Effects of SR 140333 and SR 48968 on antigen and substance P-induced activation of guinea-pig alveolar macrophages

Background Tachykinins, such as substance P, might be involved in the devel opment of airway hyperresponsiveness and airway inflammation. Objective This study was designed to investigate the effects of the tachyki nin NK1 receptor antagonist SR 140333 (Nolpitantium) and the NK2 receptor a ntagonist SR 48968 (Saredutant) on the activation of alveolar macrophages i n the guinea-pig. Methods Guinea-pigs sensitized and challenged by ovalbumin administered by aerosol or naive guinea-pigs were exposed by aerosol to the neutral endopep tidase, phosphoramidon and, 15 min later, to substance P. Twenty-four hours later, bronchoalveolar lavages were performed and the cell composition of bronchoalveolar lavage fluids and the arachidonate release from alveolar ma crophages stimulated in vitro with fMLP were evaluated. Results Antigen challenge in sensitized guinea-pigs induced an increase in the total number of cells and granulocytes in the bronchoalveolar lavage fl uids that was not reduced by pre-treatment of guinea-pigs with a single dos e of SR 140333 or SR 48968 (1 mg/kg). Substance P exposure in phosphoramido n-pretreated guinea-pigs did not induce an increase in the total number of cells. In contrast, antigen or substance P exposure induced a significant i ncrease in the in vitro fMLP-induced arachidonate release from alveolar mac rophages. Pre-treatment of the guinea pigs with SR 140333 or SR 48968 did n ot reduce the increase in arachidonate release from fMLP-stimulated alveola r macrophages from sensitized and challenged guinea-pigs. Pre-treatment of the animals by SR 140333 and SR 48968 reduced the enhanced arachidonate rel ease induced by fMLP from substance P-exposed guinea-pigs. Conclusion The present data demonstrate the importance of NK1- and NK2-rece ptor stimulation in the development of substance P-induced increased reacti vity of alveolar macrophages.