title: Histamine, carbachol, and serotonin induce hyperresponsiveness to ATP in guinea pig tracheas: involvement of COX-2 pathway.
abstract: Extracellular ATP promotes an indirect contraction of airway smooth muscle via the secondary release of thromboxane A2 (TXA2) from airway epithelium. Our aim was to evaluate if common contractile agonists modify this response to ATP. Tracheas from sensitized guinea pigs were used to evaluate ATP-induced contractions before and after a transient contraction produced by histamine, carbachol, or serotonin. Epithelial mRNA for COX-1 and COX-2 was measured by RT-PCR and their expression assessed by immunohistochemistry. Compared with the initial response, ATP-induced contraction was potentiated by pretreatment with histamine, carbachol, or serotonin. Either suramin (antagonist of P2X and P2Y receptors) plus RB2 (antagonist of P2Y receptors) or indomethacin (inhibitor of COX-1 and COX-2) annulled the ATP-induced contraction, suggesting that it was mediated by P2Y receptor stimulation and TXA2 production. When COX-2 was inhibited by SC-58125 or thromboxane receptors were antagonized by SQ-29548, just the potentiation was abolished, leaving the basal response intact. Airway epithelial cells showed increased COX-2 mRNA after stimulation with histamine or carbachol, but not serotonin, while COX-1 mRNA was unaffected. Immunochemistry corroborated this upregulation of COX-2. In conclusion, we showed for the first time that histamine and carbachol cause hyperresponsiveness to ATP by upregulating COX-2 in airway epithelium, which likely increases TXA2 production. Serotonin-mediated hyperresponsiveness seems to be independent of COX-2 upregulation, but nonetheless is TXA2 dependent. Because acetylcholine, histamine, and serotonin can be present during asthmatic exacerbations, their potential interactions with ATP might be relevant in its pathophysiology.
authors.affiliation: Departamento de Farmacología, Edificio de Investigación, sexto piso, laboratorio 3, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad Universitaria, CP 04510, Mexico D. F., Mexico. lmmr@unam.mx
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montaño
authors.forename: Verónica
authors.initials: V
authors.lastname: Carbajal
authors.forename: Mario H
authors.initials: MH
authors.lastname: Vargas
authors.forename: Luz M
authors.initials: LM
authors.lastname: García-Hernández
authors.forename: Verónica
authors.initials: V
authors.lastname: Díaz-Hernández
authors.forename: Marco
authors.initials: M
authors.lastname: Checa
authors.forename: Carlos
authors.initials: C
authors.lastname: Barajas-López
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000235:genetics; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D058469:Receptors, Purinergic P2X / Q000235:genetics / Q000378:metabolism; D058470:Receptors, Purinergic P2Y / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000235:genetics / Q000378:metabolism; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D058920:Purinergic P2X Receptor Antagonists; D058921:Purinergic P2Y Receptor Antagonists; D012333:RNA, Messenger; D058469:Receptors, Purinergic P2X; D058470:Receptors, Purinergic P2Y; D012701:Serotonin; D013928:Thromboxane A2; D006632:Histamine; D000255:Adenosine Triphosphate; D002217:Carbachol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2