Neutral endopeptidase inhibitor potentiates allergic bronchoconstriction in guinea pigs in vivo

To determine whether endogenous tachykinins are released in allergic airway response to contribute to bronchoconstriction and whether neutral endopeptidase (NEP), which effectively cleaves tachykinins, modulates that bronchoconstriction, we studied the effects of the NEP inhibitor phosphoramidon on bronchoconstriction induced by allergic response in anesthetized guinea pigs. We mechanically ventilated the guinea pigs sensitized with ovalbumin (OVA) in a bodyplethysmograph and measured the pulmonary resistance (RL). We exposed the sensitized guinea pigs to doubling concentrations of OVA aerosols from 2(-5)% (wt/vol) until the transpulmonary pressure increased more than twofold from the baseline. After the final exposure, we exposed them to phosphoramidon (10(-4) M) or its vehicle. Phosphoramidon significantly potentiated the increased RL induced by OVA challenge. Phosphoramidon also significantly potentiated the increased RL in the guinea pigs treated with atropine, but the potentiation was significantly reduced. In contrast, phosphoramidon failed to potentiate the increased RL induced by OVA in guinea pigs pretreated with capsaicin. These results suggest that 1) endogenous tachykinin-like substances are released in allergic airway response and that 2) when endogenous NEP is inhibited in the guinea pig airways in vivo, the substances contribute to bronchoconstriction by partly activating the parasympathetic nerve.