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.
Research Institute, Hospital for Sick Children, Toronto, ON, Canada.
F
F
Coceani
L
L
Kelsey
E
E
Seidlitz
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