MODULATION OF THE EFFECT OF ATRIAL-NATRIURETIC-PEPTIDE IN HUMAN AND BOVINE BRONCHI BY PHOSPHORAMIDON

1. We have previously shown that atrial natriuretic peptide causes bro nchodilatation and reduces bronchial reactivity when administered intr avenously or by inhalation to asthmatic patients. We wished to determi ne the direct effect of exogenously applied atrial natriuretic peptide on isolated airway and the role of proteases important in atrial natr iuretic peptide degradation in other organ systems. 2. The ability of atrial natriuretic peptide (alpha-human atrial natriuretic peptide 28- amino acid) to relax precontracted tissues and to protect against meth acholine-induced contraction was studied in human and bovine tissue. T he role of neutral endopeptidase-24.11 and other proteases in regulati ng the effect of atrial natriuretic peptide on bronchial smooth muscle was also examined by studying the influence of phosphoramidon, a prot ease inhibitor, whose actions include the inhibition of neutral endope ptidase-24.11, and the protease inhibitors leupeptin, aprotinin and so ybean trypsin inhibitor on the airway response to atrial natriuretic p eptide. 3. In human and bovine tissue atrial natriuretic peptide (10(- 6) mol/l) caused a slight relaxation of methacholine-contracted tissue [mean (SEM) percentage inhibition of contraction of 13.2 (3.02)% and 9.41 (2.63)% respectively] and evoked a significant rightward shift of the cumulative concentration-response curve to methacholine [pD(2) 5. 15 (0.23) and 4.85 (0.1) compared with control values of 6.14 (0.1) an d 5.85 (0.16), respectively]. 4. Phosphoramidon potentiated atrial nat riuretic peptide-induced relaxation of methacholine-induced tone and t he ability of atrial natriuretic peptide to protect against methacholi ne-induced contraction. The combination of leupeptine, aprotinin and s oybean trypsin inhibitor did not significantly alter the bronchial res ponse to atrial natriuretic peptide in either human or bovine tissues. 5. We conclude that in human and bovine tissue, atrial natriuretic pep tide confers protection against methacholine-induced contraction and c an relax induced tone and that inhibition of phosphoramidon-sensitive protease increases these effects of atrial natriuretic peptide on airw ay smooth muscle.