bluuebunny/crossref_metadata_2025 huggingface dataset:
Tachykinins mediate slow excitatory postsynaptic transmission in guinea pig sphincter of Oddi ganglia
Authors: Manning Brian P. , Mawe Gary M.
Published: December 2017

Intracellular recording techniques were used to test whether tachykinins could be mediators of slow excitatory postsynaptic potentials (EPSPs) in guinea pig sphincter of Oddi (SO) ganglia. Application of the tachykinin substance P (SP) onto SO neurons caused a prolonged membrane depolarization that was reminiscent of the slow EPSP in these cells. Pressure ejection of the neurokinin 3 (NK3) receptor-specific agonist senktide caused a similar depolarization; however, no responses were detected on application of NK1 or NK2 receptor agonists. The NK3 receptor antagonist SR-142801 (100 nM) significantly inhibited both SP-induced depolarization and the stimulation-evoked slow EPSP, as did NK3 receptor desensitization with senktide. Capsaicin, which causes the release of SP from small-diameter afferent fibers, induced a depolarization that was similar to the evoked slow EPSP in both amplitude and duration. The capsaicin-induced depolarization was significantly attenuated in the presence of SR-142801. These data indicate that tachykinins, released from extrinsic afferent fibers, act via NK3 receptors to provide slow excitatory synaptic input to SO neurons.
Mac-1 (CD11b/CD18) and intercellular adhesion molecule-1 in ischemia-reperfusion injury of rat liver
Authors: Kobayashi Akira , Imamura Hiroshi , Isobe Mitsuaki , Matsuyama Yutaka , Soeda Junpei , Matsunaga Kotaro , Kawasaki Seiji
Published: December 2017

The chronological expression (over 24 h) of two adhesion molecules [intercellular adhesion molecule-1 (ICAM-1) and CD11b/CD18 (Mac-1)] and the extent of liver damage, including injury to sinusoidal endothelial cells (SECs) and hepatocyte apoptosis, were investigated under two conditions of rat liver ischemia-reperfusion (I/R) injury: reversible (30 min) and fatal I/R (60 min). The chronological profiles of upregulation of ICAM-1 on hepatocytes and Mac-1 showed changes in parallel with the other liver damage parameters, and the extent of upregulation and various parameters of liver injury were more advanced in the 60-min I/R group. Paradoxically, the degree of ICAM-1 upregulation of SECs decreased significantly in the 60-min I/R group vs. the 30-min I/R group. Repression of hepatocyte apoptosis by administration of the caspase inhibitor ZVAD-fmk resulted in attenuation of neutrophil infiltration and liver injury. These findings indicate that 1) neutrophil infiltration is involved in the development of liver I/R injury; 2) interaction between ICAM-1 on SECs and Mac-1 on neutrophils is not an essential step for neutrophil transmigration through the endothelial layer because SECs, specifically, were impaired in the early stages of liver I/R injury; 3) the role of ICAM-1 and Mac-1 is to adhere neutrophils firmly to hepatocytes and activate neutrophils; and 4) excessive parenchymal apoptosis may be the signal for the neutrophil-induced inflammatory and necrotic reaction.
NO-mesalamine protects colonic epithelial cells against apoptotic damage induced by proinflammatory cytokines
Authors: Fiorucci Stefano , Distrutti Eleonora , Ajuebor Maureen N. , Mencarelli Andrea , Mannucci Roberta , Palazzetti Barbara , Del Soldato Piero , Morelli Antonio , Wallace John L.
Published: December 2017

The activation of a self-amplifying cascade of caspases, of which caspase-8 is the apical protease, mediates Fas-, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-, and TNF-α-induced apoptosis in colon cell lines. Nitric oxide (NO) protects from apoptosis induced by Fas and TNF-α. We examined whether NCX-456, an NO-releasing derivative of mesalamine, protects colon epithelial cells from cytokine-induced apoptosis. Caco-2 and HT-29 cell lines express death factor receptors and are driven to apoptosis in response to incubation with Fas-agonistic antibody, TNF-α/interferon-γ, and TRAIL. The two novel observations reported here are that 1) cotreatment of cells with NCX-456, but not mesalamine, resulted in concentration-dependent protection against death factor-induced apoptosis and inhibition of caspase activity, and 2) exposure to dithiothreitol, an agent that effectively removes NO from thiol groups, resulted in a 70% recovery of caspase activity, which is consistent with S-nitrosation as a major mechanism for caspase inactivation. These data suggest that caspase S-nitrosation represents a mechanism for protection of colonic mucosal epithelial cells from death factor-induced death.
GLUT-5 expression in neonatal rats: crypt-villus location and age-dependent regulation
Authors: Jiang Lan , David Elmer S. , Espina Noel , Ferraris Ronaldo P.
Published: December 2017

The rat fructose transporter normally appears after completion of weaning but can be precociously induced by early feeding of a high-fructose diet. In this study, the crypt-villus site, the metabolic nature of the signal, and the age dependence of induction were determined. In weaning rats fed high-glucose pellets, GLUT-5 mRNA expression was modest, localized mainly in the upper three-fourths of the villus, and there was little expression in the villus base. When fed high-fructose pellets, GLUT-5 mRNA expression was two to three times greater in all regions except the villus base. Intestinal perfusion in vivo of a nonmetabolizable fructose analog, 3- O-methylfructose, tended to increase fructose uptake rate and moderately increased GLUT-5 mRNA abundance but had no effect on glucose uptake rates and SGLT1 mRNA abundance. Gavage feeding of high-fructose, but not high-glucose, solutions enhanced fructose uptake only in pups ≥14 days, suggesting that GLUT-5 regulation is markedly age dependent. Fructose or its metabolites upregulate GLUT-5 expression in all enterocytes, except those in the crypt and villus base and in pups <14 days old.
Proliferation, not apoptosis, alters epithelial cell migration in small intestine of CFTR null mice
Authors: Gallagher Ann Marie , Gottlieb Roberta A.
Published: December 2017

Expression of a mutated cystic fibrosis transmembrane conductance regulator (CFTR) has been shown to enhance proliferation within CF airways, and cells expressing a mutated CFTR have been shown to be less susceptible to apoptosis. Because the CFTR is expressed in the epithelial cells lining the gastrointestinal tract and all CF mouse models are characterized by gastrointestinal obstruction, we hypothesized that CFTR null mice would have increased epithelial cell proliferation and reduced apoptosis within the small intestine. The rate of intestinal epithelial cell migration from crypt to villus was increased in CFTR null mice relative to mice expressing the wild-type CFTR. This difference in migration could be explained by an increase in epithelial cell proliferation but not by a difference in apoptosis within the crypts of Lieberkühn. In addition, using two independent sets of CF cell lines, we found that epithelial cell susceptibility to apoptosis was unrelated to the presence of a functional CFTR. Thus increased proliferation but not alterations in apoptosis within epithelial cells might contribute to the pathophysiology of CF.
Cyclooxygenase-2 downregulates inducible nitric oxide synthase in rat intestinal epithelial cells
Authors: Kobayashi Osamu , Miwa Hiroto , Watanabe Sumio , Tsujii Masahiko , Dubois Raymond N. , Sato Nobuhiro
Published: December 2017

Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression has been demonstrated in inflamed intestinal mucosa. Although regulation of COX-2 and iNOS expression has been studied extensively, the interplay between these two enzymes remains unclear. Because they play crucial roles in inflammation and/or carcinogenesis, we investigated whether COX-2 regulates iNOS expression and evaluated the effects of COX-2 inhibitor and arachidonic acid (AA) on iNOS induction. The COX-2 gene coding region was stably transfected into rat intestinal epithelial cells (RIE sense cells). After interferon-γ (IFN-γ) and lipopolysaccharide (LPS) administration, iNOS and COX-2 expression was evaluated by Western blotting. PGE2was measured by the enzyme immunoassay (EIA) method. Expression of IFN response factor-1, phosphorylated extracellular signal-related kinase-1 and -2, and Iκ-Bα was evaluated. Activator protein-1 and nuclear factor-κB (NF-κB) were examined by gel mobility shift assay; a supershift assay was performed to identify the NF-κB complex components. JTE-522 or AA was added before IFN-γ and LPS administration, and effects on iNOS and PGE2induction were evaluated by Western blotting or EIA. iNOS protein and mRNA expression was inhibited in RIE sense cells. Although NF-κB activation was suppressed and Iκ-Bα protein was more stable, respectively, in RIE sense cells, no difference was noted in other transcription factors. JTE-522 increased iNOS protein expression in RIE cells. We conclude that COX-2 suppressed iNOS expression in RIE cells through suppression of NF-κB by stabilizing Iκ-Bα.
Neutrophil-mediated epithelial injury during transmigration: role of elastase
Authors: Ginzberg Hedy H. , Cherapanov Vera , Dong Qin , Cantin Andre , McCulloch Christopher A. G. , Shannon Patrick T. , Downey Gregory P.
Published: December 2017

Neutrophil-mediated injury to gut epithelium may lead to disruption of the epithelial barrier function with consequent organ dysfunction, but the mechanisms of this are incompletely characterized. Because the epithelial apical junctional complex, comprised of tight and adherens junctions, is responsible in part for this barrier function, we investigated the effects of neutrophil transmigration on these structures. Using a colonic epithelial cell line, we observed that neutrophils migrating across cell monolayers formed clusters that were associated with focal epithelial cell loss and the creation of circular defects within the monolayer. The loss of epithelial cells was partly attributable to neutrophil-derived proteases, likely elastase, because it was prevented by elastase inhibitors. Spatially delimited disruption of epithelial junctional complexes with focal loss of E-cadherin, β-catenin, and zonula occludens 1 was observed adjacent to clusters of transmigrating neutrophils. During neutrophil transmigration, fragments of E-cadherin were released into the apical supernatant, and inhibitors of neutrophil elastase prevented this proteolytic degradation. Addition of purified leukocyte elastase also resulted in release of E-cadherin fragments, but only after opening of tight junctions. Taken together, these data demonstrate that neutrophil-derived proteases can mediate spatially delimited disruption of epithelial apical junctions during transmigration. These processes may contribute to epithelial loss and disruption of epithelial barrier function in inflammatory diseases.
Mesalamine induces manganese superoxide dismutase in rat intestinal epithelial cell lines and in vivo
Authors: Valentine J. F.
Published: December 2017

Mesalamine (5-ASA) is effective in the treatment of inflammatory bowel diseases. However, the mechanisms of action of 5-ASA remain unclear. IEC-6 and IRD-98, nontransformed rat small intestinal epithelial cell lines, were used to examine the effect of 5-ASA on the expression of manganese superoxide dismutase (MnSOD). Rats were given 5-ASA enemas to determine the effect on colonic MnSOD expression. Treatment with 5-ASA at 0.02 or 2 mg/ml induced MnSOD mRNA levels 2.67-fold or 5.66-fold, respectively. Inhibition of 5-lipoxygenase activating protein with MK-886 or cyclooxygenase with indomethacin did not influence the level of MnSOD mRNA. Nuclear run-on experiments demonstrated an increase in de novo transcription following treatment with 5-ASA. MnSOD protein levels were induced 2-fold at 24 h and 4.23-fold at 48 h following treatment with 1 mg/ml 5-ASA. 5-ASA increased MnSOD 1.7-fold in vivo. Pretreatment with 5-ASA significantly protected IRD-98 cells from tumor necrosis factor-α cytotoxicity. This is the first example of transcriptional gene regulation by 5-ASA. The induction of MnSOD by 5-ASA may contribute to the therapeutic mechanism of 5-ASA.
Cytochrome c release into cytosol with subsequent caspase activation during warm ischemia in rat liver
Authors: Soeda Junpei , Miyagawa Shinichi , Sano Kenji , Masumoto Junya , Taniguchi Shun'Ichiro , Kawasaki Seiji
Published: December 2017

Apoptosis plays an important role in liver ischemia and reperfusion (I/R) injury. However, the molecular basis of apoptosis in I/R injury is poorly understood. The aims of this study were to ascertain when and how apoptotic signal transduction occurs in I/R injury. The apoptotic pathway in rats undergoing 90 min of warm ischemia with reperfusion was compared with that of rats undergoing prolonged ischemia alone. During ischemia, mitochondrial cytochrome c was released into the cytosol in a time-dependent manner in hepatocytes and sinusoidal endothelial cells, and caspase-3 and an inhibitor of caspase-activated DNase were cleaved. However, apoptotic manifestation and DNA fragmentation were not observed. After reperfusion, nuclear condensation, cells positive for terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling, and DNA fragmentation were observed and caspase-8 and Bid cleavage occurred. In contrast, prolonged ischemia alone induced necrosis rather than apoptosis. In summary, our results show that release of mitochondrial cytochrome c and caspase activation proceed during ischemia, although apoptosis is manifested after reperfusion.
Effects of CYP7A1 overexpression on cholesterol and bile acid homeostasis
Authors: Pandak W. M. , Schwarz C. , Hylemon P. B. , Mallonee D. , Valerie K. , Heuman D. M. , Fisher R. A. , Redford Kaye , Vlahcevic Z. R.
Published: December 2017

The initial and rate-limiting step in the classic pathway of bile acid biosynthesis is 7α-hydroxylation of cholesterol, a reaction catalyzed by cholesterol 7α-hydroxylase (CYP7A1). The effect of CYP7A1 overexpression on cholesterol homeostasis in human liver cells has not been examined. The specific aim of this study was to determine the effects of overexpression of CYP7A1 on key regulatory steps involved in hepatocellular cholesterol homeostasis, using primary human hepatocytes (PHH) and HepG2 cells. Overexpression of CYP7A1 in HepG2 cells and PHH was accomplished by using a recombinant adenovirus encoding a CYP7A1 cDNA (AdCMV-CYP7A1). CYP7A1 overexpression resulted in a marked activation of the classic pathway of bile acid biosynthesis in both PHH and HepG2 cells. In response, there was decreased HMG-CoA-reductase (HMGR) activity, decreased acyl CoA:cholesterol acyltransferase (ACAT) activity, increased cholesteryl ester hydrolase (CEH) activity, and increased low-density lipoprotein receptor (LDLR) mRNA expression. Changes observed in HMGR, ACAT, and CEH mRNA levels paralleled changes in enzyme specific activities. More specifically, LDLR expression, ACAT activity, and CEH activity appeared responsive to an increase in cholesterol degradation after increased CYP7A1 expression. Conversely, accumulation of the oxysterol 7α-hydroxycholesterol in the microsomes after CYP7A1 overexpression was correlated with a decrease in HMGR activity.
EPEC-activated ERK1/2 participate in inflammatory response but not tight junction barrier disruption
Authors: Savkovic Suzana D. , Ramaswamy Akila , Koutsouris Athanasia , Hecht Gail
Published: December 2017

Enteropathogenic Escherichia coli (EPEC) alters many functions of the host intestinal epithelia. Inflammation is initiated by activation of nuclear factor (NF)-κB, and paracellular permeability is enhanced via a Ca2+- and myosin light-chain kinase (MLCK)-dependent pathway. The aims of this study were to identify signaling pathways by which EPEC triggers inflammation and to determine whether these pathways parallel or diverge from those that alter permeability. EPEC-induced phosphorylation and degradation of the primary inhibitor of NF-κB (IκBα) were tumor necrosis factor (TNF)-α and interleukin (IL)-1β independent. In contrast to Salmonella typhimurium, EPEC-stimulated IκBα degradation and IL-8 expression did not require Ca2+. Instead, extracellular signal-regulated kinase (ERK)-1/2 was significantly and rapidly activated. ERK1/2 inhibitors attenuated IκBα degradation and IL-8 expression. Although ERK1/2 can activate MLCK, its inhibition had no impact on EPEC disruption of the tight junction barrier. In conclusion, EPEC-induced inflammation 1) is TNF-α and IL-1β receptor independent, 2) utilizes pathways differently from S. typhimurium, 3) requires ERK1/2, and 4) employs signals that are distinct from those that alter permeability. This is the first time that EPEC-activated signaling cascades have been linked to independent functional consequences.
Prostanoids stimulate K secretion and Cl secretion in guinea pig distal colon via distinct pathways
Authors: Halm Dan R. , Halm Susan Troutman
Published: December 2017

Short-circuit current ( Isc) and transepithelial conductance ( Gt) were measured in guinea pig distal colonic mucosa isolated from submucosa and underlying muscle layers. Indomethacin (2 μM) and NS-398 (2 μM) were added to suppress endogenous production of prostanoids. Serosal addition of PGE2(10 nM) stimulated negative Iscconsistent with K secretion, and concentrations >30 nM stimulated positive Iscconsistent with Cl secretion. PGE2also stimulated Gtat low and high concentrations. Dose responses to prostanoids specific for EP prostanoid receptors were consistent with stimulating K secretion through EP2receptors, based on a rank order potency (from EC50values) of PGE2(1.9 nM) > 11-deoxy-PGE1(8.3 nM) > 19( R)-hydroxy-PGE2(13.9 nM) > butaprost (67 nM) > 17-phenyl-trinor-PGE2(307 nM) ≫ sulprostone (>10 μM). An isoprostane, 8-iso-PGE2, stimulated K secretion with an EC50of 33 nM. Cl secretory response was stimulated by PGD2and BW-245C, a DP prostanoid receptor-specific agonist: BW-245C (15 nM) > PGD2(30 nM) > PGE2(203 nM). Agonists specific for FP, IP, and TP prostanoid receptors were ineffective in stimulating Iscand Gtat concentrations <1 μM. These results indicate that PGE2stimulated electrogenic K secretion through activation of EP2receptors and electrogenic KCl secretion through activation of DP receptors. Thus stimulation of Cl secretion in vivo would occur either via physiological concentrations of PGD2(<100 nM) or pathophysiological concentrations of PGE2(>100 nM) that could occur during inflammatory conditions.
Nitric oxide donors retard wound healing in cultured rabbit gastric epithelial cell monolayers
Authors: Kiviluoto Tuula , Watanabe Sumio , Hirose Miyoko , Sato Nobuhiro , Mustonen Harri , Puolakkainen Pauli , Rönty Mikko , Ranta-Knuuttila Tuula , Kivilaakso Eero
Published: December 2017

Effects of nitric oxide (NO) on gastric wound healing were investigated in primary rabbit gastric epithelial cell cultures. We analyzed the speed of cell migration, proliferation, and apoptosis after creating a round wound on the cell cultures. The monolayers were incubated with or without the NO donor sodium nitroprusside, oxatriazolimine 1,2,3,4-oxatriazolium, 5amino-3-(3,4-dichlorophenylchloride), or the peroxynitrite generator 3-morpholinosydnomine- N-ethylcarbamide. The possible role of cGMP as a second messenger of NO was investigated with 8-bromo-cGMP. The role of O[Formula: see text]· was evaluated using diethyldithiocarbamate and pyrogallol. The effects of superoxide dismutase and allopurinol were also investigated. NO inhibited the speed of cell migration and proliferation and induced cell apoptosis in a dose- and time-dependent manner. The effects were augmented with O[Formula: see text]· generators and ameliorated by O[Formula: see text]· scavengers, whereas cGMP had no significant effect on wound healing. NO donors retard gastric wound healing by inhibiting migration and proliferation and inducing cell apoptosis. These effects do not seem to be mediated via cGMP, but O[Formula: see text]· or peroxynitrites may be involved.
Colitis induces CRF expression in hypothalamic magnocellular neurons and blunts CRF gene response to stress in rats
Authors: Kresse Adelheid E. , Million Mulugeta , Saperas Esteban , Taché Yvette
Published: December 2017

We investigated hypothalamic neuronal corticotropin-releasing factor (CRF) gene expression changes in response to visceral inflammation induced by 2,4,6-trinitrobenzenesulfonic acid (TNB) and acute stress. Seven days after TNB, rats were subjected to water-avoidance stress (WAS) or restraint for 30 min and euthanized. Hypothalamic CRF primary transcripts (heteronuclear RNA, hnRNA) and CRF and arginine vasopressin (AVP) mRNAs were assessed by in situ hybridization. Antisense 35S-labeled cRNA probes against CRF mRNA intronic and exonic sequences and an oligonucleotide probe against the AVP mRNA were used. TNB induced macroscopic lesions and a fivefold elevation in myeloperoxidase activity in the colon. Colitis increased CRF hnRNA and mRNA signals in the magnocellular part of the paraventricular nucleus of the hypothalamus (PVN) and supraoptic neurons, whereas AVP mRNA was not altered. Colitis did not modify CRF hnRNA signal in the parvocellular part of the PVN (pPVN), plasma corticosterone, and serum osmolarity levels. However, CRF hnRNA expression in the pPVN and the rise in corticosterone and defecation induced by WAS or restraint were blunted in colitic rats. These data show that colitis upregulates CRF gene synthesis in magnocellular hypothalamic neurons but dampens CRF gene transcription in the pPVN and plasma corticosterone responses to environmental acute stressors.
Dietary induction of angiotensin-converting enzyme in proximal and distal rat small intestine
Authors: Erickson Roger H. , Yoon Byung-Chul , Koh Danielle Y. , Kim Do Hyong , Kim Young S.
Published: December 2017

Induction of angiotensin-converting enzyme was examined in proximal and distal intestinal segments of rats fed a low-protein (4%) diet and then switched to a high-protein (gelatin) diet. Animals were killed at varying time points, and brush-border membranes and total RNA were prepared from the segments. In the proximal intestine, there was a fivefold increase in angiotensin-converting enzyme levels after 14 days but only a twofold change in mRNA. In the distal intestine, there was no increase in enzyme activity but mRNA increased 2.4-fold. Organ culture was used to measure changes in enzyme biosynthesis. There was a 5- to 6-fold increase in the biosynthesis of angiotensin-converting enzyme in the proximal intestine 24 h after the switch to the gelatin diet and a 1.6-fold increase in mRNA levels. No change in biosynthesis was observed in the distal small intestine despite an increase in mRNA. These results support the conclusion that rapid dietary induction of intestinal angiotensin-converting enzyme is differentially regulated in proximal and distal segments of the small intestine.
III. Peroxisomal β-oxidation, PPARα, and steatohepatitis
Authors: Reddy Janardan K.
Published: December 2017

Peroxisomes are involved in the β-oxidation chain shortening of long-chain and very-long-chain fatty acyl-CoAs, long-chain dicarboxylyl-CoAs, the CoA esters of eicosanoids, 2-methyl-branched fatty acyl-CoAs, and the CoA esters of the bile acid intermediates, and in the process, they generate H2O2. There are two complete sets of β-oxidation enzymes present in peroxisomes, with each set consisting of three distinct enzymes. The classic PPARα-regulated and inducible set participates in the β-oxidation of straight-chain fatty acids, whereas the second noninducible set acts on branched-chain fatty acids. Long-chain and very-long-chain fatty acids are also metabolized by the cytochrome P-450 CYP4A ω-oxidation system to dicarboxylic acids that serve as substrates for peroxisomal β-oxidation. Evidence derived from mouse models of PPARα and peroxisomal β-oxidation deficiency highlights the critical importance of the defects in PPARα-inducible β-oxidation in energy metabolism and in the development of steatohepatitis.
Cardiovascular effects of increasing airway pressure in the dog
Authors: Scharf S. M. , Caldini P. , Ingram R. H.
Published: December 2017

In paralyzed anesthetized dogs the cardiovascular effects of increasing positive end-expiratory pressure (PEEP) were explored under two conditions: a) end-expiratory lung volume increasing, b) end-expiratory lung volume kept nearly constant by matching pleural pressure rise to end-expiratory airway pressure rise. Two series of experiments were done: I) xenous return was allowed to fall, II) venous return was kept constant by infusion of volume. Right atrial pressure, pulmonary arterial pressure, and left atrial pressure increased under all conditions when measured relative to atmospheric pressure, but increased relative to pleural pressure only under condition a. The rise in left atrial relative to pleural pressure may indicate a degree of left ventricular dysfunction associated with increasing end-expiratory lung volume. Furthermore, when end-expiratory lung volume increased, inequality of the rise in pulmonary artery wedge pressure exceeded the rise in left atrial pressure in series I. From plots of cardiac output as a function of right atrial pressure it was possible to conclude that the decrease in venous return is partially offset by an increase in mean circulatory pressure.
Distribution of cardiac output in ovine pregnancy
Authors: Rosenfeld C. R.
Published: December 2017

Cardiac output and organ blood flows were measured in 6 nonpregnant and 24 pregnant ewes from 38 to 141 days of gestation employing radionuclide-labeled microspheres. From the nonpregnant state to term increases in cardiac output, from 73.7 +/- 4.6 ml/min-kg of maternal weight to 148 +/- 2.4 ml/min-kg, and heart rate, from 88.5 +/- 10.3 to 106 +/- 4.6 beats/min, were noted, while mean arterial blood pressure was unchanged. Near term, the blood flows to the uterus and mammary gland represented approximately 18% of cardiac output. The blood flow to nonreproductive organs increased from 76.6 +/- 6.8 ml/min-kg of nonreproductive tissue in the nonpregnant state to 132 +/- 3.5 ml/min-kg at 130-140 days' gestation (P less than 0.01). No significant changes in renal blood flow were detected.
Carbon monoxide exchanges between the human fetus and mother: a mathematical model
Authors: Hill E. P. , Hill J. R. , Power G. G. , Longo L. D.
Published: December 2017

A mathematical model was developed to calculate maternal and fetal carboxyhemoglobin concentrations, [HbCO], as functions of time during and after exposure of the mother to various inspired CO concentrations. Effects of variation in alveolar ventilation rates, pulmonary and placental fiffusing capacities, cardiac output, endogenous carbon monoxide production and other factors were studied. Following a change in the inspired CO concentration, fetal HbCO lags behind maternal HbCO by several hours. During CO uptake, fetal HbCO eventually overtakes maternal, and approaches an equilibrium value as much as 10% higher than the mother's. During CO washout the fetal levels again lag behind the mothers. Results indicate that treatment of pregnant women who have elevated HbCO levels with 100% oxygen reduces the time necessary to reduce the maternal HbCO level as expected, but that the rate of fetal CO elimination is not increased as much as that of the mother. Changes in maternal and fetal HbCO were also calculated for a representative exposure to changing inspired CO levels produced by fluctuating levels of air pollution. Finally, the effects of carboxyhemoglobin on fetal oxygenation were studied, including the effects of high altitude and exercise.
Hyperfunction with normal inotropic state of the hypertrophied left ventricle
Authors: Sasayama S. , Franklin D. , Ross J.
Published: December 2017

Conscious dogs were instrumented with an inflatable cuff around the ascending aorta, a high-fidelity micromanometer in the left ventricle (LV), and pairs of ultrasonic crystals for measurements of LV wall thickness and internal LV diameter. Wall stress (WSt) and mean velocity of wall shortening (VCF) were calculated. Mean force-velocity relations and WSt-diameter loops in single contractions were then analyzed over a range of matched systolic pressures during acute aortic constrictions both before and after induction of chronic hypertrophy by sustained aortic constriction. At normal LV systolic pressures and at each matched level of systolic LV pressure, wall shortening velocity was increased in the hypertrophied ventricle. However, force-velocity relations obtained by relating mean VCF to mean WSt at various stress levels fell on the same relation as during control. The linear relation between LV diameter and pressure at the end of ventricular ejection was shifted to the left in the hypertrophied ventricle, indicating enhanced shortening. However, linear WSt-diameter relations at end-ejection were not different in control and hypertrophied hearts. These findings indicate that the ventricle hypertrophied by pressure overload exhibited hyperfunction as a pump but that its myocardium had a normal level of inotropic state.
Central angiotensin II-induced responses in spontaneously hypertensive rats
Authors: Hoffman W. E. , Phillips M. I. , Schmid P. G.
Published: December 2017

The brain isorenin angiotensin system has been implicated in the development of spontaneous hypertension by several investigators. The experiments reported here were designed to test the responsiveness of unanesthetized spontaneous hypertensive (SH) rats to intracerebroventricular angiotensin II injections compared to Wistar-Kyoto (WK) normotensive controls. The results indicate that there is no difference between SH and WK animals in drinking responses or antidiuretic hormone release to central angiotensin II injections; however, an increased pressor responsiveness to intraventricular angiotensin II in SH as compared to WK was observed. The results of intravenous infusions of pressor substances in these experiments and reports by other investigators suggest that the increased blood pressure effects to central angiotensin are due to three possible factors: 1) increased vascular responsiveness of SH to vasoconstrictor substances in general, 2) increased vascular sensitivity of SH rats to sympathetic outflow, and 3) decreased baroreceptor reflexes to acute increases in blood pressure. We suggest that the brain isorenin-angiotensin system may be involved in spontaneous hypertension by increased production of angiotensin II or by activation of a potentiated sympathetic system, but not by a generalized increased sensitivity of brain receptors to central angiotensin.
Responses of the canine myocardium to stimulation of thoracic cardiac nerves
Authors: Norris J. E. , Randall W. C.
Published: December 2017

The thoracic cardiac nerves were stimulated in each of 21 dogs anesthetized with alpha chloralose. Recordings were made of heart rate, blood pressure, and contractile force from all four cardiac chambers. Walton-Brodie strain-gauge arches were sutured to both atria, and to three locations of each ventricle, representing both anterior and posterior surfaces. The functional autonomic components of each nerve were summarized and classified into four basic types. Types I and II were both located medial to the thoracic vagi. These were shown to contain both sympathetic and parasympathetic components traveling to all four chambers of the heart. The sympathetic componnent of the type II nerves produced reflex changes in force of contraction and systemic blood pressure. Nerves classified as types III and IV produced no parasympathetic effect on the heart. These were all located lateral to the thoracic vagi. While the type III nerves carried sympathetic efferent fibers to all four chambers, the type IV nerve carried sympathetic fibers predominantly to the right atrium.
Effects of methylprednisolone on cardiac lymph in acute myocardial ischemia in dogs
Authors: Ali M. , Ellis A. , Glick G.
Published: December 2017

It has been proposed that administration of pharmacologic doses of glucocorticoids may be beneficial in the setting of acute myocardial ischemia because of their ability to stabilize lysosomal membranes and thereby to prevent the leakage of proteolytic enzymes into the cytoplasm and interstitium. We collected cardiac lymph in anesthetized open-chest dogs in successive 2-h periods and used acid phosphatase as our marker lysosomal enzyme. In group 1 (n=5), we studied the effect of time alone. In these dogs, the total amount of acid phosphatase decreased (P less than 0.05). In group 2 (n=5), methylprednisolone, 30 mg/kg iv, was given. This drug did not change any variable we measured. Ligation of the circumflex coronary artery in group 3 (n=7), produced a significant increase (P less than 0.05) in the amount of acid phosphatase drained from the heart compared to group 1. In the dogs of group 4 (n=5), methylprednisolone did not reduce, and may have augmented, the total amount of acid phosphatase draining from the heart. Thus glucocorticoids do not appear to reduce the amount of acid phosphatase released by the ischemic myocardium into the cardiac lymph.
Effects of increased intracranial pressure on pulmonary vascular resistance of fetal and neonatal goats
Authors: Hessler J. R. , Cassin S.
Published: December 2017

The effects of increased intracranial pressure on the pulmonary circulation were investigated in fetal and neonatal goats. Pulmonary vascular resistance and systemic arterial pressure increased with elevation of intracranial pressure in neonatal animals. Alpha-adrenergic blockade completely eliminated both of these responses. The response of the fetal pulmonary circulation was unlike that seen in the postnatal animal. Although there was a slight elevation of pulmonary vascular resistance initially, the predominant response was a decrease in resistance. The decrease in fetal pulmonary vascular resistance was unaffected by phenoxybenzamine, but reversed by propranolol. After the beta-adrenergic blockade, increased intracranial pressure produced an increase in pulmonary vascular resistance. Similarly, ventilation of fetal lungs resulted in an increase in pulmonary vascular resistance after increased intracranial pressure. These results demonstrate for the first time that pulmonary vascular resistance may be altered in fetal and neonatal animals by increasing intracranial pressure. The elevation of pulmonary vascular resistance after elevated intracranial pressure must be due to an active pulmonary vascular constriction.
Cardiorespiratory effects of Pseudomonas and E. coli endotoxins in the awake dog
Authors: Miller T. H. , Priano L. L. , Jorgensen J. H. , Traber D. L.
Published: December 2017

A comparison of the cardiovascular and respiratory effects of Pseudomonas aeruginosa and Escherichia coli endotoxins was investigated in the unanesthetized dog. Animals were anesthetized with halothane for placement of cardiovascular catheters and then allowed to awaken prior to collection of control data and experimentation. One group of 12 animals was given E. coli endotoxin (5 mg/kg), another group of 13 received Pseudomonas endotoxin (8 mg/kg). Variables were collected for 6 h after endotoxin injection. A third group of 13 animals serving as sham animals received no endotoxin. When major cardiovascular variables, such as arterial blood pressure, cardiac output, right atrial pressure, and left ventricular pressure and dP/dt were monitored, it was seen that the basic patterns of response to endotoxins were quite similar, with differences between groups being primarily quantitative. Analysis of respiratory data showed that animals receiving Pseudomonas developed an earlier respiratory response. Nevertheless, blood gas data were similar in the two groups.
Prostaglandin and histaminergic mediation of prolonged vasodilation after exercise
Authors: Morganroth M. L. , Young E. W. , Sparks H. V.
Published: December 2017

An extended period of recovery of vascular resistance, far outlasting the recovery period of oxygen consumption, follows exercise of dog skeletal muscle when flow is restricted relative to the intensity of the exercise pattern. The duration of this postexercise prolonged vasodilation is graded and is related to the blood flow, duration of muscle stimulation, fatigue of the muscles, and total muscle tension development. To test whether prolonged vasodilation is mediated by prostaglandins or histamine, the prostaglandin synthetase inhibitors indomethacin or meclofenamate and the antihistamine tripelennamine were administered intravenously to anesthetized dogs between two 20-min exercise bouts of the anterior calf muscles at 4 twitches/s. Blood flow was held constant at approximately 20 ml 100 g-1 min-1, typically resulting in a venous O2 content below 2.0 ml/100 ml during exercise. The duration of vascular resistance recovery was evaluated by measuring the time at which vascular resistance returned to 90% (t90) of the recovery level (mean +/- SE). All the drugs caused a significant decline in the t90, but none reduced the recovery time to that following free-flow exercise, where the t90 is less than 1 min and the return of vascular resistance parallels the return of oxygen consumption to control. Thus, prostaglandin and/or histamine release may be at least partially responsible for prolonged vasodilation.
Prostaglandin metabolism in the kidneys of spontaneously hypertensive rats
Authors: Limas C. J. , Limas C.
Published: December 2017

Renal prostaglandins have been implicated in the regulation of blood pressure. We have therefore compared prostaglandin metabolism in the kidneys of spontaneously hypertensive rats (SHR's) of the Aoki-Okamoto strain and normotensive Wistar-Kyoto (WKY) controls. The microsomal fraction of the renal medulla contained most of the prostaglandin synthetase activity in both groups; SHR's had significantly higher enzymatic activity than their normotensive controls at age 10 wk and thereafter; furthermore, synthetase activity in SHR's increased with age. Two forms of 15-hydroxyprostaglandin dehydrogenases were demonstrated: an NAD+-dependent form which was localized mainly in the cortex and an NADP+-dependent form, higher in the medulla. The activities of these enzymes were lower in the hypertensive animals at all ages studied; this depression was more pronounced for the NAD+-dependent dehydrogenase. The results indicate that, in hypertension, renal prostaglandin metabolism is altered so that enhanced synthesis is accompanied by decreased degradation rate.
Differential sensitivity to neurotransmitters in denervated canine sinus node
Authors: Hageman G. R. , Urthaler F. , James T. N.
Published: December 2017

This investigation determined the chronotropic effects of norepinephrine and acetylcholine (ACh) administered selectively into the canine sinus node artery after cardiac denervation. In 42 dogs the cervical vagi were isolated, the heart was exposed, and vagal stimulations were performed before and after sham procedure or extrinsic cardiac parasympathectomy. Four additional dogs underwent bilateral stellectomy. The dogs were reanesthetized 4-23 days later, and blood pressure, heart rate, ECG, and local cardiac electrograms were recorded. The vagi were again stimulated and the effectiveness of the parasympathectomy was verified in 11 of the dogs. On selective perfusion of the sinus node with 0.001- to 1-microgram doses of ACh, the sinus bradycardias of the parasympathectomized and the sham-operated dogs were not significantly different. The responses to norepinephrine (0.01 and 0.1 microgram/ml) administered via the same route in the stellectomized dogs were significantly greater than those in the sham-operated dogs, thus verifying this technique for the assessment of sinus node sensitivity to neurotrasmitters. We conclude that extrinsic denervation of the canine sinus node leads to development of a differential response between adrenergic and cholinergic neurotransmitters. These differential sensitivities may be important when considering the pharmacological responses and electrical stability of the denervated and/or transplanted heart.
Cerebral circulation: effect of stimulation and blockade of dopamine receptors
Authors: McCulloch J. , Harper A. M.
Published: December 2017

The effects of stimulation and blockade of dopaminergic receptors on cerebral blood flow and metabolism were investigated in 15 anesthetized baboons. The intravenous administration of apomorphine resulted in immediate, dose-dependent increases in cerebral blood flow (increased by 58% following 0.1 mg/kg apomorphine) which were always accompanied by increases in cerebral oxygen consumption (increased by 36% with 0.1 mg/kg) and glucose uptake (increased by 72% with 0.1 mg/kg). It is suggested that the primary action of apomorphine is on cerebral metabolism and secondarily on cerebral blood flow rather than directly on cerebral vascular smooth muscle. Pimozide, at doses that totally blocked apomorphine-induced increases, was without effect on cerebral blood flow and metabolism. The dilatatory response of the cerebral circulation to hypercapnia was preserved during dopamine-receptor blockade. The basal level of overall cerebral metabolism and hemispheric cerebral blood flow does not appear to be dependent to any large extent on the activity of the dopaminergic pathways in the central nervous system.
Involvement of cAMP-dependent protein kinase in the regulation of heart contractile force
Authors: Keely S. L. , Corbin J. D.
Published: December 2017

The effects of perfusate epinephrine, 1-methyl-3-isobutylxanthine, calcium, and filling pressure were investigated in the perfused working rat heart. Epinephrine produced a rapid increase in cAMP, in the protein kinase activity ratio, and in active phosphorylase. These effects preceded the increase in contractile force produced by the hormone. There was good correlation between protein kinase activation and the increase in force. Epinephrine and the phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine were synergistic in their stimulatory effects on cAMP, protein kinase activity, active phosphorylase, and contractile force. When an increase in the force of contraction was produced either by increasing the filling pressure of the heart or by increasing the perfusate Ca2+ concentration, there was no change in either cAMP levels or protein kinase activity. These data suggest that the effect of beta-adrenergic catecholamines on contractile force is due, at least in part, to cAMP-dependent protein kinase activation. The increase in contractile force produced either by increasing the filling pressure (Frank-Starling phenomenon) or by increasing the perfusate Ca2+ concentration is apparently not mediated by cAMP or the protein kinase.
Effect of a left atrium-pulmonary vein baroreflex on peripheral vascular beds
Authors: Lloyd T. C. , Fried J. J.
Published: December 2017

A step increase of left atrial and pulmonary venous pressure from 0 to 25 mmHg was used in anesthetized dogs with controlled arterial blood pressure to generate reflex systemic vasodilation. The resultant response of total peripheral resistance was an initial transient fall of about 40% which spontaneously regressed while the stimulus was maintained. Injections of differently tagged radioactive microspheres were used to measure selected organ blood flows prior to raising atrial pressure, at the response peak, during the steady state, and after recovery. Resistances of skin, skeletal muscle, kidney, and large intestine significantly fell upon atriovenous distention. The response in muscle, which greatly exceeded that of the other organs, was not sustained, whereas resistances of other responding beds remained depressed until the stimulus was removed. No significant responses occurred in small intestine, liver (hepatic artery), or adrenal gland.
End-diastolic and end-systolic ventricular volume clamper for isolated canine heart
Authors: Suga H. , Sagawa K.
Published: December 2017

We devised a servo-controlled pump system which can clamp both end-diastolic and end-systolic volumes of the left ventricle of an excised, supported canine heart at desirable values in the face of changing patterns of ejection and filling. The system consists of a Bellofram cylinder and a powerful electromagnetic shaker which is driven by a position servo circuit. A water-filled balloon placed in the ventricle was connected to the water housing of the cylinder. As the ECG triggered the system, a fixed amount of water reciprocated between the heart and the cylinder in a programmed manner. The onset, duration, and speed of ejection and those of filling can be programmed separately. The performance of this pump system was tested in experiments on 15 cross-circulated hearts and proved satisfactory for precise analysis of the instantaneous pressure-volume relation in the ventricle.
Contractile state of hypertrophied left ventricle in long-standing volume overload
Authors: Newman W. H.
Published: December 2017

The purpose of this investigation was to evaluate the contribution of hypertrophy, the length-tension phenomenon, and inotropism to adaptation of the left ventricle (LV) to volume overload of up to 3 yr duration. Overload was produced in dogs by heart block, and contractile state was evaluated with a Walton-Brodie arch. Recording of contractile force (CF) in grams vs. muscle length from the LV indicated that dogs with hypertrophy were functioning at a higher point on the ascending limb of the length-tension curve than normals (76 percent Lmax in hypertrophy vs. 61 percent Lmax in normal). Additionally, in hypertrophy, all points on the length-tension curve above 80 percent Lmax were significantly elevated. None of these changes were seen in dogs in which block was induced on the day of the experiment. When CF was normalized for hypertrophy and expressed as CF/cm2, the length-tension curves were practically superimposable. These data suggest that adaptation was accomplished by hypertrophy, a shift up the length-tension curve without a depression of inotropic state.
Heart rate response to isocapnic hypoxia in conscious man
Authors: Slutsky A. S. , Rebuck A. S.
Published: December 2017

We studied the effect of acute progressive hypoxia on heart rate in conscious healthy subjects. The PCO2 was held constant (+/- 1.5 mmHg) midway between the resting end-tidal and mixed-venous levels. Hypoxia was induced by having the subject rebreathe from a small bag so that the PO2 fell at a rate related to the subject's oxygen consumption. Arterial oxygen saturation (Sao2) was measured continuously during the procedure with an ear oximeter. We found that heart rate (HR) was best fitted to an inverse linear relation to arterial oxygen saturation and a power relation to PO2. The range of deltaHR/deltaSao2 was 0.62-1.46 beats/min per 1% fall in Sao2 (mean +/- SE = 0.98 +/- 0.06). There was no relationship between heart rate and ventilatory responses to hypoxia.
Antagonism of histamine edema formation by catecholamines
Authors: Marciniak D. L. , Dobbins D. E. , Maciejko J. J. , Scott J. B. , Haddy F. J. , Grega G. J.
Published: December 2017

Histamine (4 microgram base/min) infused into the brachial artery for 60 min greatly increases skin lymph flow and lymph protein concentration in forelimbs perfused either naturally or at constant inflow. In contrast, the simultaneous intrabrachial infusion of histamine and norepinephrine (4 microgram base/min of each) or histamine and isoproterenol (4 microgram base/min and 3 microgram/min, respectively) for 60 min failed to alter lymph protein concentration in forelimbs perfused either naturally or at constant inflow. The edema in forelimbs naturally perfused by histamine (4 microgram base/min) infused into the brachial artery for 60 min was also greatly reduced by the simultaneous histamine-catecholamine infusions. Phentolamine (in concentrations that antagonize the vascular actions of norepinephrine) failed to prevent the antagonism of histamine protein efflux by norepinephrine. Hence, it must be concluded that catecholamines antagonize the protein efflux by locally infused histamine, independent of alpha-adrenergic receptor activity.