Role of 5‐HT_2A, 5‐HT₄ and 5‐HT₇ receptors in the antigen‐induced airway hyperresponsiveness in guinea‐pigs

<jats:title>Summary</jats:title><jats:p><jats:bold>Background </jats:bold> A possible role of 5‐hydroxytryptamine (5‐HT) in the origin of antigen‐induced airway hyperresponsiveness (AI‐AHR) has been scarcely investigated.</jats:p><jats:p><jats:bold>Objective </jats:bold> To explore the participation of different 5‐HT receptors in the development of AI‐AHR in guinea‐pigs.</jats:p><jats:p><jats:bold>Methods </jats:bold> 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 (PD<jats:sub>200</jats:sub>). Organ bath experiments, confocal microscopy and RT‐PCR were additionally used. The 5‐HT content in lung homogenates was measured by HPLC.</jats:p><jats:p><jats:bold>Results </jats:bold> Antigenic challenge significantly decreased PD<jats:sub>200</jats:sub>, indicating the development of AI‐AHR. This hyperresponsiveness was abolished by a combination of methiothepin (5‐HT<jats:sub>1</jats:sub>/5‐HT<jats:sub>2</jats:sub>/5‐HT<jats:sub>5</jats:sub>/5‐HT<jats:sub>6</jats:sub>/5‐HT<jats:sub>7</jats:sub> receptors antagonist) and tropisetron (5‐HT<jats:sub>3</jats:sub>/5‐HT<jats:sub>4</jats:sub> antagonist). Other 5‐HT receptor antagonists showed three different patterns of response. Firstly, WAY100135 (5‐HT<jats:sub>1A</jats:sub> antagonist) and ondansetron (5‐HT<jats:sub>3</jats:sub> antagonist) did not modify the AI‐AHR. Secondly, SB269970 (5‐HT<jats:sub>7</jats:sub> antagonist), GR113808 (5‐HT<jats:sub>4</jats:sub> antagonist), tropisetron or methiothepin abolished the AI‐AHR. Thirdly, ketanserin (5‐HT<jats:sub>2A</jats:sub> 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‐HT<jats:sub>7</jats:sub> and 5‐HT<jats:sub>4</jats:sub> 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‐HT<jats:sub>2A</jats:sub> receptor mRNA levels.</jats:p><jats:p><jats:bold>Conclusions </jats:bold> Our results suggested that 5‐HT was involved in the development of AI‐AHR to ACh in guinea‐pigs. Specifically, 5‐HT<jats:sub>2A</jats:sub>, 5‐HT<jats:sub>4</jats:sub> and 5‐HT<jats:sub>7</jats:sub> 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.</jats:p><jats:p> <jats:italic>Cite this as</jats:italic>: 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, <jats:italic>Clinical & Experimental Allergy</jats:italic>, 2010 (40) 327– 338.</jats:p>