Phosphoramidon potentiates the contractile response to endothelin-3, but not endothelin-1 in isolated airway tissue.

1. Phosphoramidon (10 microM) markedly increased the contractile response to endothelin-3 in human and rabbit bronchus in vitro. In human tissue the contractile response to 0.3 microM endothelin-3 was significantly increased from 54 +/- 12% to 137 +/- 34% (of the response to 1 nM acetylcholine) in the presence of phosphoramidon. Similarly, in rabbit isolated bronchus, the endothelin-3-induced response was increased from 34 +/- 5% to 61 +/- 7%. 2. In addition, the potency (as measured by EC30 values) of this peptide in human and rabbit airways was significantly augmented in the presence of the enzyme inhibitor. The geometric mean EC30 value was decreased from 53 nM (95% CI:15, 190) to 8 nM (95% CI:3, 23) in human bronchus and from 150 nM (95% CI:89, 250) to 23 nM (95% CI:11, 50) in rabbit tissue. 3. Neither the potency nor the response (at 0.3 microM) to endothelin-3 in canine bronchial rings was altered after incubation of the tissue in phosphoramidon. 4. A previous study carried out in human airways has implied that the difference in potency between endothelin-1 and endothelin-3 may be attributed to a heterogeneous endothelin receptor population. The results of our study, while also demonstrating this difference in potency, have shown that this marked difference, as well as that obvious in rabbit airway tissue can be abolished in the presence of phosphoramidon. 5. Phosphoramidon produced no change in the cumulative concentration-response curve for endothelin-1 in airway tissue from the three species studied. 6. These results suggest that a phosphoramidon-sensitive enzyme (probably neutral endopeptidase) found in lung, may be responsible for local degradation of endothelin-3, but not endothelin-l in human and rabbit isolated bronchus.