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

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‐HT_1A 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‐HT_2A 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‐HT_2A 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‐HT_2A, 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.