Indomethacin promotes nitric oxide function in the ductus arteriosus in the mouse.
OBJECTIVE
Prenatal patency of ductus arteriosus is maintained by prostaglandin (PG) E(2) in concert with nitric oxide (NO) and carbon monoxide (CO). Accordingly, we have previously found that NO activity increases upon deletion of either COX. Here, we have examined whether COX inhibition by indomethacin mimics COX deletion in promoting NO.


METHODS
Experiments were performed in vitro and in vivo with wild-type (WT) and eNOS-/-, near-term mouse foetuses. Indomethacin was given p.o. to the mother as single (acute treatment) or repeated (daily for 3 days; chronic treatment) doses within a therapeutic range (2 mg kg(-1)).


RESULTS
Indomethacin promoted eNOS mRNA expression in the WT ductus. Coincidentally, the drug enhanced the contraction of the isolated ductus to the NOS inhibitor, N(G)-nitro-L-arginine methyl ester, and its effect augmented with the length of treatment. No such enhancement was seen with the eNOS-/- ductus. Chronic indomethacin also increased, albeit marginally, the contraction of the WT ductus to the CO synthesis inhibitor, zinc protoporphyrin. Whether given acutely or chronically, indomethacin induced a little narrowing of the ductus antenatally and had no effect on postnatal closure of the vessel.


CONCLUSIONS
We conclude that activation of NO and, to a much lesser degree, CO mechanisms is an integral part of the indomethacin effect on the ductus. This relaxing influence may oppose the contraction from PGE(2) suppression and could explain the failures of indomethacin therapy in premature infants with persistent duct.
Sodini
D
D
Scuola Superiore Sant'Anna, Pisa, Italy.
Baragatti
B
B
Barogi
S
S
Laubach
V E
VE
Coceani
F
F
D000284:Administration, Oral; D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004334:Drug Administration Schedule; D004373:Ductus Arteriosus / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology*; D018811:Maternal Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects* / Q000235:genetics; D011247:Pregnancy; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D012333:RNA, Messenger; D009569:Nitric Oxide; D002248:Carbon Monoxide; D052250:Nitric Oxide Synthase Type III; D015232:Dinoprostone; D007213:Indomethacin