Modulation of endothelin production and metabolism in guinea-pig tracheal epithelial cells by peptidase inhibitors.

Endothelins (ET-1, ET-2, ET-3) are potent bronchoconstrictors and growth-promoting mediators. They are released from various cells such as endothelial and epithelial cells. In the airways, ETs are released under basal and stimulated conditions. In patients with status asthmaticus and other pulmonary disorders, the expression and production of ET-1 are increased. We investigated the activities of endothelin-converting enzymes (ECE) and endothelin-degrading enzymes, mostly neutral endopeptidases (NEP), in guinea-pig tracheal epithelial cells in culture through the use of various enzyme inhibitors. We found that among ETs, only ET-1 was steadily released under basal conditions over 24 h. The basal production was attenuated by both phosphoramidon and CGS 26 303, dual NEP and ECE inhibitors. Conversely, thiorphan, a selective NEP inhibitor, did not attenuate but rather increased the concentration of ET-1 in cell supernatants. CGS 24 592 and SQ 28 603, other NEP inhibitors, also increased the concentrations of ET-1 in cell supernatants in a concentration-dependent manner. However, at a high concentration, SQ 28 603 also inhibited the basal release of ET-1, which would suggest a non-selective inhibitory activity against ECE. These data suggest that ET-1 is simultaneously produced and degraded by guinea-pig tracheal epithelial cells via phosphoramidon-sensitive ECE and NEP pathways, respectively. This observation is of interest when considering that asthmatic patients were shown to have a damaged airway epithelium combined with the loss of NEP activity, which was associated with an increased expression and production of ET-1.