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KMID : 0043320110340010169
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Archives of Pharmacal Research
2011 Volume.34 No. 1 p.169 ~ p.176
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Lysophosphatidic acid presynaptically blocks NO uptake during electric field stimulation-induced relaxation via LPA1 receptor in cat lower esophageal sphincter
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Lee Jun-Woo
Kim Chung-Hyo
Wang Yi Yi
Yan Xiang Mei
Sohn Uy-Dong
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Abstract
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Lysophosphatidic acid (LPA) is a lipid mediator that is involved in many biological responses, such as, in the stimulation/inhibition of proliferation, in cell migration, antiapoptosis, tumor cell invasion, platelet aggregation, vascular remodeling, and neurotransmitter release. In addition, LPA indirectly enhances the contractility of smooth muscle. Furthermore, electric field stimulation (EFS) causes contractions of isolated cat esophageal smooth muscle and relaxations of isolated cat lower esophageal sphincter (LES). To test whether or not LPA enhances postsynaptically-mediated contraction in cat esophageal smooth muscle and LES, both types of muscle strips were stimulated with muscarinic agonists. However, no significant effects were observed, and therefore, to investigate whether LPA is involved in presynaptic signal transduction, cat esophageal smooth muscle and LES were pretreated with LPA and stimulated using EFS. LPA had no effect on EFS-induced contraction in esophageal smooth muscle but the EFSinduced LES relaxation was dose-dependently inhibited by LPA. To identify the LPA receptor subtype that inhibits EFS-induced LES relaxation, we used the specific LPA1/LPA3 antagonist Ki16425 and the LPA3 agonist OMPT. Ki16425 significantly blocked the inhibitory effect of LPA on EFS-induced relaxation, but OMPT did not enhance the effect of LPA. These results suggest that LPA inhibits EFS-induced relaxation in LES via LPA1 receptor-mediated signaling. It is well known that EFS-induced LES relaxation is related to the release of neurotransmitters, such as, nitric oxide, vasoactive intestinal polypeptide, and calcitonin gene-related peptide. We then investigated whether LPA selectively blocks NO-mediated signaling. Sodium nitroprusside-induced LES relaxation was found to be inhibited in the same manner as EFS-induced LES relaxation by LPA. This result suggests that LPA partially blocks NO uptake by presynaptic pathways, and thus, inhibits LES relaxation.
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KEYWORD
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Smooth muscle, Contraction, Lysophosphatidic acid receptor, Nitric oxide, Lower esophageal sphincter
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