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

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 resistanc...

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Veröffentlicht in:Clinical and experimental allergy 2010-02, Vol.40 (2), p.327-338
Hauptverfasser: Segura, P., Vargas, M. H., Córdoba-Rodríguez, G., Chávez, J., Arreola, J. L., Campos-Bedolla, P., Ruiz, V., García-Hernández, L. M., Méndez, C., Montaño, L. M.
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Zusammenfassung: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,
ISSN:0954-7894
1365-2222
DOI:10.1111/j.1365-2222.2009.03412.x