BRD 7552 Our results in the present study
Our results in the present study demonstrate that CysLT1 mediates leukotriene-induced contraction in the fundus and suggest that both CysLT1 and CysLT2 mediate leukotriene-induced contraction in the antrum in vitro. Further studies on the effects of leukotrienes in vivo are required to elucidate the leukotriene influence on the gastric motility. In the gastrointestinal system, cysteinyl leukotrienes have been implicated in eosinophilic esophagitis and eosinophilic gastroenteritis. CysLT1 receptor antagonists are used clinically as therapeutic agents in these diseases (Brink et al., 2003, Kanaoka and Boyce, 2004, Capra et al., 2007, Khan, 2005, Attwood et al., 2003). Recently, fundic relaxants are a new approach to treatment of impaired gastric accommodation in functional dyspepsia. Emerging therapeutic agents include the 5-HT1A agonist (Tack, 2009). CysLT1 receptor antagonists inhibit cysteinyl leukotriene-induced contraction in the fundus. Therefore they might be potential fundic relaxants. On the other hand, gastric distension, especially the antral distension, by food is important in regulation of food intake and appetite (Delzenne et al., 2010). CysLT2 and CysLT1 related agents, influencing antral and gastric contraction, respectively, might have therapeutic potential in appetite modulation and obesity.
Conclusion The results of the present study demonstrate that cysteinyl leukotrienes LTC4, LTD4 and LTE4 cause moderate to marked whereas the dihydroxy leukotriene LTB4 causes small muscle contraction in the stomach in vitro. The LTD4-induced contraction is mediated by CysLT1 in fundus but by CysLT1 and CysLT2 in antrum.
Conflict of interest statement
Acknowledgments This work was supported by National Science Council of Taiwan (NSC 97-2314-B-303-012-MY3), Buddhist Tzu Chi General Hospital, Hualien, and E-Da Hospital. The author thanks Yu-Shyuan Wang, Ling-Jung Chiu, Mei-Ling Chen and Cai-Jing Lee for their excellent technical assistance.
Introduction Cysteinyl leukotrienes (CysLTs), namely LTC4, LTD4 and LTE4, are 5-lipoxygenase metabolites of arachidonic BRD 7552 (Funk, 2001, Samuelsson, 1983). They are involved in various inflammatory diseases including bronchial asthma, allergic rhinitis, atopic dermatitis, urticaria, and cerebral ischemia (Capra et al., 2007, Back et al., 2011). CysLTs act on G protein-coupled receptors, cysteinyl leukotriene receptors (CsyLT1 and CysLT2) as well as GPR17 that has been reported to respond to both uracil nucleotides and CysLTs (Samuelsson, 1983, Metters, 1995, Ciana et al., 2006, Kanaoka and Boyce, 2004). In addition, GPR99 is a possible CysLT receptor with a preference for LTE4. CysLT1 and CysLT2 receptors mediate distinct or similar responses (Ciana et al., 2006, Heise et al., 2000, Sarau et al., 1999). The CysLT1 receptor is mainly expressed in peripheral blood leukocytes, spleen, and smooth muscles (Figueroa et al., 2001); while the CysLT2 receptor is highly expressed in peripheral blood leukocytes, spleen, adrenal medulla, heart, and brain (Heise et al., 2000). Currently, the roles of CysLT1 receptors have been extensively investigated because selective CysLT1 receptor antagonists are available. In contrast, the roles of CysLT2 receptors are poorly understood because of the previous lack of selective antagonists (other than the non-selective antagonist Bay u9773) (Ni et al., 2011). Recently, HAMI3379 and Bay CysLT2 have been reported to be selective CysLT2 receptor antagonists (Ni et al., 2011, Wunder et al., 2010). HAMI3379, 3-( [(1S,3S)-3-carboxycyclohexyl]amino carbonyl)-4-(3- 4-[4-(cyclo-hexyloxy) butoxy] phenyl propoxy) benzoic acid, is devoid of CysLT receptor agonism, and shows >10,000-fold affinity for CysLT2vs CysLT1 receptors (Wunder et al., 2010). However, the signal pathways after CysLT2 receptor activation are little known. The responses of CysLT2 receptor have been reported to be related to several isolated signaling events, such as induction of early growth response-1 (Egr-1) (Uzonyi et al., 2006), eliciting β-arrestin-2 binding (Yan et al. (2011)), production of inositol phosphates and phosphorylation of NF-κB p65 (Brochu-Bourque et al., 2011), and phosphorylation of JUN, ERK and p38 (Brochu-Bourque et al., 2011, Qi et al., 2011). In human umbilical vein cells (HUVECs), LTD4 induces synthesis of Egr-1, a transcriptional factor localized in the nucleus, and promotes interleukin-8 (IL-8) synthesis and secretion (Uzonyi et al., 2006). This finding suggests one of the possible signaling pathways of CysLT2 receptors, i.e. Egr-1 may be involved in CysLT2 receptor-mediated IL-8 production; however, the details remain to be clarified. In another study, LTC4via the CysLT2 receptor transcriptionally activates IL-8 production through induction of NF-κB and AP-1 transcription factors, namely the PKCɛ/NF-κB and PKCδ/AP-1 pathways (Thompson et al., 2008). Also, LTD4-induced IL-8 promoter activity is a CysLT2 receptor response in HEK293 cells expressing wild-type or M201V mutant CysLT2 receptors, which is associated with phosphorylation of the mitogen-activated protein kinases (MAPKs) ERK1/2, JUN and p38 (Brochu-Bourque et al., 2011).