• Archives of Pharmacal Research
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• v.29 no.5
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• pp.400-404
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• 2006

This study examined the effect of Gamma-Amino butyric acid (GABA) and selective GABA receptor related drugs on the electrically stimulated relaxation in the lower esophageal sphincter muscle (LES) of a cat. Tetrodotoxin $(10^{-6}\;M)$ suppressed the electrically stimulated (0.5-5 Hz) relaxation of the LES. However, guanethidine $(10^{-6}\;M)$ and atropine $(10^{-6}\;M)$ had no effect indicating that the relaxations were neurally mediated via the nonadrenergic and noncholinergic (NANC) pathways. NG-nitro-L-arginine methyl ester ($10^{-4}M$, L-NAME) also inhibited the relaxant response but did not completely abolish the electrically stimulated relaxation with 60% inhibition, which suggests the involvement of nitric oxide as an inhibitory transmitter. This study examined the role of GABA, an inhibitory neurotransmitter, on neurally mediated LES relaxation. GABA ($10^{-3}-10^{-5}M$, non selective receptor agonist), muscimol ($10^{-3}-10^{-5}M$, GABA-A agonist), and baclofen ($10^{-3}-10^{-5}M$, GABA-B agonist) had no significant effect on the electrically stimulated relaxation. Moreover, bicuculline ($10^{-5}M$, GABA-A antagonist) and phaclofen ($10^{-5}M$, GABA-B antagonist) had no inhibitory effect on the electrically stimulated relaxation. This suggests that GABA and the GABA receptor are not involved in the electrically stimulated NANC relaxation in the cat LES.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.3
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• pp.303-313
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• 1997

The role of the lower esophageal sphincter(LES) is characterized by the ability to maintain tone and to relax allowing the passage of a bolus. It is known that LES relaxation during swallowing may be induced by the cessation of the tonic neural excitation and the activation of non-adrenergic, non-cholinergic(NANC) inhibitory neurons. Furthermore, it is generally accepted that the relaxation of the smooth muscle is mediated primarily by the elaboration of adenosine 3',5'-cyclic monophosphate(cyclic AMP) and guanosine 3',5'-cyclic mono-phosphate(cyclic GMP) via activation of adenylate cyclase and guanylate cyclase, respectively. It is thus possible that cyclic nucleotides might be a second messenger involved in neural stimulation-induced relaxation of LES, although a relationship between relaxation and changes in cyclic nucleotides after neural stimulation has not been established. The present study was performed to define the participation of cyclic nucleotides in the relaxation of LES of dog in response to neural stimulation. Electrical field stimulation(EFS) caused relaxation of the canine isolated LES strips in a frequency-dependent manner, which was eliminated by pretreatment with tetrodotoxin$(1{\mu}M)$, but not by atropine$(100{\mu}M)$, guanethidine$(100{\mu}M)$ and indomethacin$(10{\mu}M)$. The nitric oxide synthase inhibitors, $N^G-nitro-L-arginine$, $N^G-nitro-L-arginine$ methyl ester and $N^G-monomethyl-L-arginine$ inhibited EFS-induced relaxation. Additions of sodium nitroprusside, a nitrovasodilator and forskolin, a direct adenylate cyclase stimulant, caused a dose-dependent relaxation of LES smooth muscle. Effects of sodium nitroprusside and forskolin were selectively blocked by the corresponding inhibitors, methylene blue for guanylate cyclase and N-ethylmaleimide(NEM) for adenylate cyclase, respectively. Dibutyryl cyclic AMP and dibutyryl cyclic GMP caused a concentration-dependent relaxation of the LES smooth muscle tone, which was not blocked by NEM or methylene blue, respectively. However, both NEM and methylene blue caused significant antagonism of the relaxation in LES tone in response to EFS. EFS increased the tissue cyclic GMP content by 124%, whereas it did not affect the tissue level of cyclic AMP. Based on these results, it is suggested that one of the components of canine LES smooth muscle relaxation in response to neural stimulation is mediated by an increase of cyclic GMP via the activation of guanylate cyclase. Additionally, an activation of cyclic AMP generation system was, in part, involved in the EFS-induced relaxation.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1997.11a
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• pp.41-46
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• 1997

Lower esophageal sphincter (LES) is characterized by the ability to maintain a sustained pressure, and to relax allowing the passage of a bolus, whereas the esophagus is normally relaxed and contracts only briefly when required to produce peristalsis (fig. 1). The neuromuscular mechanisms that participate in the physiological regulation of these functions are not well understood, but it is thought that LES tone is spontaneous and regulated mostly through myogenic mechanisms, whereas LES relaxation and esophageal contraction are induced by neural mechanisms. Gastroesophageal reflux represents the effortless movement of gastric contents from stomach to esophagus. Because this phenomenon occurs in virtually everyone multiple times every day and in the majority of people without clinical consequences, the reflux per se is not disease. However in some cases, it can be pathologic, producing symptoms and signs called gastroesophageal reflux disease (GERD), which mechanism is not well known. It may result in heart burn, chronic esophagitis, aspiration pneumonia, esophageal strictures, and Barrett's esophagus.

• Archives of Pharmacal Research
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• v.24 no.6
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• pp.546-551
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• 2001

We have previously shown that, in circular muscle cells of the lower esophageal sphincter (LES) isolated by enzymatic digestion, contraction in response to maximally effective doses of acetylcholine (ACh) or Inositol Triphosphate ($IP_3$) depends on the release of $Ca^{2+}$ from intracellular stores and activation of a $Ca6{2+}$-calmodulin (CaM)-dependent pathway. On the contrary, maintenance of LES tone, and response to low doses of ACh or $IP_3$ depend on a protein kinase C (PKC) mediated pathway. In the present investigation, we have examined requirements for $Ca6{2+}$ regulation of the interaction between CaM- and PKC-dependent pathways in LES contraction. Thapsigargin (TG) treatment for 30 min dose dependently reduced ACh-induced contraction of permeable LES cells in free $Ca6{2+}$ medium. ACh-induced contraction following the low level of reduction of $Ca6{2+}$ stores by a low dose of TG ($10^{-9}{\;}M$) was blocked by the CaM antagonist, CCS9343B but not by the PKC antagonists chelerythrine or H7, indicating that the contraction is CaM-dependent. After maximal reduction in intracellular $Ca{2+}$ from $Ca6{2+}$stores by TG ($10^{-6}{\;}M$), ACh-induced contraction was blocked by chelerythrine or H7, but not by CCS9343B, indicating that it is PKC-dependent. In normal $Ca^{2+}$medium, the contraction by ACh after TG ($10^{-9}{\;}M$) treatment was also CaM-dependent, whereas the contraction by ACh after TG ($10^{-9}{\;}M$) treatment was PKC-dependent. We examined whether PKC activation was inhibited by activated CaM. CCS 7343B Inhibited the CaM-induced contraction, but did not inhibit the DAC-induced contraction. CaM inhibited the DAC-induced contraction in the presence of CCS 9343B. This inhibition by CaM was $Ca{2+}$dependent. These data are consistent with the view that the switch from a PKC-dependent pathway to a CaM dependent pathway can occur and can be regulated by cytosolic $Ca{2+}$ in the LES.

• Journal of Gastric Cancer
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• v.24 no.2
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• pp.137-144
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• 2024

Purpose: Laparoscopic proximal gastrectomy (LPG) is a viable choice for treating proximal gastric lesions. However, the occurrence of severe reflux has limited its widespread adoption. To address this issue, the double flap technique (DFT), which incorporates artificial lower esophageal sphincteroplasty, has been developed to prevent reflux problems after proximal gastrectomy. In this study, we aimed to investigate the usefulness of this technique using high-resolution manometry (HRM), impedance pH monitoring, and esophagogastroduodenoscopy (EGD). Materials and Methods: The findings of pre- and postoperative 6-month HRM, pH monitoring, and EGD were compared for 9 patients who underwent LPG with DFT for various proximal gastric lesions at Incheon St. Mary's Hospital from January 2021 to December. Results: A total of 9 patients underwent proximal gastrectomy. Approximately half of the patients had Hill's grade under II preoperatively, whereas all patients had Hill's grades I and II in EGD findings. In the HRM test, there was no significant difference between distal contractile integral (1,412.46±1,168.51 vs. 852.66±495.62 mmHg·cm·s, P=0.087) and integrated relaxation pressure (12.54±8.97 vs. 8.33±11.30 mmHg, P=0.27). The average lower esophageal sphincter (LES) pressure was 29.19±14.51 mmHg preoperatively, which did not differ from 19.97±18.03 mmHg after the surgery (P=0.17). DeMeester score (7.02±6.36 vs. 21.92±36.17, P=0.21) and total acid exposure time (1.49±1.48 vs. 5.61±10.17, P=0.24) were slightly higher, but the differences were not statistically significant. Conclusions: There is no significant functional difference in HRM and impedance pH monitoring tests after DFT. DFT appears to be useful in preserving LES function following proximal gastrectomy.

• Journal of the Korean Society of Laryngology, Phoniatrics and Logopedics
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• v.27 no.2
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• pp.73-77
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• 2016

Laryngopharyngeal reflux disease (LPRD) is different with gastroesophageal reflux disease (GERD). The lower esophageal sphincter (LES) possesses an intrinsic nervous plexus that allows the LES to have a considerable degree of independent neural control. Sympathetic control of the LES and stomach stems from cholinergic preganglionic neurons in the intermediolateral column of the thoracic spinal cord (T6 through T9 divisions), which impinge on postganglionic neurons in the celiac ganglion, of which the catecholaminergic neurons provide the LES and stomach with most of its sympathetic supply. Sympathetic regulation of motility primarily involves inhibitory presynaptic modulation of vagal cholinergic input to postganglionic neurons in the enteric plexus. The magnitude of sympathetic inhibition of motility is directly proportional to the level of background vagal efferent input. Recognizing that the LES is under the dual control of the sympathetic and parasympathetic nervous systems, we refer the reader to other comprehensive reviews on the role of the sympathetic and parasympatetic control of LES and gastric function. The present review focuses on the functionally dominant parasympathetic control of the LES and stomach via the dorsal motor nucleus of the vagus.

• The Korean Journal of Nuclear Medicine
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• v.29 no.1
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• pp.61-72
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• 1995

The author performed radionuclide esophageal transit studies(RETS) with liquid and solid boluses using the same day protocol in 90 normal controls and 164 patients with various primary esophageal motility disorders who were diagnosed by manometric criteria and clinical courses. The authors calculated mean esophageal transit time(MTT) and mean residual retention(MRR) in each of the liquid and solid studies, and classified time-activity curve(TAC) patterns. The normal criteria of RETS with liquid bolus were MTT<24 sec, MRR<9%, and the TAC pattern that showed rapid declining slope and flat low residual(Type 1). The normal criteria of RETS with solid bolus were MTT<35 sec, MRR<9% and TAC of type 1. With these normal criteria, the sensitivity and the specificity of the liquid study were 62.2 % and 97.8%, respectively. The sensitivity increased to 75.4% with the solid study. The author also found that the RETS was highly reproducible. The achalasia typically showed no effective emptying of both liquid and solid boluses during the whole study period, and was well differentiated by its extremely long transit time and high retention from the other motility disorders. The diffuse esophageal spasm (DES) and nonspecific esophageal motility disorder(NEMD) showed intermediate delay in transit time and increased retention. In the groups of hypertensive lower esophageal sphincter(LES), hypotensive LES and nutcracker, there noted no significant difference with the normal control group in terms of MTT and MRR. The DES and NEMD could be more easily identified by solid studies that showed more marked delay in MTT and increased MRR as compared with the liquid study. In conclusion, esophageal scintigraphy is a safe, noninvasive and physiologic method for the evaluation of esophageal emptying.

• The Korean Journal of Physiology and Pharmacology
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• v.7 no.6
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• pp.349-355
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• 2003

We previously shown that LES contraction depends on $M_3$ receptors linked to PTX insensitive $G_q$ protein and activation of PLC. This results in production of $IP_3$, which mediates calcium release, and contraction through a CaM dependent pathway. In the esophagus ACh activates $M_2$ receptors linked to PTX sensitive $G_{i3}$ protein, resulting in activation of PLD, presumably, production of DAG. We investigated the role of PLC isozymes which can be activated by $G_q$ or $G{\beta}$ protein on ACh-induced contraction in LES and esophagus. Immunoblot analysis showed the presence of 3 types of PLC isozymes, $PLC-{\beta}1$, $PLC-{\beta}3$, and $PLC-{\gamma}1$, but not $PLC-{\beta}2$, $PLC-{\beta}4$, $PLC-{\gamma}2$, $PLC-{\delta}1$, and $PLC-{\delta}2$ from both LES and esophageal muscle. ACh produced contraction in a dose dependent manner in LES and esophageal muscle cells obtained by enzymatic digestion with collagenase. $PLC-{\beta}1$ or $PLC-{\beta}3$ antibody incubation reduced contraction in response to ACh in LES but not in esophageal permeabilized cells, but $PLC-{\gamma}1$ antibody incubation did not have an inhibitory effect. The inhibition by $PLC-{\beta}1$ or $PLC-{\beta}3$ antibody on Ach-induced contraction was antibody concentration dependent. The combination with $PLC-{\beta}_1$ and $PLC-{\beta}_3$ antibody completely abolished the contraction, suggesting that $PLC-{\beta}1$ and $PLC-{\beta}3$ have a synergism to inhibit the contraction in LES. $PLC-{\beta}1$, -${\beta}3$ or -${\gamma}1$ antibody did not reduce the contraction of LES cells in response to DAG ($10^{-6}$ M), suggesting that this isozyme of PLC may not activate PKC. When $G_{q/11}$ antibody was incubated, the inhibitory effect of the incubation of PLC ${\beta}3$, but not of PLC ${\beta}_1$ was additive (Fig. 6). In contrast, when $G_{\beta}$ antibody was incubated, the inhibitory effect of the incubation of PLC ${\beta}_1$, but not of PLC ${\beta}_3$ was additive. This data suggest that $G_{q/11}$/11 or $G{\beta}$ may activate cooperatively different PLC isozyme, $PLC{\beta}_1$ or $PLC{\beta}_3$ respectively.

• Journal of the Korean Society of Laryngology, Phoniatrics and Logopedics
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• v.19 no.2
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• pp.136-141
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• 2008

Background and Objectives: Laryngopharyngeal reflux (LPR) is a very common disease among outpatients of department of otorhinolaryngology. Although there are several diagnostic tools for LPR disease and ambulatory 24-hour double-probe pH monitoring is gold standard method, empirical diagnosis by reflux symptom index and reflux finding score (RFS) are mainly used. So we analyzed the relationship between ambulatory 24-hour double-probe pH monitoring and RFS in patients with LPR. Subjective and Method: Fifty patients with LPR symptoms and abnormal RFS and ambulatory 24-hour double probe monitoring were enrolled. Each items and sum of laryngeal reflux score were compared the results of ambulatory 24-hour double-probe pH monitoring in upper (UES) and lower (LES) esophageal sphincter. Results: There were no significant correlation between the results of ambulatory 24-hour double-probe pH monitoring in UES (pH<4 and pH<5) and each item and sum of RFS. However, supine time and reflux number of UES (pH<5) were showed the partial correlations with diffuse laryngeal edema and thick endolaryngeal mucus (p=0.03, p=0.01). Although there were no relationship between the results of ambulatory 24-hour double-probe pH monitoring in LES and sum of RFS, the significant correlations presented between granuloma and total time (p=0.008), upright time (p=0.008, reflux number (p=0.049) of LES. Conclusion: Although granuloma among items of RFS showed significantly correlation with the results of ambulatory 24-hour double-probe pH monitoring in LES, there were no significant correlation between the results of ambulatory 24-hour double-probe pH monitoring in UES and LES and items and sum of RFS.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.4
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• pp.287-297
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• 2001

Contraction of smooth muscle is initiated by an increase in cytosolic $Ca^{2+}$ leading to activation of $Ca^{2+}$/ calmodulin-dependnet myosin light chain (MLC) kinase and phosphorylation of MLC. The types of contraction and signaling mechanisms mediating contraction differ depending on the region. The involvement of these different mechanisms varies depending on the source of $Ca^{2+}$ and the kinetic of $Ca^{2+}$ mobilization. $Ca^{2+}$ mobilizing agonists stimulate different phospholipases $(PLC-{\beta},\;PLD\;and\;PLA_2)$ to generate one or more $Ca^{2+}$ mobilizing messengers $(IP_3\;and\;AA),$ and diacylglycerol (DAG), an activator of protein kinase C (PKC). The relative contributions of $PLC-{\beta},\;PLA_2$ and PLD to generate second messengers vary greatly between cells and types of contraction. In smooth muscle cell derived form the circular muscle layer of the intestine, preferential hydrolysis of $PIP_2$ and generation of $IP_3$ and $IP_3-dependent\;Ca^{2+}$ release initiate the contraction. In smooth muscle cells derived from longitudinal muscle layer of the intestine, preferential hydrolysis of PC by PLA2, generation of AA and AA-mediated $Ca^{2+}$ influx, cADP ribose formation and $Ca^{2+}-induced\;Ca^{2+}$ release initiate the contraction. Sustained contraction, however, in both cell types is mediated by $Ca^{2+}-independent$ mechanism involving activation of $PKC-{\varepsilon}$ by DAG derived form PLD. A functional linkage between $G_{13},$ RhoA, ROCK, $PKC-{\varepsilon},$ CPI-17 and MLC phosphorylation in sustained contraction has been implicated. Contraction of normal esophageal circular muscle (ESO) in response to acetylcholine (ACh) is linked to $M_2$ muscarinic receptors activating at least three intracellular phospholipases, i.e. phosphatidylcholine-specific phospholipase C (PC-PLC), phospholipase D (PLD) and the high molecular weight (85 kDa) cytosolic phospholipase $A_2\;(cPLA_2)$ to induce phosphatidylcholine (PC) metabolism, production of diacylglycerol (DAG) and arachidonic acid (AA), resulting in activation of a protein kinase C (PKC)-dependent pathway. In contrast, lower esophageal sphincter (LES) contraction induced by maximally effective doses of ACh is mediated by muscarinic $M_3$ receptors, linked to pertussis toxin-insensitive GTP-binding proteins of the $G_{q/11}$ type. They activate phospholipase C, which hydrolyzes phosphatidylinositol bisphosphate $(PIP_2),$ producing inositol 1, 4, 5-trisphosphate $(IP_3)$ and DAG. $IP_3$ causes release of intracellular $Ca^{2+}$ and formation of a $Ca^{2+}$-calmodulin complex, resulting in activation of myosin light chain kinase and contraction through a calmodulin-dependent pathway.