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

To determine whether the ductus arteriosus can form endothelium-derived relaxing factor - nitric oxide, we use isolated ductal strips from near-term fetal lamb and examined their response to bradykinin (a nitric 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 = 133.3 Pa) than low (15-25 mmHg) PO2. Bradykinin relaxation was nearly completely or completely abolished in endothelium-denuded preparations and, in its place, there was often a small contraction. Pretreatment with nitric oxide inhibitors also prevented. in part (methylene blue, 1 muM) or in full (N(omega)-nitro-L-arginine, 100 muM), the relaxant effect of bradykinin. Paradoxically, L-arginine (10 muM) had an inhibiting rather than an enhancing effect on the bradykinin relaxation. N(omega)-Nitro-L-arginine (100 muM) and methylene blue (1 - 100 muM) contracted by themselves the untreated ductus, and their action persisted after removal of the endothelium. These findings indicate the presence in the ductus arteriosus of a nitric oxide based relaxing mechanism, which may supplement prostaglandin E2 in keeping the vessel patent in the fetus. This mechanism may, on one hand, afford protection against nonsteroidal anti-inflammatory drugs in utero and may, on the other hand, complicate the management of prematures with persistent ductus and account for failures of the indomethacin therapy.