Occurrence of endothelium-derived relaxing factor – nitric oxide in the lamb ductus arteriosus
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abstract
To determine whether the ductus arteriosus can form endothelium-derived relaxing factor – nitric oxide, we used 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 (Nω-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) [Formula: see text]. 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 μM) or in full (Nω-nitro-L-arginine, 100 μM), the relaxant effect of bradykinin. Paradoxically, L-arginine (10 μM) had an inhibiting rather than an enhancing effect on the bradykinin relaxation. Nω-Nitro-L-arginine (100 μM) and methylene blue (1–100 μM) 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 antiinflammatory 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.Key words: ductus arteriosus patency and closure, endothelium-derived relaxing factor – nitric oxide, prostaglandin.
