bluuebunny/crossref_metadata_2025 huggingface dataset:
Simulation study of control of hepatic glycogen synthesis by glucose and insulin
Authors: El-Refai M , Bergman RN
Published: December 2017

The plausibility of various hypotheses concerning the effects of glucow dynamic model of glucose metabolism in the liver. The model consisted of six compartments representing extracellular glucose, and intracellular glucose, glucose 6-phosphate, glucose 1-phosphate, uridine diphosphate glucose, obtained from literature reports, the model predicted values of intermediates which were close to those reported for the liver, sampled from fasting animals. The model predicts that glucose can generate significant glycogen deposition by engendering the inhibition of glucose-6-phosphatase, but not by mass action, glycogen synthase activation, or phosphorylase deactivation. The model predicts that, although insulin can inhibit glucose production by lowering phosphorylase and gluconeogenesis, only an insulin-mediated induction of glucokinase can account for insulin's action to potentiate the effect of glucose alone on glycogen synthesis.
Persistence of febrile response to pyrogens after PO/AH lesions in squirrel monkeys
Authors: Lipton JM , Trzcinka GP
Published: December 2017

Observation of a patient who developed fever in spite of severe CNS sarcoidosis led us to test the idea that febrile responses require mediation by neurons in the preoptic/anterior hypothalamic (PO/AH) region. Changes in rectal and skin temperatures and oxygen consumption were recorded after intravenous and intracerebroventricular injections of endotoxin, after intracerebroventricular prostaglandin E1 (PGE1), and after intravenous injections of leukocyte pyrogens in animals in which the PO/AH region had been destroyed. The capacity to develop fever persisted after PO/AH destruction, and the patterns of heat production and heat loss were unchanged. Pyrogens were still effective after intracerebroventricular 6-hydroxydopamine and intraperitoneal reserpine given to reduce brain amines in monkeys with PO/AH lesions. It is unlikely that a secondary control in the medulla oblongata is responsible for the persisting sensitivity to pyrogens, since multiple injections of endotoxin into this region did not cause fever either before or after the PO/AH region was destroyed. The results do not support the idea that control of fever is localized in the PO/AH region alone. Rather, it appears that in the brains of primates there is either multiple central representation of fever control or an inherent capacity to develop sensitivity to pyrogens and to produce coordinated febrile responses.
Response to angiotensins I and II and to AI-converting-enzyme inhibitor in a shark
Authors: Opdyke DF , Holcombe R
Published: December 2017

The spiny dogfish shark, which does not have renal juxtaglomerular cells, exhibits a strong pressor response to both angiotensin I and II. A nonapeptide, angiotensin I-converting-enzyme inhibitor, blocks the pressor response to angiotensin I in this fish. The pressor response to both angiotensin II and norepinephrine is completely blocked by the adrenergic blocking drug phentolamine.
Central antihypertensive effects of inhibitors of the renin-angiotensin system in rats
Authors: Sweet CS , Columbo JM , Gaul SL
Published: December 2017

The possibility that mean arterial pressure (MA) might be maintained by an effect of angiotensin II or its precursors on the central nervous system in rats made hypertensive by occluding the aorta between the renal arteries was investigated. Aortic coarctation produced severe hypertension (MAP greater than 150 mmHg) and plasma renin activity values (radioimmunoassay) at least 10 times normal within 2-6 days after surgery. [Sar1, IIe8]angiotensin II, an angiotensin II antagonist administered centrally via an intracerebroventricular (icv) injection (10-100 mug), lowered the MAP in a dose-dependent manner. Peripheral administration of [Sar1, IIe8]angiotensin II (bolus injection) at 100 mug intra-arterially was ineffective, but the antagonist did lower arterial pressure when infused intravenously for 1 h at 4 times this dose. Less than Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro, a converting enzyme inhibitor, and pepstatin, a renin inhibitor, were ineffective via an icv injection. These results suggest that angiotensin II is in part responsible for the elevation in blood pressure following aortic coarctation in rats. Both central and peripheral administration of [Sar1, Ile8]-angiotensin II lowered mean arterial pressure but the antagonist lowered arterial pressure at lower doses and produced a more rapid decline in arterial pressure when administered into the central nervous system then when administered intra-arterially or intravenously.
Endotoxin stimulates the expression of group II PLA2 in rat lung in vivo and in isolated perfused lungs
Authors: Ljungman A. G. , Tagesson C. , Lindahl M.
Published: December 2017

Injection of endotoxin in vivo leads to increased phospholipase A2 (PLA2) activity in the lung, but neither the type(s) of PLA2 involved nor the importance of blood components and/or different inflammatory cytokines has been clarified. In the present study, injection of endotoxin in rats caused increased lung levels of group II PLA2, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1 beta mRNA, while group I PLA2 mRNA levels were unaffected. The augmented group II PLA2 mRNA levels corresponded to a rise in membrane-associated PLA2 enzymatic activity that was inhibited by rutin, an inhibitor of group II PLA2. In blood-free, salt-perfused lungs, addition of endotoxin to the perfusate caused elevated group II PLA2, TNF-alpha, and IL-1 beta mRNA levels and release of PLA2 and TNF-alpha activity into the perfusate, and when instilled intratracheally, endotoxin caused increased PLA2 activity in the lung tissue. It is concluded that 1) endotoxin stimulates group II PLA2, but not group I PLA2, in rat lung cells, 2) this stimulation is accompanied by increased expression of TNF-alpha and IL-1 beta, and 3) endotoxin-induced PLA2 activation and cytokine production in the lung are not dependent on circulating blood components.
Migratory responses of PMN after intraperitoneal and intratracheal administration of lipopolysaccharide
Authors: Hirano S.
Published: December 2017

The present study was undertaken primarily to investigate accumulation of polymorphonuclear leukocytes (PMN) within the lung vasculature after intraperitoneal injection of lipopolysaccharide (LPS) and migratory responses of those intravascular PMN to intratracheally instilled LPS in mice. Intraperitoneally injected LPS was absorbed into the blood rapidly, and the concentration of circulating LPS peaked at 1 h postinjection. Tumor necrosis factor concentration in blood began to increase at 0.5 h and also peaked at 1 h postinjection. The number of lung vascular-associated PMN was increased 7.5-fold at 0.5 h post-intraperitoneal injection. However, neither diapedesis of PMN nor injury was observed in the lung, while mixed cell infiltration was observed in the liver. Although intraperitoneally injected LPS caused a significant PMN accumulation within the lung vasculature, pre-intraperitoneal injection of LPS dramatically and dose dependently abolished both intratracheal LPS-inducible PMN infiltration and apparent plasma protein leakage into the alveolar space. On the other hand, pre-intratracheal instillation of LPS enhanced rather than reduced intraperitoneal LPS-inducible PMN infiltration into the peritoneal cavity. In rats, a sublethal dose of intraperitoneally injected LPS caused a modest increase in alveolar PMN and yet reduced intratracheal LPS-inducible robust transpulmonary PMN infiltration. Although mechanisms of different migratory responses of the lung vasculature-associated PMN are unknown, the inhibitory effects of intraperitoneally injected LPS on transpulmonary PMN infiltration may be applicable to treatments for septic lung diseases.
Association ofl-arginine transporters with fodrin: implications for hypoxic inhibition of arginine uptake
Authors: Zharikov S. I. , Block E. R.
Published: December 2017

In this study, we investigated the possible interaction between the cationic amino acid transporter (CAT)-1 arginine transporter and ankyrin or fodrin. Because ankyrin and fodrin are substrates for calpain and because hypoxia increases calpain expression and activity in pulmonary artery endothelial cells (PAEC), we also studied the effect of hypoxia on ankyrin, fodrin, and CAT-1 contents in PAEC. Exposure to long-term hypoxia (24 h) inhibited l-arginine uptake by PAEC, and this inhibition was prevented by calpain inhibitor 1. The effects of hypoxia and calpain inhibitor 1 were not associated with changes in CAT-1 transporter content in PAEC plasma membranes. However, hypoxia stimulated the hydrolysis of ankyrin and fodrin in PAEC, and this could be prevented by calpain inhibitor 1. Incubation of solubilized plasma membrane proteins with anti-fodrin antibodies resulted in a 70% depletion of CAT-1 immunoreactivity and in a 60% decrease in l-arginine transport activity in reconstituted proteoliposomes (3,291 ± 117 vs. 8,101 ± 481 pmol ⋅ mg protein−1⋅ 3 min−1in control). Incubation with anti-ankyrin antibodies had no effect on CAT-1 content or l-arginine transport in reconstituted proteoliposomes. These results demonstrate that CAT-1 arginine transporters in PAEC are associated with fodrin, but not with ankyrin, and that long-term hypoxia decreases l-arginine transport by a calpain-mediated mechanism that may involve fodrin proteolysis.
Glucocorticoid-induced contractility and F-actin content of human lung fibroblasts in three-dimensional culture
Authors: Miki Hiroyuki , Mio Tadashi , Nagai Sonoko , Hoshino Yuma , Tsutsumi Takeo , Mikuniya Takeshi , Izumi Takateru
Published: December 2017

Fibroblast contractility plays a useful role in the wound healing process but contributes to architectural distortion in the lungs. Glucocorticoids (GCs) have been reported to reduce dermal fibroblast contractility, which may result in delaying wound healing, but the effects on lung fibroblasts are unknown. In this study, we examined how human lung fibroblast contractility is altered in the presence of GCs. Lung fibroblast cell lines ( n = 5) were established from normal parts of surgically resected lung tissue. The effects of GCs on contractility were investigated with a type I collagen gel contraction assay. Filamentous actin (F-actin) content was detected by confocal microscopy and measured with a fluorescent phalloidin binding assay. GCs augmented fibroblast contraction in a concentration-dependent manner, with an approximate EC50of 1.8 × 10−8M, whereas other steroid derivatives had no effects. GC contractility needed de novo protein synthesis. The GC-induced increase in contractility was found to be consistent with an increase in F-actin content. In conclusion, lung fibroblast contractility was enhanced with GCs through an upregulation of lung fibroblast F-actin.
Agarose plug instillation causes goblet cell metaplasia by activating EGF receptors in rat airways
Authors: Lee Heung-Man , Takeyama Kiyoshi , Dabbagh Karim , Lausier James A. , Ueki Iris F. , Nadel Jay A.
Published: December 2017

We hypothesized that foreign bodies in airways cause inflammation leading to goblet cell metaplasia. Instilled agarose plugs lodged in the bronchi of pathogen-free rats caused a time-dependent increase in Alcian blue-periodic acid-Schiff staining that was detected within 24 h and markedly increased at 72 h. Control bronchi contained no pregoblet or goblet cells, but plugged bronchi contained many pregoblet and goblet cells and a decrease in nongranulated secretory cells. In situ hybridization showed no expression of MUC5AC in control airways, but plugged airways showed a marked expression. Control bronchi showed sparse staining for epidermal growth factor receptor (EGFR) protein, but plugged bronchi showed intense EGFR staining in the epithelium. Pretreatment with an EGFR tyrosine kinase inhibitor (BIBX1522) prevented Alcian blue-periodic acid-Schiff staining and MUC5AC gene expression in plugged bronchi. Pretreatment with tumor necrosis factor-α neutralizing antibody or pretreatment with cyclophosphamide abolished plug-induced EGFR protein expression and goblet cell metaplasia. Thus instillation of agarose plugs induces profound goblet cell metaplasia by causing EGFR expression and activation.
Is dipalmitoylphosphatidylcholine a substrate for convertase?
Authors: Dhand Rajiv , Young Jared , Teng Andelle , Krishnasamy Subbiah , Gross Nicholas J.
Published: December 2017

Convertase has homology with carboxylesterases, but its substrate(s) is not known. Accordingly, we determined whether dipalmitoylphosphatidylcholine (DPPC), the major phospholipid in surfactant, was a substrate for convertase. We measured [3H]choline release during cycling of the heavy subtype containing [3H]choline-labeled DPPC with convertase, phospholipases A2, B, C, and D, liver esterase, and elastase. Cycling with liver esterase or peanut or cabbage phospholipase D produced the characteristic profile of heavy and light peaks observed on cycling with convertase. In contrast, phospholipases A2, B, and C and yeast phospholipase D produced a broad band of radioactivity across the gradient without distinct peaks. [3H]choline was released when natural surfactant containing [3H]choline-labeled DPPC was cycled with yeast phospholipase D but not with convertase or peanut and cabbage phospholipases D. Similarly, yeast phospholipase D hydrolyzed [3H]choline from [3H]choline-labeled DPPC after incubation in vitro, whereas convertase, liver esterase, or peanut and cabbage phospholipases D did not. Thus convertase, liver esterase, and plant phospholipases D did not hydrolyze choline from DPPC either on cycling or during incubation with enzyme in vitro. In conclusion, conversion of heavy to light subtype of surfactant by convertase may require a phospholipase D type hydrolysis of phospholipids, but the substrate in this reaction is not DPPC.
p53-independent induction ofGADD45andGADD153in mouse lungs exposed to hyperoxia
Authors: O'Reilly Michael A. , Staversky Rhonda J. , Watkins Richard H. , Maniscalco William M. , Keng Peter C.
Published: December 2017

Previous studies have shown that lungs of adult mice exposed to >95% oxygen have increased terminal deoxyribonucleotidyltransferase dUTP nick end-label staining and accumulate p53, the expression of which increases in cells exposed to DNA-damaging agents. The present study was designed to determine whether hyperoxia also increased expression of the growth arrest and DNA damage ( GADD) gene 45 and GADD153, which are induced by genotoxic stress through p53-dependent and -independent pathways. GADD proteins have been shown to inhibit proliferation and stimulate DNA repair and/or apoptosis. GADD45 and GADD153 mRNAs were not detected in lungs exposed to room air but were detected after 48 and 72 h of exposure to hyperoxia. In situ hybridization and immunohistochemistry revealed that hyperoxia increased GADD45 and GADD153 expression in the bronchiolar epithelium and GADD45 expression predominantly in alveolar cells that were morphologically consistent with type II cells. Hyperoxia also increased GADD expression in p53-deficient mice. Terminal deoxyribonucleotidyltransferase dUTP nick end-label staining of lung cells from p53 wild-type and p53-null mice exposed to hyperoxia for 48 h revealed that hyperoxia-induced DNA fragmentation was not modified by p53 deficiency. These studies are consistent with the hypothesis that hyperoxia-induced DNA fragmentation is associated with the expression of GADD genes that may participate in DNA repair and/or apoptosis.
Lipopolysaccharide induces functional ICAM-1 expression in rat alveolar epithelial cells in vitro
Authors: Madjdpour Caveh , Oertli Beat , Ziegler Urs , Bonvini John M. , Pasch Thomas , Beck-Schimmer Beatrice
Published: December 2017

Lipopolysaccharide (LPS)-induced lung inflammation is known to increase pulmonary intercellular adhesion molecule-1 (ICAM-1) expression. In the present study, L2 cells, a cell line of alveolar epithelial cells, were stimulated with LPS, and ICAM-1 expression was studied. ICAM-1 protein on L2 cells peaked at 6 (38% increase; P < 0.01) and 10 (48% increase; P < 0.001) h after stimulation with Escherichia coli and Pseudomonas aeruginosa LPS, respectively. ICAM-1 mRNA expression was markedly increased, with a peak at 2–4 ( E. coli) and 4–6 ( P. aeruginosa) h. Adherence assays of neutrophils to LPS-stimulated L2 cells showed a threefold increase in adherence ( P < 0.001). Pretreatment of the neutrophils with anti-lymphocyte function-associated antigen-1 and anti-Mac-1 antibodies reduced adherence by 54% ( P < 0.001). Analysis of immunofluorescence staining for ICAM-1 showed an exclusive apical expression of ICAM-1. These results indicate that LPS upregulates functional active ICAM-1 on the apical part of the membrane in rat pneumocytes.
Internalized SP-A and lipid are differentially resecreted by type II pneumocytes
Authors: Wissel Heide , Zastrow Stefan , Richter Ekkehard , Stevens Paul A.
Published: December 2017

Biochemical and morphological assays were developed to study surfactant protein A (SP-A) and lipid resecretion kinetics by isolated type II cells in vitro. After a 10-min uptake period with SP-A (3 μg/106cells) in combination with liposomes (60 μg/106cells), the cells were allowed to resecrete. After 5 min of resecretion, only 21.7 ± 4.6% of the internalized SP-A remained intracellularly compared with 54 ± 2.9% of the lipids. Extracellular SP-A present during the resecretion period partially inhibited resecretion (SP-A, 36% at 5 min; lipid, ∼16% at 5 min). Lipid resecretion was also dependent on the SP-A concentration present during the uptake period. Although, as shown by confocal laser scanning microscopy, after a 10-min uptake period at 37°C, most of the fluorescein isothiocyanate-labeled SP-A and rhodamine-phosphatidylethanolamine-labeled lipids colocalized within the cells, after an additional 10 min of resecretion, both the strength of the fluorescence signals and the extent of colocalization had markedly decreased. These data indicate that internalized lipid and SP-A can be resecreted rapidly by type II cells, likely via different pathways.
Carbon dioxide enhances nitration of surfactant protein A by activated alveolar macrophages
Authors: Zhu Sha , Basiouny Khaled F. , Crow John P. , Matalon Sadis
Published: December 2017

We assessed whether reactive oxygen-nitrogen intermediates generated by alveolar macrophages (AMs) oxidized and nitrated human surfactant protein (SP) A. SP-A was exposed to lipopolysaccharide (100 ng/ml)-activated AMs in 15 mM HEPES (pH 7.4) for 30 min in the presence and absence of 1.2 mM CO2. In the presence of CO2, lipopolysaccharide-stimulated AMs had significantly higher nitric oxide synthase (NOS) activity (as quantified by the conversion ofl-[U-14C]arginine tol-[U-14C]citrulline) and secreted threefold higher levels of nitrate plus nitrite in the medium [28 ± 3 vs. 6 ± 1 (SE) nmol ⋅ 6.5 h−1 ⋅ 106AMs−1]. Western blotting studies of immunoprecipitated SP-A indicated that CO2 enhanced SP-A nitration by AMs and decreased carbonyl formation. CO2(0–1.2 mM) also augmented peroxynitrite (0.5 mM)-induced SP-A nitration in a dose-dependent fashion. Peroxynitrite decreased the ability of SP-A to aggregate lipids, and this inhibition was augmented by 1.2 mM CO2. Mass spectrometry analysis of chymotryptic fragments of peroxynitrite-exposed SP-A showed nitration of two tyrosines (Tyr164 and Tyr166) in the absence of CO2 and three tyrosines (Tyr164, Tyr166, and Tyr161) in the presence of 1.2 mM CO2. These findings indicate that physiological levels of peroxynitrite, produced by activated AMs, nitrate SP-A and that CO2 increased nitration, at least partially, by enhancing enzymatic nitric oxide production.
Diminished injury in hypotransferrinemic mice after exposure to a metal-rich particle
Authors: Ghio Andrew J. , Carter Jacqueline D. , Richards Judy H. , Crissman Kay M. , Bobb Heather H. , Yang Funmei
Published: December 2017

Using the hypotransferrinemic (Hp) mouse model, we studied the effect of altered iron homeostasis on the defense of the lung against a catalytically active metal. The homozygotic ( hpx/ hpx) Hp mice had greatly diminished concentrations of both serum and lavage fluid transferrin relative to wild-type mice and heterozygotes. Fifty micrograms of a particle containing abundant concentrations of metals (a residual oil fly ash) was instilled into wild-type mice and heterozygotic and homozygotic Hp animals. There was an oxidative stress associated with particle exposure as manifested by decreased lavage fluid concentrations of ascorbate. However, rather than an increase in lung injury, diminished transferrin concentrations in homozygotic Hp mice were associated with decreased indexes of damage, including concentrations of relevant cytokines, inflammatory cell influx, lavage fluid protein, and lavage fluid lactate dehydrogenase. Comparable to other organs in the homozygotic Hp mouse, siderosis of the lung was evident, with elevated concentrations of lavage fluid and tissue iron. Consequent to these increased concentrations of iron, proteins to store and transport iron, ferritin, and lactoferrin, respectively, were increased when assayed by immunoprecipitation and immunohistochemistry. We conclude that the lack of transferrin in Hp mice did not predispose the animals to lung injury after exposure to a particle abundant in metals. Rather, these mice demonstrated a diminished injury that was associated with an increase in the metal storage and transport proteins.
Alterations of nitric oxide synthase expression and activity during rat lung transplantation
Authors: Liu Mingyao , Tremblay Lorraine , Cassivi Stephen D. , Bai Xiao-Hui , Mourgeon Eric , Pierre Andrew F. , Slutsky Arthur S. , Post Martin , Keshavjee Shaf
Published: December 2017

Decreased nitric oxide (NO) production has been reported during lung transplantation in patients. To study the effects of ischemia and reperfusion on endogenous NO synthase (NOS) expression, both an ex vivo and an in vivo lung injury model for transplantation were used. Donor rat lungs were flushed with cold low-potassium dextran solution and subjected to either cold (4°C for 12 h) or warm (21°C for 4 h) ischemic preservation followed by reperfusion with an ex vivo model. A significant increase in inducible NOS and a decrease in endothelial NOS mRNA was found after reperfusion. These results were confirmed in a rat single-lung transplant model after warm preservation. Interestingly, protein contents of both inducible NOS and endothelial NOS increased in the transplanted lung after 2 h of reperfusion. However, the total activity of NOS in the transplanted lungs remained at very low levels. We conclude that ischemic lung preservation and reperfusion result in altered NOS gene and protein expression with inhibited NOS activity, which may contribute to the injury of lung transplants.
Aquaporin water channels and lung physiology
Authors: Verkman A. S. , Matthay Michael A. , Song Yuanlin
Published: December 2017

Fluid transport across epithelial and endothelial barriers occurs in the neonatal and adult lungs. Biophysical measurements in the intact lung and cell isolates have indicated that osmotic water permeability is exceptionally high across alveolar epithelia and endothelia and moderately high across airway epithelia. This review is focused on the role of membrane water-transporting proteins, the aquaporins (AQPs), in high lung water permeability and lung physiology. The lung expresses several AQPs: AQP1 in microvascular endothelia, AQP3 in large airways, AQP4 in large- and small-airway epithelia, and AQP5 in type I alveolar epithelial cells. Lung phenotype analysis of transgenic mice lacking each of these AQPs has been informative. Osmotically driven water permeability between the air space and capillary compartments is reduced ∼10-fold by deletion of AQP1 or AQP5 and reduced even more by deletion of AQP1 and AQP4 or AQP1 and AQP5 together. AQP1 deletion greatly reduces osmotically driven water transport across alveolar capillaries but has only a minor effect on hydrostatic lung filtration, which primarily involves paracellular water movement. However, despite the major role of AQPs in lung osmotic water permeabilities, AQP deletion has little or no effect on physiologically important lung functions, such as alveolar fluid clearance in adult and neonatal lung, and edema accumulation after lung injury. Although AQPs play a major role in renal and central nervous system physiology, the data to date on AQP knockout mice do not support an important role of high lung water permeabilities or AQPs in lung physiology. However, there remain unresolved questions about possible non-water-transporting roles of AQPs and about the role of AQPs in airway physiology, pleural fluid dynamics, and edema after lung infection.
NO+but not NO radical relaxes airway smooth muscle via cGMP-independent release of internal Ca2+
Authors: Janssen Luke J. , Premji Mahmood , Lu-Chao Hwa , Cox Gerard , Keshavjee Shaf
Published: December 2017

We compared the effects of two redox forms of nitric oxide, NO+[liberated by S-nitroso- N-acetyl-penicillamine (SNAP)] and NO ⋅ [liberated by 3-morpholinosydnonimine (SIN-1) in the presence of superoxide dismutase], on cytosolic concentration of Ca2+([Ca2+]i; single cells) and tone (intact strips) obtained from human main stem bronchi and canine trachealis. SNAP evoked a rise in [Ca2+]ithat was unaffected by removing external Ca2+but was markedly reduced by depleting the internal Ca2+pool using cyclopiazonic acid (10−5M). Dithiothreitol (1 mM) also antagonized the Ca2+transient as well as the accompanying relaxation. SNAP attenuated responses to 15 and 30 mM KCl but not those to 60 mM KCl, suggesting the involvement of an electromechanical coupling mechanism rather than a direct effect on the contractile apparatus or on Ca2+channels. SNAP relaxations were sensitive to charybdotoxin (10−7M) or tetraethylammonium (30 mM) but not to 4-aminopyridine (1 mM). Neither SIN-1 nor 8-bromoguanosine 3′,5′-cyclic monophosphate had any significant effect on resting [Ca2+]i, although both of these agents were able to completely reverse tone evoked by carbachol (10−7M). We conclude that NO+causes release of internal Ca2+in a cGMP-independent fashion, leading to activation of Ca2+-dependent K+channels and relaxation, whereas NO ⋅ relaxes the airways through a cGMP-dependent, Ca2+-independent pathway.
Mediators of alkalosis-induced relaxation of piglet pulmonary veins
Authors: Halla Ted R. , Madden Jane A. , Gordon John B.
Published: December 2017

Pulmonary venous constriction leads to significant pulmonary hypertension and increased edema formation in several models using newborns. Although alkalosis is widely used in treating neonatal and pediatric pulmonary hypertension, its effects on pulmonary venous tone have not previously been directly measured. This study sought to determine whether alkalosis caused pulmonary venous relaxation and, if so, to identify the mediator(s) involved. Pulmonary venous rings (500-μm external diameter) were isolated from 1-wk-old piglets and precontracted with the thromboxane mimetic U-46619. Responses to hypocapnic alkalosis were then measured under control conditions after inhibition of endothelium-derived modulator activity or K+channels. In control rings, alkalosis caused a 34.4 ± 4.8% decrease in the U-46619-induced contraction. This relaxation was significantly blunted in rings without functional endothelium and in rings treated with nitric oxide synthase or guanylate cyclase inhibitors. However, neither cyclooxygenase inhibition nor voltage-dependent, calcium-dependent, or ATP-dependent K+-channel inhibitors altered alkalosis-induced relaxation. These data suggest that alkalosis caused significant dilation of piglet pulmonary veins that was mediated by the nitric oxide-cGMP pathway.
Transient circadian internal desynchronization after light-dark phase shift in monkeys
Authors: Moore-Ede M. C. , Kass D. A. , Herd J. A.
Published: December 2017

In four conscious chair-acclimatized squirrel monkeys (Saimiri sciureus) studied with lights on (600 lx) from 0800 to 2000 h daily (LD 12:12), prominent 24-h rhythms in feeding, drinking, activity, body temperature, and urinary potassium, sodium, and water excretion were seen. When the monkeys were subjected to 36 h of darkness followed by 36 h of light each variable demonstrated a circadian rhythm which was not passively dependent on the light-dark cycle. After the 24-h light-dark cycle was abruptly phase-delayed by 8 h, all the rhythms resynchronized with the new light-dark cycle phase, demonstrating that light-dark cycles are an effective zeitgeber. However, the resynchronization of the rhythms of feeding, drinking, activity, and body temperature was 90% complete within approximately 2 days while the 90% resynchronization of the urinary rhythms took approximately 5 days. These results suggest that the circadian timing system in S. sciureus may consist of several spontaneously oscillating units which can become transiently uncoupled during pertubations of environmental time cues.
Thirst following water deprivation in dogs
Authors: Ramsay D. J. , Rolls B. J. , Wood R. J.
Published: December 2017

Eight dogs were prepared with unilateral carotid loops, and trained to stand quietly in a modified Pavlov stand. They were deprived of water for 24 h, which significantly depleted both the cellular and extracellular fluid (ECF) compartments. When they were allowed access to water for 5 min, they promptly drank amounts sufficient to make up their fluid deficits. Infusion of water into the unilateral carotid loop to reduce the cerebral blood osmolality to normal did not consistently reduce drinking because of inadequate mixing in the Circle of Willis. The eight dogs were then prepared with bilateral loops and deprived of water. Infusion of water at 0.6 ml-kg-1-,min-1 reduced the jugular plasma osmolality to control levels but did not affect systemic osmolality and reduced the drinking by 72%. Intracarotid infusion of water at differing rates reduced drinking in a dose related fashion. Intravenous infusion of 0.15 M NaCl in an amount designed to expand the ECF volume to normal reduced drinking by 27%. Expansion of the ECF volume plus bilateral intracarotid infusion of water to remove the central osmotic stimulus completely inhibited drinking. It is concluded that drinking following water deprivation in dogs is controlled by both central osmotic and by extracellular fluid volume factors, and that the osmotic factor is the more important. The drinking stopped well before these fluid deficits, as judged by body fluid analysis, had been restored. Some other mechanisms, therefore, must be involved in satiety.
A numerical method for fitting compartmental models directly to tracer data
Authors: Feldman H. A.
Published: December 2017

A numerical method is presented for obtaining the exchange rates of a metabolic compartmental system, working directly from the time course of tracer activity and excretion after bolus injection. The conventional mathematical formulation of this problem, in terms of sums of exponential functions, is bypassed, enabling implementation of the method in a short computer program. An important by-product of the method is a set of variance-covariance estimates for the fitted parameters. The method is tested on "classic" data, both simulated and real. Its capabilities and limitations are demonstrated, and the strategy of its effective application is discussed.
Renin-angiotensin-aldosterone system of the normothermic marmot
Authors: Kastner P. R. , Zatzman M. L. , South F. E. , Johnson J. A.
Published: December 2017

Adrenal steroid secretion rates and the renin-angiotensin-aldosterone (RAA) system were studied in the normothermic marmot. Adrenal secretion by the anesthetized, laparotomized marmot was (mean +/- SEM); aldosterone 1.2 +/- 0.3 ng/min, deoxycorticosterone 16.7 +/- 11.5 ng/min, corticosterone 15.2 +/- 7.8 ng/min, and cortisol 554 +/- 108 ng/min. Four forcings were investigated that affect feedback control at different sites: adrenocorticotropic hormone (ACTH) and angiotensin II (AII) infusion, sodium (Na) depletion, and Na loading. Plasma aldosterone, cortisol, Na, and potassium (K) concentrations as well as plasma renin activity (PRA) hematocrit (Hct), and in some studies, blood pressure were measured. ACTH infusion increased the plasma concentrations of aldosterone and cortisol. AII infusion increased aldosterone concentration, blood pressure, and Hct. Na depletion increased aldosterone, Hct, and PRA; plasma Na and K were decreased. Aldosterone concentration, Hct, and PRA decreased after salt loading. Normothermic, salt-depleted marmots demonstrated a pronounced fall in blood pressure following infusion of the AII analog, 1-sarcosine-8-alanine AII. The average plasma values for aldosterone, PRA, and cortisol found in 44 control animals were: aldosterone 3.8 +/- 0.3 ng/100 ml, PRA 1.9 +/- 0.2 ng AI-ml-1-h-1, and cortisol 54 +/- 4 ng/ml. It was concluded that normothermic marmots have a RAA system comparable to other mammalian species.
Respiratory gases in uterine circulation of pregnant domestic swine as sampled by indwelling catheters
Authors: Caton D. , Bazer F. W.
Published: December 2017

Data dealing with placental respiratory gas exchange are scant for species with an epitheliochorial placenta. None have been obtained from awake, unstressed animals. For this reason 18 pregnant swine were prepared with chronically implanted polyvinyl catheters. Respiratory gases in arterial and uterine venous blood were observed between the 30th day of gestation and term (110 days). There was a statistically significant relationship between uterine venous oxygen partial pressure (Po2 and the day of gestation. The value for Po2, fell from a mean of 70 to 57 Torr. The latter appears to be the highest mean value yet observed in uterine vein of any species at term.

pregnancy; chronic preparation

Submitted on March 7, 1977
Periventricular preoptic-hypothalamus is vital for thirst and normal water economy
Authors: Johnson A. K. , Buggy J.
Published: December 2017

A midline stereotaxic lesion in rats destroying the periventricular tissue (lamina terminalis and preoptic-anterior hypothalamic periventricular stratum) surrounding the anteroventral third ventricle (AV3V) produces adipsia without other marked behavioral changes. Although food consumption is reduced in animals rendered adipsic by the lesion, feeding continued and intake is comparable to that of water-deprived-sham-lesioned animals. About half the rats recover drinking after a period of adipsia, but the others never resume water intake and become moribund. An analysis of urinary output indicates that adipsic animals fail to reduce urine volume and continue to elaborate an inappropriately dilute urine. The periventricular lesion-induced adipsia without compensating antidiuresis produces a significant rise in plasma protein, sodium, osmolality, and urea nitrogen which if untreated often results in acute encephalopathy leading to death. These data suggest that preoptic-anterior hypothalamic periventricular tissue houses vital neural elements which function in the modulation of water ingestive and conservation mechanisms directed at the maintenance of body fluid homeostasis.
Temperature dynamics of the fertile chicken egg
Authors: Kaplan S. , Kolesari G. L. , Bahr J. P.
Published: December 2017

Two thermistor temperature probes were mounted in fertile chicken eggs, one at the position normally occupied by an early embryo and the other in the center of the yolk. Temperature changes were constantly monitored while the eggs were removed from holding refrigerator to incubator, incubator to room temperature, or room temperature to incubator. Computer analysis was used to develop a mathematical model of heat fluxes in the egg. Graphs derived from this model are presented which permit any investigator to predict approximate time and temperature variables under conditions commonly encountered when using the chicken egg in biological research. We found that when the egg is moved from an incubator (38 degrees C) to laboratory bench (25 degrees C), there was a very rapid initial heat loss (over 8 degrees C in 10 min) at a site in the egg which would be occupied by an early embryo. Conversely, when the egg is moved from the bench back to the incubator, nearly 2 h is required for the egg to recover 90% of the heat that it had lost while cooling to 25 degrees C.
Actions of some transmitters and their antagonists on salivary secretion in a tick
Authors: Kaufman W. R.
Published: December 2017

Cholinomimetics (pilocarpine, carbachol, physostigmine, acetylcholine, acetyl-beta-methylcholine) and sympathomimetics (dopamine, epinephrine), when injected into the hemolymph, provoked salivary fluid secretion in the female ixodid tick Amblyomma hebraeum Koch. Atropine, but not tubocurarine or toxiferine, abolished pilocarpine-induced secretion without reducing the response to dopamine. Reserpine and guanethidine likewise selectively attenuated pilocarpine-induced secretion. Following extirpation of the synganglion, pilocarpine no longer provoked a secretory response whereas dopamine did. Thus, the salivary gland appears to be innervated directly by catecholaminergic rather than cholinergic secretory nerves. It is suggested that pilocarpine elicits salivation by interacting with muscarinic-type cholinergic receptors situated either on the cell bodies of the secretory nerves, or alternatively in the integrative or sensory pathway.
A chronic cannula for obtaining CSF from the cisterna magna of awake dogs
Authors: Jennings D. B. , Tobin P.
Published: December 2017

We have designed a cannula system that can be chronically implanted to end above the dura of the cisterna magna of the dog. During experiments in the awake dog, a screw cap with stylet is removed from the cannula and a spinal needle inserted for the withdrawal of samples of cisternal cerebrospinal fluid (CSF) or for making continuous measurements of pressure. The system can be used for repeated experiments extending over several weeks.
Effects of vagotomy with and without pyloroplasty on weight and food intake in rats
Authors: Mordes J. P. , el Lozy M. , Herrera M. G. , Silen W.
Published: December 2017

Bilateral truncal vagotomy performed in 13 rats reduced weight gain by 26% compared to controls, but also produced gastric distension. Addition of pyloroplasty was found to facilitate gastric drainage in vagotomized rats, and both procedures were then performed in 57 rats of both sexes and varying initial weights. When fed ad libitum, vagotomized animals maintained a weight 14-30% less than controls over periods of 30-300 days. When pair fed, normal rats and rats with vagotomy and pyloroplasty weighed the same. Various partial vagotomies had no effect on weight gain. It was concluded that vagotomy reduces weight gain in rats, that the reduction is the result of decreased food intake, and that the effect of vagotomy is probably not due to gastric distension.
Effects of central injection of biogenic amines during arousal from hibernation
Authors: Glass J. D. , Wang L. C.
Published: December 2017

Simultaneous measurements of heat production (HP) and heat loss (HL) and brain and rectal temperatures were made in Richardon's ground squirrels (Spermophilus richardsonii) rewarming from hibernation at an ambient temperature of 6.0 +/- 0.5 degrees C. Calculations from HP and HL measurements from control animals showed that due to differential rewarming, there was a reduction of apparent specific heat of the animal to 0.59 cal/g. degrees C. This resulted in an energy saving of 30%. Three intracerebroventricular injections of 5-hydroxytryptamine (5-HT) of 56 microgram each at brain temperatures of 10, 20, and 30 degrees C caused initial suppression of HP and a greater overall HL, which resulted in a slower rate of arousal as compared to the controls. Injections of norepinephrine (NE) of 12.5 microgram each at similar brain temperatures caused a greater rate of HP, which resulted in a faster rate of arousal as compared to the controls. The respective actions of 5-HT and NE on thermoregulation during rewarming are similar to those in some euthermic hibernators and nonhibernating species. Our data indicated that these substances evoke thermoregulatory responses during arousal in much the same manner as during normothermia.
Renal and hindlimb vascular control during acute emotion in the baboon
Authors: Smith O. A. , Hohimer A. R. , Astley C. A. , Taylor D. J.
Published: December 2017

Blood pressure, heart rate, oxygen consumption, and blood flow to the renal and hind-limb vasculatures were measured in healthy, unanesthetized baboons (Papio cynocephalus) in a controlled environment. Appropriate behavioral techniques were applied to allow the reproducible elicitation of a conditional emotional response (CER). Section of renal nerves and autonomic pharmacologic interventions were used to determine the mechanisms for the cardiovascular responses accompanying the CER. The resistance changes in the renal and hind-limb vascular beds were generated by rapid, neurally mediated vasoconstriction of the renal vasculature and by a slower acting, circulating vasoactive agent, most probably epinephrine, which causes a delayed second constriction in the renal bed and a net dilation in the hind limbs.
Calories and gastric emptying: a regulatory capacity with implications for feeding
Authors: McHugh P. R. , Moran T. H.
Published: December 2017

Gastric emptying in four unanesthetized male Macaca mulatta was studied with the serial test meal method of Hunt and Spurrell. Liquid meals were infused into the stomach through a chronic indwelling Silastic cannula. Saline meals empty rapidly and exponentially. Doubling the volume of saline from 150 to 300 ml increased the emptying rate so that the half-life remained unchanged (15 min). The 150-ml glucose meals (0.05, 0.125, and 0.25 g/ml) emptied more slowly than saline, progressively more slowly with increasing concentrations (0.05--1.8, 0.125--0.78, and 0.25--0.37 ml/min) and linearly through most of their course. Doubling the volume of 0.125 g/ml-glucose meal did not change the rate of emptying. Converting grams of glucose to their caloric content, the emptying rate in kcal/min becomes constant (approx 0.4 kcal/min) in this range of concentrations. Isocaloric casein hydrolysate and medium-chain triglyceride oil meals at 0.5 kcal/ml empty at the same rate as glucose. The precision of this regulation is sufficient to give it a role in preabsorptive satiety and the control of caloric intake.
Response of supraoptic neurosecretory cells to changes in left atrial distension
Authors: Menninger R. P.
Published: December 2017

Acute studies were conducted in cats to determine the effects of small changes in left atrial pressure (LAP) on the activity of antidromically identified neurons in the supraoptic nucleus (SON). Inflation of left atrial balloons reproducibly altered the frequency of 15% of the SON neurons. More than half of these increased frequency, probably due to a simultaneous increase in arterial pressure. In a second series, the firing rates of 20% of the SON neurons tested were inversely related to changes in LAP produced by pumping blood into or out of the left atrium. A third series of experiments were conducted in which the left atrium was directly stretched by pulling on a suture placed in the atrial wall in addition to one of the above methods of changing LAP. Directly stretching the left atrium inhibited over 70% of the SON neurons; this included all the neurons that responded to changes in LAP. The results suggest that these SON neurons have differential sensitivities to inputs from left atrial receptors.
Renal function in Lophius americanus: effects of angiotensin II
Authors: Churchill P. C. , Malvin R. L. , Churchill M. C. , McDonald F. D.
Published: December 2017

Arterial blood pressure, urine flow rate, and plasma and urine electrolytes were measured in the aglomerular goosefish (L. americanus) before, during, and after the intravenous infusion of angiotensin II (from 5 to 280 ng/min.kg body wt). Increases in arterial blood pressure were directly related to the logarithm of the angiotensin infusion rate (r = 0.62, P less than 0.005). Angiotensin also increased urine flow from 0.676 +/- 0.065 to 0.755 +/- 0.068 ml/h.kg body wt (P less than 0.005) and Na excretion from 41.0 +/- 5.5 to 54.4 +/- 7.0 mumol/h.kg body wt (P less than 0.001). In 17 of the 19 fish infused with angiotensin the diuretic and natriuretic effects were directly related to the logarithm of the infusion rate (r = 0.44, P less than 0.04 and r = 0.51, P less than 0.02, respectively). There was no relationship between the pressor and the diuretic or natriuretic effects of angiotensin II. These results are consistent with inhibitory effects of angiotensin on solute transport by aglomerular tubules.
Sympathetic hyperresponsiveness to hypothalamic stimulation in young hypertensive rats
Authors: Bunag R. D. , Takeda K.
Published: December 2017

The possible occurrence of central sympathetic dysfunction during development of spontaneous hypertension was studied by recording aortic pressure and sympathetic nerve activity concurrently during electrical stimulation of the posterior hypothalamus in 9-wk-old Kyoto-Wistar rats. Even at this early age, basal levels for both measurements were already elevated significantly in those with spontaneous hypertension. Increases in sympathetic neural firing induced by graded hypothalamic stimulation were always followed by corresponding increases in blood pressure; magnitude of both effects was appreciably larger in spontaneously hypertensive than in normotensive rats, as was the vasodepression caused by blocking autonomic ganglia with pentolinium. By contrast, pressor responses to injected norepinephrine were almost equal thereby suggesting that cardiovascular reactivity was unaltered and that enhanced responsiveness to hypothalamic stimulation was directly due to the concomitant increase in sympathetic nerve activity. Although the exact site from which sympathetic hyperactivity originates was unidentified, our results support the interpretation that sympathetic mechanisms involving the posterior hypothalamus participate in elevating blood pressure during development of spontaneous hypertension in rats.
O2 delivery to the pregnant uterus: its relationship to O2 consumption
Authors: Caton D. , Crenshaw C. , Wilcox C. J. , Barron D. H.
Published: December 2017

Normal sheep were studied at intervals of 3-5 days during the last weeks of pregnancy in order to evaluate variability in rate of O2 consumption (QO2) of the uterus in relation to several variables involved in delivery of O2 to the organ. Among-animal differences of uterine QO2 were statistically significant and directly related to birthweight of the lamb. Among-animal differences of uterine blood flow (UBF) and uterine arteriovenous O2 content difference [C(a-v)O2] also were statistically significant, though neither was related to birthweight, presumably since they tended to vary inversely with one another. In a given ewe relative magnitude of UBF and of C(a-v)O2 was related to maternal arterial O2 content (CaO2), day of pregnancy, and whether the animal carried singlets or twins. Variability in QO2 was most closely related to UBF, although its relations to C(a-v)O2 and CaO2 were significant also. These data suggest there are systematic relationships among variables involved in the delivery of O2 to the uterus of pregnant sheep.