bluuebunny/crossref_metadata_2025 huggingface dataset:
Sulfate and chloride transport in Caco-2 cells: differential regulation by thyroxine and the possible role ofDRAgene
Authors: Alrefai W. A. , Tyagi S. , Mansour F. , Saksena S. , Syed I. , Ramaswamy K. , Dudeja P. K.
Published: December 2017

The current studies were undertaken to establish an in vitro cellular model to study the transport of SO[Formula: see text] and Cl−and hormonal regulation and to define the possible function of the downregulated in adenoma ( DRA) gene. Utilizing a postconfluent Caco-2 cell line, we studied the OH−gradient-driven35SO[Formula: see text] and36Cl−uptake. Our findings consistent with the presence of an apical carrier-mediated35SO[Formula: see text]/OH−exchange process in Caco-2 cells include: 1) demonstration of saturation kinetics [Michaelis-Menten constant ( Km) of 0.2 ± 0.08 mM for SO[Formula: see text] and maximum velocity of 1.1 ± 0.2 pmol · mg protein−1· 2 min−1]; 2) sensitivity to inhibition by DIDS ( Ki= 0.9 ± 0.3 μM); and 3) competitive inhibition by oxalate and Cl−but not by nitrate and short chain fatty acids, with a higher Ki(5.95 ± 1 mM) for Cl−compared with oxalate ( Ki= 0.2 ± 0.03 mM). Our results also suggested that the SO[Formula: see text]/OH−and Cl−/OH−exchange processes in Caco-2 cells are distinct based on the following: 1) the SO[Formula: see text]/OH−exchange was highly sensitive to inhibition by DIDS compared with Cl−/OH−exchange activity ( Kifor DIDS of 0.3 ± 0.1 mM); 2) Cl−competitively inhibited the SO[Formula: see text]/OH−exchange activity with a high Kicompared with the Kmfor SO[Formula: see text], indicating a lower affinity for Cl−; 3) DIDS competitively inhibited the Cl−/OH−exchange process, whereas it inhibited the SO[Formula: see text]/OH−exchange activity in a mixed-type manner; and 4) utilizing the RNase protection assay, our results showed that 24-h incubation with 100 nM of thyroxine significantly decreased the relative abundance of DRA mRNA along with the SO[Formula: see text]/OH−exchange activity but without any change in Cl−/OH−exchange process. In summary, these studies demonstrated the feasibility of utilizing Caco-2 cell line as a model to study the apical SO[Formula: see text]/OH−and Cl−/OH−exchange processes in the human intestine and indicated that the two transporters are distinct and that DRA may be predominantly a SO[Formula: see text]transporter with a capacity to transport Cl−as well.
Role of cholecystokinin in the intestinal phase of pancreatic circulation in dogs
Authors: Nakajima Morio , Naruse Satoru , Kitagawa Motoji , Ishiguro Hiroshi , Jin Chunxiang , Ito Osamu , Hayakawa Tetsuo
Published: December 2017

The regulatory mechanisms of postprandial pancreatic hyperemia are not well characterized. The aim of this study is to clarify the role of cholecystokinin (CCK) in the intestinal phase of pancreatic circulation. Pancreatic, gastric, and intestinal blood flows were measured by ultrasound transit-time blood flowmeters in five conscious dogs. Pancreatic and gastric secretion and blood pressure were also monitored. Synthetic CCK octapeptide (CCK-8) or gastrin heptadecapeptide (gastrin-17) was infused intravenously, and milk was infused into the duodenum with or without loxiglumide, a specific CCK-A receptor antagonist. CCK-8 induced dose-related increases of pancreatic, but not gastric or intestinal, blood flow and protein secretion without affecting systemic blood pressure. Gastrin-17 did not affect pancreatic blood flow. An intraduodenal infusion of milk increased pancreatic and intestinal blood flows and pancreatic protein secretion. Loxiglumide completely inhibited pancreatic blood flow and protein responses to CCK-8 and milk but not the intestinal blood flow response. CCK is a potent and specific pancreatic vasodilator, with its effect mediated by CCK-A receptors. CCK plays an important role in the regulation of the intestinal phase of the pancreatic circulation in dogs.
Direct cell-to-cell contact between Kupffer cells and hepatocytes augments endotoxin-induced hepatic injury
Authors: Hoebe Kasper H. N. , Witkamp Renger F. , Fink-Gremmels Johanna , Van Miert Adelbert S. J. P. A. M. , Monshouwer Mario
Published: December 2017

This study focuses on the importance of direct contact between Kupffer cells (KCs) and hepatocytes (HCs) during the hepatic inflammatory response using an in vitro approach. The lipopolysaccharide (LPS)-induced inflammatory response in monocultures of porcine HCs and KCs were compared with cocultures prepared either with direct contact between KCs and HCs (DC cocultures) or without direct contact using cell culture membrane inserts. Our data show that DC cocultures exhibited the highest production of tumor necrosis factor (TNF)-α, interleukin-6, and nitric oxide (NO) compared with the other cultures. Immunohistochemical studies revealed that TNF-α was exclusively produced by KCs, whereas HCs were responsible for NO production after LPS stimulation. Biotransformation capacity, as determined by cytochrome P-450 and UDP glucuronosyl transferase enzyme activities, was most significantly decreased in DC cocultures. These results provide evidence that direct contact between KCs and HCs favors the extensive TNF-α production by KCs but in turn affects HC functionality and viability. These findings suggest that direct contact between KCs and HCs plays a key role in the development of a fulminating hepatic inflammatory response.
Neutrophil transepithelial migration: regulation at the apical epithelial surface by Fc-mediated events
Authors: Reaves Titus A. , Colgan Sean P. , Selvaraj Periasamy , Pochet Mildred M. , Walsh Shaun , Nusrat Asma , Liang Tony W. , Madara James L. , Parkos Charles A.
Published: December 2017

Neutrophil (PMN) transepithelial migration is a major effector of epithelial defense in inflammatory diseases involving mucosal surfaces. However, major receptor-ligand interactions between epithelial cells and PMN remain incompletely characterized. To better define the molecular events involved in PMN interactions with epithelial cells, we produced a monoclonal antibody called g82 that inhibited PMN transepithelial migration in the physiological basolateral-to-apical direction. The g82 antigen localized to the apical surface of human colonic epithelium and was significantly upregulated under inflammatory conditions. Immunoprecipitation revealed two polypeptides of Mr207 and 32 kDa. F(ab′)2fragments from g82 IgG had no effect on transmigration, suggesting Fc dependence. Further experiments confirmed dependence on the PMN Fc receptor CD32A and that the observed effects were secondary to a failure of PMN to detach from the apical epithelial surface. These Fc-mediated events were epitope specific since binding, isotype-matched antibodies did not affect detachment. These results identify a new mechanism for retention of PMN at the apical epithelial surface following transepithelial migration. This pathway may be important in pathogen clearance and mucosal pathophysiology associated with autoimmunity.
Epidermal growth factor increases surface hydrophobicity and resistance to acid in the rat duodenum
Authors: Lugea Aurelia , Mourelle Marisabel , Domingo Ana , Salas Antonio , Guarner Francisco , Malagelada Juan-R.
Published: December 2017

Epidermal growth factor (EGF) is produced in Brunner's glands and plays a role in healing and repair of duodenal ulcers. We examined the participation of zwitterionic phospholipids of mucus in the effects of EGF. Under anesthesia, groups of rats received an intraduodenal bolus of either saline or EGF. Some rats received subcutaneous indomethacin followed by EGF or EGF followed by a detergent (5% Brij 35, a nonionic detergent that solubilizes luminal phospholipids). Thirty minutes after treatment, mucosal surface hydrophobicity and phospholipid concentration in the mucus layer were measured. Matched groups of rats were challenged with 0.5 M HCl, instilled intraduodenally 30 min after treatment, and mucosal damage was assessed 1 h after acid challenge. Exogenous EGF significantly increased surface hydrophobicity and phosphatidylcholine concentration in the mucus layer. EGF treatment also reduced mucosal damage induced by acid. However, indomethacin pretreatment or detergent administration after EGF abolished both protection against acid and changes in the mucus layer. These data suggest that EGF increases duodenal resistance to luminal acid via stimulation of mucosal zwitterionic phospholipids.
Intraluminal modulation of gastric sensitivity to distension: effects of hydrochloric acid and meal
Authors: Coffin Benoit , Chollet Robert , Flourié Bernard , Lémann Marc , Franchisseur Claire , Rambaud Jean-Claude , Jian Raymond
Published: December 2017

Conscious sensations in response to gut distensions may be modulated by temporospatial interactions among different stimuli. This study investigated whether symptoms induced by gastric distension may be modified by hydrochloric acid (HCl) gastric infusion and meal ingestion. In nine healthy subjects, fixed pressure (isobaric) and fixed volume (isovolumetric) distensions were performed during continuous (4 ml/min) intragastric saline or HCl infusion, during fasting and after meal ingestion, until the maximal distension step defined as discomfort or a predefined maximal volume. During fasting isobaric distensions, the maximal distension step was significantly decreased during HCl compared with saline. The intragastric volumes were not significantly different, but the wall tension was significantly lower during HCl than saline. HCl increased gastric compliance. Meal ingestion relaxed the stomach and decreased the pressure at the maximal distension step during saline, but HCl did not further decrease it compared with fasting. During isovolumetric distensions, HCl also increased gastric compliance, but in both fasted and fed states it did not modify the maximal distension steps. In conclusion, sensations in response to gastric isobaric distensions, but not to isovolumetric distensions, are influenced by gastric acid infusion and meal ingestion. The effects of HCl might be related to a sensitization of mucosal mechanoreceptors.
II. Excitatory amino acid receptors in the brain-gut axis
Authors: Hornby Pamela J.
Published: December 2017

In the last decade, there has been a dramatic increase in academic and pharmaceutical interest in central integration of vago-vagal reflexes controlling the gastrointestinal tract. Associated with this, there have been substantial efforts to determine the receptor-mediated events in the dorsal vagal complex that underlie the physiological responses to distension or variations in the composition of the gut contents. Strong evidence supports the idea that glutamate is a transmitter in afferent vagal fibers conveying information from the gut to the brain, and the implications of this are discussed in this themes article. Furthermore, both ionotropic and metabotropic glutamate receptors mediate pre- and postsynaptic control of glutamate transmission related to several reflexes, including swallowing motor pattern generation, gastric accommodation, and emesis. The emphasis of this themes article is on the potential therapeutic benefits afforded by modulation of these receptors at the site of the dorsal vagal complex.
α1-Adrenoceptor-induced Mg2+extrusion from rat hepatocytes occurs via Na+-dependent transport mechanism
Authors: Fagan Theresa E. , Romani Andrea
Published: December 2017

The stimulation of the α1-adrenergic receptor by phenylephrine results in a sizable extrusion of Mg2+from liver cells. Phenylephrine-induced Mg2+extrusion is almost completely abolished by the removal of extracellular Ca2+or in the presence of SKF-96365, an inhibitor of capacitative Ca2+entry. In contrast, Mg2+extrusion is only partially inhibited by the Ca2+-channel blockers verapamil, nifedipine, or (+)BAY-K8644. Furthermore, Mg2+extrusion is almost completely prevented by TMB-8 (a cell-permeant inhibitor of the inositol trisphosphate receptor), 1,2-bis(2-aminophenoxy)ethane- N,N,N′,N′-tetraacetic acid (an intracellular Ca2+-chelating agent), or W-7 (a calmodulin inhibitor) Thapsigargin can mimic the effect of phenylephrine, and the coaddition of thapsigargin and phenylephrine does not result in an enlarged extrusion of Mg2+from the hepatocytes. Regardless of the agonist used, Mg2+extrusion is inhibited by >90% when hepatocytes are incubated in the presence of physiological Ca2+but in the absence of extracellular Na+. Together, these data suggest that the stimulation of the hepatic α1-adrenergic receptor by phenylephrine results in an extrusion of Mg2+through a Na+-dependent pathway and a Na+-independent pathway, both activated by changes in cellular Ca2+.
Functional overlap of IP3- and cADP-ribose-sensitive calcium stores in guinea pig myenteric neurons
Authors: Turner Douglas J. , Segura Bradley J. , Cowles Robert A. , Zhang Weizhen , Mulholland Michael W.
Published: December 2017

In myenteric neurons two different receptor subtypes govern the intracellular Ca2+ stores: the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) and the ryanodine receptor (RyR). Their degree of functional overlap was determined by examining Ca2+ release in these cells through both superfusion techniques and intracellular microinjection. Microinjection of IP3 (50 μM) and cADP-ribose (cADPr, 50 μM), specific ligands for the IP3R and RyR, respectively, demonstrated mobilization of intracellular Ca2+ stores. Perfusion with cinnarizine (50 μM) or dantrolene (10 μM), antagonists of the IP3R and RyR, respectively, eliminated the Ca2+response to microinjected IP3 and cADPr. Superfusion of the neurons with 100 μM ATP, an IP3-mediated Ca2+-mobilizing agonist, caused intracellular Ca2+ increments, which were antagonized by cinnarizine, and the RyR antagonists dantrolene, procaine (5 mM), and ryanodine (1 μM). Caffeine (10 mM) was applied repetitively in Ca2+-free conditions to deplete RyR-sensitive stores; subsequent perfusion with ATP demonstrated a Ca2+ response. Conversely, caffeine caused a Ca2+ response after repetitive ATP exposures. The internal Ca2+ stores of myenteric neurons are governed by two receptor subtypes, IP3R and RyR, which share partial functional overlap.
Hepatic parasympathetic (HISS) control of insulin sensitivity determined by feeding and fasting
Authors: Lautt W. W. , Macedo M. P. , Sadri P. , Takayama S. , Duarte Ramos F. , Legare D. J.
Published: December 2017

In response to insulin, a hormone [hepatic insulin sensitizing substance (HISS)] is released from the liver to stimulate glucose uptake in skeletal muscle but not liver or gut. The aim was to characterize dynamic control of HISS action in response to insulin and regulation of release by hepatic parasympathetic nerves. Insulin action was assessed by the rapid insulin sensitivity test, where the index is the glucose required (mg/kg) to maintain euglycemia after a bolus of insulin. Blocking HISS release by interruption of the hepatic parasympathetic nerves by surgical denervation, atropine, or blockade of hepatic nitric oxide synthase produced similar degrees of insulin resistance and revealed a similar dynamic pattern of hormone action that began 3–4 min after, and continued for 9–10 min beyond, insulin action (50 mU/kg). HISS action accounted for 56.5 ± 3.5% of insulin action at insulin doses from 5 to 100 mU/kg (fed). We also tested the hypothesis that HISS release is controlled by the feed/fast status. Feeding resulted in maximal HISS action, which decreased progressively with the duration of fasting.
Helicobacter pylorilipopolysaccharide induces apoptosis of cultured guinea pig gastric mucosal cells
Authors: Kawahara Tsukasa , Teshima Shigetada , Kuwano Yuki , Oka Ayuko , Kishi Kyoichi , Rokutan Kazuhito
Published: December 2017

Helicobacter pylori lipopolysaccharide (LPS) is generally accepted as a low-toxicity virulence. Primary cultures of guinea pig gastric mucosal cells expressed the Toll-like receptor 4 and were sensitive to H. pylori LPS as well as Escherichia coli LPS. H. pylori LPS stimulated phosphorylation of transforming growth factor-β-activated kinase 1 (TAK1), TAK1-binding protein 1 (TAB1), and c-Jun NH2-terminal kinase (JNK) 2. H. pylori LPS at >2.1 endotoxin unit/ml (>1 ng/ml) activated caspase-8, stimulated cytochrome c release from mitochondria, and subsequently activated caspases-9 and -3, leading to apoptosis. Epidermal growth factor blocked all of these apoptotic processes and inhibited apoptosis, whereas it did not modify the phosphorylation of TAK1, TAB1, and JNK2. A comparatively specific inhibitor of caspase-8 or -9 blocked apoptosis, whereas cytochrome c release was prevented only with a caspase-8-like inhibitor. Our results suggest that caspase-8 and mitochondria may play crucial roles in H. pylori LPS-induced apoptosis and that this accelerated apoptosis may be involved in abnormal cell turnover of H. pylori-infected gastric mucosa.
Gastrin induces CXC chemokine expression in gastric epithelial cells through activation of NF-κB
Authors: Hiraoka Shintaro , Miyazaki Yoshiji , Kitamura Shinji , Toyota Miyuki , Kiyohara Tatsuya , Shinomura Yasuhisa , Mukaida Naofumi , Matsuzawa Yuji
Published: December 2017

Although hypergastrinemia is frequently observed in individuals with a chronic Helicobacter pylori infection, its pathophysiological significance in gastric mucosal inflammation is unclear. The present study was designed to determine if gastrin induces the expression of CXC chemokines in gastric epithelial cells. Human and rat gastric epithelial cells, transfected with gastrin receptor, were stimulated with gastrin. The expression of mRNAs for human interleukin-8 (IL-8) and rat cytokine-induced neutrophil chemoattractant-1 and release of human IL-8 protein were then determined by Northern blot analysis and ELISA, respectively. Gastrin not only induced the expression of mRNAs for these chemokines but also stimulated IL-8 protein release. A luciferase assay using IL-8 promoter genes showed that nuclear factor (NF)-κB is absolutely required and activator protein-1 (AP-1) is partly required for the maximum induction of IL-8 by gastrin. An electrophoretic mobility shift assay revealed that gastrin is capable of activating both NF-κB and AP-1. In addition, the inhibition of NF-κB abrogated gastrin-induced chemokine expression. These results suggest that gastrin is capable of upregulating CXC chemokines in gastric epithelial cells and therefore may contribute to the progression of the inflammatory process in the stomach.
Single amino acid substitution of rat MRP2 results in acquired transport activity for taurocholate
Authors: Ito Kousei , Suzuki Hiroshi , Sugiyama Yuichi
Published: December 2017

Multidrug resistance-associated protein 3 (MRP3), unlike other MRPs, transports taurocholate (TC). The difference in TC transport activity between rat MRP2 and MRP3 was studied, focusing on the cationic amino acids in the transmembrane domains. For analysis, transport into membrane vesicles from Sf9 cells expressing wild-type and mutated MRP2 was examined. Substitution of Arg at position 586 with Leu and Ile and substitution of Arg at position 1096 with Lys, Leu, and Met resulted in the acquisition of TC transport activity, while retaining transport activity for glutathione and glucuronide conjugates. Substitution of Leu at position 1084 of rat MRP3 (which corresponds to Arg-1096 in rat MRP2) with Lys, but not with Val or Met, resulted in the loss of transport activity for TC and glucuronide conjugates. These results suggest that the presence of the cationic charge at Arg-586 and Arg-1096 in rat MRP2 prevents the transport of TC, whereas the presence of neutral amino acids at the corresponding position of rat MRP3 is required for the transport of substrates.
Acid inhibition by intestinal nutrients mediated by CCK-A receptors but not plasma CCK
Authors: Lloyd K. C. Kent , Wang Jiafang , Solomon Travis E.
Published: December 2017

We examined the role of CCK-A receptors in acid inhibition by intestinal nutrients. Gastric acid and plasma CCK and gastrin levels were measured in rats with gastric and duodenal fistulas during intragastric 8% peptone and duodenal perfusion with saline, complete liquid diet (CLD; 20% carbohydrate, 6% fat, and 5% protein), and the individual components of CLD. Acid output was significantly inhibited (50–60%) by CLD, lipid, and dextrose. Plasma CCK was significantly increased by CLD (from 2.6 ± 0.3 to 4.8 ± 0.5 pM) and lipid (4.6 ± 0.5 pM). CCK levels 50-fold higher (218 ± 33 pM) were required to achieve similar acid inhibition by exogenous CCK-8 (10 nmol · kg−1 · h−1 iv). Intestinal soybean trypsin inhibitor elevated CCK (10.9 ± 2.5 pM) without inhibiting acid secretion. The CCK-A antagonist MK-329 (1 mg/kg iv) reversed acid inhibition caused by CLD, lipid, and dextrose. Peptone-stimulated gastrin (21.7 ± 1.9 pM) was significantly inhibited by CLD (14.5 ± 3.6 pM), lipid (12.3 ± 2.2 pM), and dextrose (11.9 ± 1.5 pM). Lipid and carbohydrate inhibit acid secretion by activating CCK-A receptors but not by altering plasma CCK concentrations.
Regulation of the rat NHE3 gene promoter by sodium butyrate
Authors: Kiela Pawel R. , Hines Eric R. , Collins James F. , Ghishan Fayez K.
Published: December 2017

Short-chain fatty acids, and especially butyrate (NaB), stimulate sodium and water absorption by inducing colonic Na+/H+exchange (NHE). NaB induces NHE3 activity and protein and mRNA expression both in vivo and in vitro. NaB, as a histone deacetylase (HDAC) inhibitor, regulates gene transcription. We therefore studied whether NaB regulates transcription of the rat NHE3 promoter in transiently transfected Caco-2 cells. NaB (5 mM) strongly stimulated reporter gene activity, and this stimulation was prevented with actinomycin D, indicating transcriptional activation. NaB effects on the NHE3 promoter depended on the activity of Ser/Thr kinases, in particular, protein kinase A (PKA). However, PKA stimulation alone did not have an effect on promoter activity, and it did not act synergistically with NaB. Another HDAC inhibitor, Trichostatin A (TSA), stimulated NHE3 promoter in a Ser/Thr kinase-independent fashion. The putative NaB-responsive elements were localized within −320/−34 bp of the NHE3 promoter. These findings suggest that PKA mediates NaB effects on NHE3 gene transcription and that the mechanism of NaB action is different from that of TSA.
Lactoferrin protects neonatal rats from gut-related systemic infection
Authors: Edde Lynn , Hipolito Ronaldo B. , Hwang Freda F. Y. , Headon Denis R. , Shalwitz Robert A. , Sherman Michael P.
Published: December 2017

Lactoferrin is a milk protein that reportedly protects infants from gut-related, systemic infection. Proof for this concept is limited and was addressed during in vivo and in vitro studies. Neonatal rats pretreated orally with recombinant human lactoferrin (rh-LF) had less bacteremia and lower disease severity scores ( P < 0.001) after intestinal infection with Escherichia coli. Control animals had 1,000-fold more colony-forming units of E. coli per milliliter of blood than treated animals ( P < 0.001). Liver cultures from control animals had a twofold increase in bacterial counts compared with cultures from rh-LF-treated pups ( P < 0.02). Oral therapy with rh-LF + FeSO4did not alter the protective effect. In vitro studies confirmed that rh-LF interacted with the infecting bacterium and rat macrophages. An in vitro assay showed that rh-LF did not kill E. coli, but a combination of rh-LF + lysozyme was microbicidal. In vitro studies showed that rat macrophages released escalating amounts of nitric oxide and tumor necrosis factor-α when stimulated with increasing concentrations of rh-LF. The in vitro studies suggest that rh-LF may act with other “natural peptide antibiotics” or may prime macrophages to kill E. coli in vivo.
Cytokine regulation of human intestinal primary epithelial cell susceptibility to Fas-mediated apoptosis
Authors: Martin Carla A. , Panja Asit
Published: December 2017

The regulatory mechanisms of nontransformed intestinal epithelial cell apoptosis have not been thoroughly investigated. We determined the susceptibility and mechanism of Fas-mediated apoptosis in nontransformed human intestinal epithelial cells (HIPEC) in the presence and absence of inflammatory cytokines. Despite ample expression of Fas, HIPEC were relatively insensitive to Fas-mediated apoptosis in that agonist anti-Fas antibody (CH11) induced a <25% increase in HIPEC apoptosis. Pretreatment of HIPEC with interferon (IFN)-γ, but not tumor necrosis factor-α or granulocyte-macrophage colony-stimulating factor, significantly increased CH11-induced apoptosis of these cells without increasing Fas expression. Increased apoptosis correlated with increased caspase 3 activation but not expression of procaspase 3. Also, there was a significant delay in the onset of Fas-mediated apoptosis in HIPEC, which correlated with the generation of an activated caspase 3 p22/20 subunit. HIPEC required both initiator caspases 8 and 9 activity but expressed significantly less of the zymogen form of these caspases than did control cells. IFN-γ-mediated sensitization of HIPEC occurred upstream of caspase 9 activation and correlated with a small increase in procaspase 8 expression (<1-fold increase) and a significant increase in expression of an intermediate form (p35) of caspase 4 (3.3-fold increase).
Potassium exchange and mechanical performance in anoxic mammalian myocardium
Authors: Rau E. E. , Shine K. I. , Langer G. A.
Published: December 2017

Mechanical performance and 42K exchange were studied during anoxia in isoalted, arterially perfused, interventricular rabbit septa at 42 beats/min and 28 degree C. The septa were perfused at 1.8 ml/min per g with a modified Tyrode solution having dextrose as the metabolic substrate. Developed tension declined to 16% of preanoxic control values during 60 min of anoxia, and returned to 65% of control during a 60–70 min recovery. Anoxia induced net potassium losses of 31+/-2, 53+/-2, and 90+/-14 mmol K+/kg dry tissue (means+/-SE) during 20, 40, and 60 min of anoxic stresses, determined by tissue probe analysis after asymptotic labeling. Potassium losses attributed to increased efflux of the ion from the cells during 20, 40, and 60 min of anoxia were determined from effluent analyses to be 32+/-4, 60+/-6, and 98+/-11 mmol K+/kg dry wt. Potassium loss began within seconds of the onset of anoxia and reoxygenation immedaitely reversed the potassium loss. These data indicate that 1) function of the membrane Na-K pump is maintained through 60 min of anoxia with the entire net potassium loss attributable to increased efflux from the cells, 2) anoxia decreases the rate of exchange of potassium after recovery, and 3) the cell membrane appears to be the rate-limiting site of potassium efflux during anoxia.
Comparison of vascular effects of gastrointestinal hormones on various organs
Authors: Chou C. C. , Hsieh C. P. , Dabney J. M.
Published: December 2017

Vascular effects of raising local arterial concentration of pentagastrin (2-1,500ng/ml), secretin (0.2-150mU/ml), and cholecystokinin (0.2-150mU/ml) in the duodenum, jejunum, heart, kidney, forelimb, spleen, and the skin and muscle of the forelimb were studied in 54 anesthetized dogs. Secretin produced similar vasodilation in all organs. The minimal increment in local blood secretin concentration for vasodilation ("concentration requirement") was between 7 and 32 mU/ml. Pentagastrin produced vasodilation only in the duodenum and jejunum and the concentration requirement was between 25 and 50 ng/ml. Cholecystokinin did not affect vascular resistance of the forelimb, skin, or muscle. In the heart, kidney, and spleen, cholecystokinin produced vasodilation but the concentration requirement was above 21-33 mU/ml. In contrast, vasodilation in the duodenum and jejunum appeared when cholecystokinin concentration was increased by only 2.5 mU/ml. Furthermore, almost all its vasodilating effect occurred below an increment of 10 mU/ml. Comparison of our data with the reported cardiovascular adjustments and blood concentration of gastrointestinal hormones following a meal suggests that cholecystokinin may contribute to postprandial intestinal hyperemia.
Occlusion cuff for routine measurement of digital blood pressure and blood flow
Authors: Lassen N. A. , Krahenbuhl B. , Hirai M.
Published: December 2017

A miniaturized blood pressure cuff made of plastic material and applicable to fingers and toes is described. The cuff was compared to rubber cuffs and to bladder-free cuffs. It was found to be more reliable than the former type and much easier to use than the latter type. It is recommended for use in conjunction with a mercury-in-Silastic strain gauge for routine measurement of digital blood pressure and blood flow in patients with arterial disease.
Capillary filtration measurement by strain gauge. II. Effects of mannitol infusion
Authors: Katz M. A.
Published: December 2017

Maintenance of normal partition of extracellular fluid into vascular and interstitial compartments is a tightly controlled system. One means of studying control of this system is to induce filtration by fluid loading, and to measure associated changes capillary filtration coefficients (CFC) and Starling pressures in a particular vascular bed. We therefore measured responses of the dog hindlimb to isotonic mannitol infusions. Using strain-gauge plethysmography to measure CFC, the Johnson zero-flow technique to measure isogravimetric capillary hydrostatic pressure, and chronically implanted capsules to measure muscular interstitial hydrostatic pressure, we infused isotonic mannitol into anesthetized dogs for 30 min at 20 ml/min and 30 ml/min. There was a sustained 75% increase in CFC in intact hindlimbs, no change in hydrostatic capillary or interstitial pressure, and a 4-5 mmHg rise in filtration pressure due to dilution of serum protein. The most likely mechanism for increased CFC is capillary recruitment, since distension of capillaries requires large increases in hydrostatic pressure. Interstitial fluid compliance appears high. These studies indicate capillary intermittency may be an important mechanism in the disposition of fluid loads.
Continuous measurement of tissue blood flow by laser-Doppler spectroscopy
Authors: Stern M. D. , Lappe D. L. , Bowen P. D. , Chimosky J. E. , Holloway G. A. , Keiser H. R. , Bowman R. L.
Published: December 2017

Laser light scattered from tissue in vivo is broadened in line width as a result of the Doppler shift produced by moving red cells in the microcirculation. A feasibility study was carried out to demonstrate use of this effect to measure and monitor tissue blood flow. Light from a helium-neon laser illuminated a 1-mm area of tissue (human skin or rat renal cortex), and the backscattered light was detected with a photomultiplier. The spectrum of the Doppler beat notes was analyzed directly with a digital spectrum analyzer, or processed by analog circuitry to yield a flow parameter based on the root-mean-square Doppler line width. This parameter was compared with 133Xe washout in the skin of volunteers subjected to UV-induced erythema and the skin of volunteers subjected to UV-induced erythema and was found to vary in an approximately linear manner with skin blood flow. The laser instrument provided continuous monitoring of blood flow fluctuations, including the pulsatile component. The instrument was used to monitor flow in the outer cortex of the rat kidney during administration of norepinephrine, angiotensin, hydralazine, dextran, dopamine, nitroprusside, and angiotensin blocked by saralasin. Dynamic and steady-state responses were consistent with known pharmacology and renal physiology, and with the assumption that vasoconstrictor angiotensin II receptors in the kidney are accessible to blood-borne inhibitors. The laser-Doppler method is a promising tool for rapid monitoring of dynamic changes in tissue perfusion.
Baroreflexive depression of oxygen consumption in the squirrel monkey at 10 degrees C
Authors: Wasserstrum N. , Herd J. A.
Published: December 2017

Unanesthetized squirrel monkeys exposed to an ambient temperature of 10 degrees C showed elevations in total body oxygen consumption (VO2), arterial blood pressure (BP), and heart rate (HR) above values recorded at 28 degrees C. Further elevation of BP in the cold by intravenous infusion of phenylephrine was accompanied by immediate reduction in VO2, inhibition of shivering, and decrease in rectal temperature, as well as immediate reduction in HR. The magnitude of reduction in VO2 correlated with the magnitude of the concomitant baroreflexive bradycardia. When the pressor effects of phenylephrine were opposed by administration of diazoxide or phentolamine, the inhibitory effects of phenylephrine on both HR and VO2 were abolished. In animals previously subjected to bilateral sinoaortic denervation, both the bradycardia and depression in oxygen consumption normally associated with BP elevation were markedly reduced. These results suggest that elevation of blood pressuere can inhibit the thermoregulatory increase in total body oxygen consumption normally produced by cold exposure, and that this inhibition, like the concomitant bradycardia, is probably mediated via the sinoaortic baroreceptors.
Direct calibration of a totally implantable pulsed Doppler ultrasonic blood flowmeter
Authors: Allen H. V. , Anderson M. F. , Meindl J. D.
Published: December 2017

A totally implantable pulsed Doppler ultrasonic blood flowmeter has recently been developed to provide information on the velocity-flow profile in a vessel as well as its diameter. Volume flow can be indirectly obtained according to the formula: Q = (phi/4)(diam)2-v. In order to determine the accuracy of this estimate, in vivo direct bleedout measurements were performed on the abdominal aorta of six dogs with an overall accuracy in 77 trials of +2.0 +/- 8.7% (mean +/- 1 SD). The best-fit mean linear regression line was found to be: flowmeter output = 1.013-true flow + 5.1 ml/min. The scatter in the flowmeter's accuracy is thought to be due to small variations in the angle of the transducer. The source of the 2% overestimation in the mean accuracy could not be directly attributed to any one condition; the error is sufficiently small that in many cases it can be neglected.
Ejection pressure and the diastolic left ventricular pressure-volume relation
Authors: Janicki J. S. , Weber K. T.
Published: December 2017

The influence of ejection pressure (EP) on the left ventricular end-diastolic pressure-volume (P-V) relation was examined in 24 paced, isolated canine hearts. A pressure servo system was used to control EP and monitor ventricular volume. For any given contractile state EP was varied: a) by 10- to 20-mmHg increments and the steady-state P-V response observed at each EP level (method A); or b) by instantaneously attaining the isovolumic condition (PO) from a given EDV and examining the immediate P-V response (method B). With either method it was possible to alter the P-V relation; the maximum variation occurred when, for a given EDV or EDP, EP was raised from a value less than 50% of its corresponding peak isovolumic pressure to PO. For the EDP range 2-25 mmHg, the direction and total magnitude of change were: 1) an increase in EDV 1.3-9 ml was required to maintain EDP constant; and 2) for a constant EDV, EDP decreased an average 16.5%+/-1.2 SE (6-23.9%; P less than .02). The EDP decline observed with method B was immediate and reversible within several beats upon returning to the ejecting mode. Thus, under the conditions of this experiment the diastolic pressure-volume relation is a physiological variable dependent on ejection pressure.
Anatomic response of canine hindlimb vasculature to chronic venous occlusion
Authors: Conrad M. C.
Published: December 2017

Total limb (iliac) flow, small-vein pressure, and total small-vessel and venous resistances were measured in the fully dilated bed 2 h, 2 wk, and 8 wk after extensive ligation of veins. Values were compared to similar measurements in the contralateral unoccluded extremity. Wall thickness, lumen size and distensibility of noncollateral veins, and enlargement of collateral veins were evaluated 8 wk after venous ligation. Two hours after ligation, anatomic vascular resistance was twice normal, and venous resistance was increased sevenfold. Eight weeks later, total limb anatomic resistance had decreased to a value slightly less than normal, suggesting an "overcompensation" in anatomic resistance. Wall thickness of noncollateral veins was greater than normal at 8 wk postligation, and lumen size and distensibility were less than normal in spite of a return of supine venous pressure to normal levels.
Central neural influence on precapillary microvessels and sphincter
Authors: Baez S. , Feldman S. M. , Gootman P. M.
Published: December 2017

The responses to central nervous system (CNS) stimulation of consecutive segments of arterioles down to the precapillary sphincter were measured in the mesoappendix and/or cremaster of nine male rats with indwelling electrodes. Under pentobarbital sodium anesthesia, vasoactive sites were stimulated at threshold for maximal constriction or lumen closure of the precapillary sphincter and/or immediately preceding precapillary arteriole (metarteriole). In all experiments, CNS stimulation induced blood pressure elevation and constriction of three consecutive segments of precapillary vessels and of the sphincter. A threefold increase in rate of vasomotion of precapillary sphincter and metarteriole was the rule, but this was noted infrequently in larger arterioles. In addition to an overall influence of the CNS on microcirculation, the data show a gradient of responses to stimulation, the slope of which is negatively related to the size of the vessels and sphincter, in both tissues studied. A complete lumen closure of the metarteriole and precapillary sphincter (when present) in response to CNS stimulation implies active participation in the regulation of local blood flow. No evidence was foun for central neural regulation of the precapillary sphincter independent of arteriolar control.
Elasticity and compliance of canine femoral and jugular vein segments
Authors: Baird R. N. , Abbott W. M.
Published: December 2017

In this study, the pressure/strain and stress/strain relatioships of 44 jugular and 31 femoral canine vein segments were compared with 17 carotid artery specimens, latex rubber, and a synthetic graft material, expanded polytetrafluoroethylene. A method is described for comparing the elastic properties of vein wall specimens of varying thicknesses such as occur after implantation into the arterial circulation. A flat sheet of opened vessel wall, fexed between retention rings at one end of a saline-filled steel cylinder, was biaxially distended to form a bubble shape. Compliance ratio and stress modulus were computed at 20-mmHg increments from 20 to 200 mmHg. In the "arterial" pressure range, vein was less compliant than artery. Vein also had a higher stress modulus E (dyn/cm2 X 10(6)) +/- SE at a chamber pressure 120 mmHg than artery (E = 11 +/- 0.6), and jugular vein was stiffer (E = 65 +/- 3.6) than femoral vein (E = 41.5 +/- 2.0). Changes in the structural properties of vein grafts measured using this technique are potentially important factors leading to graft failure.
Solute permeability of the alveolar epithelium in acute hemodynamic pulmonary edema in dogs
Authors: Egan E. A. , Nelson R. M. , Gessner I. H.
Published: December 2017

Ten anesthetized dogs, 48 h postintravenous 131I-albumin injection, had a segment of lung airspace isolated by a balloon-tipped catheter lodged in a bronchus. An isotonic saline solution containing trace amounts of Blue Dextran, 125I-albumin, and 57Co-cyanocobalamin was instilled into the lung segment. During control periods, lung saline was absorbed at a rate of 0.133% per minute as measured by indicator dilution of Blue Dextran. Only 57Co-cyanocobalamin crossed the epithelium. Acute hemodynamic pulmonary edema was produced by aortic constriction plus saline overload. In pulmonary edema the fluid volume in the airspace increased at the rate of 0.96% per minute, and there was a significant influx of 131I-albumin into the lung saline from the blood in all animals. However, neither 125I-albumin nor Blue Dextran diffused from the airspace into blood during edema; both were merely diluted by fluid influx. The rate of diffusion of 57Co-cyanocobalamin increased fivefold during edema. A small number of discrete breaks in the lung epithelium allowing bulk flow of interstitial fluid is proposed to account for the one-way movement of albumin in hemodynamic alveolar edema.
Improved signal processor for the ultrasonic dimension gauge
Authors: Rubinstein M. L. , Carlson C. J. , Rapaport E.
Published: December 2017

Inexpensive modifications and additions to improve the performance of a widely used ultrasonic dimension gauge are presented in detail. These include a pulse width demodulator, averaging peak detector, and improved signal processing circuits. Benefits of the modifications are improved frequency response (to 1 kHz), lowered drift, increased sensitivity (to 128 mV/mm), rational gain calibration, calibrated zero suppression, and improved recovery from signal dropout. The modifications result in the ability to take the derivatives of ventricular wall motion with greater reliability.
Physiological parameters of indicator dilution curves
Authors: Homer L. D. , Small A.
Published: December 2017

A model incorporating the effects of recirculation time lag, cardiac output, clearance, volume of distribution, and the variance of the distribution of recirculation times is applied to the analysis of indicator dilution curves. Experiments on dogs with use of radioactively labeled diethylenetriaminepentaacetic acid were done to evaluate the model. This five-parameter model can be fitted to data obtained during the period from less than 1 min to 3 h after a single injection of indicator. Estimates of cardiac output and clearance are in satisfactory agreement with estimates obtained by alternative techniques. Estimates of the time lag and volume of distribution are of physiologically plausible magnitude. The variance of the distribution of recirculation times is a new parameter, of which the possible usefulness to physiologists is discussed.
Effect of hyperosmotic mannitol on myocardial oxygen consumption
Authors: Vlahakes G. J. , Powell W. J.
Published: December 2017

Hyperosmotic mannitol produces salutary hemodynamic and histologic effects during experimental myocardial ischemia. However, the administration of hyperosmotic mannitol is associated with a positive inotropic influence. Positive inotropic interventions, which increase myocardial oxygen consumption (MVO2), also tend to increase the extent of ischemic myocardial injury. Thus, the purpose of this study was to determine the effect of mannitol on MVO2. Anesthetized dogs on right-heart bypass under conditions of controlled hemodynamics were studied. Both coronary arteries were perfused; mannitol was infused via the coronary perfusion cannulas to produce a 35 mosmol increase in osmolality. Heart rate was maintained constant. Cardiac output was held constant or deliberately increased so that left ventricular end-diastolic pressure and tension-time index, two other hemodynamic correlates of MVO2, remained constant or increased. MVO2 significantly decreased under conditions of decreased myocardial perfusion (P less than 0.025). This was in spite of a significant increase (P less than 0.001) in the peak rate of rise of left ventricular pressure (LV dP/dt), a hemodynamic correlate of MVO2. Thus, hyperosmotic mannitol under conditions of reduced coronary perfusion increases myocardial efficiency.
Glucagon inhibition of hepatic arterial responses to hepatic nerve stimulation
Authors: Richardson P. D. , Withrington P. G.
Published: December 2017

The hepatic arterial vascular bed of the chloaralose-urethan-anesthetized dog was perfused with blood from a cannulated femoral artery. Hepatic arterial blood flow and perfusion pressure were measured. The hepatic periarterial postganglionic sympathetic nerves were stimulated supramaximally at 0.1, 0.5, 1, 2, 5, 10, and 20 Hz; this caused frequency-dependent rises in the calculated hepatic arterial vascular resistance at all frequencies above the threshold of 0.1 or 0.5 Hz. Glucagon was infused intra-arterially in dosese from 0.25 to 10 microgram/min; glucagon antagonized both the vasoconstrictor effects of hepatic nerve stimulation and of intra-arterial injections of norepinephrine. The degree of antagonism of these responses was significantly correlated with the calculated hepatic arterial glucagon concentration. It is possible that glucagon released physiologically in stress and hypoglycemia may protect the hepatic arterial vasculature from the effects of increased sympathetic discharge.
Noninvasive analysis of regional myocardial wall motion: cardiokymography
Authors: Vas R. , Diamond G. A. , Wyatt H. L. , da Luz P. L. , Swan H. J. , Forrester J. S.
Published: December 2017

The validity of a new noninvasive device, the cardiokymograph, was assessed as to its ability to detect regional myocardial wall motion by direct comparison of the analog tracing with that of an epicardial length gauge in 11 open-chest dogs. The correlation of the two methods was excellent both during control conditions and following changes induced by acute coronary occlusion. The average difference between the methods in timing of various cardiac events was only 6.2 +/- 1.9 ms at rest and 6.8 +/- 1.5 ms following ischemia (P = NS). Relative amplitude ratio correlations, determined for the four portions of the cardiac cyele (isovolumic systole, ejection, isovolumic relaxation, and diastole), were also excellent. The average correlation of the kymograph to the length gauge was r = 0.896 +/- 0.018 at rest (K = 0.977 LG + 0.033) and r = 0.932 +/- 0.013 following occlusion (K = 1.071 LG + 0.101). Thus, the cardiokymograph is a sensitive and accurate noninvasive method for detection of regional ischemic dysfunction and produces an analog tracing essentially identical to that of the epicardial length gauge.
Low-grade intravascular coagulation and reticuloendothelial function
Authors: Kaplan J. E. , Saba T. M.
Published: December 2017

The present study evaluated the influence of experimentally produced intravascular coagulation on reticuloendothelial (RE) stability. Intravascular coagulation was initiated by the intraperitoneal injection of bovine thrombin (500 U/100 g body wt) into male rats. RE function was evaluated by the vascular clearance of an 131I-labeled RE test colloid. Thrombin injection resulted in a transient (0.5-2 h) (P less than .05) depression of the phagocytic index (K) with maximal depression at 1 h postthrombin challenge. The phagocytic index was unaltered after injection of saline or heat-inactivated thrombin. Vascular clearance depression was primarily due to a 37% decrease (P less than .001) in hepatic Kupffer cell colloid clearance and was associated with increments in lung (82%) and marrow (100%) colloid localization with no splenic alterations. While intravascular coagulation was associated with decreased hepatic blood flow at 30 min and 120 min, sinusoidal flow was normal during maximum RE impairment at 60 min. The in vivo clearance depression was not reflected as an intrinsic Kupffer cellular deficit when evaluated in an in vitro system. The results indicate a transient RE dysfunction during intravascular coagulation, the mechanism of which remains to be elucidated.