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 grow th-promoting mediators. They are released from various cells such as e ndothelial and epithelial cells. In the airways, ETs are released unde r 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 endope ptidases (NEP), in guinea-pig tracheal epithelial cells in culture thr ough the use of various enzyme inhibitors. We found that among ETs, on ly ET-1 was steadily released under basal conditions over 24 h. The ba sal production was attenuated by both phosphoramidon and CCS 26 303, d ual NEP and ECE inhibitors. Conversely, thiorphan, a selective NEP inh ibitor, did not attenuate but rather increased the concentration of ET -1 in cell supernatants. CCS 24 592 and SQ 28 603, other NEP inhibitor s, 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 tha t ET-1 is simultaneously produced and degraded by guinea-pig tracheal epithelial cells via phosphoramidon-sensitive ECE and NEP pathways, re spectively. This observation is of interest when considering that asth matic 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.