PHOSPHORAMIDON POTENTIATES THE CONTRACTILE RESPONSE TO ENDOTHELIN-3, BUT NOT ENDOTHELIN-1 IN ISOLATED AIRWAY TISSUE

1. Phosphoramidon (10-mu-M) markedly increased the contractile respons e to endothelin-3 in human and rabbit bronchus in vitro. In human tiss ue the contractile response to 0.3-mu-M endothelin-3 was significantly increased from 54 +/- 12% to 137 +/- 34% (of the response to 1 mM ace tylcholine) in the presence of phosphoramidon. Similarly, in rabbit is olated bronchus, the endothelin-3-induced response was increased from 34 +/- 5% to 61 +/- 7%. 2. In addition, the potency (as measured by EC 30 values) of this peptide in human and rabbit airways was significant ly augmented in the presence of the enzyme inhibitor. The geometric me an EC30 value was decreased from 53 nM (95% CI:15, 190) to 8 nM (95% C I: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 respons e (at 0.3-mu-M) to endothelin-3 in canine bronchial rings was altered after incubation of the tissue in phosphoramidon. 4 A previous study c arried out in human airways has implied that the difference in potency between endothelin-1 and endothelin-3 may be attributed to a heteroge neous endothelin receptor population. The results of our study, while also demonstrating this difference in potency, have shown that this ma rked difference, as well as that obvious in rabbit airway tissue can b e abolished in the presence of phosphoramidon. 5 Phosphoramidon produc ed no change in the cumulative concentration-response curve for endoth elin-1 in airway tissue from the three species studied. 6 These result s suggest that a phosphoramidon-sensitive enzyme (probably neutral end opeptidase) found in lung, may be responsible for local degradation of endothelin-3, but not endothelin-1 in human and rabbit isolated bronc hus.