IL-1β signaling in cat lower esophageal sphincter circular muscle

2006 ◽  
Vol 291 (4) ◽  
pp. G672-G680 ◽  
Author(s):  
Weibiao Cao ◽  
Ling Cheng ◽  
Jose Behar ◽  
Piero Biancani ◽  
Karen M. Harnett
Keyword(s):  
Lower Esophageal Sphincter ◽  
P38 Mapk ◽  
Circular Muscle ◽  
Circular Smooth Muscle ◽  
Sequential Activation ◽  
Cox 2 ◽  
Esophageal Sphincter ◽  
Sb 203580

In a cat model of acute experimental esophagitis, resting in vivo lower esophageal sphincter (LES) pressure and in vitro tone are lower than in normal LES, and the LES circular smooth muscle layer contains elevated levels of IL-1β that decrease the LES tone of normal cats. We now examined the mechanisms of IL-1β-induced reduction in LES tone. IL-1β significantly reduced acetylcholine-induced Ca2+ release in Ca2+-free medium, and this effect was partially reversed by catalase, demonstrating a role of H2O2 in these changes. IL-1β significantly increased the production of H2O2, and the increase was blocked by the p38 MAPK inhibitor SB-203580, by the cytosolic phospholipase A2 (cPLA2) inhibitor AACOCF3, and by the NADPH oxidase inhibitor apocynin, but not by the MEK1 inhibitor PD-98059. IL-1β significantly increased the phosphorylation of p38 MAPK and cPLA2. IL-1β-induced cPLA2 phosphorylation was blocked by SB-203580 but not by AACOCF3, suggesting sequential activation of p38 MAPK-phosphorylating cPLA2. The IL-1β-induced reduction in LES tone was partially reversed by AACOCF3 and by the Ca2+-insensitive PLA2 inhibitor bromoenol lactone (BEL). IL-1β significantly increased cyclooxygenase (COX)-2 and PGE2 levels. The increase in PGE2 was blocked by SB-203580, AACOCF3, BEL, and the COX-2 inhibitor NS-398 but not by PD-98059 or the COX-1 inhibitor valeryl salicylate. The data suggested that IL-1β reduces LES tone by producing H2O2, which may affect Ca2+-release mechanisms and increase the synthesis of COX-2 and PGE2. Both H2O2 and PGE2 production depend on sequential activation of p38 MAPK and cPLA2. cPLA2 activates NADPH oxidases, producing H2O2, and may produce arachidonic acid, converted to PGE2 via COX-2.

MAPK mediates PKC-dependent contraction of cat esophageal and lower esophageal sphincter circular smooth muscle

2003 ◽  
Vol 285 (1) ◽  
pp. G86-G95 ◽  
Author(s):  
Weibiao Cao ◽  
Uy Dong Sohn ◽  
Khalil N. Bitar ◽  
Jose Behar ◽  
Piero Biancani ◽  
...  
Keyword(s):  
Lower Esophageal Sphincter ◽  
P38 Mapk ◽  
Kinase Inhibitor ◽  
Circular Muscle ◽  
Circular Smooth Muscle ◽  
Mapk Activity ◽  
Esophageal Sphincter ◽  
P38 Mapk Inhibitor ◽  
Sb 203580 ◽  
Mapk Inhibitor

Esophageal (ESO) circular muscle contraction and lower esophageal sphincter (LES) tone are PKC dependent. Because MAPKs may be involved in PKC-dependent contraction, we examined ERK1/ERK2 and p38 MAPKs in ESO and LES. In permeabilized LES muscle cells, ERK1/2 antibodies reduced 1,2-dioctanoylglycerol (DG)- and threshold ACh-induced contraction, which are PKC dependent, but not maximal ACh, which is calmodulin dependent. LES tone was reduced by the ERK1/2 kinase inhibitor PD-98059 and by the p38 MAPK inhibitor SB-203580. In permeable ESO cells, ACh contraction was reduced by ERK1/ERK2 and p38 MAPK antibodies and by PD-98059 and SB-203580. ACh increased MAPK activity and phosphorylation of MAPK and of p38 MAPK. The 27-kDa heat shock protein (HSP27) antibodies reduced ACh contraction. HSP27 and p38 MAPK antibodies together caused no greater inhibition than either one alone. p38 MAPK and HSP27 coprecipitated after ACh stimulation, suggesting that HSP27 is linked to p38 MAPK. These data suggest that PKC-dependent contraction in ESO and LES is mediated by the following two distinct MAPK pathways: ERK1/2 and HSP27-linked p38 MAPK.

Inhibition of lower esophageal sphincter circular muscle by female sex hormones.

1978 ◽  
Vol 234 (3) ◽  
pp. E243 ◽  
Author(s):  
R S Fisher ◽  
G S Roberts ◽  
C J Grabowski ◽  
S Cohen
Keyword(s):  
Lower Esophageal Sphincter ◽  
Sex Hormones ◽  
Circular Muscle ◽  
Response Curves ◽  
Circular Smooth Muscle ◽  
Female Sex ◽  
Female Sex Hormones ◽  
Esophageal Sphincter ◽  
Muscle Responses

To determine the effect of estrogenic and progesteronic activity on lower esophageal sphincter (LES) circular muscle, studies were performed on 20 adult opossums. Does-response curves on circular smooth muscle strips from the LES were constructed for gastrin and acetylcholine alone, and with 17beta-estradiol and/or progesterone added. Each female hormone significantly decreased the maximal LES muscle responses to gastrin and acetylcholine. A combination of 17beta-estradiol and progesterone abolished the response to gastrin. In contrast, the male sex hormone, dihydrotestosterone, had no effect. In conclusion, administration of estrogen and progesteron, but not dihydrotestosterone, in vitro reduced LES muscle responses to gastrin and acetylcholine. These studies suggest that the female sex hormones can alter LES function and potentially may be of importance in the pathogenesis of heartburn of pregnancy.

VIP-induced alterations in cAMP and inositol phosphates in the lower esophageal sphincter

1990 ◽  
Vol 259 (2) ◽  
pp. G239-G244 ◽  
Author(s):  
S. M. Szewczak ◽  
J. Behar ◽  
G. Billett ◽  
C. Hillemeier ◽  
B. Y. Rhim ◽  
...  
Keyword(s):  
Lower Esophageal Sphincter ◽  
Inositol Phosphates ◽  
Inositol Phosphate ◽  
Circular Muscle ◽  
Tissue Samples ◽  
Cyclic Monophosphate ◽  
Circular Smooth Muscle ◽  
Esophageal Sphincter ◽  
Camp Levels

Adenosine 3',5'-cyclic monophosphate (cAMP), guanosine 3',5'-cyclic monophosphate (cGMP), and inositol phosphate (IP) levels were measured in thin tissue samples from the circular smooth muscle of the cat lower esophageal sphincter (LES) at 37 degrees C during vasoactive intestinal peptide (VIP)-induced relaxation. On exposure of in vitro LES circular muscle strips to 10(-6) M VIP at the same temperature, relaxation of spontaneous resting tone begins within 3-6 s, is half maximal at 30 s, and maximal at 1 min. VIP-induced changes in cAMP, cGMP, and IP metabolite levels were measured at 5 and 30 s after the addition of 10(-6) M VIP. At 5 s cAMP levels increased significantly with respect to time-matched unstimulated controls, whereas inositol 1,4,5-trisphosphate (1,4,5-IP3) decreased and these changes remained constant at 30 s. cGMP levels were unchanged at either 5 or 30 s after exposure to 10(-6) M VIP. These data suggest that VIP-induced relaxation is temporally linked to decreased 1,4,5-IP3 as well as increased cAMP levels.

Mechanism of cholecystokinin inhibition of lower esophageal sphincter pressure

1975 ◽  
Vol 228 (5) ◽  
pp. 1469-1473 ◽  
Author(s):  
RS Fisher ◽  
AJ DiMarino ◽  
S Cohen
Keyword(s):  
Lower Esophageal Sphincter ◽  
Circular Muscle ◽  
Lower Esophageal Sphincter Pressure ◽  
Sphincter Pressure ◽  
Response Curves ◽  
Site Of Action ◽  
Threshold Doses ◽  
Esophageal Sphincter

The purpose of this study were 1) to quantify the lower esophageal sphincter (LES) response to intravenous cholecystokinin (CCK) in both man and the opossum in vivo, 2) to characterize the interaction of CCK and gastrin on circular muscle of the LES, and 3) to determine the site of action of CCK on LES muscle. In both man and the opossum LES pressure was decreased significantly by either constant intravenous infusion or bolus injection of CCK. In vitro dose-response curves to gastrin I, CCK, and the octapeptide of CCK (OP) demonstrated that both CCK and OP were partial agonists on the LES muscle. Both CCK and OP contract LES muscle at lower threshold doses, but give smaller maximum responses than gastrin I. The maximum response of LES muscle to CCK was antagonized only by atropine and tetrodotoxin, but not by other antagonists, suggesting that CCK contracts LES muscle by acetylcholine release. In vitro studies on LES muscle showed that CCK selectively antagonized the effect of gastrin I, but not other agonists. These studied suggest that CCK reduces LES pressure in vivo by inhibition of the endogenous gastrin effect.

scholarly journals Bakuchiol Suppresses Inflammatory Responses Via the Downregulation of the p38 MAPK/ERK Signaling Pathway

2019 ◽  
Vol 20 (14) ◽  
pp. 3574 ◽  
Author(s):  
Hye-Sun Lim ◽  
Yu Jin Kim ◽  
Bu-Yeo Kim ◽  
Soo-Jin Jeong
Keyword(s):  
Mrna Expression ◽  
P38 Mapk ◽  
Inflammatory Responses ◽  
Mitogen Activated Protein Kinase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mice Model ◽  
Tnf Α ◽  
Cox 2

The purpose of the present study was to evaluate the effects of bakuchiol on the inflammatory response and to identify the molecular mechanism of the inflammatory effects in a lipopolysaccharide (LPS)-stimulated BV-2 mouse microglial cell line and mice model. The production of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) was measured by enzyme-linked immunosorbent assay. The mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, and IL-6 was measured using reverse transcription–polymerase chain reaction analysis. Mitogen-activated protein kinase (MAPK) phosphorylation was determined by western blot analysis. In vitro experiments, bakuchiol significantly suppressed the production of PGE2 and IL-6 in LPS-stimulated BV-2 cells, without causing cytotoxicity. In parallel, bakuchiol significantly inhibited the LPS-stimulated expression of iNOS, COX-2, and IL-6 in BV-2 cells. However, bakuchiol had no effect on the LPS-stimulated production and mRNA expression of TNF-α or on LPS-stimulated c-Jun NH2-terminal kinase phosphorylation. In contrast, p38 MAPK and extracellular signal-regulated kinase (ERK) phosphorylation were inhibited by bakuchiol. In vivo experiments, Bakuchiol reduced microglial activation in the hippocampus and cortex tissue of LPS-injected mice. Bakuchiol significantly suppressed LPS-injected production of TNF-α and IL-6 in serum. These results indicate that the anti-neuroinflammatory effects of bakuchiol in activated microglia are mainly regulated by the inhibition of the p38 MAPK and ERK pathways. We suggest that bakuchiol may be beneficial for various neuroinflammatory diseases.

Opposing roles of K+and Cl−channels in maintenance of opossum lower esophageal sphincter tone

2000 ◽  
Vol 279 (6) ◽  
pp. G1226-G1234 ◽  
Author(s):  
Yong Zhang ◽  
David V. Miller ◽  
William G. Paterson
Keyword(s):  
Lower Esophageal Sphincter ◽  
Circular Muscle ◽  
Isometric Tension ◽  
Niflumic Acid ◽  
Resting Membrane Potential ◽  
Channel Blockers ◽  
Microelectrode Recordings ◽  
Basal Tone ◽  
Esophageal Sphincter

The ionic basis underlying the maintenance of myogenic tone of lower esophageal sphincter circular muscle (LES) was investigated in opossum with the use of standard isometric tension and conventional intracellular microelectrode recordings in vitro. In tension recording studies, nifedipine (1 μM) reduced basal tone to 27.7 ± 3.8% of control. The K+channel blockers tetraethylammonium (TEA, 2 mM), charybdotoxin (100 nM), and 4-aminopyridine (4-AP, 2 mM) enhanced resting tone, whereas apamin and glibenclamide were without affect. Cl−channel blockers DIDS (500 μM) and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (500 μM), as well as niflumic acid (0.1–300 μM), decreased basal tone, but tamoxifen was without effect. Intracellular microelectrode recordings revealed ongoing, spontaneous, spike-like action potentials (APs). Nifedipine abolished APs and depolarized resting membrane potential (RMP). Both TEA and 4-AP significantly depolarized RMP and augmented APs, whereas niflumic acid dose-dependently hyperpolarized RMP and abolished APs. These data suggest that, in the opossum, basal tone is associated with continuous APs and that K+and Ca2+-activated Cl−channels have important opposing roles in the genesis of LES tone.

Regional differences in cholinergic activity of muscle fibers from the human gastroesophageal junction

1997 ◽  
Vol 272 (6) ◽  
pp. G1321-G1327 ◽  
Author(s):  
H. G. Preiksaitis ◽  
N. E. Diamant
Keyword(s):  
Regional Differences ◽  
Gastroesophageal Junction ◽  
Circular Muscle ◽  
Gastric Fundus ◽  
Isometric Tension ◽  
Cholinergic Activity ◽  
Esophageal Sphincter ◽  
The Right

Muscles of the gastroesophageal junction that contribute to the lower esophageal sphincter (LES) include clasplike semicircular fibers on the right and slinglike oblique gastric fibers on the left. This study examined whether in vitro differences between the sling and clasp muscles could account for the in vivo asymmetry of LES pressure and its cholinergic contribution. Isometric tension was recorded from muscle strips of the sling, clasp, and circular layers of the esophagus and gastric fundus isolated from surgical specimens. The sling developed less spontaneous tension (8.9 +/- 4.3 mN/mm2) than the clasp (25.0 +/- 7.4 mN/mm2, P < 0.01) but showed a fivefold greater increase in response to carbachol. Eserine (1 microM) increased tension in the sling muscle (64.5 +/- 29.7%), but not in the clasp, whereas 1 microM atropine or 1 microM tetrodotoxin had no significant effect in either muscle. In both muscles, tension was reduced by 10 microM sodium nitroprusside. Sling or clasp muscle differed from circular muscle of the esophagus or gastric fundus in spontaneous tension, carbachol response, or responses to electrical stimulation. Thus the clasp muscle develops greater spontaneous tension, whereas the sling is more sensitive to cholinergic stimulation, providing a potential explanation for the in vivo asymmetry of the LES pressure and its response to cholinergic blockade.

Effects of KC 2450 on the lower esophageal sphincter in vivo and in vitro

1987 ◽  
Vol 142 (2) ◽  
pp. 225-233 ◽  
Author(s):  
Philip J. Fowler ◽  
Allen H. Nelson ◽  
William J. Price ◽  
Henry M. Sarau ◽  
Marilyn Grous ◽  
...  
Keyword(s):  
Lower Esophageal Sphincter ◽  
Esophageal Sphincter

scholarly journals Insights from a novel model of slow-transit constipation generated by partial outlet obstruction in the murine large intestine

2012 ◽  
Vol 303 (9) ◽  
pp. G1004-G1016 ◽  
Author(s):  
Dante J. Heredia ◽  
Nathan Grainger ◽  
Conor J. McCann ◽  
Terence K. Smith
Keyword(s):  
Outlet Obstruction ◽  
Circular Muscle ◽  
Slow Transit Constipation ◽  
Purse String ◽  
Slow Transit ◽  
Cox 2 ◽  
Transit Constipation ◽  
Novel Model

The mechanisms underlying slow-transit constipation (STC) are unclear. In 50% of patients with STC, some form of outlet obstruction has been reported; also an elongated colon has been linked to patients with STC. Our aims were 1) to develop a murine model of STC induced by partial outlet obstruction and 2) to determine whether this leads to colonic elongation and, consequently, activation of the inhibitory “occult reflex,” which may contribute to STC in humans. Using a purse-string suture, we physically reduced the maximal anal sphincter opening in C57BL/6 mice. After 4 days, the mice were euthanized (acutely obstructed), the suture was removed (relieved), or the suture was removed and replaced repeatedly (chronically obstructed, over 24–31 days). In partially obstructed mice, we observed increased cyclooxygenase (COX)-2 levels in muscularis and mucosa, an elongated impacted large bowel, slowed transit, nonpropagating colonic migrating motor complexes (CMMCs), a lack of mucosal reflexes, a depolarized circular muscle with slow-wave activity due to a lack of spontaneous inhibitory junction potentials, muscle hypertrophy, and CMMCs in mucosa-free preparations. Elongation of the empty obstructed colon produced a pronounced occult reflex. Removal of the obstruction or addition of a COX-2 antagonist (in vitro and in vivo) restored membrane potential, spontaneous inhibitory junction potentials, CMMC propagation, and mucosal reflexes. We conclude that partial outlet obstruction increases COX-2 leading to a hyperexcitable colon. This hyperexcitability is largely due to suppression of only descending inhibitory nerve pathways by prostaglandins. The upregulation of motility is suppressed by the occult reflex activated by colonic elongation.

Differential signal transduction pathways in cat lower esophageal sphincter tone and response to ACh

1994 ◽  
Vol 266 (5) ◽  
pp. G767-G774 ◽  
Author(s):  
P. Biancani ◽  
K. M. Harnett ◽  
U. D. Sohn ◽  
B. Y. Rhim ◽  
J. Behar ◽  
...  
Keyword(s):  
Phospholipase C ◽  
Lower Esophageal Sphincter ◽  
Calcium Release ◽  
Circular Muscle ◽  
Dependent Manner ◽  
Differential Signal ◽  
Esophageal Sphincter ◽  
Resting Tone ◽  
Dependent Pathway

Lower esophageal sphincter (LES) basal tone and contraction in response to maximally effective doses (Emax) of acetylcholine (ACh) may be mediated by different intracellular transduction pathways. In the basal state resting tone, inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] formation and levels of diacylglycerol (DAG) (C. Hillemeier, K. N. Bitar, and P. Biancani, unpublished data) are higher in LES circular muscle than in esophageal muscle, which does not maintain tone. In vitro resting tone and spontaneously elevated formation of Ins(1,4,5)P3 in LES circular muscle strips decrease in a dose-dependent manner in response to the phospholipase C antagonist 1-[6-([(17-beta)-3-methoxyestra-1,3, 5(10)-trien-17-yl]amino)hexyl]-1H-pyrrole-2,5-dione (U-73122). Basal Ins(1,4,5)P3 formation, however, is submaximal, since it can be increased by cholinergic stimulation. These data suggest that LES tone is associated with partial activation of phospholipase C. We therefore tested submaximal doses of Ins(1,4,5)P3 and DAG in permeabilized LES muscle cells and found that they act synergistically; their interaction depends on calcium release and is mediated through a protein kinase C (PKC)-dependent pathway. In contrast, we have previously shown that contraction induced by Emax of ACh is mediated through calmodulin-dependent mechanisms (14). To investigate these differences, we tested high and low doses of ACh. Contraction induced by high doses of ACh was inhibited by calmodulin but not by PKC antagonists, as previously reported, but low ACh doses were preferentially inhibited by PKC antagonists. Similarly, low Ins(1,4,5)P3 concentrations activated a PKC-dependent pathway, whereas contraction induced by Emax of Ins(1,4,5)P3 was calmodulin dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

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