtration rate (GFR) of 0.07 ml · min−1· g wet wt−1and decreased to 46, 14, and 7%, respectively, on a fivefold increase in GFR. Under the same conditions, θ for albumin increased from 0.15 to 0.74%, and similar behavior was observed for larger Ficolls ( aSE>45 Å). Pore analysis showed that the “apparent neutral” solute radii of Ficoll, albumin, bikunin, and hyaluronan were 35, 64, 33, and 24 Å, respectively, despite similar aSE. In addition, the properties of the glomerular filter changed with increasing GFR and hydrostatic pressure. We conclude that elongated shape, irrespective of size and charge, drastically increases the transglomerular passage of a solute, an effect that is related to its frictional ratio.
α1-Adrenoceptor subtypes on rat afferent arterioles assessed by radioligand binding and RT-PCR
Authors: Salomonsson Max , Oker Melinda , Kim Susan , Zhang Hua , Faber James E. , Arendshorst William J.
Published: December 2017

We utilized [3H]prazosin saturation and competition radioligand binding studies to characterize the expression of α1-adrenoceptors in preglomerular vessels. mRNA for adrenoceptor subtypes was assayed using RT-PCR. The vessels were isolated using an iron oxide-sieving method. [3H]prazosin bound to a single class of binding sites ( K d0.087 ± 0.012 nM, Bmax 326 ± 56 fmol/mg protein). Phentolamine displaced [3H]prazosin (0.2 nM) with a p K i of 8.37 ± 0.09. Competition with the selective α1A-adrenoceptor antagonist 5-methylurapidil fit a two-site model (p K i9.38 ± 0.21 and 7.04 ± 0.15); 59 ± 3% of the sites were high-affinity, and 41 ± 3% were low-affinity binding sites. Competition with the α1D-adrenoceptor antagonist 8-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-8-azaspiro[4.5]decane-7,9-dione dihydrochloride (BMY-7378) fit a one-site model with low affinity (p K i 6.83 ± 0.03). The relative contents of α1A-, α1B-, and α1D-adrenoceptor mRNAs were 64 ± 5, 25 ± 5, and 11 ± 1%, respectively. Thus there was a very good correlation between mRNA and receptor binding for the subtypes. These data indicate a predominance of the α1A-adrenoceptor subtype in rat renal resistance vessels, with smaller densities of α1B- and α1D-adrenoceptors.
Recovery after relief of fetal urinary obstruction: morphological, functional and molecular aspects
Authors: Edouga Didier , Hugueny Brigitte , Gasser Bernard , Bussières Laurence , Laborde Kathleen
Published: December 2017

The effects of obstruction [urinary tract obstruction (UTO)] and relief on renal development were examined in an experimental model in the fetal lamb. Bladder outlet obstruction was performed at 60 days of gestation; relief was performed by vesicoamniotic shunting at 90 days of gestation. Studies were carried out in obstructed (OF60; n = 11), shunted (SF; n = 5), and control fetuses (CF; n= 11) at 120 days of gestation. Fetal UTO produced either hydronephrosis (64%) or dysplasia (36%); dysplasia was always associated with a reduction in the number of glomeruli [950 ± 99 (dysplasia) vs. 1,852 ± 249 (CF) glomeruli/section]. Obstructed fetuses had lower creatinine clearance [0.76 ± 0.41 (OF60) vs. 0.96 ± 0.21 (CF) ml · min−1· kg−1], higher sodium fractional excretion [17.2 ± 20.3 (OF60) vs. 2.4 ± 3.7% (CF)], and higher urinary concentration [80 ± 30 (OF60) vs. 43 ± 22 (CF) μmol/l] than controls. In SF, the number of glomeruli was increased at 120 days of gestation (1,643 ± 106 glomeruli/section) compared with nondiverted fetuses (1,379 ± 502 glomeruli/section), and the temporal pattern of PAX2, disrupted after obstruction, was restored. In conclusion, early fetal UTO leads to either renal hydronephrosis with normal glomerular development or dysplasia with a decreased number of glomeruli; in utero urine diversion performed before the end of nephrogenesis may allow a reversal of the glomerulogenesis arrest observed.
Mechanism of increased renal gene expression during metabolic acidosis
Authors: Curthoys Norman P. , Gstraunthaler Gerhard
Published: December 2017

Increased renal catabolism of plasma glutamine during metabolic acidosis generates two ammonium ions that are predominantly excreted in the urine. They function as expendable cations that facilitate the excretion of acids. Further catabolism of α-ketoglutarate yields two bicarbonate ions that are transported into the venous blood to partially compensate for the acidosis. In rat kidney, this adaptation is sustained, in part, by the induction of multiple enzymes and various transport systems. The pH-responsive increases in glutaminase (GA) and phospho enolpyruvate carboxykinase (PEPCK) mRNAs are reproduced in LLC-PK1-fructose 1,6-bisphosphatase (FBPase) cells. The increase in GA activity results from stabilization of the GA mRNA. The 3′-untranslated region of the GA mRNA contains a direct repeat of an eight-base AU sequence that functions as a pH-response element. This sequence binds ζ-crystallin/NADPH:quinone reductase with high affinity and specificity. Increased binding of this protein during acidosis may initiate the pH-responsive stabilization of the GA mRNA. In contrast, induction of PEPCK occurs at the transcriptional level. In LLC-PK1-FBPase+kidney cells, a decrease in intracellular pH leads to activation of the p38 stress-activated protein kinase and subsequent phosphorylation of transcription factor ATF-2. This transcription factor binds to cAMP-response element 1 within the PEPCK promoter and may enhance its transcription during metabolic acidosis.
Reduced genioglossal activity with upper airway anesthesia in awake patients with OSA
Authors: Fogel Robert B. , Malhotra Atul , Shea Steven A. , Edwards Jill K. , White David P.
Published: December 2017

We examined whether topical upper airway anesthesia leads to a reduction in genioglossal (GG) electromyogram (EMG) in patients with obstructive sleep apnea (OSA). Airway mechanics were also evaluated. In 13 patients with OSA, we monitored GG EMG during tidal breathing and during the application of pulses of negative airway pressure (−10 to −12 cmH2O). Airflow resistance and airway collapsibility were determined. All measurements were performed with and without topical anesthesia (lidocaine). Anesthesia led to a significant fall in the peak GG EMG response to negative pressure from 36.1 ± 4.7 to 24.8 ± 5.3% (SE) of maximum ( P < 0.01). This was associated with a fall in phasic and tonic EMG during tidal breathing (phasic from 24.4 ± 4.1 to 16.4 ± 3.4% of maximum and tonic from 10.9 ± 1.6 to 8.0 ± 1.3% of maximum, P < 0.01). A significant rise in pharyngeal airflow resistance was also observed. Our results demonstrate that topical receptor mechanisms in the nasopharynx importantly influence dilator muscle activity and are likely important in driving the augmented dilator muscle activity seen in the apnea patient.
Nitric oxide and cerebral blood flow responses to hyperbaric oxygen
Authors: Demchenko Ivan T. , Boso Albert E. , O'Neill Thomas J. , Bennett Peter B. , Piantadosi Claude A.
Published: December 2017

We have tested the hypothesis that cerebral nitric oxide (NO) production is involved in hyperbaric O2 (HBO2) neurotoxicity. Regional cerebral blood flow (rCBF) and electroencephalogram (EEG) were measured in anesthetized rats during O2 exposure to 1, 3, 4, and 5 ATA with or without administration of the NO synthase inhibitor ( N ω-nitro-l-arginine methyl ester), l-arginine, NO donors, or the N-methyl-d-aspartate receptor inhibitor MK-801. After 30 min of O2 exposure at 3 and 4 ATA, rCBF decreased by 26–39% and by 37–43%, respectively, and was sustained for 75 min. At 5 ATA, rCBF decreased over 30 min in the substantia nigra by one-third but, thereafter, gradually returned to preexposure levels, preceding the onset of EEG spiking activity. Rats pretreated with N ω-nitro-l-arginine methyl ester and exposed to HBO2 at 5 ATA maintained a low rCBF. MK-801 did not alter the cerebrovascular responses to HBO2at 5 ATA but prevented the EEG spikes. NO donors increased rCBF in control rats but were ineffective during HBO2 exposures. The data provide evidence that relative lack of NO activity contributes to decreased rCBF under HBO2, but, as exposure time is prolonged, NO production increases and augments rCBF in anticipation of neuronal excitation.
Middle cerebral artery blood velocity during a Valsalva maneuver in the standing position
Authors: Pott Frank , van Lieshout Johannes J. , Ide Kojiro , Madsen Per , Secher Niels H.
Published: December 2017

Occasionally, lifting of a heavy weight leads to dizziness and even to fainting, suggesting that, especially in the standing position, expiratory straining compromises cerebral perfusion. In 10 subjects, the middle cerebral artery mean blood velocity ( V mean) was evaluated during a Valsalva maneuver (mouth pressure 40 mmHg for 15 s) both in the supine and in the standing position. During standing, cardiac output decreased by 16 ± 4 (SE) % ( P < 0.05), and at the level of the brain mean arterial pressure (MAP) decreased from 89 ± 2 to 78 ± 3 mmHg ( P < 0.05), as did V mean from 73 ± 4 to 62 ± 5 cm/s ( P < 0.05). In both postures, the Valsalva maneuver increased central venous pressure by ∼40 mmHg with a nadir in MAP and cardiac output that was most pronounced during standing (MAP: 65 ± 6 vs. 87 ± 3 mmHg; cardiac output: 37 ± 3 vs. 57 ± 4% of the resting value; P < 0.05). Also, V mean was lowest during the standing Valsalva maneuver (39 ± 5 vs. 47 ± 4 cm/s; P < 0.05). In healthy individuals, orthostasis induces an ∼15% reduction in middle cerebral artery V mean that is exaggerated by a Valsalva maneuver performed with 40-mmHg mouth pressure to ∼50% of supine rest.
Involvement of cGMP-dependent protein kinase in the relaxation of ovine pulmonary arteries to cGMP and cAMP
Authors: Dhanakoti Srinivas N. , Gao Yuansheng , Nguyen Minh Q. , Raj J. Usha
Published: December 2017

Agonist-induced smooth muscle relaxation occurs following an increase in intracellular concentrations of cGMP or cAMP. However, the role of protein kinase G (PKG) and/or protein kinase A (PKA) in cGMP- or cAMP-mediated pulmonary vasodilation is not clearly elucidated. In this study, we examined the relaxation responses of isolated pulmonary arteries of lambs (age = 10 ± 1 days), preconstricted with endothelin-1, to increasing concentrations of 8-bromo-cGMP (8-BrcGMP) or 8-BrcAMP (cell-permeable analogs), in the presence or absence of Rp-8-β-phenyl-1, N2-etheno-bromoguanosine cyclic monosphordthioate ( Rp-8-PET-BrcGMPS) or KT-5720, selective inhibitors of PKG and PKA, respectively. When examined for specificity, Rp-8-Br-PET-cGMPS abolished PKG, but not PKA, activity in pulmonary arterial extracts, whereas KT-5720 inhibited PKA activity only. 8-BrcGMP-induced relaxation was inhibited by the PKG inhibitor only, whereas 8-BrcAMP-induced relaxation was inhibited by both inhibitors. A nearly fourfold higher concentration of cAMP than cGMP was required to relax arteries by 50% and to activate PKG by 50%. Our results demonstrate that relaxation of pulmonary arteries is more sensitive to cGMP than cAMP and that PKG plays an important role in both cGMP- and cAMP-mediated relaxation.
Cardiac troponin T alterations in myocardium and serum of rats after stressful, prolonged intense exercise
Authors: Chen Yingjie , Serfass Robert C. , Mackey-Bojack Shannon M. , Kelly Karen L. , Titus Jack L. , Apple Fred S.
Published: December 2017

The goal of this study was to determine whether the stress of forced exercise would result in injury to the myocardium. Male rats with 8% of body weight attached to the tail were forced to swim 3.5 h (3.5S), forced to swim 5 h (5S), or pretrained for 8 days and then forced to swim 5 h (T5S). Rats were killed immediately after they swam (0 h PS) and at 3 h (3 h PS), 24 h (24 h PS), and 48 h after they swam (48 h PS). Tissue homogenates of the left ventricle were analyzed by Western blot analysis for cardiac troponin T (cTnT). Serum cTnT was quantified by immunoassay. Results indicated that, in the 3.5S, 5S, and T5S groups, serum cTnT was significantly ( P < 0.01) increased at 0 and 3 h PS. The 5S group demonstrated a greater increase in serum cTnT than the 3.5S group ( P < 0.01) and the T5S group ( P < 0.01) at 0 h PS. Western blot analysis indicated significant decreases ( P < 0.01) in myocardial cTnT in the 5S group only at 0 h PS ( P < 0.01) and 3 h PS ( P < 0.05). Histological evidence of localized myocyte damage demonstrated by interstitial inflammatory infiltrates consisting of neutrophils, lymphocytes, and histiocytes, as well as vesicular nuclei-enlarged chromatin patterns, was observed in left ventricle specimens from the 5S group at 24 and 48 h PS. Our findings demonstrate that stressful, forced exercise induces alterations in myocardial cTnT and that training before exercise attenuates the exercise-induced heart damage.
PGH2-TxA2-receptor blockade restores vasoreactivity in a new rodent model of genetic hypertension
Authors: Suzuki Hideyuki , Ikezaki Hiroyuki , Hong Dennis , Rubinstein Israel
Published: December 2017

The purpose of this study was to determine whether activation of prostaglandin H2-thromboxane A2(PGH2-TxA2) receptors impedes vasodilation in the in situ peripheral microcirculation of spontaneously hypertensive hamsters, a new rodent model of high-renin genetic hypertension. Using intravital microscopy, we found that vasodilation elicited by suffusion of acetylcholine and vasoactive intestinal peptide (VIP), two neurotransmitters localized in perivascular nerves in the peripheral circulation, on the in situ cheek pouch was significantly attenuated in spontaneously hypertensive hamsters relative to age- and genetically matched normotensive hamsters ( P < 0.05). However, nitroglycerin-induced vasodilation was similar in both groups. Pretreatment with SQ-29548, a selective and potent PGH2-TxA2-receptor antagonist, restored acetylcholine- and VIP-induced vasodilation in spontaneously hypertensive hamsters. SQ-29548 had no significant effects on resting arteriolar diameter and on nitroglycerin-induced vasodilation in both groups. SQ-29548 slightly but significantly potentiated VIP- but not acetylcholine-induced vasodilation in normotensive hamsters. Collectively, these data indicate that activation of PGH2-TxA2 receptors impedes agonist-induced vasodilation in the in situ cheek pouch of spontaneously hypertensive hamsters. We suggest that this model is suitable for studying the role of prostanoids in mediating vasomotor dysfunction observed in genetic hypertension.
Dietary carbohydrate, muscle glycogen content, and endurance performance in well-trained women
Authors: Walker J. Lynne , Heigenhauser George J. F. , Hultman Eric , Spriet Lawrence L.
Published: December 2017

This study examined the ability of well-trained eumenorrheic women to increase muscle glycogen content and endurance performance in response to a high-carbohydrate diet (HCD; ∼78% carbohydrate) compared with a moderate-carbohydrate diet (MD; ∼48% carbohydrate) when tested during the luteal phase of the menstrual cycle. Six women cycled to exhaustion at ∼80% maximal oxygen uptake (V˙o 2 max) after each of the randomly assigned diet and exercise-tapering regimens. A biopsy was taken from the vastus lateralis before and after exercise in each trial. Preexercise muscle glycogen content was high after the MD (625.2 ± 50.1 mmol/kg dry muscle) and 13% greater after the HCD (709.0 ± 44.8 mmol/kg dry muscle). Postexercise muscle glycogen was low after both trials (MD, 91.4 ± 34.5; HCD, 80.3 ± 19.5 mmol/kg dry muscle), and net glycogen utilization during exercise was greater after the HCD. The subjects also cycled longer at ∼80%V˙o 2 max after the HCD vs. MD (115:31 ± 10:47 vs. 106:35 ± 8:36 min:s, respectively). In conclusion, aerobically trained women increased muscle glycogen content in response to a high-dietary carbohydrate intake during the luteal phase of the menstrual cycle, but the magnitude was smaller than previously observed in men. The increase in muscle glycogen, and possibly liver glycogen, after the HCD was associated with increased cycling performance to volitional exhaustion at ∼80%V˙o 2 max.
Pulmonary expression of early growth response-1: biphasic time course and effect of oxygen concentration
Authors: Yan Shi-Fang , Lu Jiesheng , Xu Linna , Zou Yu Shan , Tongers Joern , Kisiel Walter , Mackman Nigel , Pinsky David J. , Stern David M.
Published: December 2017

Hypoxia induces complex adaptive responses. In this report, induction of early growth response-1 (Egr-1) transcripts in lungs of mice subjected to hypoxia is shown to be dose and time dependent. Within 30 min of hypoxia, Egr-1 transcripts were ∼20-fold elevated in 6% oxygen, ∼5.2-fold increased by 10% oxygen, and returned to the normoxic baseline by 12% oxygen. Time course studies up to 48 h showed a biphasic profile with an initial steep rise in Egr-1 transcripts after 0.5 h of hypoxia and a second elevation beginning after 20–24 h. Hypoxic induction of Egr-1 was paralleled by enhanced expression of the downstream target gene tissue factor. Egr-1 and tissue factor antigen were visualized in bronchial and vascular smooth muscle and in alveolar macrophages. Egr-1 has the capacity to modulate expression of genes involved in the remodeling of the extracellular matrix and properties of smooth muscle, thus possibly contributing to the pulmonary response to chronic hypoxia.
Exercise induces lipoprotein lipase and GLUT-4 protein in muscle independent of adrenergic-receptor signaling
Authors: Greiwe Jeffrey S. , Holloszy John O. , Semenkovich Clay F.
Published: December 2017

Exercise increases the expression of lipoprotein lipase (LPL) and GLUT-4 in skeletal muscle. Intense exercise increases catecholamines, and catecholamines without exercise can affect the expression of both LPL and GLUT-4. To test the hypothesis that adrenergic-receptor signaling is central to the induction of LPL and GLUT-4 by exercise, six untrained individuals [age 28 ± 4 (SD) yr, peak oxygen uptake 3.6 ± 0.3 l/min] performed two exercise bouts within 12 days. Exercise consisted of cycling at ∼65% peak oxygen uptake for 60 min with (block trial) and without (control trial) adrenergic-receptor blockade. Exercise intensity was the same during the block and control trials. Plasma catecholamine concentrations were significantly higher and heart rates were significantly lower during the block trial compared with the control trial, consistent with known effects of adrenergic-receptor blockade. However, blockade did not prevent the induction of either LPL or GLUT-4 proteins assayed in biopsies of skeletal muscle. LPL was significantly increased by 170–240% and GLUT-4 was significantly increased by 32–51% at 22 h after exercise compared with before exercise during both the control and block trials. These findings provide evidence that exercise increases muscle LPL and GLUT-4 protein content via signals generated by alterations in cellular homeostasis and not by adrenergic-receptor stimulation.
Role of core temperature as a stimulus for cold acclimation during repeated immersion in 20°C water
Authors: O'Brien Catherine , Young Andrew J. , Lee Dae T. , Shitzer Avraham , Sawka Michael N. , Pandolf Kent B.
Published: December 2017

The relative importance of skin vs. core temperature for stimulating cold acclimation (CA) was examined by 5 wk of daily 1-h water immersions (20°C) in resting (RG) and exercising (EG) subjects. Rectal temperature fell (0.8°C; P < 0.05) during immersion only in RG. Skin temperature fell ( P < 0.05) similarly in both groups. Physiological responses during cold-air exposure (90 min, 5°C) were assessed before and after CA. Body temperatures and metabolic heat production were similar in both groups with no change due to CA. Cardiac output was lower ( P < 0.05) in both groups post-CA (10.4 ± 1.2 l/min) than pre-CA (12.2 ± 1.0 l/min), but mean arterial pressure was unchanged (pre-CA 107 ± 2 mmHg, post-CA 101 ± 2 mmHg). The increase in norepinephrine was greater ( P < 0.05) post-CA (954 ± 358 pg/ml) compared with pre-CA (1,577 ± 716 pg/ml) for RG, but CA had no effect on the increase in norepinephrine for EG (pre-CA 1,288 ± 438 pg/ml, post-CA 1,074 ± 279 pg/ml). Skin temperature reduction alone may be a sufficient stimulus during CA for increased vasoconstrictor response, but core temperature reduction appears necessary to enhance sympathetic activation during cold exposure.
Age-dependent core temperature responses of conscious rabbits to acute hypoxemia
Authors: Fewell James E. , Wong Sarah H. M. , Crisanti Kim C.
Published: December 2017

Experiments were carried out on chronically instrumented newborn and older rabbits to characterize their core temperature (Tc) responses to acute hypoxemia and to differentiate “forced” vs. “regulated” thermoregulatory responses. Three age ranges of kits were studied: 4–6, 9–11, and 28–30 days of age. During an experiment, Tc, selected ambient temperature (Ta), and oxygen consumption were measured from kits studied in a thermocline during a control period of normoxemia, an experimental period of normoxemia or hypoxemia (fraction of inspired oxygen 0.10), and a recovery period of normoxemia. We reasoned that no change or a decrease in Tawhile Tc decreased during hypoxemia would indicate a regulated thermoregulatory response, whereas an increase in Ta while Tc decreased during hypoxemia would indicate a forced thermoregulatory response. Tc decreased during acute hypoxemia in the older kits but not in the 4- to 6-day-old kits; the decrease in Tc was accentuated on postnatal days 28–30 compared with postnatal days 9–11. Ta decreased or stayed the same during exposure to acute hypoxemia. Our data provide evidence that postnatal maturation influences the Tc response of rabbits to acute hypoxemia and that the decrease in Tc during hypoxemia in the older kits results from a regulated thermoregulatory response.
Sustained isocapnic hypoxia suppresses the perception of the magnitude of inspiratory resistive loads
Authors: Orr R. S. , Jordan A. S. , Catcheside P. , Saunders N. A. , McEvoy R. D.
Published: December 2017

The sensation of increased respiratory resistance or effort is likely to be important for the initiation of alerting or arousal responses, particularly in sleep. Hypoxia, through its central nervous system-depressant effects, may decrease the perceived magnitude of respiratory loads. To examine this, we measured the effect of isocapnic hypoxia on the ability of 10 normal, awake males (mean age = 24.0 ± 1.8 yr) to magnitude-scale five externally applied inspiratory resistive loads (mean values from 7.5 to 54.4 cmH2O · l−1 · s). Each subject scaled the loads during 37 min of isocapnic hypoxia (inspired O2 fraction = 0.09, arterial O2 saturation of ∼80%) and during 37 min of normoxia, using the method of open magnitude numerical scaling. Results were normalized by modulus equalization to allow between-subject comparisons. With the use of peak inspiratory pressure (PIP) as the measure of load stimulus magnitude, the perception of load magnitude (Ψ) increased linearly with load and, averaged for all loaded breaths, was significantly lower during hypoxia than during normoxia (20.1 ± 0.9 and 23.9 ± 1.3 arbitrary units, respectively; P = 0.048). Ψ declined with time during hypoxia ( P = 0.007) but not during normoxia ( P= 0.361). Our result is remarkable because PIP was higher at all times during hypoxia than during normoxia, and previous studies have shown that an elevation in PIP results in increased Ψ. We conclude that sustained isocapnic hypoxia causes a progressive suppression of the perception of the magnitude of inspiratory resistive loads in normal subjects and could, therefore, impair alerting or arousal responses to respiratory loading.
Water balance in rats exposed to chronic centrifugation
Authors: Ortiz Rudy M. , Wade Charles E.
Published: December 2017

Changes in gravitational load have been shown to alter renal function, which could potentially affect water balance. Therefore, the present study was conducted to determine the effects of chronic centrifugation on water balance. Eight Sprague-Dawley rats were centrifuged (12 days at 2 G), and eight rats were used as a control group. Water balance over the course of the study was determined by quantifying the percentage (%) of total body water [TBW; (TBW/body mass)] and water flux (water consumption − urine volume). TBW was estimated, by means of deuterium oxide dilution, before the study and after 3 days of centrifugation and by means of desiccation after 12 days of centrifugation. %TBW did not change in the centrifuged rats from initial levels or relative to controls over the course of the study. Differences between the sum of water consumption and sum of urine volume for the 12-day period were the same in both groups. Although an initial period of negative water balance was observed, the lack of a change in %TBW among the three measurement periods or in water flux over the 12 days of centrifugation suggests that water balance is not negatively affected as a result of centrifugation at 2 G.
Effects of inertial load and countermeasures on the distribution of pulmonary blood flow
Authors: Chornuk Myron A. , Bernard Susan L. , Burns John W. , Glenny Robb W. , Sheriff Don D. , Sinclair Scott E. , Polissar Nayak L. , Hlastala Michael P.
Published: December 2017

We assessed the influence of cranial-to-caudal inertial force (+G z ) and the countermeasures of anti-G suit and positive pressure breathing during G (PBG), specifically during +G z , on regional pulmonary blood flow distribution. Unanesthetized swine were exposed randomly to 0 G z (resting), +3 G z , +6 G z , and +9 G z , with and without anti-G suit and PBG with the use of the Air Force Research Laboratory centrifuge at Brooks Air Force Base (the gravitational force of the Earth, that is, the dorsal-to-ventral inertial force, was present for all runs). Fluorescent microspheres were injected into the pulmonary vasculature as a marker of regional pulmonary blood flow. Lungs were excised, dried, and diced into ∼2-cm3 pieces, and the fluorescence of each piece was measured. As +G z was increased from 0 to +3 G z , blood flow shifted from cranial and hilar regions toward caudal and peripheral regions of the lung. This redistribution shifted back toward cranial and hilar regions as anti-G suit inflation pressure increased at +6 and +9 G z . Perfusion heterogeneity increased with +G z stress and decreased at the higher anti-G suit pressures. The distribution of pulmonary blood flow was not affected by PBG. ANOVA indicated anatomic structure as the major determinant of pulmonary blood flow.
On-line monitoring of intrinsic PEEP in ventilator-dependent patients
Authors: Nucci G. , Mergoni M. , Bricchi C. , Polese G. , Cobelli C. , Rossi A.
Published: December 2017

Measurement of the intrinsic positive end-expiratory pressure (PEEPi) is important in planning the management of ventilated patients. Here, a new recursive least squares method for on-line monitoring of PEEPiis proposed for mechanically ventilated patients. The procedure is based on the first-order model of respiratory mechanics applied to experimental measurements obtained from eight ventilator-dependent patients ventilated with four different ventilatory modes. The model PEEPi(PEEPi,mod) was recursively constructed on an inspiration-by-inspiration basis. The results were compared with two well-established techniques to assess PEEPi: end-expiratory occlusion to measure static PEEPi(PEEPi,st) and change in airway pressure preceding the onset of inspiratory airflow to measure dynamic PEEPi(PEEPi,dyn). PEEPi,modwas significantly correlated with both PEEPi,dyn( r = 0.77) and PEEPi,st( r= 0.90). PEEPi,mod(5.6 ± 3.4 cmH2O) was systematically >PEEPi,dynand PEEPi,st(2.7 ± 1.9 and 8.1 ± 5.5 cmH2O, respectively), in all the models without external PEEP. Focusing on the five patients with chronic obstructive pulmonary disease, PEEPi,modwas significantly correlated with PEEPi,st( r = 0.71), whereas PEEPi,dyn( r = 0.22) was not. When PEEP was set 5 cmH2O above PEEPi,st, all the methods correctly estimated total PEEP, i.e., 11.8 ± 5.3, 12.5 ± 5.0, and 12.0 ± 4.7 cmH2O for PEEPi,mod, PEEPi,st, and PEEPi,dyn, respectively, and were highly correlated (0.97–0.99). We interpreted PEEPi,modas the lower bound of PEEPi,stand concluded that our method is suitable for on-line monitoring of PEEPiin mechanically ventilated patients.
Increased spinal monoamine concentrations after chronic thoracic dorsal rhizotomy in goats
Authors: Mitchell Gordon S. , Bach Karen B. , Martin Patricia A. , Foley Kevin T. , Olson E. B. , Brownfield Mark S. , Miletic Vjeko , Behan Mary , McGuirk Sheila , Sloan Harry E.
Published: December 2017

In goats, bilateral thoracic dorsal rhizotomy (TDR) causes severe ventilatory failure during exercise, followed by progressive functional recovery. We investigated spinal neurochemical changes associated with TDR and/or functional recovery by measuring spinal concentrations of the monoamines serotonin (5-HT), norepinephrine, and dopamine via HPLC. Changes in 5-HT and calcitonin gene-related peptide were visualized with immunohistochemistry. Goat spinal cords were compared 4–15 mo after TDR from T2to T12 ( n = 7) with sham-operated ( n = 4) or unoperated controls ( n = 4). TDR increased the concentration of cervical 5-HT (C5–C6; 122% change), caudal thoracic norepinephrine (T7–T11; 53% change), and rostral thoracic dopamine (T3–T6; 234% change). TDR increased 5-HT-immunoreactive terminal density (dorsal and ventral horns) and nearly eliminated calcitonin gene-related peptide immunoreactivity in the superficial laminae of the dorsal horn in rostral thoracic segments; both effects became less pronounced in caudal thoracic segments. Thus TDR elevates monoamine concentrations in discrete spinal regions, including possible compensatory changes in descending serotonergic inputs to spinal segments not directly affected by TDR (i.e., cervical) but associated with functionally related motor nuclei (i.e., phrenic nucleus).
Renal responsiveness to aldosterone during exposure to simulated microgravity
Authors: Convertino Victor A. , Luetkemeier Maurie J. , Elliott James J. , Ludwig David A. , Wade Charles E.
Published: December 2017

We measured renal functions and hormones associated with fluid regulation after a bolus injection of aldosterone (Ald) during head-down tilt (HDT) bed rest to test the hypothesis that exposure to simulated microgravity altered renal responsiveness to Ald. Six male rhesus monkeys underwent two experimental conditions (HDT and control, 72 h each) with each condition separated by 9 days of ambulatory activities to produce a crossover counterbalance design. One test condition was continuous exposure to 10° HDT; the second was a control, defined as 16 h per day of 80° head-up tilt and 8 h prone. After 72 h of exposure to either test condition, monkeys were moved to the prone position, and we measured the following parameters for 4 h after injection of 1-mg dose of Ald: urine volume rate (UVR); renal Na+/K+ excretion ratio; renal clearances of creatinine, Na+, osmolality, and free water; and circulating hormones [Ald, renin activity (PRA), vasopressin (AVP), and atrial natriuretic peptide (ANP)]. HDT increased Na+ clearance, total renal Na+ excretion, urine Na+ concentration, and fractional Na+excretion, compared with the control condition, but did not alter plasma concentrations of Ald, PRA, and AVP. Administration of Ald did not alter UVR, creatinine clearance, Ald, PRA, AVP, or ANP but reduced Na+ clearance, total renal Na+ excretion, urinary Na+/K+ ratio, and osmotic clearance. Although reductions in Na+ clearance and excretion due to Ald were greater during HDT than during control, the differential (i.e., interaction) effect was minimal between experimental conditions. Our data suggest that exposure to microgravity increases renal excretion of Na+ by a natriuretic mechanism other than a change in renal responsiveness to Ald.
Effects of sevoflurane on the contractility of ferret ventricular myocardium
Authors: Bartunek Anna E. , Housmans Philippe R.
Published: December 2017

Isotonic and isometric variables of contractility and relaxation of isolated ferret right ventricular papillary muscles were measured before and during exposure to incremental concentrations of sevoflurane (0–4.9% vol/vol) (30°C) ( n = 9). In a second group of muscles ( n = 8), effects of sevoflurane were compared with those of low [Ca2+]o(0.45–2.25 mM in steps of 0.45 mM). Sevoflurane caused a reversible concentration-dependent decrease in contractility (ED50of developed force 4.6 ± 0.9% vol/vol). When compared with twitches of equal amplitude in low extracellular Ca2+concentration, sevoflurane accelerated both isometric and isotonic relaxation. The myocardial depressant effect of sevoflurane is less than that of isoflurane and results mainly from a decrease of intracellular Ca2+availability. The abbreviated isometric relaxation likely reflects a decrease in Ca2+sensitivity and the faster isotonic relaxation may reflect a mild stimulation of Ca2+uptake by the sarcoplasmic reticulum.
Feedforward sympathetic coronary vasodilation in exercising dogs
Authors: Gorman Mark W. , Tune Johnathan D. , Richmond Keith Neu , Feigl Eric O.
Published: December 2017

The hypothesis that exercise-induced coronary vasodilation is a result of sympathetic activation of coronary smooth muscle β-adrenoceptors was tested. Ten dogs were chronically instrumented with a flow transducer on the circumflex coronary artery and catheters in the aorta and coronary sinus. During treadmill exercise, coronary venous oxygen tension decreased with increasing myocardial oxygen consumption, indicating an imperfect match between myocardial blood flow and oxygen consumption. This match was improved after α-adrenoceptor blockade with phentolamine but was significantly worse than control after α + β-adrenoceptor blockade with phentolamine plus propranolol. The response after α-adrenoceptor blockade included local metabolic vasodilation plus a β-adrenoceptor vasodilator component, whereas the response after α + β-adrenoceptor blockade contained only the local metabolic vasodilator component. The large difference in coronary venous oxygen tensions during exercise between α-adrenoceptor blockade and α + β-adrenoceptor blockade indicates that there is significant feedforward β-adrenoceptor coronary vasodilation in exercising dogs. Coronary venous and estimated myocardial interstitial adenosine concentrations did not increase during exercise before or after α + β-adrenoceptor blockade, indicating that adenosine levels did not increase to compensate for the loss of feedforward β-adrenoceptor-mediated coronary vasodilation. These results indicate a meaningful role for feedforward β-receptor-mediated sympathetic coronary vasodilation during exercise.
Total power output generated during dynamic knee extensor exercise at different contraction frequencies
Authors: Ferguson Richard A. , Aagaard Per , Ball Derek , Sargeant Anthony J. , Bangsbo Jens
Published: December 2017

A novel approach has been developed for the quantification of total mechanical power output produced by an isolated, well-defined muscle group during dynamic exercise in humans at different contraction frequencies. The calculation of total power output comprises the external power delivered to the ergometer (i.e., the external power output setting of the ergometer) and the “internal” power generated to overcome inertial and gravitational forces related to movement of the lower limb. Total power output was determined at contraction frequencies of 60 and 100 rpm. At 60 rpm, the internal power was 18 ± 1 W (range: 16–19 W) at external power outputs that ranged between 0 and 50 W. This was less ( P < 0.05) than the internal power of 33 ± 2 W (27–38 W) at 100 rpm at 0–50 W. Moreover, at 100 rpm, internal power was lower ( P < 0.05) at the higher external power outputs. Pulmonary oxygen uptake was observed to be greater ( P< 0.05) at 100 than at 60 rpm at comparable total power outputs, suggesting that mechanical efficiency is lower at 100 rpm. Thus a method was developed that allowed accurate determination of the total power output during exercise generated by an isolated muscle group at different contraction frequencies.
Tracheal constrictor drive above the apneic threshold in anesthetized dogs
Authors: Silverman J. A. , Sommer L. Z. , Robicsek A. , Dickstein J. , Greenberg A. , Kruger J. , Rucker J. , Volgyesi G. , Fisher J. A. , Iscoe S.
Published: December 2017

We have previously shown that raising arterial Pco 2 (PaCO2 ) by small increments in dogs ventilated below the apneic threshold (AT) results in almost complete tracheal constriction before the return of phrenic activity (Dickstein JA, Greenberg A, Kruger J, Robicsek A, Silverman J, Sommer L, Sommer D, Volgyesi G, Iscoe S, and Fisher JA. J Appl Physiol 81: 1844–1849, 1996). We hypothesized that, if increasing chemical drive above the AT mediates increasing constrictor drive to tracheal smooth muscle, then pulmonary slowly adapting receptor input should elicit more tracheal dilation below the AT than above. In six methohexital sodium-anesthetized, paralyzed, and ventilated dogs, we measured changes in tracheal diameter in response to step increases in tidal volume (Vt) or respiratory frequency (f) below and above the AT at constant PaCO2 (∼40 and 67 Torr, respectively). Increases in Vt(400–1,200 ml) caused significantly more ( P = 0.005) tracheal dilation below than above AT (7.0 ± 2.2 vs. 2.8 ± 1.0 mm, respectively). In contrast, increases in f (14–22 breaths/min) caused similar ( P = 0.93) tracheal dilations below and above (1.0 ± 1.3 and 1.0 ± 0.8 mm, respectively) AT. The greater effectiveness of dilator stimuli below compared with above the AT is consistent with the hypothesis that drive to tracheal smooth muscle increases even after attainment of maximal constriction. Our results emphasize the importance of controlling Pco 2 with respect to the AT when tracheal smooth muscle tone is experimentally altered.
Vasomotor tone does not affect perfusion heterogeneity and gas exchange in normal primate lungs during normoxia
Authors: Glenny Robb W. , Robertson H. Thomas , Hlastala Michael P.
Published: December 2017

To determine whether vasoregulation is an important cause of pulmonary perfusion heterogeneity, we measured regional blood flow and gas exchange before and after giving prostacyclin (PGI2) to baboons. Four animals were anesthetized with ketamine and mechanically ventilated. Fluorescent microspheres were used to mark regional perfusion before and after PGI2 infusion. The lungs were subsequently excised, dried inflated, and diced into ∼2-cm3 pieces ( n = 1,208–1,629 per animal) with the spatial coordinates recorded for each piece. Blood flow to each piece was determined for each condition from the fluorescent signals. Blood flow heterogeneity did not change with PGI2 infusion. Two other measures of spatial blood flow distribution, the fractal dimension and the spatial correlation, did not change with PGI2 infusion. Alveolar-arterial O2 differences did not change with PGI2 infusion. We conclude that, in normal primate lungs during normoxia, vasomotor tone is not a significant cause of perfusion heterogeneity. Despite the heterogeneous distribution of blood flow, active regulation of regional perfusion is not required for efficient gas exchange.