OCCURRENCE OF ENDOTHELIUM-DERIVED RELAXING FACTOR - NITRIC-OXIDE IN THE LAMB DUCTUS-ARTERIOSUS

To determine whether the ductus arteriosus can form endothelium-derive d relaxing factor - nitric oxide, we use isolated ductal strips from n ear-term fetal lamb and examined their response to bradykinin (a nitri c oxide stimulator), L-arginine (a nitric oxide precursor), and agents interfering with the synthesis (N(omega)-nitro-L-arginine) and action (methylene blue) of nitric oxide. Bradykinin relaxed the indomethacin -contracted ductus dose dependently from a threshold of about 10(-10)) M, and peak relaxation was greater at high (176-210 mmHg; 1 mmHg = 13 3.3 Pa) than low (15-25 mmHg) PO2. Bradykinin relaxation was nearly co mpletely or completely abolished in endothelium-denuded preparations a nd, in its place, there was often a small contraction. Pretreatment wi th nitric oxide inhibitors also prevented. in part (methylene blue, 1 muM) or in full (N(omega)-nitro-L-arginine, 100 muM), the relaxant eff ect of bradykinin. Paradoxically, L-arginine (10 muM) had an inhibitin g rather than an enhancing effect on the bradykinin relaxation. N(omeg a)-Nitro-L-arginine (100 muM) and methylene blue (1 - 100 muM) contrac ted by themselves the untreated ductus, and their action persisted aft er removal of the endothelium. These findings indicate the presence in the ductus arteriosus of a nitric oxide based relaxing mechanism, whi ch may supplement prostaglandin E2 in keeping the vessel patent in the fetus. This mechanism may, on one hand, afford protection against non steroidal anti-inflammatory drugs in utero and may, on the other hand, complicate the management of prematures with persistent ductus and ac count for failures of the indomethacin therapy.