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 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 (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 microM) or in full (N omega-nitro-L-arginine, 100 microM), the relaxant effect of bradykinin. Paradoxically, L-arginine (10 microM) had an inhibiting rather than an enhancing effect on the bradykinin relaxation. N omega-Nitro-L-arginine (100 microM) and methylene blue (1-100 microM) 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.
Coceani
F
F
Research Institute, Hospital for Sick Children, Toronto, ON, Canada.
Kelsey
L
L
Seidlitz
E
E
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001920:Bradykinin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004373:Ductus Arteriosus / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D005333:Fetus / Q000378:metabolism; D007213:Indomethacin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008751:Methylene Blue / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009129:Muscle Tonus / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011247:Pregnancy; D012756:Sheep
D009569:Nitric Oxide; D001120:Arginine; D001920:Bradykinin; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin