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 development of airway hyperresponsiveness and airway inflammation.


OBJECTIVE
This study was designed to investigate the effects of the tachykinin NK1 receptor antagonist SR 140333 (Nolpitantium) and the NK2 receptor antagonist SR 48968 (Saredutant) on the activation of alveolar macrophages in 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 endopeptidase, 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 macrophages 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 fluids that was not reduced by pre-treatment of guinea-pigs with a single dose of SR 140333 or SR 48968 (1 mg/kg). Substance P exposure in phosphoramidon-pretreated guinea-pigs did not induce an increase in the total number of cells. In contrast, antigen or substance P exposure induced a significant increase in the in vitro fMLP-induced arachidonate release from alveolar macrophages. Pre-treatment of the guinea pigs with SR 140333 or SR 48968 did not reduce the increase in arachidonate release from fMLP-stimulated alveolar macrophages from sensitized and challenged guinea-pigs. Pre-treatment of the animals by SR 140333 and SR 48968 reduced the enhanced arachidonate release induced by fMLP from substance P-exposed guinea-pigs.


CONCLUSIONS
The present data demonstrate the importance of NK1- and NK2-receptor stimulation in the development of substance P-induced increased reactivity of alveolar macrophages.
Boichot
E
E
INSERM U456, Laboratoire de Pharmacodynamie et de Pharmacologie Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes, Rennes, France.
Germain
N
N
Emonds-Alt
X
X
Advenier
C
C
Lagente
V
V
D000818:Animals; D000941:Antigens / Q000276:immunology*; D016718:Arachidonic Acid / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology*; D018893:Bronchoalveolar Lavage; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D010450:Endopeptidases / Q000494:pharmacology; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D008262:Macrophage Activation / Q000187:drug effects*; D016676:Macrophages, Alveolar / Q000276:immunology*; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010047:Ovalbumin / Q000276:immunology; D010880:Piperidines / Q000494:pharmacology*; D011812:Quinuclidines / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000502:physiology; D013373:Substance P / Q000494:pharmacology*
D000941:Antigens; D001549:Benzamides; D006020:Glycopeptides; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; C085215:SR 140333; D016718:Arachidonic Acid; D013373:Substance P; C073839:SR 48968; D010047:Ovalbumin; D010450:Endopeptidases; C008890:phosphoramidon