RESUMEN
We evaluated the contribution of neuropeptides to antigen-induced contractions of isolated bronchi and tracheae of passively sensitized guinea pigs using CP-96345 and SR 48968, specific antagonists of NK(1) and NK(2) receptors, respectively, in combination with treatment by an antihistaminic and a cysteinyl leukotriene antagonist. SR-48968 but not CP-96345, significantly inhibited the late phase of the bronchial contraction. Phosphoramidon, a neutral endopeptidase inhibitor, tended to potentiate bronchial contraction. Posttreatment with SR-48968 decreased the enhanced contraction induced by the inhibitor as well as the nonenhanced contraction to similar levels of tension. On the other hand, antigen-induced tracheal contraction was not altered by either neuropeptide antagonist. These results suggest that neuropeptides mediate the antigen-induced contractile response of the guinea pig bronchus partly through NK(2) receptor stimulation.
Asunto(s)
Benzamidas/farmacología , Compuestos de Bifenilo/farmacología , Bronquios/efectos de los fármacos , Broncoconstricción , Antagonistas del Receptor de Neuroquinina-1 , Neuropéptidos/efectos de los fármacos , Piperidinas/farmacología , Receptores de Neuroquinina-2/antagonistas & inhibidores , Animales , Bencenoacetamidas , Bronquios/metabolismo , Broncoconstricción/efectos de los fármacos , Femenino , Cobayas , Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de Leucotrieno/farmacología , Masculino , Neuropéptidos/metabolismo , Penicilina G/análogos & derivados , Penicilina G/farmacología , Pirilamina/farmacología , Sustancia P/antagonistas & inhibidores , Tiazoles/farmacología , Tráquea/efectos de los fármacos , Tráquea/metabolismo , gammaglobulinas/farmacologíaRESUMEN
We investigated the effects of ONO-1078, a newly synthesized peptide leukotriene (p-LT antagonist, on the specific binding of radiolabelled [3H]-LTC4, [3H]-LTD4 and [3H]-LTE4 to a human lung crude membrane fraction (HLMF). The binding assay was performed under conditions in which [3H]-LTC4 and [3H]-LTD4 were not metabolized by HLMF; that is, the metabolism of LTC4 to LTD4 or LTE4 was almost completely prevented by pretreating HLMF with 5 mM acivicin at 37 degrees C for 180 min, and metabolism of LTD4 to LTE4 was inhibited by including 5 mM L-cysteine and 5 mM glycine in the assay. [3H]-LTD4 specific binding was potently and concentration-dependently dissociated by ONO-1078. Its potency was 180-fold stronger than that of FPL 55712, a standardized p-LT antagonist, whereas high concentrations of ONO-1078 similar to those of FPL 55712 were required to inhibit [3H]-LTC4 specific binding. The rank order of the inhibitory potencies of p-LT agonists and antagonists for [3H]-LTD4 specific binding was LTD4 > ONO-1078 > LTE4 > LTC4 > FPI 55712. On the other hand, not only high concentrations of ONO-1078 and FPL 55712 but also more than a 100-fold excess of unlabelled LTE4 was required to inhibit [3H]-LTE4 specific binding, indicating that the binding sites do not appear to be receptors of LTE4. From these results, it is suggested that ONO-1078 is a highly potent LTD4 antagonist which is expected to be very effective on bronchial asthma.