title: Leukotriene C4 induces bronchoconstriction and airway vascular hyperpermeability via the cysteinyl leukotriene receptor 2 in S-hexyl glutathione-treated guinea pigs.
abstract: Cysteinyl leukotrienes act through G-protein-coupled receptors termed cysteinyl leukotriene 1 (CysLT1) and cysteinyl leukotriene 2 (CysLT2) receptors. However, little is known about the pathophysiological role of CysLT2 receptors in asthma. To elucidate the possible involvement of CysLT2 receptors in bronchoconstriction and airway vascular hyperpermeability, we have established a novel guinea pig model of asthma. In vitro study confirmed that CHO-K1 cells, expressing guinea pig CysLT2 and CysLT1 receptors are selectively stimulated by LTC4 and LTD4, respectively. However, when LTC4 was intravenously injected to guinea pigs, the resulting bronchoconstriction was fully abrogated by montelukast, a CysLT1 receptor antagonist, indicating rapid metabolism of LTC4 to LTD4 in the lung. We found that treatment with S-hexyl glutathione (S-hexyl GSH), an inhibitor of gamma-glutamyl transpeptidase, significantly increased LTC4 content and LTC4/(LTD4 plus LTE4) ratio in the lung. Under these circumstances, LTC4-induced bronchoconstriction became resistant to montelukast, but sensitive to Compound A, a CysLT2 receptor antagonist, depending on the dose of S-hexyl GSH. Combination with montelukast and Compound A completely abrogated this spasmogenic response. Additionally, we confirmed that LTC4 elicits airway vascular hyperpermeability via CysLT2 receptors in the presence of high dose of S-hexyl GSH as evidenced by complete inhibition of LTC4-induced hyperpermeability by Compound A, but not montelukast. These results suggest that CysLT2 receptors mediate bronchoconstriction and airway vascular hyperpermeability in guinea pigs and that the animal model used in this study may be useful to elucidate the functional role of CysLT2 receptors in various diseases, including asthma.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan. Electronic address: yonetomi@ono.co.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yonetomi
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Sekioka
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kadode
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kitamine
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kamiya
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsumura
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Kawabata
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D006168:Guinea Pigs; D017997:Leukotriene C4 / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D008297:Male; D011804:Quinolines / Q000494:pharmacology; D018077:Receptors, Leukotriene / Q000819:agonists / Q000187:drug effects / Q000502:physiology*; D013440:Sulfides; D014230:Triazoles / Q000494:pharmacology
chemical_list: D000085:Acetates; D003521:Cyclopropanes; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; D014230:Triazoles; C524574:compound A (octyltriazole); D017997:Leukotriene C4; D017998:Leukotriene D4; C412375:cysteinyl leukotriene receptor 2; D005978:Glutathione; C083169:leukotriene D4 receptor; C033550:hexylglutathione; C093875:montelukast; D002118:Calcium
keywords: Asthma; CysLT(2) receptor; CysLTs; Glutathione; Glutathione (Pubchem CID: 124886); LTC(4) metabolism