Effect of enkephalinase inhibitor on endothelin-1 induced bronchoconstriction in guinea pigs

Endothelin-1 (ET-1) is one of the most potent bronchoconstrictors in the guinea pig. The mechanism of its metabolism is still unclear. Phosphoramidon is known to be an enkephalinase inhibitor. We studied the effect of phosphoramidon on bronchoconstriction induced by ET-1. In the first in vitro study, a tracheal preparation was mounted in oxygenated Krebs-Ringer solution. The response was monitored by isometric transducer. Dose-response curves to ET-1 with or without phosphoramidon were obtained. Phosphoramidon potentiated ET-1 induced bronchoconstriction significantly. Next, the specific airway conductance (sGaw) was measured in conscious guinea pigs exposed to an aerosol of phosphoramidon or saline, followed by ET-1 aerosol inhalation. The ET-1 dose was increased by successively doubling the concentration. sGaw, after inhalation of phosphoramidon, was significantly reduced when exposed to ET-1. Phosphoramidon also potentiated ET-1 induced bronchoconstriction in vivo. Next, lung parenchymal tissues were prepared and placed in oxygenated Krebs-Ringer solution with or without phosphoramidon. ET-1 was added and incubated, and samples were injected into a high performance liquid chromatography column. Phosphoramidon inhibited an analysis of ET-1. These data suggest that enkephalinase plays a role in the break down of ET-1 in the airway of the guinea pig. Under the condition of decreased enkephalinase, ET-1 would potentiate bronchoconstriction.