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Histamine, carbachol, and serotonin induce hyperresponsiveness to ATP in guinea pig tracheas: involvement of COX-2 pathway

  • Molecular and Cellular Mechanisms of Disease
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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.

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Acknowledgments

This study was partly supported by a grant from CONACYT (81409) and DGAPA-UNAM (IN201810-3 and IN200613) to Dr. Luis M. Montaño.

Conflict of interest

No conflicts of interest are declared by the authors.

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Authors and Affiliations

  1. 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

    Luis M. Montaño & Luz M. García-Hernández

  2. Departamento de Investigación en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias, Mexico D. F., Mexico

    Verónica Carbajal & Mario H. Vargas

  3. Departamento de Embriología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico

    Verónica Díaz-Hernández

  4. Departamento de Fibrosis Pulmonar, Instituto Nacional de Enfermedades Respiratorias, Mexico D. F., Mexico

    Marco Checa

  5. División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica, San Luis Potosí, SLP, Mexico

    Carlos Barajas-López

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  1. Luis M. Montaño
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  2. Verónica Carbajal
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Correspondence to Luis M. Montaño.

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Montaño, L.M., Carbajal, V., Vargas, M.H. et al. Histamine, carbachol, and serotonin induce hyperresponsiveness to ATP in guinea pig tracheas: involvement of COX-2 pathway. Pflugers Arch - Eur J Physiol 465, 1171–1179 (2013). https://doi.org/10.1007/s00424-013-1253-9

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  • DOI: https://doi.org/10.1007/s00424-013-1253-9

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