INHIBITION OF NEUTRAL ENDOPEPTIDASE POTENTIATES BRONCHIAL CONTRACTION INDUCED BY IMMUNE-RESPONSE IN GUINEA-PIGS INVITRO

To study the role of tachykinins and neutral endopeptidase (NEP), an enzyme that degrades tachykinins, in the immune response in the airways of guinea pigs sensitized to ovalbumin (OVA), we examined the bronchial contractile response to OVA by inhibiting NEP in vitro. After incubating bronchial tissues with the NEP inhibitors phosphoramidon and thiorphan, we added 10(-5)% (10-mu-g/ml) OVA. Phosphoramidon and thiorphan (10(-5) M) significantly maintained the contraction that followed the peak contraction. In the next stages of the experiment, when the contraction induced by 10(-5)% OVA reached a plateau and began to relax, we added 10(-5) M phosphoramidon. Phosphoramidon inhibited the relaxation and significantly potentiated the contraction. In tissues treated with 10(-5) M capsaicin to deplete tachykinins, phosphoramidon did not potentiate the OVA-induced contraction, but substance P (10(-6) M) caused contraction. These results suggest that the immune response causes the release of tachykinin-like substances from capsaicin-sensitive nerves to induce bronchial contraction in part. To confirm the mediators that cause the release of the tachykinin-like substances from the bronchus, we also examined whether phosphoramidon potentiates the effect of leukotriene C4 (LTC4), serotonin, histamine, and platelet-activating factor on bronchial contraction. When the contractions induced by these agonists reached a plateau and began to relax, we added phosphoramidon. Phosphoramidon inhibited the relaxation and significantly potentiated the contractile response to 10(-5) M LTC4, and it significantly reduced the relaxing rate of the 10(-6) M serotonin-induced contraction. However, it did not change the effect of histamine and platelet-activating factor. From these results, we conclude that (1) some chemical mediators released by the immune response stimulate the release of tachykinin-like substances, (2) NEP plays an important role in modulating the bronchial contraction induced by substances in the immune response, and (3) LTC4 and serotonin are chemical mediators that release these substances.