bluuebunny/crossref_metadata_2025 huggingface dataset:
Localization of the extracellular Ca(2+)-sensing receptor and PTH/PTHrP receptor in rat kidney
Authors: Riccardi D. , Lee W. S. , Lee K. , Segre G. V. , Brown E. M. , Hebert S. C.
Published: December 2017

Using a strategy based on homology to the bovine parathyroid Ca(2+)-sensing receptor previously identified by us (5), we have recently isolated an extracellular, G protein-coupled Ca2+/ polyvalent cation-sensing receptor, RaKCaR (22), from rat kidney. The localization and physiological role(s) of this receptor in the kidney are not well understood. In the present study, we assessed the distribution of mRNAs for RaKCaR and the parathyroid hormone/parathyroid hormone-related protein (PTH/PTHrP) receptor along the rat nephron by in situ hybridization and reverse transcriptase-polymerase chain reaction of microdissected nephron segments. Our results show that transcripts for both receptors coexpress at glomeruli, proximal convoluted tubule, proximal straight tubule, cortical thick ascending limb, distal convoluted tubule, and cortical collecting duct. In addition, RaKCaR (but not PTH/PTHrP receptor) transcripts were found in the medullary thick ascending limb and outer medullary and inner medullary collecting ducts. These findings raise the possibility of roles for RaKCaR not only in the regulation of divalent mineral reabsorption but also in water reabsorption and urinary concentration. Taken together, our results provide new insights in understanding the effects of hypercalcemia on hormone-stimulated salt and water transport.
Localization of the high-affinity glutamate transporter EAAC1 in rat kidney
Authors: Shayakul Chairat , Kanai Yoshikatsu , Lee Wen-Sen , Brown Dennis , Rothstein Jeffrey D. , Hediger Matthias A.
Published: December 2017

Most amino acids filtered by the glomerulus are reabsorbed in the kidney via specialized transport systems. Recently, the cDNA encoding a high-affinity glutamate transporter, EAAC1, has been isolated and shown to be expressed at high levels in the kidney. To determine the potential role of EAAC1 in renal acidic amino acid reabsorption, the distribution of EAAC1 mRNA and protein in rat kidney was examined. In situ hybridization revealed that EAAC1 mRNA is expressed predominantly in S2 and S3 segments of the proximal tubules and at low levels in the inner stripe of outer medulla and inner medulla. Polyclonal antibodies raised against the carboxy terminus of EAAC1 recognized a single band of ∼70 kDa on Western blots of membrane protein from kidney cortex and medulla. Immunofluorescence microscopy revealed intense signals in the luminal membrane of S2 and S3 segments and weaker signals in S1 segments, descending thin limbs of long-loop nephrons, medullary thick ascending limbs, and distal convoluted tubules. These results are consistent with EAAC1 encoding the previously described apical high-affinity glutamate transporter in the kidney that mediates reabsorption of acidic amino acids in tubules beyond early proximal tubule S1 segments. Potential additional roles of EAAC1 in acid/base balance, cell volume regulation, and amino acid metabolism are discussed.
Renal Na-Sicotransporter NaSi-1 is inhibited by heavy metals
Authors: Markovich Daniel , Knight David
Published: December 2017

Heavy metal intoxication leads to a number of reabsorptive and secretory defects in renal transport systems. We have studied the effects of several heavy metals on the expression of the renal Na-Sicotransporter NaSi-1. NaSi-1 cRNA was injected into Xenopusoocytes, and Na-Sicotransport activity was measured in the presence of mercury, lead, cadmium, or chromium. Mercury strongly inhibited NaSi-1 transport irreversibly by reducing both maximal velocity ( Vmax) and Michaelis constant ( Km) for inorganic sulfate (Si). Lead inhibited NaSi-1 transport reversibly by decreasing Vmaxbut not Kmfor Si. Cadmium showed weak reversible inhibition of NaSi-1 transport by decreasing only NaSi-1 Vmax. Chromium strongly inhibited NaSi-1 cotransport reversibly by reducing Kmfor Siby sevenfold, most probably by binding to the Sisite, due to the strong structural similarity between the C[Formula: see text] and[Formula: see text] substrates. In conclusion, this study presents an initial report demonstrating heavy metals inhibit renal brush border Na-Sicotransport via the NaSi-1 protein through various mechanisms and that this blockade may be responsible for sulfaturia following heavy metal intoxication.
Heterogeneity of glutathione synthesis and secretion in the proximal tubule of the rabbit
Authors: Parks Lisa D. , Zalups Rudolfs K. , Barfuss Delon W.
Published: December 2017

This study was designed to examine the synthesis and possible secretion of glutathione (GSH) in the S1, S2, and S3segments of the rabbit proximal tubule. GSH synthesis and secretion rates were measured in the three segments of the proximal tubule, using the isolated perfused renal tubule technique. Tritiated (3H) glycine was perfused into segments and synthesized[Formula: see text]GSH (3H on the glycine residue) was measured in the bathing solution, collectate, and tubule extract. In the S1segments, GSH was synthesized at the rate of 8.65 ± 0.88 fmol ⋅ min−1⋅ mm−1tubule length and preferentially secreted into the lumen at the rate of 7.28 ± 0.74 fmol ⋅ min−1⋅ mm−1. The difference between synthesis and secretion appeared in the bathing solution. The S2segment synthesized GSH at the rate of 3.88 ± 0.82 and secreted GSH at the rate of 2.78 ± 0.57 fmol ⋅ min−1⋅ mm−1. GSH synthesis and secretion rates in the S3segment were 5.45 ± 1.19 and 4.22 ± 1.16 fmol ⋅ min−1⋅ mm−1, respectively. Cellular concentrations of[Formula: see text]GSH increased along the length of the proximal tubule, with the highest concentrations in the S3segment. The respective GSH cellular concentrations in the S1, S2, and S3segments were 35.89 ± 10.51, 49.65 ± 9.32, and 116.90 ± 15.76 μM. These findings indicate that there is heterogeneity of GSH synthesis along the proximal tubule and that synthesized GSH is secreted preferentially into the lumen.
Potassium permeability in the absence of fluid reabsorption in proximal tubule of the anesthetized rat
Authors: Wilson Rod W. , Wareing Mark , Kibble Jon , Green Roger
Published: December 2017

A luminal microperfusion technique was used to examine the K+ permeability of surface proximal convoluted tubules (PCT) in the kidney of anesthetized rats. Transtubular potassium concentration ([K+]) gradients were varied by altering the concentration of KCl in luminal perfusates, to which 32 mmol/l of the impermeant solute raffinose was also added to prevent net fluid reabsorption. The arithmetic mean transtubular [K+] gradient was highly predictive of net potassium flux, yielding an apparent K+ permeability of 31.9 ± 1.7 × 10−5 cm/s in the absence of fluid reabsorption. When compared using identical calculation techniques, we found this was not significantly different from the permeability derived in a previous study when fluid reabsorption was present [J. D. Kibble, M. Wareing, R. W. Wilson, and R. Green. Am. J. Physiol. 268 ( Renal Fluid Electrolyte Physiol. 27): F778–F783, 1995]. We conclude that fluid reabsorption does not affect the apparent permeability of the proximal tubule to potassium. The apparent permeability to86Rb, measured following its addition to luminal perfusates, was not significantly different from the value obtained for K+, suggesting that rubidium is a useful marker for net potassium movements in the PCT of the rat.
A combination of NaCl and urea enhances survival of IMCD cells to hyperosmolality
Authors: Santos Bento C. , Chevaile Alejandro , Hébert Marie-Josée , Zagajeski Jane , Gullans Steven R.
Published: December 2017

Physiological adaptation to the hyperosmolar milieu of the renal medulla involves a complex series of signaling and gene expression events in which NaCl and urea activate different cellular processes. In the present study, we evaluated the effects of NaCl and urea, individually and in combination, on the viability of murine inner medullary collecting duct (mIMCD3) cells. Exposure to hyperosmolar NaCl or urea caused comparable dose- and time-dependent decreases in cell viability, such that 700 mosmol/kgH2O killed >90% of the cells within 24 h. In both cases, cell death was an apoptotic event. For NaCl, loss of viability at 24 h paralleled decreases in RNA and protein synthesis at 4 h, whereas lethal doses of urea had little or no effect on these biosynthetic processes. Cell cycle analysis showed both solutes caused a slowing of the G2/M phase. Surprisingly, cells exposed to a combination of NaCl + urea were significantly more osmotolerant such that 40% survived 900 mosmol/kgH2O. Madin-Darby canine kidney cells but not human umbilical vein endothelial cells also exhibited a similar osmotolerance response. Enhanced survival was not associated with a restoration of normal biosynthetic rates or cell cycle progression. However, the combination of NaCl + urea resulted in a shift in Hsp70 expression that appeared to correlate with survival. In conclusion, hyperosmolar NaCl and urea activate independent and complementary cellular programs that confer enhanced osmotolerance to renal medullary epithelial cells.
Hensin, the polarity reversal protein, is encoded by DMBT1, a gene frequently deleted in malignant gliomas
Authors: Takito Jiro , Yan Lunbiao , Ma Jian , Hikita Chinami , Vijayakumar S. , Warburton D. , Al-Awqati Qais
Published: December 2017

The band 3 anion exchanger is located in the apical membrane of a β-intercalated clonal cell line, whereas the vacuolar H+-ATPase is present in the basolateral membrane. When these cells were seeded at confluent density, they converted to an α-phenotype, localizing each of these proteins to the opposite cell membrane domain. The reversal of polarity is induced by hensin, a 230-kDa extracellular matrix protein. Rabbit kidney hensin is a multidomain protein composed of eight SRCR (“scavenger receptor, cysteine rich”), two CUB (“C1r/C1s Uegf Bmp1”), and one ZP (“zona pellucida”) domain. Other proteins known to have these domains include CRP-ductin, a cDNA expressed at high levels in mouse intestine (8 SRCR, 5 CUB, 1 ZP), ebnerin, a protein cloned from a rat taste bud library (4 SRCR, 3 CUB, 1 ZP), and DMBT1, a sequence in human chromosome 10q25–26 frequently deleted in malignant gliomas (9 SRCR, 2 CUB, 1 ZP). Rabbit and mouse hensin genomic clones contained a new SRCR that was not found in hensin cDNA but was homologous to the first SRCR domain in DMBT1. Furthermore, the 3′-untranslated regions and the signal peptide of hensin were homologous to those of DMBT1. Mouse genomic hensin was localized to chromosome 7 band F4, which is syntenic to human 10q25–26. These data suggest that hensin and DMBT1 are alternatively spliced forms of the same gene. The analysis of mouse hensin bacterial artificial chromosome (BAC) genomic clone by sequencing and Southern hybridization revealed that the gene also likely encodes CRP-ductin. A new antibody against the mouse SRCR1 domain recognized a protein in the mouse and rabbit brain but not in the immortalized cell line or kidney, whereas an antibody to SRCR6 and SRCR7 domains which are present in all the transcripts, recognized proteins in intestine, kidney, and brain from several species. The most likely interpretation of these data is that one gene produces at least three transcripts, namely, hensin, DMBT1, and CRP-ductin. Hensin may participate in determining the polarized phenotype of other epithelia and brain cells.
Receptors for PTH and PTHrP: their biological importance and functional properties
Authors: Mannstadt Michael , Jüppner Harald , Gardella Thomas J.
Published: December 2017

The type 1 receptor (PTH1R) for parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) is a G protein-coupled receptor that is highly expressed in bone and kidney and mediates in these tissues the PTH-dependent regulation of mineral ion homeostasis. The PTH1R also mediates the paracrine actions of PTHrP, which play a particularly vital role in the process of endochondral bone formation. These important functions, the likely involvement of the PTH1R in certain genetic diseases affecting skeletal development and calcium homeostasis, and the potential utility of PTH in treating osteoporosis have been the driving force behind intense investigations of both the receptor and its peptide ligands. Recent lines of work have led to the identification of constitutively active PTH1Rs in patients with Jansen's metaphyseal chondrodysplasia, the demonstration of inverse agonism by certain ligand analogs, and the discovery of the PTH-2 receptor subtype that responds to PTH but not PTHrP. As reviewed herein, a detailed exploration of the receptor-ligand interaction process is currently being pursued through the use of site-directed mutagenesis and photoaffinity cross-linking methods; ultimately, such work could enable the development of novel PTH receptor ligands that have therapeutic value in treating diseases such as osteoporosis and certain forms of hypercalcemia.
Nitric oxide activates PKCα and inhibits Na+-K+-ATPase in opossum kidney cells
Authors: Liang Mingyu , Knox Franklyn G.
Published: December 2017

Nitric oxide (NO) reduces the molecular activity of Na+-K+-ATPase in opossum kidney (OK) cells, a proximal tubule cell line. In the present study, we investigated the cellular mechanisms for the inhibitory effect of NO on Na+-K+-ATPase. Sodium nitroprusside (SNP), a NO donor, inhibited Na+-K+-ATPase in OK cells, but not in LLC-PK1cells, another proximal tubule cell line. Similarly, phorbol 12-myristate 13-acetate, a protein kinase C (PKC) activator, inhibited Na+-K+-ATPase in OK, but not in LLC-PK1, cells. PKC inhibitors staurosporine or calphostin C, but not the protein kinase G inhibitor KT-5823, abolished the inhibitory effect of NO on Na+-K+-ATPase in OK cells. Immunoblotting demonstrated that treatment with NO donors caused significant translocation of PKCα from cytosolic to particulate fractions in OK, but not in LLC-PK1, cells. Furthermore, the translocation of PKCα in OK cells was attenuated by either the phospholipase C inhibitor U-73122 or the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one. U-73122 also blunted the inhibitory effect of SNP on Na+-K+-ATPase in OK cells. The phospholipase A2inhibitor AACOCF3 did not blunt the inhibitory effect of SNP on Na+-K+-ATPase in OK cells. AACOCF3 alone, however, also decreased Na+-K+-ATPase activity in OK cells. In conclusion, our results demonstrate that NO activates PKCα in OK, but not in LLC-PK1, cells. The activation of PKCα in OK cells by NO is associated with inhibition of Na+-K+-ATPase.
Effects of variations in food intake on renal sodium pump activity and its gene expression inPsammomyskidney
Authors: Scherzer P. , Nachliel I. , Ziv E. , Bar-On H. , Popovtzer M. M.
Published: December 2017

Psammomys obesus lives in an arid environment and feeds on saltbush. When animals are fed a laboratory diet, urine osmolarity drops. To explore the mechanism(s) of water conservation, we measured renal function, kidney solute content, Na-K-ATPase activity, and mRNA in several groups: group I (saltbush diet, 18 g/day, 4.2 g protein); group II (laboratory diet, 10 g/day, 1.8 g protein); and group III, the same as group I, and group IV, the same as group II, both plus a 1-day fast. Urine osmolarity was 2,223 ± 160, 941 ± 144, 1,122 ± 169 and 648 ± 70.9 mosM in groups I, II, III, and IV, respectively. Tissue osmolarities in cortex, outer medulla, and inner medulla, respectively, were 349 ± 14, 644 ± 63, and 1,152 ± 34 μosM/mg tissue in group I; 317 ± 24, 493 ± 17, and 766 ± 60 μosM/mg tissue in group II; 335 ± 6, 582 ± 15, 707 ± 35 μosM/mg tissue in group III; and 314 ± 18, 490 ± 22, and 597 ± 29 μosM/mg tissue in group IV. There were no differences in Na-K-ATPase activity and mRNA in cortex and in medulla between groups I and II, whereas in group III Na-K-ATPase activity and mRNA increased in cortex and outer medulla. These results suggest a key role for urea in corticomedullary osmotic gradient of Psammomys. The absence of differences in Na-K-ATPase activity and mRNA between groups I and II despite differences in tissue sodium concentrations is consistent with Na-K-ATPase-independent Na absorption. Increased Na-K-ATPase activity and mRNA in fasting suggest transition to Na-K-ATPase- dependent Na transport.
CytochromeP-450 as a source of catalytic iron in minimal change nephrotic syndrome in rats
Authors: Liu Hua , Shah Sudhir V. , Baliga Radhakrishna
Published: December 2017

We have recently demonstrated an important pathogenic role for glomerular catalytic iron in the puromycin aminonucleoside (PAN) induced minimal change nephrotic syndrome (MCNS). The source of this iron capable of catalyzing free radical reactions is not known. We examined the role of cytochrome P-450 (CYP) as a source of catalytic iron in a model MCNS induced by single injection of PAN to rats. Treatment of PAN resulted in a marked increase in the catalytic iron associated with significant loss of glomerular CYP content. Administration of CYP inhibitors significantly prevented the injury-induced loss of CYP content and the increase in the catalytic iron in the glomeruli accompanied by a marked decrease in proteinuria. In an in vitro study utilizing glomerular epithelial cells (GEC), CYP inhibitors also markedly prevented the PAN-induced increase in the catalytic iron and hydroxyl radical formation accompanied by significant protection against PAN-induced cytotoxicity. Taken together our data indicate that the CYP, a group of heme protein, may serve as a significant source of this catalytic iron.
Arginine vasopressin stimulates mesangial cell proliferation by activating the epidermal growth factor receptor
Authors: Ghosh Paramita M. , Mikhailova Margarita , Bedolla Roble , Kreisberg Jeffrey I.
Published: December 2017

The potent vasoconstrictor arginine vasopressin (AVP) is also a mitogen for mesangial cells. Treatment with AVP decreased transit time through the cell cycle. AVP-stimulated mesangial cell growth by activating both the Ras mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K) cell signaling pathways. Both the selective PI3K inhibitor LY-294002 and the MAPK kinase (MEK) inhibitor PD-98059 inhibited AVP-stimulated mesangial cell proliferation. However, LY-294002 was more potent, indicating an important role for PI3K activation in AVP-stimulated mesangial cell proliferation. AVP appeared to exert its effect on MAPK and PI3K activation, as well as on cell proliferation, by activating the epidermal growth factor receptor (EGF-R). Pretreatment with the tyrphostin-derived EGF-R antagonist AG-1478 inhibited mesangial cell proliferation as well as the activation of extracellular signal-regulated kinase 1/2 (ERK1/2 or p42/p44MAPK), and p70S6 kinase, a downstream effector of PI3K, providing evidence that MAPK and PI3K activation, respectively, occurred downstream of EGF-R activation. Treatment with rapamycin, an inhibitor of the p70S6 kinase activator mTOR, also resulted in growth inhibition, further suggesting the importance of the PI3K signaling pathway in AVP-induced proliferation. AVP treatment appeared to transactivate EGF-R by inducing tyrosine phosphorylation of the Ca2+/protein kinase C (PKC)-dependent nonreceptor tyrosine kinase, Pyk2, leading to Pyk2/c-Src association and c-Src activation. This was followed by association of c-Src with EGF-R and EGF-R activation. These data suggested that AVP-stimulated Pyk2 tyrosine phosphorylation to activate c-Src, thereby leading to EGF-R transactivation.
Delayed branching of endothelial capillary-like cords in glycated collagen I is mediated by early induction of PAI-1
Authors: Chen Jun , Brodsky Sergey , Li Hong , Hampel Dierk J. , Miyata Toshio , Weinstein Talia , Gafter Uzi , Norman Jill T. , Fine Leon G. , Goligorsky Michael S.
Published: December 2017

Development of micro- and macrovascular disease in diabetes mellitus (DM) warrants a thorough investigation into the repertoire of endothelial cell (EC) responses to diabetic environmental cues. Using human umbilical vein EC (HUVEC) cultured in three-dimensional (3-D) native collagen I (NC) or glycated collagen I (GC), we observed capillary cord formation that showed a significant reduction in branching when cells were cultured in GC. To gain insight into the molecular determinants of this phenomenon, HUVEC subjected to GC vs. NC were studied using a PCR-selected subtraction approach. Nine different genes were identified as up- or downregulated in response to GC; among those, plasminogen activator inhibitor-1 (PAI-1) mRNA was found to be upregulated by GC. Western blot analysis of HUVEC cultured on GC showed an increase in PAI-1 expression. The addition of a neutralizing anti-PAI-1 antibody to HUVEC cultured in GC restored the branching pattern of formed capillary cords. In contrast, supplementation of culture medium with the constitutively active PAI-1 reproduced defective branching patterns in HUVEC cultured in NC. Ex vivo capillary sprouting in GC was unaffected in PAI-1 knockout mice but was inhibited in wild-type mice. This difference persisted in diabetic mice. In conclusion, the PCR-selected subtraction technique identified PAI-1 as one of the genes characterizing an early response of HUVEC to the diabetic-like interstitial environment modeled by GC and responsible for the defective branching of endothelial cells. We propose that an upregulation of PAI-1 is causatively linked to the defective formation of capillary networks during wound healing and eventual vascular dropout characteristic of diabetic nephropathy.
Transport of plasma proteins across vasa recta in the renal medulla
Authors: Zhang Wensheng , Edwards Aurélie
Published: December 2017

In this study, we have extended a mathematical model of microvascular exchange in the renal medulla to elucidate the mechanisms by which plasma proteins are transported between vasa recta and the interstitium. In contrast with other work, a distinction was made between the paracellular pathway and the transcellular route (i.e., water channels) in descending vasa recta (DVR). Our model first indicates that concentration polarization on the interstitial side of vasa recta has a negligible effect on medullary function. Our results also suggest that, whereas proteins are cleared from the interstitium by convection, both diffusion and convection play a role in carrying proteins to the interstitium. In those regions where transcapillary oncotic pressure gradients favor volume influx through the paracellular pathway in DVR, diffusion is the only means by which proteins can penetrate the interstitium. Whether the source of interstitial protein is DVR or ascending vasa recta depends on medullary depth, vasa recta permeability to proteins, and vasa recta reflection coefficients to small solutes and proteins. Finally, our model predicts significant axial protein gradients in the renal medullary interstitium.
Effects of plasma proteins on sieving of tracer macromolecules in glomerular basement membrane
Authors: Lazzara Matthew J. , Deen William M.
Published: December 2017

It was found previously that the sieving coefficients of Ficoll and Ficoll sulfate across isolated glomerular basement membrane (GBM) were greatly elevated when BSA was present at physiological levels, and it was suggested that most of this increase might have been the result of steric interactions between BSA and the tracers (5). To test this hypothesis, we extended the theory for the sieving of macromolecular tracers to account for the presence of a second, abundant solute. Increasing the concentration of an abundant solute is predicted to increase the equilibrium partition coefficient of a tracer in a porous or fibrous membrane, thereby increasing the sieving coefficient. The magnitude of this partitioning effect depends on solute size and membrane structure. The osmotic reduction in filtrate velocity caused by an abundant, mostly retained solute will also tend to elevate the tracer sieving coefficient. The osmotic effect alone explained only about one-third of the observed increase in the sieving coefficients of Ficoll and Ficoll sulfate, whereas the effect of BSA on tracer partitioning was sufficient to account for the remainder. At physiological concentrations, predictions for tracer sieving in the presence of BSA were found to be insensitive to the assumed shape of the protein (sphere or prolate spheroid). For protein mixtures, the theoretical effect of 6 g/dl BSA on the partitioning of spherical tracers was indistinguishable from that of 3 g/dl BSA and 3 g/dl IgG. This suggests that for partitioning and sieving studies in vitro, a good experimental model for plasma is a BSA solution with a mass concentration matching that of total plasma protein. The effect of plasma proteins on tracer partitioning is expected to influence sieving not only in isolated GBM but also in intact glomerular capillaries in vivo.
Ca-induced Ca release: lessons regarding cell models
Authors: Harder David R.
Published: December 2017

This essay looks at the historical significance of an APS classic paper that is freely available online:

Fabiato A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol Cell Physiol 245: C1—C14, 1983 ( http://ajpcell.physiology.org/cgi/reprint/245/1/C1 ).
Comparative study on the erythropoietic effects of androgens and their mode of action
Authors: Gorshein Dov , Murphy Scott , Gardner Frank H.
Published: December 2017

The comparative erythropoietic activity of eight androgens in mice is reported. Polycythemic mice were used in the posthypoxic interval for determination of 59Fe utilization and reticulocyte count. The most potent compounds were 19-nortestosterone decanoate and 19-nortestosterone phenylpropionate. The mechanism of erythropoietic stimulation by 19-nortestosterone decanoate is similar to that of testosterone.
Metabolic and thermal responses of women during cooling in water
Authors: Kollias J. , Barlett L. , Bergsteinova V. , Skinner J. S. , Buskirk E. R. , Nicholas W. C.
Published: December 2017

The metabolic and thermal responses of 10 young women, 3 lean (21–24% fat) and 7 obese (29–41% fat), were measured during head-out immersion in a stirred water bath maintained at 20°C. Continuous measurements of heat production (M), rectal (Tre, esophageal (Tes), and skin temperatures were obtained. The rate and magnitude of the increase in M and decrease in core temperatures were significantly greater in the lean than the obese group. Tissue insulation values for lean women were similar to those reported for diving and nondiving Korean women in 30°C water. Lean women with 22% body fat have a larger SA/mass ratio than men of comparable body fat content and cool at a greater rate. It is concluded that SA/mass as well as body fatness and size must be considered in the overall metabolic and thermal responses to cold exposure.
Additive effects of acetylcholine released by vagal nerve stimulation on atrial rate
Authors: Hondeghem L. M. , Mouton E. , Stassen T. , De Geest H.
Published: December 2017

In reserpinized dogs, the decrease in atrial rate (AR) as a function of the frequency of stimulation (supramaximal strength) of a single vagal nerve can be described satisfactorily by a rectangular hyperbola (RH). If the RH of one vagal nerve has been determined and if one point of the RH of the other vagal nerve is known, then the latter RH can be determined. Both RHs being known and assuming that the acetylcholine released by the right and left vagal nerves is additive, the slowing of AR by simultaneous stimulation of both nerves can be predicted. A minor systematic deviation from the predicted AR during simultaneous stimulation is usually found, which could be accounted for by a time dependent decrease of the effect of vagal nerve stimulation. The results are qualitatively similar during norepinephrine infusion. We propose that, although the vagal innervation may vary from pacemaker cell to pacemaker cell, the ratio of the activities of the two vagal nerves is constant throughout the sinoatrial node.
De novo biosynthesis of plasminogen in the anephric rat
Authors: Siefring G. E. , Castellino F. J.
Published: December 2017

Two major forms of plasminogen exist in the plasma of many different species. Each form is present in normal amounts in anephric patients and each form is synthesized de novo in bilaterally nephrectomized rats. Although the rate of synthesis of each form of plasminogen is lower than normal immediately after nephrectomy, the rate of plasma protein synthesis is also apparently lower than normal in these cases. This is thought to reflect the fact that the nephrectomized rat is in a state of circulatory distress immediately after kidney ligation. It is concluded that the kidney is not responsible for de novo biosynthesis of plasminogen. This point has been the subject of some confusion.
Specificity of swim training on maximum oxygen uptake
Authors: Magel J. R. , Foglia G. F. , McArdle W. D. , Gutin B. , Pechar G. S. , Katch F. I.
Published: December 2017

The present study was designed to evaluate the specificity-generality of the cardiorespiratory adaptation to swim training. Fifteen male, college age, recreational swimmers utilized interval swim training procedures 1 h/day, 3 days/wk for 10 wk. Maximum physiological measures (Vo2, Ve, HR, R, and work time) were determined prior to and following swim training during treadmill running and tethered swimming Vo2max tests. Identical measures were made on 15 control subjects who did not participate in any form of training. As a result of training, the experimental subjects significantly increased (all P is less than 0.01) their swimming Vo2max (380 ml/min) max Ve (14.9 l/min,btps) and max swim time (4.0 min), and significantly decreased (P is less than 0.05) their max HR (3.5 beats/min). However, there was no significant improvement in Vo2max when the same subjects were evaluated by the treadmill running test. Differences in Vo2max and associated measures during running and swimming tests remained essentially unchanged for control subjects. The results of the present study clearly demonstrate the specificity of the cardiorespiratory adaptation to swim training in male recreational swimmers.
Ventilatory effects of hypoxia and their dependence on PCO2
Authors: Rebuck A. S. , Woodley W. E.
Published: December 2017

In 11 healthy subjects the effect of progressive hypoxia on pulmonary ventilation at various alveolar carbon dioxide pressures was studied. A rebreathing technique was used to produce hypoxia, CO2 was held constant and oxygen saturation was taken as the independent variable. We found a linear relationship between ventilation and falls in oxygen saturation when Pco2 was held at the resting mixed venous, end-tidal, or any intermediate level. Within this range of Pco2, a family of ventilation-So2 response curves was obtained for each subject. The effect of altering the isocapnic level was to change the slope and position of the ventilation-So2 response curve, the amount by which the slope changed being related to the slope for that subject at their mixed venous Pco2.
Selective parasympathectomy of the heart
Authors: Kaye M. P. , Hageman G. R. , Randall W. C.
Published: December 2017

Attempts to devise a chronic animal model with parasympathetic cardiac denervation have been complicated by early mortality due to pulmonary and esophagogastric dysfunction. By use of surgical techniques confined to the intrapericardial left atrium and immediately adjacent vena cava, selective cardiac parasympathectomy was performed on dogs. Verification of denervation was performed at the time of surgery by electrical stimulation of the cervical and thoracic vagi and stellate ganglia while recording blood pressure, ECG, and atrial and ventricular contractile force. Results demonstrate complete efferent parasympathetic denervation and abolition of the Bezold-Jurish reflex. Tachycardia at approximately 140/min was noted in all animals immediately and for several weeks postoperatively. No extracardiac complications were noted in any of the animals subjected to this procedure. Right heart catheterization of the conscious sedated dog revealed no evidence of right heart failure. Evidence of parasympathetic efferent reinnervation (sinus arrhythmia) was seen in some animals. This preparation should prove useful in studies of parasympathetic control of the heart, coronary vessels, and cardiovascular reflexes.
Forearm blood flow during body temperature transients produced by leg exercise
Authors: Wenger C. B. , Roberts M. F. , Stolwijk J. A. , Nadel E. R.
Published: December 2017

Subjects exercised for 30 min on a bicycle ergometer at 30, 50, and 70% of maximal aerobic power in ambient temperatures of 15, 25, and 35 degrees C and vapor pressures of less than 18 Torr. Exercise was used to vary internal temperature during an experiment, and different ambient temperatures were used to vary skin temperatures independently of internal temperature. Forearm skin temperature was fixed at about 36.5 degrees C. Esophageal temperature (Tes) was measured with a thermocouple at the level of the left atrium, and mean skin temperature (Tsk) was calculated from a weighted mean of thermocouple temperatures at eight skin sites. Forearm blood flow (BF) was measured by electrocapacitance plethysmography. Our data are well accounted for by an equation of the form BF = a1Tes + q2Tsk + b, independent of exercise intensity, although some subjects showed an equivocal vasodilator effect of exercise. The ratios a1/a2 (7.5, 9.6, 11.7) are quite similar to the ratios (8.6, 10.4) of the corresponding coefficients in two recent models of thermoregulatory sweating.
Role of inertia in the measurement of dynamic compliance
Authors: Dosman J. , Bode F. , Urbanetti J. , Antic R. , Martin R. , Macklem P. T.
Published: December 2017

Dynamic compliance (Cdyn) was measured at different frequencies (breaths/min) in 30 nonsmoking males and females aged 30–59 yr. In those aged 30–49 yr Cydn at 90 breaths/min was significantly higher than at 15 breaths/min while those aged 50–59 yr showed no significant difference. Assuming an inertance of 0.01 cmH2O/l per s-2, and a sinusoidal breathing frequency, Cydn at 60 and 90 breaths/min was corrected for inertia. In the 30–49 yr age group corrected Cydn did not change with increasing frequency of breathing whereas in the 50–59 yr age group Cydn at 15 breaths/min was significantly higher than at 90 breaths/min (P is less than 0.05). In this age group, four of eight subjects were frequency dependent when corrected for inertia. These findings indicate that inertia influences Cydn at breathing frequencies of 60 per min and above. Unless this is taken into account, frequency dependence of compliance may be missed. The results also indicate that frequency dependence of compliance is normal in some older individuals but is not normal in the younger age group.
Mechanical properties of the lungs and experimental asthma in conscious allergic dogs
Authors: Dain D. , Gold W. M.
Published: December 2017

Three allergic dogs were trained to swallow an esophageal balloon, breathe through a tracheostomy tube, and stand quietly in a wooden stall. The mechanical properties of their lungs were measured reproducibly over many months. Average values were: pulmonary resistance 1.33 cmH2O/l per s, static lung compliance 104 ml/cmH2O, and functional residual capacity 982 ml. In two dogs inhalation of histamine aerosol caused a 374% increase in resistance; inhalation of Ascaris suum aerosol caused a 307% increase in resistance. The increased resistance was associated with mild-to-moderate respiratory distress and slightly increased functional residual capacity. Aerosols of isoproterenol or atropine sulfate inhibited the increased resistance. We conclude that the conscious allergic dog is a suitable subject for the long-term study of asthma. Our present results are consistent with our earlier findings in anesthetized dogs, that a vagal reflex is involved in acute bronchomotor responses to inhalation of histamine as well as specific antigen.
A test of time invariance in models of ferrokinetics
Authors: Johnson L. E. , McKee L. C.
Published: December 2017

Application of a particular mathematical property of time-invariant systems to experimental data obtained from injection and infusion of radioactive tracer iron in normal subjects is used to show that the generally applied assumption of time invariance to ferrokinetic systems is unjustified and may lead to substantial errors in analysis.
A method for the assessment of phasic vagal influence on tidal volume
Authors: Younes M. , Iscoe S. , Milic-Emili J.
Published: December 2017

Vagal influence related to lung volume changes results in reduction in tidal volume during spontaneous breathing due primarily to premature termination of inspiration. The strength of this vagal influence was traditionally assessed by the duration of apnea following lung inflation, a method recently shown to be inadequate and potentially misleading. An alternate method is described utilizing analysis of the volume tracing of spontaneous breaths and the tracheal pressure tracing during the first breath following airway occlusion at FRC. A formula was devised which, on the basis of previous observations, should predict the tidal volume to be obtained in the absence of phasic vagal influence. The formula was tested in four pentobarbital-anesthetized rabbits using a technique of vagal cooling which rapidly eliminated the vagal influence under study. It was found that the tidal volume obtained following vagal block could be accurately predicted provided allowances were made for the vagally mediated terminal inhibition during spontaneous breathing and the relative stiffness of the respiratory system at high lung volumes.
Cardiopulmonary responses to exercise in obese girls and young women
Authors: Davies C. T. , Godfrey S. , Light M. , Sargeant A. J. , Zeidifard E.
Published: December 2017

A study of exercise performance was carried out in 17 obese girls and young adults. During submaximal steady-state bicycle exercise oxygen intake (Vo2) for a given work output (W) was raised in obese subjects but minute ventilation at a fixed carbon dioxide output, gas exchange, blood gases, and cardiac output at a given VO2 were similar to the values previously found for normals. In obese subjects high levels of VO2 for fixed W were also obtained on the treadmill but when these were standardized for body weight (unlike the bicycle test) it was shown that the obese girls and women exercised within the normal (expected) range of aerobic energy expenditure. During maximal performance the absolute VO2 max was the same in obese and nonobese subjects but for a given body weight, lean body mass, and leg muscle (plus) bone volume, VO2max was reduced by 23.8, 16.3, and 24.5% respectively, in the former group. It was concluded that obesity though having minimal affect on responses to submaximal exercise is nevertheless associated with a marked reduction in physiological performance at or near maximal effort.
Surfactant inactivation by hyperventilation: conservation by end-expiratory pressure
Authors: Wyszogrodski I. , Kyei-Aboagye K. , Taeusch H. W. , Avery M. E.
Published: December 2017

Hyperventilation, defined as repeated hyperinflations, for three hours in open-chested anesthetized cats increased elastic recoil and elevated minimum surface tension of lung extracts as measured on a surface film balance. Equivalent hyperventilation from an elevated lung volume did not alter the pressure-volume relationships. When a mixture of [3H]glycerol and [14C]palmitate had been injected 17 h before the three hour period of phyerventilation, an increase in the ratio of specific activity in wash to tissue lecithin occurred in the hyperventilated cats compared to controls. These findings suggest that hyperventilation promotes release of surface active material from tissue to alveolus, but the released material is inactivated. The application of 2.5 cmH2O positive end-expiratory pressure prevented the adverse effects of hyperventilation. The same increase in wash to tissue lecithin occurred during this study; since the material was appropriately surface active, we conclude that the positive end-expiratory pressure prevented its inactivation.
CSF bicarbonate regulation in respiratory acidosis and alkalosis
Authors: Wichser J. , Kazemi H.
Published: December 2017

CSF bicarbonate regulation was studied in respiratory acidosis and alkalosis of 4h duration in antsthetized dogs. PCO2, pH, HCO3, ammonia, and lactate in CSF and arterial and safittal sinus bloof were measured when equal volumes of saline or acetazolamide (8 mg) were injected into lateral cerebral ventricles. The brain CO2 dissociation curve was determined at the end of all experiments. CSF and arterial bicarbonate increased 11.8 and 5.9 meg/l, respectively, in acidosis. Acetazolamide limited the rise in CSF bicarbonate to 4.2 meg/l, and prevented the CSF bicarbonate increase associated with hyperammonemia. During alkalosis CSF bicarbonate fell 6.5 meg/l and CSF lactate increased almost 2 meg/l while arterial bicarbonate fell 5.7 meg/l and lactate remained unchanged. Thus plasma bicarbonate changes account for some of the CSF unchanged. Thus plasma bicarbonate changes account for some of the CSF bicarbonate alterations in respiratory acid-base-disturbances. In acidosis additional CSF bicarbonate is formed by the choroid plexus and glial cells on the inner and outer surfaces of the brain--a reaction catalyzed by the locally present carbonic anhydrase. In alkalosis the greater fall in CSF bicarbonate than blood is due to selective brain and CSF lactic acidosis.
A safe and fast-acting surgical anesthetic for use in the guinea pig
Authors: Shucard D. W. , Andrew M. , Beauford C.
Published: December 2017

Ketamine [dl-2-(o-chlorophenyl)-2-(methylamino)cyclohexanone] hydrochloride was used in conjunction with Acepromazine [10–3-(dimethylamino)-propyl]phenothiazin-2-yl-methyl ketone] Maleate to produce surgical depth anesthesia in guinea pigs. In tests with 97 animals, an intramuscular injection of 44 mg/kg ketamine hydrochloride plus 2 mg Acepromazine Maleate was found to be effective in producing a surgical level of anesthesia within 2 min after administration. The anesthetic state lasted for an average of 1.5 h and could be safely extended by supplemental administrations of the drugs. This anesthetic combination was found to be fast acting, safe, and easily controlled.
A sinusoidal load generator for use in cycle ergometry
Authors: Torres P. F. , Whipp B. J. , Steen S. N. , Wasserman K.
Published: December 2017

We have modified an electromagnetically braked cycle ergometer to provide a sinusoidally varying work load. This was accomplished by applying a low-frequency sinusoidal voltage at the inputs of the electromagnets using a sinusoidal potentiometer, whose shaft was driven by a variable-speed motor, and a voltage-programmable power supply to amplify the signal. The frequency range is currently 0.0017–0.3 Hz. This technique for sinusoidal work loads allow the period, amplitude, and mean position to be easily changed from a console, even during a test if required.
Thermoregulatory, metabolic, and cardiovascular response of rats to microwaves
Authors: Phillips R. D. , Hunt E. L. , Castro R. D. , King N. W.
Published: December 2017

This study was undertaken to determine the effects of 2,450-MHz microwave irradiation on thermoregulation, metabolism, and cardiovascular function of rats. Young adult male animals (430 g) were exposed for 30 min to 2,450-MHz microwaves in a cavity at absorbed dose rates of 0, 4.5, 6.5, or 11.1 mW/G. For animals of the size used in this study, these dose rates represent absorption of energy at the rate of 27.7, 40.1, and 68.2 cal/min, respectively. For a period of 5 h following exposure, measurements were made of colonic temperature, skin temperature, oxygen consumption, carbon dioxide production, respiratory quotient, and heart rate. Rats that received 27.7 cal/min for 30 min exhibited an initial transient increase in colonic and skin temperatures but no alterations in other functions. The group irradiated at 40.1 cal/min had greater elevations in colonic and skin temperatures immediately after exposure, followed by overcompensation and lower than normal colonic temperatures for about 3 h. The metabolic rate was depressed in this group for 3 h. Bradycardia developed within 20 min after exposure and persisted for about 3 h. The group of rats that received 68.2 cal/min for 30 min had responses similar to those of the 40.1 cal/min group, but the changes were more severe and lasted longer. In addition, a number of transient abnormalities were noted in the ECG tracings of rats that had received the highest dose, including irregular rhythms and incomplete heart block. The physiological changes observed in this study can be attributed to the heating induced by irradiation.
Regulation of arterial PCO2 during intravenous CO2 loading
Authors: Wasserman K. , Whipp B. J. , Casaburi R. , Huntsman D. J. , Castagna J. , Lugliani R.
Published: December 2017

Increased CO2 flow to the lung produced by increasing cardiac output (with constant PVCO2) results in hyperpnea with arterial PCO2 maintained at its control value (J. Appl. Physiol. 36: 457, 1974). To study if arterial PCO2 could be similarly regulated when CO2 flow was elevated by increasing PVCO2 (without changing cardiac output), we produced graded increases in PVCO2 (up to a mean of 69 mmHg) using an extracorporeal gas exchanger in five chloralose-urethan-anesthetized dogs. CO2 output increased up to fourfold. Ventilation increased in proportion to the additional CO2 flow to the lung with consequent regulation of arterial PCO2 at its control value. Comparable increases in VE produced by “conventional” airway loading resulted in arterial hypercapnia. The resulting CO2 response curve was similar to that found in unanesthetized dogs. We conclude that intravenous delivery of CO2 to the lung results in infinite “sensitivity” when computed as Delta VE/Delta paco2. These results provide evidence for a CO2-linked hyperpnea which is not mediated by measurable increases in mean arterial PCO2.
Measurement of axial diffusivities in a model of the bronchial airways
Authors: Scherer P. W. , Shendalman L. H. , Greene N. M. , Bouhuys A.
Published: December 2017

Values for the effective axial diffusivity D for laminar flow of a gas species in the bronchial airways have been obtained as a function of the mean axial gas velocity u by experiment measurements of benzene vapor dispersion in a five generation glass tube model of the bronchial tree. For both inspiration and expiration D is seen to be approximately a linear function of u over the range of Reynolds' numbers 30–2,000 corresponding to peak flows in bronchial generations 0–13 under resting breathing conditions. The diffusivity for expiration is seen to be approximately one-third that for inspiration due presumably to increased radial mixing at bifurcations during expiration. The effective diffusivities relative to the molecular diffusivity can be expressed by the formulas D/Dmol = 1 + 1.08 NPe for inspiration and D/Dmol = 1 + .37 N-Pe for expiration. These velocity dependent diffusivities help to explain the short transit times of gas boluses from mouth to alveoli and will aid in the analysis of airway gas mixing by mathematical transport equations.