scholarly journals Stimulation of mucosal secretion by lubiprostone (SPI-0211) in guinea pig small intestine and colon

2009 ◽  
Vol 296 (4) ◽  
pp. G823-G832 ◽  
Author(s):  
Guijun Fei ◽  
Yu-Zhong Wang ◽  
Sumei Liu ◽  
Hong-Zhen Hu ◽  
Guo-Du Wang ◽  
...  
Keyword(s):  
Small Intestine ◽  
Guinea Pig ◽  
Short Circuit ◽  
Enteric Neurons ◽  
Resting Membrane Potential ◽  
Small Intestinal Mucosa ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Mucosal Secretion ◽  
Stimulation Of

Actions of lubiprostone, a selective type-2 chloride channel activator, on mucosal secretion were investigated in guinea pig small intestine and colon. Flat-sheet preparations were mounted in Ussing flux chambers for recording short-circuit current ( Isc) as a marker for electrogenic chloride secretion. Lubiprostone, applied to the small intestinal mucosa in eight concentrations ranging from 1–3000 nM, evoked increases in Isc in a concentration-dependent manner with an EC50 of 42.5 nM. Lubiprostone applied to the mucosa of the colon in eight concentrations ranging from 1–3000 nM evoked increases in Isc in a concentration-dependent manner with an EC50 of 31.7 nM. Blockade of enteric nerves by tetrodotoxin did not influence stimulation of Isc by lubiprostone. Antagonists acting at prostaglandin (PG)E2, EP1–3, or EP4 receptors did not suppress stimulation of Isc by lubiprostone but suppressed or abolished PGE2-evoked responses. Substitution of gluconate for chloride abolished all responses to lubiprostone. The selective CFTR channel blocker, CFTR(inh)-172, did not suppress lubiprostone-evoked Isc. The broadly acting blocker, glibenclamide, suppressed ( P < 0.001) lubiprostone-evoked Isc. Lubiprostone, in the presence of tetrodotoxin, enhanced carbachol-evoked Isc. The cholinergic component, but not the putative vasoactive intestinal peptide component, of neural responses to electrical field stimulation was enhanced by lubiprostone. Application of any of the prostaglandins, E2, F2, or I2, evoked depolarization of the resting membrane potential in enteric neurons. Unlike the prostaglandins, lubiprostone did not alter the electrical behavior of enteric neurons. Exposure to the histamine H2 receptor agonists increased basal Isc followed by persistent cyclical increases in Isc. Lubiprostone increased the peak amplitude of the dimaprit-evoked cycles.

Actions of nitric oxide-generating sodium nitroprusside in myenteric plexus of guinea pig small intestine

1993 ◽  
Vol 265 (5) ◽  
pp. G887-G893 ◽  
Author(s):  
K. Tamura ◽  
M. Schemann ◽  
J. D. Wood
Keyword(s):  
Nitric Oxide ◽  
Small Intestine ◽  
Guinea Pig ◽  
Sodium Nitroprusside ◽  
Myenteric Plexus ◽  
Membrane Properties ◽  
Dependent Manner ◽  
Membrane Excitability ◽  
Concentration Dependent Manner ◽  
Myenteric Neurons

Sodium nitroprusside (NaNP) was used as a donor of nitric oxide (NO) to investigate actions of NO on electrical and synaptic behavior of single myenteric neurons in guinea pig small intestine. NaNP (10 microM-1 mM) did not affect resting membrane properties of the neurons, except for an occasional decrease in input resistance and hyperpolarization attributable to suppression of excitatory transmitter release. NaNP did not alter fast nicotinic neurotransmission but suppressed noncholinergic slow excitatory postsynaptic potentials (slow EPSPs) in a concentration-dependent manner. Pretreatment with either methylene blue or oxyhemoglobin reduced the inhibitory action of NaNP on the slow EPSPs. Slow EPSP-like responses to microejected substance P or 5-hydroxytryptamine were unaffected by NaNP. The nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester, did not affect resting membrane excitability or excitatory synaptic events in any of the myenteric neurons. The results suggest that NO may not be released extensively as a neurotransmitter at synapses within the myenteric plexus. If myenteric neurons are exposed to NO released from nonneural sources, then the principal action is expected to be presynaptic inhibition of slow synaptic excitation.

Expression of proteinase-activated receptor 2 on human primary gastrointestinal myofibroblasts and stimulation of prostaglandin synthesis

2005 ◽  
Vol 83 (7) ◽  
pp. 605-616 ◽  
Author(s):  
Michelle L Seymour ◽  
David G Binion ◽  
Steven J Compton ◽  
Morley D Hollenberg ◽  
Wallace K MacNaughton
Keyword(s):  
Small Intestine ◽  
Dependent Manner ◽  
Intestinal Epithelial ◽  
Rt Pcr ◽  
Concentration Dependent Manner ◽  
Cell Functions ◽  
Cox 2 ◽  
Colonic Cells ◽  
Cox 1 ◽  
Stimulation Of

It is known that subepithelial myofibroblast-derived prostaglandin (PG)E2 can regulate intestinal epithelial cell functions, and that proteinase-activated receptor-2 (PAR2) is abundantly expressed in the gastrointestinal tract. Since PAR2 activation has previously been associated with stimulation of PGE2 synthesis, we hypothesized that PAR2 expressed on primary human gastrointestinal myofibroblasts regulates PGE2 synthesis via cyclooxygenase (COX)-1 and (or) COX-2, and associated PGE synthases. Primary human myofibroblasts were isolated from the resection tissue of the esophagus, small intestine, and colon. Expression of functional PAR2 was determined by RT-PCR and by calcium mobilization in Fura-2/AM-loaded cells. Trypsin and the selective PAR2-activating peptide (PAR2-AP) SLIGRL-NH2 stimulated PGE2 synthesis in a concentration-dependent manner, as measured by enzyme immunoassay. Selective COX inhibition showed PAR2-induced PGE2 synthesis to be COX-1 dependent in esophageal myofibroblasts and both COX-1 and COX-2 dependent in colonic cells, consistent with the distribution of COX-1 and COX-2 expression. Although both cytosolic and microsomal PGE synthases were expressed in cells from all tissues, microsomal PGE synthases were expressed at highest levels in the colonic myofibroblasts. Activation of PAR2 on gastrointestinal myofibroblasts stimulates PGE2 synthesis via different pathways in the colon than in the esophagus and small intestine. Key words: Proteinase-activated receptor, myofibroblast, cyclooxygenase, PGE synthase, prostaglandin E2, esophagus, small intestine, colon.

scholarly journals Glucagon-like peptide-1 modulates neurally evoked mucosal chloride secretion in guinea pig small intestine in vitro

2012 ◽  
Vol 302 (3) ◽  
pp. G352-G358 ◽  
Author(s):  
Sara Baldassano ◽  
Guo-Du Wang ◽  
Flavia Mulè ◽  
Jackie D. Wood
Keyword(s):  
Small Intestine ◽  
Guinea Pig ◽  
Receptor Antagonist ◽  
Vasoactive Intestinal Peptide ◽  
Short Circuit ◽  
Chloride Secretion ◽  
Dependent Manner ◽  
Evoked Responses ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) acts at the G protein-coupled receptor, GLP-1R, to stimulate secretion of insulin and to inhibit secretion of glucagon and gastric acid. Involvement in mucosal secretory physiology has received negligible attention. We aimed to study involvement of GLP-1 in mucosal chloride secretion in the small intestine. Ussing chamber methods, in concert with transmural electrical field stimulation (EFS), were used to study actions on neurogenic chloride secretion. ELISA was used to study GLP-1R effects on neural release of acetylcholine (ACh). Intramural localization of GLP-1R was assessed with immunohistochemistry. Application of GLP-1 to serosal or mucosal sides of flat-sheet preparations in Ussing chambers did not change baseline short-circuit current ( Isc), which served as a marker for chloride secretion. Transmural EFS evoked neurally mediated biphasic increases in Iscthat had an initial spike-like rising phase followed by a sustained plateau-like phase. Blockade of the EFS-evoked responses by tetrodotoxin indicated that the responses were neurally mediated. Application of GLP-1 reduced the EFS-evoked biphasic responses in a concentration-dependent manner. The GLP-1 receptor antagonist exendin-(9–39) suppressed this action of GLP-1. The GLP-1 inhibitory action on EFS-evoked responses persisted in the presence of nicotinic or vasoactive intestinal peptide receptor antagonists but not in the presence of a muscarinic receptor antagonist. GLP-1 significantly reduced EFS-evoked ACh release. In the submucosal plexus, GLP-1R immunoreactivity (IR) was expressed by choline acetyltransferase-IR neurons, neuropeptide Y-IR neurons, somatostatin-IR neurons, and vasoactive intestinal peptide-IR neurons. Our results suggest that GLP-1R is expressed in guinea pig submucosal neurons and that its activation leads to a decrease in neurally evoked chloride secretion by suppressing release of ACh at neuroepithelial junctions in the enteric neural networks that control secretomotor functions.

Action of pituitary adenylate cyclase-activating polypeptide on ion transport in guinea pig distal colon

1993 ◽  
Vol 264 (3) ◽  
pp. G433-G441 ◽  
Author(s):  
A. Kuwahara ◽  
Y. Kuwahara ◽  
T. Mochizuki ◽  
N. Yanaihara
Keyword(s):  
Adenylate Cyclase ◽  
Guinea Pig ◽  
Ion Transport ◽  
Short Circuit ◽  
Distal Colon ◽  
Chloride Secretion ◽  
Dependent Manner ◽  
Evoked Responses ◽  
Concentration Dependent Manner ◽  
Pituitary Adenylate Cyclase

The aim of the present study was to investigate the action of pituitary adenylate cyclase-activating polypeptide (PACAP) on ion transport in the guinea pig distal colon. Submucosal/mucosal segments from distal colon were mounted in Ussing flux chambers, and increases in short-circuit current (Isc) were used as an index of secretion. Serosal addition of PACAP-38 and PACAP-27 produced concentration-dependent (10(-10)-10(-6) M) increases in Isc. Furosemide and chloride-free solutions significantly reduced the PACAP-evoked responses. Tetrodotoxin (TTX) completely blocked PACAP-evoked responses. Atropine significantly reduced the PACAP-evoked responses but did not abolish the responses. The results suggest that PACAP evokes chloride secretion through cholinergic and noncholinergic neural mechanism. Vasoactive intestinal polypeptide (VIP), peptide histidine-isoleucine amide, and helodermin evoked Isc in a concentration-dependent manner. Atropine reduced but did not abolish the VIP- and related peptides-evoked responses. TTX also significantly decreased the responses to higher concentrations of VIP and related peptides but did not abolish the responses. The results suggest that VIP and related peptides act on both submucosal neurons and the epithelial cell itself. VIP tachyphylaxis significantly decreased PACAP-38- and PACAP-27-evoked responses. These results provide evidence that PACAP recognizes, in some part, VIP receptors in the submucosal neurons to evoke chloride secretion.

Presynaptic modulation by GABAB receptors of glutamatergic excitation and GABAergic inhibition of neostriatal neurons

1992 ◽  
Vol 67 (2) ◽  
pp. 477-481 ◽  
Author(s):  
E. S. Nisenbaum ◽  
T. W. Berger ◽  
A. A. Grace
Keyword(s):  
White Matter ◽  
Gabab Receptor ◽  
Input Resistance ◽  
Subcortical White Matter ◽  
Gabab Receptors ◽  
Resting Membrane Potential ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Current Voltage ◽  
Stimulation Of

1. The present experiments investigated the effects of gamma-amino-butyric acidB (GABAB) receptor stimulation on the excitatory and inhibitory responses of neostriatal neurons evoked by stimulation of the subcortical white matter in a rat neostriatal slice preparation. 2. Intracellular recordings showed that single-impulse stimulation of the corpus callosum evoked monosynaptic, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)-sensitive excitatory postsynaptic potentials (EPSPs) that were attenuated by the GABAB receptor agonist, p-chlorophenyl-GABA (baclofen, 0.5-10 microM) in a concentration-dependent manner. Baclofen also blocked the GABAA-mediated inhibition of neostriatal cell responses, which were revealed by paired-impulse stimulation of the subcortical white matter. Both of these effects persisted in slices in which the anterior cortex was removed, indicating that the site of action for baclofen was intrinsic to the neostriatum. The GABAB antagonist 3-amino-2-hydroxy-2-(4-chlorophenyl)-propanesulfonic acid (saclofen, 250-500 microM) reversed the depressant actions of baclofen on both the excitatory and inhibitory responses of neostriatal cells. 3. Concentrations of baclofen as high as 100 microM, which markedly attenuated EPSP amplitude, did not exert direct effects on resting membrane potential, current-voltage relationship, input resistance, or spike threshold and thus appeared to have no postsynaptic effect on the population of neurons recorded. 4. These results indicate that, in contrast to other regions of the CNS, the depressant effects of baclofen on glutamate-dependent EPSPs are mediated exclusively through GABAB receptors located presynaptically on the terminals of glutamatergic afferents.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of Ca2+-activated Cl−channels and MLCK in slow IJP in opossum esophageal smooth muscle

2002 ◽  
Vol 283 (1) ◽  
pp. G104-G114 ◽  
Author(s):  
Yong Zhang ◽  
William G. Paterson
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Nerve Stimulation ◽  
Resting Membrane Potential ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Circular Smooth Muscle ◽  
Cl Channels ◽  
Muscle Nerve

The possible contribution of Ca2+-activated Cl− channel [ICl(Ca)] and myosin light-chain kinase (MLCK) to nonadrenergic, noncholinergic slow inhibitory junction potentials (sIJP) was studied using conventional intracellular microelectrode recordings in circular smooth muscle of opossum esophageal body and guinea pig ileum perfused with Krebs solution containing atropine (3 μM), guanethidine (3 μM), and substance P (1 μM). In opossum esophageal circular smooth muscle, resting membrane potential (MP) was −51.9 ± 0.7 mV ( n = 89) with MP fluctuations of 1–3 mV. A single square-wave nerve stimulation of 0.5 ms duration and 80 V induced a sIJP with amplitude of 6.3 ± 0.2 mV, half-amplitude duration of 635 ± 19 ms, and rebound depolarization amplitude of 2.4 ± 0.1 mV ( n = 89). 9-Anthroic acid (A-9-C), niflumic acid (NFA), wortmannin, and 1-(5-chloronaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine (ML-9) abolished MP fluctuations, sIJP, and rebound depolarization in a concentration-dependent manner. A-9-C and NFA but not wortmannin and ML-9 hyperpolarized MP. In guinea pig ileal circular smooth muscle, nerve stimulation elicited an IJP composed of both fast (fIJP) and slow (sIJP) components, followed by rebound depolarization. NFA (200 μM) abolished sIJP and rebound depolarization but left the fIJP intact. These data suggest that in the tissues studied, activation of ICl(Ca), which requires MLCK, contributes to resting MP, and that closing of ICl(Ca) is responsible for sIJP.

Protein kinase C potentiates cAMP-stimulated mouse duodenal mucosal bicarbonate secretion in vitro

2004 ◽  
Vol 286 (5) ◽  
pp. G814-G821 ◽  
Author(s):  
Bi-Guang Tuo ◽  
Jimmy Y. C. Chow ◽  
Kim E. Barrett ◽  
Jon I. Isenberg
Keyword(s):  
Short Circuit ◽  
Short Circuit Current ◽  
Duodenal Mucosa ◽  
Bicarbonate Secretion ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ussing Chambers ◽  
Duodenal Bicarbonate Secretion

PKC has been shown to regulate epithelial Cl- secretion in a variety of models. However, the role of PKC in duodenal mucosal bicarbonate secretion is less clear. We aimed to investigate the role of PKC in regulation of duodenal mucosal bicarbonate secretion. Bicarbonate secretion by murine duodenal mucosa was examined in vitro in Ussing chambers using a pH-stat technique. PKC isoform expression and activity were assessed by Western blotting and in vitro kinase assays, respectively. PMA (an activator of PKC) alone had no effect on duodenal bicarbonate secretion or short-circuit current ( Isc). When PMA and dibutyryl-cAMP (db-cAMP) were added simultaneously, PMA failed to alter db-cAMP-stimulated duodenal bicarbonate secretion or Isc ( P > 0.05). However, a 1-h preincubation with PMA potentiated db-cAMP-stimulated duodenal bicarbonate secretion and Isc in a concentration-dependent manner (from 10-8 to 10-5M) ( P < 0.05). PMA preincubation had no effects on carbachol- or heat-stable toxin-stimulated bicarbonate secretion. Western blot analysis revealed that PKCα, -γ, -ϵ, -θ, -μ, and -ι/λ were expressed in murine duodenal mucosa. Ro 31–8220 (an inhibitor active against PKCϵ, -α, -β, and -γ), but not Gö 6983 (an inhibitor active against PKCα, -γ, -β, and -δ), reversed the potentiating effect of PMA on db-cAMP-stimulated bicarbonate secretion. PMA also time- and concentration-dependently increased the activity of PKCϵ, an effect that was prevented by Ro 31–8220 but not Gö 6983. These results demonstrate that activation of PKC potentiates cAMP-stimulated duodenal bicarbonate secretion, whereas it does not modify basal secretion. The effect of PKC on cAMP-stimulated bicarbonate secretion is mediated by the PKCϵ isoform.

Endothelium and mechanical responses of isolated monkey pulmonary veins to histamine

1990 ◽  
Vol 259 (4) ◽  
pp. H1032-H1037 ◽  
Author(s):  
T. Matsuki ◽  
T. Ohhashi
Keyword(s):  
Pulmonary Veins ◽  
Dependent Manner ◽  
High Concentration ◽  
Concentration Dependent Manner ◽  
Mechanical Responses ◽  
Relaxing Factor ◽  
Prostaglandin F2 Alpha ◽  
H2 Receptors ◽  
Endothelium Derived Relaxing Factor ◽  
Stimulation Of

Ring strips of monkey pulmonary veins precontracted with a high concentration of prostaglandin F2 alpha (PGF2 alpha) relaxed in a concentration-dependent manner in response to histamine. Treatment with mepyramine and/or famotidine attenuated the relaxation. 2-Pyridylethylamine (2PEA) and dimaprit caused relaxations in the precontracted preparations, which were inhibited by pretreatment with mepyramine and famotidine, respectively. Removal of endothelium reversed the histamine- and 2PEA-induced relaxations to dose-related contractions. On the other hand, the removal had no effect on the dimaprit-induced relaxations, which were significantly reduced by pretreatment with famotidine. Histamine-induced relaxations in the precontracted strips with endothelium in the presence and absence of famotidine were suppressed or abolished by treatment with methylene blue or hemoglobin but were unaffected by aspirin. It may be concluded that histamine-induced relaxation in monkey pulmonary veins precontracted with PGF2 alpha is mediated by H2-receptors in smooth muscle and H1-receptors in endothelium. Also, stimulation of the endothelial H1-receptors liberates an endothelium-derived relaxing factor.

Abstract 16939: Metabolic and Electrophysiological Alterations Underlie Proarrhythmic Properties of Highly Reactive Isolevuglandins in Atrial Cardiomyocytes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Tuerdi Subati ◽  
Zhenjiang Yang ◽  
Isis L Christopher ◽  
Joseph C Van Amburg ◽  
Matthew B Murphy ◽  
...  
Keyword(s):  
Membrane Potential ◽  
High Throughput Screening ◽  
Cell Metabolism ◽  
Resting Membrane Potential ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Atp Production ◽  
Atrial Cardiomyocytes ◽  
Extracellular Flux ◽  
Mitochondrial Transition Pore

Background: Hypertension is one of the most common risk factors for atrial fibrillation (AF), although the precise cellular and molecular mechanism(s) by which hypertension leads to AF are not well understood. Isolevuglandins (IsoLGs) are highly reactive dicarbonyl products of lipid peroxidation responsible for a major component of oxidative stress-related injury. In a mouse model of hypertension, we recently demonstrated that IsoLGs are elevated in hypertensive mouse atria and that an IsoLG scavenger reduced both IsoLG burden and AF susceptibility. Hypothesis: In this study, we hypothesized that IsoLGs can promote AF by inducing proarrhythmic metabolic and electrophysiologic (EP) changes in atrial cardiomyocytes. Methods and Results: Using standard patch clamp methods, we found significant changes in action potential properties of isolated mouse atrial cardiomyocytes exposed to IsoLGs (1μM, n=15 cells), including elevation of resting membrane potential, shortening of APD and reduction of V max . Acute IsoLG treatment led to a reduction of intracellular ATP production in atrial HL-1 cardiomyocytes, as measured by using a luminescence assay. Employing TMRM and Mitotracker Green staining for confocal and high-throughput screening (HTS) live-cell imaging assays, we also found that IsoLGs decreased mitochondrial membrane potential (compared to control, TMRM fluorescence decreased by 23%, 28%, 36% and 42%, respectively, when exposed to 0.01, 0.1, 0.5 and 1μM concentrations of IsoLG) accompanied by increased apoptosis (Cell Event Caspase-3/7 Green Detection Reagent) in a concentration-dependent manner, suggesting a prolonged mitochondrial transition pore opening. Moreover, cell metabolism assays performed using Agilent’s Seahorse XF96 extracellular flux analyzer revealed that IsoLGs exert a concentration dependent decrease in basal oxygen consumption rate and ATP production in HL-1 atrial cardiomyocytes. Conclusion: Together, these findings indicate that IsoLGs promote proarrhythmic EP and mitochondrial effects in atrial cells and thus may provide a novel therapeutic target for AF.

Some species differences in the intrinsic factor stimulation of B12 uptake by small intestine in vitro

1959 ◽  
Vol 197 (4) ◽  
pp. 926-928 ◽  
Author(s):  
T. Hastings Wilson ◽  
Elliott W. Strauss
Keyword(s):  
Small Intestine ◽  
Guinea Pig ◽  
Species Differences ◽  
Intrinsic Factor ◽  
Vitamin B ◽  
Guinea Pig Ileum ◽  
Rat Intestine ◽  
Intrinsic Factors ◽  
Stimulation Of

Sacs of everted small intestine from a variety of animals were incubated in bicarbonate-saline containing vitamin B12 with and without intrinsic factor (IF). B12 uptake by rat intestine was stimulated only by its own intrinsic factor. Guinea pig ileum responded to all intrinsic factors tested (guinea pig, rat, hog, hamster, human being and rabbit). The intestines of hamster and rabbit were intermediate in specificity, responding to some, but not all, of the IF preparations. Species differences occur in both the intestine and intrinsic factor preparations. The guinea pig ileum was suggested as a possible assay for both hog and human IF.

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