Role of 5-HT2A, 5-HT4 and 5-HT7 receptors in the antigen-induced airway hyperresponsiveness in guinea-pigs

Authors

  • P. Segura,

    1. Departamento de Investigación en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias, México DF, México
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  • M. H. Vargas,

    1. Departamento de Investigación en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias, México DF, México
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    • *Dr Vargas and Dr Montaño contributed equally to this work.

  • G. Córdoba-Rodríguez,

    1. Departamento de Investigación en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias, México DF, México
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  • J. Chávez,

    1. Departamento de Investigación en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias, México DF, México
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  • J. L. Arreola,

    1. Departamento de Investigación en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias, México DF, México
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  • P. Campos-Bedolla,

    1. Unidad de Investigación Médica en Enfermedades Neurológicas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México DF, México
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  • V. Ruiz,

    1. Departamento de Investigación en Biología Molecular, Instituto Nacional de Enfermedades Respiratorias, México DF, México
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  • L. M. García-Hernández,

    1. Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, México DF, México
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  • C. Méndez,

    1. Departamento de Embriología, Facultad de Medicina, Universidad Nacional Autónoma de México, México DF, México
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  • L. M. Montaño

    1. Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, México DF, México
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    • *Dr Vargas and Dr Montaño contributed equally to this work.


Correspondence:
Dr Luis M. Montaño, Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, México DF, México. E-mail: lmmr@servidor.unam.mx

Summary

Background A possible role of 5-hydroxytryptamine (5-HT) in the origin of antigen-induced airway hyperresponsiveness (AI-AHR) has been scarcely investigated.

Objective To explore the participation of different 5-HT receptors in the development of AI-AHR in guinea-pigs.

Methods Lung resistance was measured in anaesthetized guinea-pigs sensitized to ovalbumin (OVA). Dose–response curves to intravenous (i.v.) acetylcholine (ACh) were performed before and 1 h after antigenic challenge and expressed as the 200% provocative dose (PD200). Organ bath experiments, confocal microscopy and RT-PCR were additionally used. The 5-HT content in lung homogenates was measured by HPLC.

Results Antigenic challenge significantly decreased PD200, indicating the development of AI-AHR. This hyperresponsiveness was abolished by a combination of methiothepin (5-HT1/5-HT2/5-HT5/5-HT6/5-HT7 receptors antagonist) and tropisetron (5-HT3/5-HT4 antagonist). Other 5-HT receptor antagonists showed three different patterns of response. Firstly, WAY100135 (5-HT1A antagonist) and ondansetron (5-HT3 antagonist) did not modify the AI-AHR. Secondly, SB269970 (5-HT7 antagonist), GR113808 (5-HT4 antagonist), tropisetron or methiothepin abolished the AI-AHR. Thirdly, ketanserin (5-HT2A antagonist) produced airway hyporresponsiveness. Animals with bilateral vagotomy did not develop AI-AHR. Experiments in tracheal rings showed that pre-incubation with LP44 or cisapride (agonists of 5-HT7 and 5-HT4 receptors, respectively) induced a significant increase of the cholinergic contractile response to the electrical field stimulation. In sensitized lung parenchyma strips, ketanserin diminished the contractile responses to ACh. Sensitization was associated with a ninefold increase in the 5-HT content of lung homogenates. Confocal microscopy showed that sensitization enhanced the immunolabelling and co-localization of nicotinic receptor and 5-HT in airway epithelium, probably located in pulmonary neuroendocrine cells (PNECs). RT-PCR demonstrated that neither sensitization nor antigen challenge modified the 5-HT2A receptor mRNA levels.

Conclusions Our results suggested that 5-HT was involved in the development of AI-AHR to ACh in guinea-pigs. Specifically, 5-HT2A, 5-HT4 and 5-HT7 receptors seem to be particularly involved in this phenomenon. Participation of 5-HT might probably be favoured by the enhancement of the PNECs 5-HT content observed after sensitization.

Cite this as: P. Segura, M. H. Vargas, G. Córdoba-Rodríguez, J. Chávez, J. L. Arreola, P. Campos-Bedolla, V. Ruiz, L. M. García-Hernández, C. Méndez and L. M. Montaño, Clinical & Experimental Allergy, 2010 (40) 327– 338.

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