bluuebunny/crossref_metadata_2025 huggingface dataset:
Gastroprotective and vasodilatory effects of epidermal growth factor: the role of sensory afferent neurons
Authors: Matsumoto Yoji , Kanamoto Kohki , Kawakubo Keishi , Aomi Hitoshi , Matsumoto Takayuki , Ibayashi Setsuro , Fujishima Masatoshi
Published: December 2017

Epidermal growth factor (EGF) has been shown to exert gastric hyperemic and gastroprotective effects via capsaicin-sensitive afferent neurons, including the release of calcitonin gene-related peptide (CGRP). We examined the protective and vasodilatory effects of EGF on the gastric mucosa and its interaction with sensory nerves, CGRP, and nitric oxide (NO) in anesthetized rats. Intragastric EGF (10 or 30 μg) significantly reduced gastric mucosal lesions induced by intragastric 60% ethanol (50.6% by 10 μg EGF and 70.0% by 30 μg EGF). The protective effect of EGF was significantly inhibited by pretreatment with capsaicin desensitization, human CGRP1 antagonist hCGRP-(8–37), or Nω-nitro-l-arginine methyl ester (l-NAME). Intravital microscopy showed that topically applied EGF (10–1,000 μg/ml) dilated the gastric mucosal arterioles dose dependently and that this vasodilatory effect was significantly inhibited by equivalent pretreatments. These findings suggest that EGF plays a protective role against ethanol-induced gastric mucosal injury, possibly by dilating the gastric mucosal arterioles via capsaicin-sensitive afferent neurons involving CGRP and NO mechanisms.
Intracisternal TRH analog induces Fos expression in gastric myenteric neurons and glia in conscious rats
Authors: Miampamba Marcel , Yang Hong , Sharkey Keith A. , Taché Yvette
Published: December 2017

Activation of gastric myenteric cells by intracisternal injection of the stable thyrotropin-releasing hormone (TRH) analog RX-77368, at a dose inducing near maximal vagal cholinergic stimulation of gastric functions, was investigated in conscious rats. Fos immunoreactivity was assessed in gastric longitudinal muscle-myenteric plexus whole mount preparations 90 min after intracisternal injection. Fos-immunoreactive cells were rare in controls (∼1 cell/ganglion), whereas intracisternal RX-77368 (50 ng) increased the number to 24.8 ± 1.8 and 26.8 ± 2.2 cells/ganglion in the corpus and antrum, respectively. Hexamethonium (20 mg/kg sc) prevented Fos expression by 90%, whereas atropine (2 mg/kg sc) had no effect. The neuronal marker protein gene product 9.5 and the glial markers S-100 and glial fibrillary acidic proteins showed that RX-77368 induced Fos in both myenteric neurons and glia. Vesicular ACh transporter and calretinin were detected around the activated myenteric neurons. These results indicated that central vagal efferent stimulation by intracisternal RX-77368 activates gastric myenteric neurons as well as glial cells mainly through nicotinic ACh receptors in conscious rats.
Evidence supporting presence of two pacemakers in rat colon
Authors: Plujà Lídia , Albertí Elena , Fernández Ester , Mikkelsen Hanne Birte , Thuneberg Lars , Jiménez Marcel
Published: December 2017

Intracellular microelectrodes and organ bath techniques were used to study spontaneous cyclic electrical and mechanical activity in the rat colon. Electron microscopy and immunohistochemical studies showed two major populations of interstitial cells of Cajal (ICC): one associated with Auerbach's plexus (ICC-AP) and one with the submuscular plexus (ICC-SMP). The ICC-SMP network partly adhered to the submucosa when removed and was generally strongly damaged after separation of musculature and submucosa. Similarly, longitudinal muscle removal severely damaged AP. Two electrical and mechanical activity patterns were recorded: pattern A, low-frequency (0.5–1.5 cycles/min), high-amplitude oscillations; and pattern B, high-frequency (13–15 cycles/min), low-amplitude oscillations. Pattern A was recorded in preparations with intact AP but absent in those without intact AP. Pattern B was recorded in preparations with intact SMP but was absent in those lacking SMP. With full-thickness strips, the superimposed patterns A and B were recorded in circular muscle. When longitudinal muscle mechanical activity was recorded, only pattern A was present. We conclude that two pacemakers regulate rat colonic cyclic activity: the ICC-SMP network (responsible for cyclic slow waves and small-amplitude contractions) and the ICC-AP network (which may drive the cyclic depolarizations responsible for high-amplitude contractions). This is the first report showing consistent slow wave activity in the rodent colon.
Free and protein-bound glutamine have identical splanchnic extraction in healthy human volunteers
Authors: Boza Julio J. , Dangin Martial , Moënnoz Denis , Montigon Franck , Vuichoud Jacques , Jarret Andrée , Pouteau Etienne , Gremaud Gerard , Oguey-Araymon Sylviane , Courtois Didier , Woupeyi Alfred , Finot Paul-André , Ballèvre Olivier
Published: December 2017

The objectives of the present study were to determine the splanchnic extraction of glutamine after ingestion of glutamine-rich protein (15N-labeled oat proteins) and to compare it with that of free glutamine and to determine de novo glutamine synthesis before and after glutamine consumption. Eight healthy adults were infused intravenously in the postabsorptive state with l-[1-13C]glutamine (3 μmol · kg−1 · h−1) andl-[1-13C]lysine (1.5 μmol · kg−1 · h−1) for 8 h. Four hours after the beginning of the infusion, subjects consumed (every 20 min) a liquid formula providing either 2.5 g of protein from 15N-labeled oat proteins or a mixture of free amino acids that mimicked the oat-amino acid profile and contained l-[2,5-15N2]glutamine andl-[2-15N]lysine. Splanchnic extraction of glutamine reached 62.5 ± 5.0% and 66.7 ± 3.9% after administration of 15N-labeled oat proteins and the mixture of free amino acids, respectively. Lysine splanchnic extraction was also not different (40.9 ± 11.9% and 34.9 ± 10.6% for15N-labeled oat proteins and free amino acids, respectively). The main conclusion of the present study is that glutamine is equally bioavailable when given enterally as a free amino acid and when protein bound. Therefore, and taking into consideration the drawbacks of free glutamine supplementation of ready-to-use formulas for enteral nutrition, protein sources naturally rich in this amino acid are the best option for providing stable glutamine.
PGE2triggers recovery of transmucosal resistance via EP receptor cross talk in porcine ischemia-injured ileum
Authors: Blikslager Anthony T. , Pell Susan M. , Young Karen M.
Published: December 2017

16,16-Dimethyl-PGE2(PGE2) may interact with one of four prostaglandin type E (EP) receptors, which signal via cAMP (via EP2or EP4receptors) or intracellular Ca2+(via EP1receptors). Furthermore, EP3receptors have several splice variants, which may signal via cAMP or intracellular Ca2+. We sought to determine the PGE2receptor interactions that mediate recovery of transmucosal resistance ( R) in ischemia-injured porcine ileum. Porcine ileum was subjected to 45 min of ischemia, after which the mucosa was mounted in Ussing chambers. Tissues were pretreated with indomethacin (5 μM). Treatment with the EP1, EP2, EP3, and EP4agonist PGE2(1 μM) elevated R twofold and significantly increased tissue cAMP content, whereas the EP2and EP4agonist deoxy-PGE1(1 μM) or the EP1and EP3agonist sulprostone (1 μM) had no effect. However, a combination of deoxy-PGE1and sulprostone stimulated synergistic elevations in R and tissue cAMP content. Furthermore, treatment of tissues with deoxy-PGE1and the Ca2+ionophore A-23187 stimulated synergistic increases in R and cAMP, indicating that PGE2triggers recovery of R via EP receptor cross talk mechanisms involving cAMP and intracellular Ca2+.
Myosin light chain kinase- and PKC-dependent contraction of LES and esophageal smooth muscle
Authors: Sohn U. D. , Cao Weibiao , Tang Da-Chun , Stull J. T. , Haeberle J. R. , Wang C.-L. A. , Harnett K. M. , Behar J. , Biancani P.
Published: December 2017

In smooth muscle cells enzymatically isolated from circular muscle of the esophagus (ESO) and lower esophageal sphincter (LES), ACh-induced contraction and myosin light chain (MLC) phosphorylation were similar. Contraction and phosphorylation induced by purified MLC kinase (MLCK) were significantly greater in LES than ESO. ACh-induced contraction and MLC phosphorylation were inhibited by calmodulin and MLCK inhibitors in LES and by protein kinase C (PKC) inhibitors in ESO. Contraction of LES and ESO induced by the PKC agonist 1,2-dioctanoylglycerol (DG) was unaffected by MLCK inhibitors. Caldesmon and calponin concentration-dependently inhibited ACh-induced contraction of ESO and not LES. In ESO, caldesmon antagonist GS17C reversed caldesmon- but not calponin-induced ACh inhibition. GS17C caused contraction of permeabilized ESO but had much less effect on LES. GS17C-induced contraction was not affected by MLCK inhibitors, suggesting that MLCK may not regulate caldesmon-mediated contraction. DG-induced contraction of ESO and LES was inhibited by caldesmon and calponinin, suggesting that these proteins may regulate PKC-dependent contraction. We conclude that calmodulin and MLCK play a role in ACh-induced LES contraction, whereas the classical MLCK may not be the major kinase responsible for contraction and phosphorylation of MLC in ESO. ESO contraction is PKC dependent. Caldesmon and/or calponin may play a role in PKC-dependent contraction.
Contribution of ion pair complexation with bile salts to biliary excretion of organic cations in rats
Authors: Song Im-Sook , Chung Suk-Jae , Shim Chang-Koo
Published: December 2017

The objective of this study was to examine whether ion pair complexation with endogenous bile salts in hepatocytes contributes to the preferential biliary excretion of organic cations (OCs). Tributylmethylammonium (TBuMA; mol wt 200) and triethylmethylammonium (TEMA; mol wt 116) were selected as model OCs that exhibit significant and negligible biliary excretion, respectively, in rats. The apparent lipophilicity of TBuMA, but not that of TEMA, was increased by the presence of either rat bile or specific bile salts, suggesting the formation of lipophilic ion pair complexes for TBuMA with bile salts in the liver. The uptake of TBuMA into canalicular liver plasma membrane (cLPM) vesicles, but not that of TEMA, was increased in the presence of bile salts, with a significant increase for both ATP-dependent transport and passive diffusion. The uptake of TBuMA in the presence of the bile salts was inhibited by representative P-glycoprotein (P-gp) substrates and vice versa, suggesting the involvement of P-gp in the canalicular excretion of TBuMA-bile salt complexes in vivo. Increased affinity toward P-gp is suggested as the mechanism responsible for the increased ATP-dependent transport for the ion pair complexes. We propose that ion pair formation with bile slats in hepatocytes may be responsible for the preferential biliary excretion of high-molecular-weight OCs including TBuMA.
Developmental variability in expression and regulation of inducible nitric oxide synthase in rat intestine
Authors: Morin Melinda J. , Karr Shannon M. , Faris Ronald A. , Gruppuso Philip A.
Published: December 2017

Inducible nitric oxide synthase (iNOS) may be a key mediator of intestinal injury, which varies with developmental age. One member of the mitogen-activated protein kinase (MAPK) family, p38, is involved in the lipopolysaccharide (LPS)-mediated iNOS induction. The involvement of p38 MAPK in basal and LPS-induced iNOS expression was examined in the rat intestine at two developmental ages. Neonatal (4 days postnatal) and adolescent (15 days postnatal) rats were injected with LPS (5 μg/g ip), a selective p38 inhibitor (SB 203580), or both. Tissue was removed after 4 h and 6 h for mRNA and protein analysis. iNOS mRNA and protein were markedly upregulated in the adolescent female following LPS exposure, whereas males had an attenuated response. Neonates had a minimal response. SB 203580 suppressed LPS-induced iNOS mRNA and protein in the ileum, more so in females than in males. Adolescent ileal p38 activation was constitutively high and nonresponsive to LPS. Basal and post-LPS p38 phosphorylation was low in neonatal ileum. We conclude that ileal iNOS expression is developmentally regulated and influenced by gender and that p38 is permissive for LPS effect. The developmental regulation of p38 may contribute to age-dependent variations of intestinal injury.
Acute cold exposure induces vagally mediated Fos expression in gastric myenteric neurons in conscious rats
Authors: Yuan Pu-Qing , Taché Yvette , Miampamba Marcel , Yang Hong
Published: December 2017

Acute cold exposure-induced activation of gastric myenteric neurons in conscious rats was examined on longitudinal muscle-myenteric plexus whole mount preparations. Few Fos-immunoreactive (IR) cells (<1/ganglion) were observed in 24-h fasted rats semirestrained at room temperature. Cold exposure (4°C) for 1–3 h induced a time-related increase of Fos-IR cells in corpus and antral myenteric ganglia with a maximal plateau response (17 ± 3 and 18 ± 3 cells/ganglion, respectively) occurring at 2 h. Gastric vagotomy partly prevented, whereas bilateral cervical vagotomy completely abolished, Fos expression in the myenteric cells induced by cold exposure (2 h). Hexamethonium (20 mg/kg) also prevented 3-h cold exposure-induced myenteric Fos expression by 76–80%, whereas atropine or bretylium had no effect. Double labeling revealed that cold (3 h)-induced Fos-IR myenteric cells were mainly neurons, including a substantial number of choline acetyltransferase-containing neurons and most NADPH-diaphorase-positive neurons. These results indicate that acute cold exposure activates cholinergic as well as nitrergic neurons in the gastric myenteric ganglia through vagal nicotinic pathways in conscious rats.
Protective role of heme oxygenase-1 on trinitrobenzene sulfonic acid-induced colitis in rats
Authors: Wang W. P. , Guo X. , Koo M. W. L. , Wong B. C. Y. , Lam S. K. , Ye Y. N. , Cho C. H.
Published: December 2017

Preliminary studies showed that the inducible form of heme oxygenase (HO-1) was induced and played a protective role in the process of inflammation. The present study investigated the possible role of HO-1 in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. We measured HO-1 activity in TNBS-induced colitis in rats and analyzed the severity of colitis along with altered HO activity by assessing lesion area and myeloperoxidase activity. HO-1 mRNA and protein expressions were determined at different time points after TNBS induction. Free radical production and inducible nitric oxide synthase (iNOS), which participate in oxidative injury, were also assayed. HO activity and HO-1 gene expression increased markedly after TNBS induction. Administration with tin mesoporphyrin (SnMP), a HO inhibitor, potentiated the colonic damage along with a reduction in HO-1 activity. Furthermore, the reduction of HO-1 expression by SnMP also enhanced reactive oxygen species and iNOS expression, both of which were dramatically increased after the TNBS enema. l-Arginine preteatment further aggravated the injurious action of SnMP. Our results indicate that HO-1 plays a protective role in the colonic damage induced by the TNBS enema, and the preventive effects probably result from decreased free radical production and inhibition of iNOS expression in colonic tissues.
Inhibition of gastric emptying by acarbose is correlated with GLP-1 response and accompanied by CCK release
Authors: Enç Feruze Y. , I˙meryüz Neşe , Akin Levent , Turoğlu Turgut , Dede Fuat , Haklar Gonca , Tekeşi˙n Ni˙lgün , Beki˙roğlu Nural , Yeğen BerrakÇ. , Rehfeld Jens F. , Holst Jens J. , Ulusoy Nefi˙se B.
Published: December 2017

We investigated the effect of acarbose, an α-glucosidase and pancreatic α-amylase inhibitor, on gastric emptying of solid meals of varying nutrient composition and plasma responses of gut hormones. Gastric emptying was determined with scintigraphy in healthy subjects, and all studies were performed with and without 100 mg of acarbose, in random order, at least 1 wk apart. Acarbose did not alter the emptying of a carbohydrate-free meal, but it delayed emptying of a mixed meal and a carbohydrate-free meal given 2 h after sucrose ingestion. In meal groups with carbohydrates, acarbose attenuated responses of plasma insulin and glucose-dependent insulinotropic polypeptide (GIP) while augmenting responses of CCK, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY). With mixed meal + acarbose, area under the curve (AUC) of gastric emptying was positively correlated with integrated plasma response of GLP-1 ( r = 0.68 , P < 0.02). With the carbohydrate-free meal after sucrose and acarbose ingestion, AUC of gastric emptying was negatively correlated with integrated plasma response of GIP, implying that prior alteration of carbohydrate absorption modifies gastric emptying of a meal. The results demonstrate that acarbose delays gastric emptying of solid meals and augments release of CCK, GLP-1, and PYY mainly by retarding/inhibiting carbohydrate absorption. Augmented GLP-1 release by acarbose appears to play a major role in the inhibition of gastric emptying of a mixed meal, whereas CCK and PYY may have contributory roles.
Epithelial and bacterial metalloproteinases and their inhibitors inH. pyloriinfection of human gastric cells
Authors: Göõz Monika , Göõz Pal , Smolka Adam J.
Published: December 2017

To test the hypothesis that Helicobacter pylori regulates gastric cell secretion of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), culture media from infected and uninfected human gastric adenocarcinoma (AGS) cells were analyzed by zymography, MMP activity assays, and immunoblotting. AGS cells secreted gelatinolytic (prominently 90 kDa) and caseinolytic (110 kDa) activity together with MMP-1, MMP-3, and TIMP-1, TIMP-2, and TIMP-3 isoforms. H. pylori secreted caseinolytic activity (60 kDa), MMP-3-like enzyme activity, and TIMP-3 immunoreactivity. H. pylori infection increased the 110-kDa caseinolytic activity and induced new gelatinolytic (∼35 kDa) and caseinolytic (22 kDa) activities. Infection also increased both basal secretion and activation of MMP-1 and MMP-3, enhanced TIMP-3 secretion, and increased the formation of MMP-3/TIMP-3 complexes. TIMP-1 and TIMP-2 secretion were unchanged. Normal AGS cells showed a pancellular distribution of TIMP-3, with redistribution of immunoreactivity toward sites of bacterial attachment after H. pylori infection. The data indicate that MMP and TIMP secretion by AGS cells is modulated by H. pylori infection and that host MMP-3 and a TIMP-3 homolog expressed by H. pylori mediate at least part of the host cell response to infection.
TGF-β and IL-10 regulation of IFN-γ produced in Th2-type schistosome granulomas requires IL-12
Authors: Qadir Khurram , Metwali Ahmed , Blum Arthur M. , Li Jie , Elliott David E. , Weinstock Joel V.
Published: December 2017

Interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) regulate CD4+T cell interferon-γ (IFN-γ) secretion in schistosome granulomas. The role of IL-12 was determined using C57BL/6 and CBA mice. C57BL/6 IL-4 −/− granuloma cells were stimulated to produce IFN-γ when cultured with IL-10 or TGF-β neutralizing monoclonal antibody. In comparison, C57BL/6 wild-type (WT) control granuloma cells produced less IFN-γ. IL-12, IL-18, and soluble egg antigen stimulated IFN-γ release from C57BL/6 IL-4 −/− and WT mice. IFN-γ production in C57 IL-4 −/− and WT granulomas was IL-12 dependent, because IL-12 blockade partly abrogated IFN-γ secretion after stimulation. All granuloma cells released IL-12 (p70 and p40), and IL-12 production remained constant after anti-TGF-β, anti-IL-10, recombinant IL-18, or antigen stimulation. C57 WT and IL-4 −/− mouse granuloma cells expressed IL-12 receptor (IL-12R) β1-subunit mRNA but little β2 mRNA. TGF-β or IL-10 blockade did not influence β1 or β2 mRNA expression. CBA mouse dispersed granuloma cells released no measurable IFN-γ, produced IL-12 p70 and little p40, and expressed IL-12R β2 and little β1 mRNA. In T helper 2 (Th2) granulomas of C57BL/6 WT and IL-4 −/− mice, cells produce IL-12 (for IFN-γ production) and IL-10 and TGF-β modulate IFN-γ secretion via mechanisms independent of IL-12 and IL-12R mRNA regulation. We found substantial differences in control of granuloma IFN-γ production and IL-12 circuitry in C57BL/6 and CBA mice.
II. CytochromeP-450 enzymes and oxidative stress
Authors: Robertson Graham , Leclercq Isabelle , Farrell Geoffrey C.
Published: December 2017

Oxidative stress is present in the liver of humans with steatosis and nonalcoholic steatohepatitis (NASH) and is a plausible mediator of cellular injury, inflammatory recruitment, and fibrogenesis. CYPs 2E1 and 4A are the microsomal oxidases involved with fatty acid oxidation. Both enzymes can reduce molecular oxygen to produce prooxidant species, which, if not countered efficiently by antioxidants, create oxidative stress. In this theme article, we present the evidence that, in the context of hepatic steatosis, CYPs 2E1 and 4A could generate the “second hit” of cellular injury, particularly when antioxidant reserves are depleted, and propose ways in which this could contribute to the pathogenesis of NASH.
Downregulated in adenoma and putative anion transporter are regulated by CFTR in cultured pancreatic duct cells
Authors: Greeley Tracy , Shumaker Holli , Wang Zhaohui , Schweinfest Clifford W. , Soleimani Manoocher
Published: December 2017

The mechanism of the pancreatic ductal HCO[Formula: see text] secretion defect in cystic fibrosis (CF) is not well defined. However, a lack of apical Cl−/HCO[Formula: see text] exchange may exist in CF. To test this hypothesis, we examined the expression of Cl−/HCO[Formula: see text] exchangers in cultured pancreatic duct epithelial cells with physiological features prototypical of CF [CFPAC-1 cells lacking a functional CF transmembrane conductance regulator (CFTR)] or normal duct cells (CFPAC-1 cells transfected with functional wild-type CFTR, CFPAC-WT). Cl−/HCO[Formula: see text] exchange activity, assayed with the pH-sensitive dye 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein in cells grown on coverslips, increased about twofold in cells transfected with functional CFTR. This correlated with increased apical36Cl influx in cells expressing functional CFTR and grown on permeable support. Northern hybridizations indicated the induction of downregulated in adenoma (DRA) in cells expressing functional CFTR. The expression of putative anion transporter PAT1 also increased significantly in cells expressing functional CFTR. DRA was detected at high levels in native mouse pancreas by Northern hybridization and localized to the apical domain of the duct cells by immunohistochemical studies. In conclusion, CFTR upregulates DRA and PAT1 expression in cultured pancreatic duct cells. We propose that the pancreatic HCO[Formula: see text] secretion defect in CF patients is partly due to the downregulation of apical Cl−/HCO[Formula: see text] exchange activity mediated by DRA (and possibly PAT1).
MAdCAM mediates lymphocyte-endothelial cell adhesion in a murine model of chronic colitis
Authors: Shigematsu Takeharu , Specian Robert D. , Wolf Robert E. , Grisham Matthew B. , Granger D. Neil
Published: December 2017

Previous studies have revealed that the expression of several endothelial cell adhesion molecules [e.g., intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and mucosal addressin cell adhesion molecule 1 (MAdCAM-1)] is dramatically elevated in the chronically inflamed colonic vasculature of severe combined immunodeficient (SCID) mice reconstituted with congenic CD4+, CD45RBhighT lymphocytes. The objective of this study was to define the contribution of different endothelial cell adhesion molecules to the lymphocyte-endothelial cell (L/E) adhesion observed in the colonic microvasculature in this experimental model of inflammatory bowel disease. Fluorescently labeled T lymphocytes, isolated from spleens of normal BALB/C mice, were injected intravenously into SCID mice that had been reconstituted with CD4+, CD45RBhighT lymphocytes either before (3 wk after reconstitution) or after (7 wk postreconstitution) the onset of clinical signs of colitis (i.e., diarrhea, loss of body wt). Intravital fluorescence microscopy was used to quantify L/E adhesion in different-sized venules of the colonic submucosa during the development of colitis. L/E adhesion was noted in some segments of the vasculature in precolitic SCID mice (3 wk after reconstitution) but not in similar-sized vessels of control (wild type and SCID) mice. L/E adhesion was observed in a greater proportion of venules and occurred with greater intensity in the mucosa of colitic mice (7 wk postreconstitution). Pretreatment with a blocking monoclonal antibody against MAdCAM-1, but not ICAM-1 or VCAM-1, significantly and profoundly reduced L/E adhesion in colitic mice. Immunohistochemical staining also revealed the localization of T cells on colonic endothelial cells expressing MAdCAM-1. These findings indicate that MAdCAM-1 is largely responsible for recruiting T lymphocytes into inflamed colonic tissue.
GABABR expressed on vagal afferent neurones inhibit gastric mechanosensitivity in ferret proximal stomach
Authors: Smid Scott D. , Young Richard L. , Cooper Nicole J. , Blackshaw L. Ashley
Published: December 2017

GABAB-receptor (GABABR) agonists reduce transient lower esophageal sphincter relaxation (TLESR) and reflux episodes through an action on vagal pathways. In this study, we determined whether GABABR are expressed on vagal afferent neurones and whether they modulate distension-evoked discharge of vagal afferents in the isolated stomach. Vagal mehanoreceptor activity was recorded following distensions of the isolated ferret proximal stomach before and after perfusion with the GABABR-selective agonists baclofen and 3-aminopropylphosphinic acid (3-APPiA). Retrograde labeling and immunohistochemistry were used to identify GABABR located on vagal afferent neurones in the nodose ganglia. Vagal afferent fibers responded to isovolumetric gastric distension with an increase in discharge. The GABAB-receptor agonists baclofen (5 × 10−5 M) and 3-APPiA (10−6 to 10−5 M) but not muscimol (GABAA-selective agonist: 1.3 × 10−5 M) significantly decreased afferent distension-response curves. The effect of baclofen (5 × 10−5 M) was reversed by the GABAB-receptor antagonist CGP 62349 (10−5 M). Over 93% of retrogradely labeled gastric vagal afferents in the nodose ganglia expressed immunoreactivity for the GABABR. GABABR expressed on vagal afferent fibers directly inhibit gastric mechanosensory activity. This is likely a contributing mechanism to the efficacy of GABAB-receptor agonists in reducing TLESR and reflux episodes in vivo.
Action of histamine and H1 and H2 blockers on the cardiopulmonary circulation
Authors: Woods J. R. , Brinkman C. R. , Dandavino A. , Murayama K. , Assali N. S.
Published: December 2017

Systemic and pulmonary hemodynamic responses to histamine were investigated inchronically instrumented unanesthetized nonpregnant ewes. Histamine was administered intravenously and into the pulmonary artery. The effects of the same doses of histamine were assessed following H1 and H2 receptor blockade. The effects ocular changes were also monitored. Results indicate that intravenous histamine produces tachycardia, systemic hypotension, pulmonary hypertension, and reduced cardiac output. The pulmonary response could be modified significantly by pentobarbital anesthesia. When injected directly into the pulmonary artery histamine failed to elicit any circulatory response. Blockade of H1 and H2 receptors, as well as autonomic ganglia, resulted in a comparable attentuation of the histamine circulatory response. It is concluded that a) central hemodynamic responses do not seem to be mediated through specific H1 and H2 receptors; b) histamine-induced pulmonary vasoconstriction can be reversed by pentobarbital anesthesia, and c) the absence of circulatory response to intrapulmonary histamine administration suggests that whatever receptors that may exist in the pulmonary vascular bed are not necessary for the central hemodynamic effects.
Left atrial size and geometry in the intact dog
Authors: Tsakiris A. G. , Padiyar R. , Gordon D. A. , Lipton I.
Published: December 2017

Multiple determination of size, shape, and diameter of the left atrium were made during the control state and under conditions of varied ventricular outflow resistance in intact anesthetized dogs with markers chronically attached to the mitral annulus and the valve cusps. Measurements were made from left atrial angiograms (120 frames/s) obtained after injections of contrast medium into the pulmonary artery. Changes in atrial size were characterized by symmetrical circumferential diameter changes and eccentric variations of anteroposterior axis due almost entirely to valve ring displacement. With normal aortic pressure, maximal atrial area averaged 11.0+/-3.1 cm2. When aortic pressure was increased maximal area increased to 12.9+/-3.7 cm2 and percent emptying decreased, whereas maximal and minimal atrial areas were similar to control values during decreased aortic pressure. These findings suggest the possibility that atrial emptying may be near maximal at the resting control state.
Arterial barostasis along the mouse tail between different steady-state flows
Authors: Reinecke R. M.
Published: December 2017

From its etymology, "barostasis" would denote homeostasis with respect to pressure in relation to the blood vascular system. Arterial pressure and flow were measured along the proximal half of the tail of the unanesthetized, intact mouse with a pneumatic cuff and just distally with a pneumatic plethysmograph at room temperatures near 20 and 25 degrees C. The pressure fell measurably from proximally to distally at both temperatures. From 20 to 25 degrees C barostasis was evident in that the local pressure changed relatively little proportionately in comparison with a considerable proportional increase in flow. As in other studies the occlusion of the circulation for some seconds was followed by a momentary increase in flow lasting less than a minute.
Contraction and resting stiffness of isolated cardiac muscle: effects of inotropic agents
Authors: Taubert K. , Willerson J. T. , Shapiro W. , Templeton G. H.
Published: December 2017

The purpose of this study was to test the hypothesis that either hypoxia and its combined effects with extracellular calcium (Ca), digoxin, and ouabain, or these positive inotropic agents acting alone or in combination, influence contraction and resting stiffness of isolated papillary muscle. Stiffness was measured utilizing the sinusoidal forcing function technique. Neither an increase in extracellular calcium concentration (from 2.5 to 4.0 mM) nor digoxin or ouabain in either Ca concentration altered contraction or resting stiffness in the well-oxygenated environment. Resting stiffness for any given resting tension was increased at the end of hypoxia only in the presence of digoxin, and this occurred in both 2.5 mM Ca (P less than 0.02) and in 4.0 mM Ca (P = 0.05). Contraction stiffness for any given tension was increased in 2.5 mM Ca by hypoxia alone (P less than 0.05) and by hypoxia in the presence of digoxin (P less than 0.005) and ouabain (P less than 0.02), but was not increased in any experiments conducted in 4.0 mM Ca. The conclusions from these data are that certain experimental conditions of the study evoked different directional changes in stiffness and contractility. Further, changes in contraction stiffness are not always paralleled by changes in resting stiffness.
Blood vessel-hormone interactions: angiotensin, bradykinin, and prostaglandins
Authors: Blumberg A. L. , Denny S. E. , Marshall G. R. , Needleman P.
Published: December 2017

Isolated Krebs-perfused rabbit-mesentery blood vessels release a prostaglandin E-like substance (PGE) when treated with angiotensin II, angiotensin I, arachidonic acid, or bradykinin. The specific competitive antagonist [Sar1,Ile8]angiotensin II, was found to inhibit angiotensin II-induced PGE release. The angiotensin antagonist did not block PGE release by bradykinin, whereas indomethacin blocked PGE release induced by all agonists. SQ-20881, the converting-enzyme and bradykininase inhibitor, decreased the PGE release by angiotensin I, enhanced the release by bradykinin, and did not affect release by angiotensin II. Pressor and depressor responses were obtained in mesenteric preparations constricted by epinephrine to a pressure of 60 mmHg. Angiotensin II induced an initial increase in mesenteric vascular resistance followed by a depressor response below basal pressure. The pressor responses were enhanced by indomethacin and the depressor responses were eliminated. Bolus injections of both bradykinin and arachidonic acid produced decreases in perfusion pressure, but indomethacin completely inhibited only the arachidonic acid-induced responses while only diminishing bradykinin-induced responses. The ability of angiotensin to increase mesenteric vascular resistance and to release PGE which decrease vascular resistance is discussed.
Relationship between microvascular blood velocity and pressure distribution
Authors: Mayrovitz H. N. , Tuma R. F. , Wiedeman M. P.
Published: December 2017

Red blood cell velocity and diameter were measured in vessels of the wing of the unanesthetized bat (Myotis lucifugus) from the supplying artery to the capillaries. These data were used to determine the manner in which velocity, shear rate, volume flow, and blood pressure depend on the vessel's hierarchical position within the vascular network. The results show that velocity decreases in an almost linear fashion as the capillary is approached but that the shear rate increases as one progresses distally from the supplying artery. Blood volume flow was found to decrease as an exponential function of the branching order. Comparison with available date in some animal species, including man, indicates some agreement in capillary velocity, although significantly lower values have been reported in some preparations. Using a method whereby blood pressure distribution could be obtained from anatomical data and center-line blood velocity, the rheologic alterations accompanying consecutive vessel branching were deduced and found to be in good agreement with data available in the literature.
Effect of hematocrit on electrocardiographic potentials and dipole moment of the pig
Authors: Hodgkin B. C. , Millard R. W. , Nelson C. V.
Published: December 2017

The Brody hypothesis posits that blood in the heart chambers enhances body surface potentials due to radially oriented excitation and diminishes those due to tangentially oriented excitation. Evidence supporting the hypothesis has been found in models and in dogs. The current study was performed in pigs (Sus scrofa), anesthetized with sodium pentobarbital, to determine whether the phenomenon could also be demonstrated in a species having a ventricular activation pattern distinctly different from that of dogs. Hematocrit was varied from normal 35.3 +/- 1.1% to as low as 19.8% by hemodilution and to as high as 68.0% by hemoconcentration. Surface potentials early in QRS increased and those late in QRS decreased in hemodilution experiments, while the reverse was true in hemoconcentration experiments. Total QRS duration was 38.0 +/- 0.8 ms. The first peak in resultant dipole moment magnitude, at 5.4 +/- 0.2 ms, was inversely related to blood resistivity with a linear regression correlation coefficient r = -0.76; the second peak, at 10.9 +/- 0.1 ms, was directly related, r = 0.52; and the third peak, at 17.5 +/- 0.2 ms, was directly related, r = 0.89. When interpreted in accordance with the Brody hypothesis, changes in body surface potentials and in resultant dipole moment were consistent with radial excitation of the apical septum, ill-defined orientation of free ventricular wall excitation, and tangential excitation of basal left ventricle and septum.
Cerebral blood flow and behavior during brain stimulation in the goat
Authors: Manrique M. , Alborch E. , Delgado J. M.
Published: December 2017

Cerebral blood flow, heart rate, arterial blood pressure, and behavior were studied in conscious goats during electrical stimulation of the diencephalon and mesencephalon. Stimulation of the subthalamic area produced a considerable increase in ipsilateral cerebral blood flow and heart rate, accompanied by either a small or a large increase in systemic arterial blood pressure. Cardiovascular effects were associated with changes in alertness. The increase in cerebral blood flow was partially abolished by previous administration of atropine directly into the internal maxillary artery. Stimulation of the mesencephalic reticular formation caused a marked increase in blood pressure with no change or with some decrease in cerebral blood flow. After administration of phentolamine into the internal maxillary artery, stimulation produced increase in cerebral blood flow. The behavioral response consisted of restlessness and attempted flight. These results suggest the existence of cholinergic vasodilator and adrenergic vasoconstrictor pathways to cerebral blood vessels that may be stimulated electrically.
Effects of renal denervation on renin release in response to tilting and furosemide
Authors: Stella A. , Zanchetti A.
Published: December 2017

In anesthetized cats head-up tilting for 30 min and infusion of furosemide at 0.75 mg/kg in 30 min significantly raised renin release from the innervated kidney (increments of 90.7 +/- 21.4 ng/min on tilting and 105.4 +/- 26.4 ng/min after furosemide); a small and inconstant increase from the contralateral denervated kidney (increments of 16.8 +/- 16.0 and 16.3 +/- 17.7 ng/min, respectively) was abolished by acute bilateral adrenalectomy. Larger doses of furosemide (6.0 mg/kg) could release renin from the denervated kidney also, but the response was still more marked on the innervated side especially in the early period of infusion (increments of 132.7 +/- 23.8 and 33.7 +/- 23.8 ng/min of innervated and denervated sides at 10 min). The response of the denervated kidney to 6.0 mg furosemide/kg was not affected by adrenalectomy. Stimulation of juxtaglomerular cells by tilting is entirely due to sympathoadrenergic activation; stimulation by furosemide is also entirely neural when the diuretic drug is given in moderate doses, but is partly independent of innervation when larger doses are administered.
Cardiorespiratory control by carotid chemoreceptors during experimental dives in the seal
Authors: de Burgh Daly M. , Elsner R. , Angell-James J. E.
Published: December 2017

The diving responses of apnea and bradycardia, produced experimentally by immersing the face in water, were successfully elicited in the harbor seal Phoca vitulina anesthetized with urethan. The role of the carotid body chemoreceptors in the production of the diving bradycardia was studied in isolated carotid sinus-body preparations autoperfused with blood from the arterial circulation. When asphyxia was well developed during a dive the chemoreceptor drive was withdrawn by temporarily perfusing the chemoreceptors with blood of high PO2 (greater than 400 mmHg) and normal PCO2 from a disk oxygenator. The heart rate immediately rose to its predive value. Reestablishing hypoxic hypercapnic blood perfusion of the chemoreceptors from the animal's own circulation caused bradycardia with persistence of the apnea. Breathing restarted only on emersion. Substitution of normal arterialized blood from the oxygenator before or at the onset of a dive had no effect on the existing heart rate. It is concluded that the carotid bodies play an important part in maintaining the diving bradycardia during developing asphyxia without affecting respiration.
Effect of sex hormones on blood pressure and vascular connective tissue in castrated and noncastrated male rats
Authors: Fischer G. M. , Swain M. L.
Published: December 2017

Aortic collagen and elastin were quantitated in three groups of castrated and two groups of noncastrated male rats treated by intramuscular injection for 3 wk with oil, testosterone, or estradiol. The greatest differences were found between the castrated rats receiving testosterone and those receiving estradiol, the estradiol-treated rats having significantly lower total collagen, percent collagen, total elastin, and collagen/elastin (C/E), and higher percent elastin than those rats receiving testosterone. In noncastrated rats, administration of estradiol resulted in significantly lower total collagen, percent collagen, total elastin, and C/E. Systolic blood pressure was highest in rats receiving testerone and lowest in rats receiving estradiol. It is concluded that 1) estradiol in the presence or absence of testosterone decreases total accumulation of vascular connective tissue and alters the proportions of collagen and elastin so that the vessel is more distensible, 2) testosterone has an opposite but less marked effect than estradiol on vascular connective tissue, and 3) estradiol and testosterone alter blood pressure in opposite directions in the male rat.
Interaction of transcapillary Starling forces in the isolated dog forelimb
Authors: Brace R. A. , Guyton A. C.
Published: December 2017

Three of the four Starling forces were measured in the intact dog forelimb after anesthetization and all four of the Starling forces were measured in the same forelimb which was surgically isolated yet innervated. In the isolated forelimb, isogravimetric capillary pressure (Pci) averaged 15.6 mmHg; colloid osmotic pressure of the plasma proteins (IIp) averaged 19.9 mmHg; mean interstitial fluid pressure (Pif) was +0.4 mmHg, and the average value of interstitial colloid osmotic pressure (IIif) was 4.9 mmHg. Thus the net imbalance in the Starling forces, i.e., (Pci - Pif) - (IIp - IIif), averaged 0.3 mmHg. Furthermore, the value of IIif was consistently decreased after isolation (average decrease of 1.2 mmHg) while Pif was always increased following isolation (average increase of 4.3 mmHg). In addition, it was found that if the forelimb was denervated during isolation, then Pif was increased by an average of 2 mmHg above Pif in the innervated, isolated forelimb. In summary, these studies show that the differences between the intact and isolated forelimb are that Pci averages 10-11 mmHg in the intact forelimb and 15-16 mmHg in the isolated innervated forelimb while interstitial fluid pressure is negative in the intact limb and positive in the isolated limb.
Effects of isoproterenol on adrenergic constriction in vascular smooth muscle
Authors: Flaim S. F. , Zelis R.
Published: December 2017

A series of isolated segments of carotid arteries from Dutch-belted, adult, male rabbits were studied with respect to their response to a beta receptor agonist. Segments of 3-cm length were mounted in a chamber with constant surrounding temperature and pressure and perfused at constant pressure. Inflow pressure, outflow pressure, and flow rate were measured, and values of resistance (R) were calculated. Subsequent to control R, each vessel was exposed to a vasoconstricting concentration of either norepinephrine (NE: 10(-8), 10(-9), 10(-10) M) or potassium (K+: 100mM, 50 mM) followed by three doses of the beta-adrenergic agonist, isoproterenol (IP: 10(-7), 10(-6), 10(-5)M) administered simultaneously with each constrictor. R was not altered by IP during NE infusion but was significantly increased at all levels of IP during both K+ infusions. When the K+ series was repeated with alpha blockade, IP did not alter R. Thus, beta receptors do not appear to be functionally present in the adult rabbit carotid artery.
Dynamics of myocardial oxygen consumption and coronary vascular resistance
Authors: Belloni F. L. , Sparks H. V.
Published: December 2017

Coronary vascular resistance may be regulated in part by substances whose concentrations are determined by or reflect the rate of myocardial oxygen consumption (e.g., adenosine, vessel wall PO2). We tested this hypothesis by comparing the time course of changes in myocardial oxygen consumption and coronary vascular resistance following 20 beat/min changes in heart rate. Main left coronary arteries of in situ dog hearts were perfused with blood at constant flow. Coronary sinus O2 content was monitored continuously with a densitometer and reflected the time course of changes in oxygen consumption and also the effects of vascular transit between tissue and the coronary sinus. These transit effects were estimated from dye transit curves and added to the time course of changes in coronary perfusion pressure which was proportional to coronary vascular resistance at constant flow. Coronary sinus O2 content changes preceded the adjusted time course of vascular resistance. This supports the hypothesis that coronary vascular resistance is regulated in part by factors closely linked to oxidative metabolism.
Chronotropic response of spontaneously beating rabbit atria to hyperosmotic media
Authors: Roberts L. A. , Hughes M. J.
Published: December 2017

Spontaneously beating rabbit atria responded to hyperosmotic Tyrode bathing media with an increase in rate, force of contraction, and passive tension dependent on the level of osmolality and the osmotic agent employed. The positive chronotropic response reached a maximum within a few minutes and then declined to a lower, maintained plateau level. The plateau change in rate was similar whether the osmotic agent added to Tyrode solution was sucrose, mannitol or NaCl. For these agents, the response increased linearly with osmotic pressure of the bathing media from 300 to 500 mosmol/kg H2O, then progressively decreased approaching zero (plateau rate = control) at about 700 mosmol/kg H2O. The chronotropic response to urea in Tyrode solution, though less than for the other three agents, progressively increased over the entire range of osmolalities tested (from 300 to 700 mosmol/kg H2O). The inotropic response was positive for all agents from 300 to 600 mosmol/kg H2O. Passive tension of atria increased with added NaCl, sucrose, or mannitol, but not with urea. Propranolol did not alter the atrial response to hyperosmolality. Thus, we find that the chronotropic response of atria to hyperosmolar solutions is positive over a wide range of agents and osmolalities, in contrast to earlier reports of a direct negative chronotropic effect.
Formation of adenosine nucleotide derivatives in isolated hog carotid artery strips
Authors: Van Harn G. L. , Rubio R. , Berne R. M.
Published: December 2017

Media strips of hog carotid artery formed hypoxanthine and inosine during incubation under conditions of normoxia (95% O2, 5% CO2). During anoxia (95% N2, 5% CO2), hypoxanthine increased fivefold and inosine twofold. Stimulation with 124 mM K+ resulted in a twofold increase in hypoxanthine and a threefold increase in inosine. Concurrent with the increase in the concentrations of purine derivatives was a decrease in tissue ATP. Although significant amounts of adenosine were not detected in the medium of incubating artery strips, the following evidence suggests adenosine was formed and rapidly deaminated to inosine: 1) Exogenous adenosine added to the medium of incubating strips was rapidly deaminated to inosine. 2) Exogenous 5'-AMP concentration decreased, whereas adenosine and, subsequently, inosine levels increased during incubation of artery strips. The reaction was specific for 5'-AMP and the data suggest that AMP is dephosphorylated to adenosine. 3) The specific activity of exogenous [U-14C]adenosine added to the medium of incubated strips decreased after 15 min. It is concluded that adenosine is formed in isolated artery strips but is rapidly deaminated to inosine.