Document Detail


Cyclooxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo.
MedLine Citation:
PMID:  10848516     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents; however, they also have adverse fetal effects such as constriction of the fetal ductus arteriosus. Recently, selective COX-2 inhibitors have been used in the management of preterm labor in the hope of avoiding fetal complications. However, both COX-1 and -2 are expressed by cells of the ductus arteriosus. We used fetal lambs (0.88 gestation) to assess the ability of selective COX-2 inhibitors celecoxib and NS398 to affect the ductus arteriosus. Both selective COX-2 inhibitors decreased PGE(2) and 6ketoPGF(1alpha) production in vitro; both inhibitors constricted the isolated ductus in vitro. The nonselective COX-1/COX-2 inhibitor indomethacin produced a further reduction in PG release and an additional increase in ductus tension in vitro. We used a prodrug of celecoxib to achieve 1.4 +/- 0.6 microg/ml, mean +/- standard deviation, of the active drug in vivo. This concentration of celecoxib produced both an increase in pressure gradient and resistance across the ductus; celecoxib also decreased fetal plasma concentrations of PGE(2) and 6ketoPGF(1alpha). Indomethacin (0.7 +/- 0.2 microg/ml) produced a significantly greater fall in ductus blood flow than celecoxib and tended to have a greater effect on ductus resistence in vivo. We conclude that caution should be used when recommending COX-2 inhibitors for use in pregnant women, because COX-2 appears to play a significant role in maintaining patency of the fetal ductus arteriosus.
Authors:
Y Takahashi; C Roman; S Chemtob; M M Tse; E Lin; M A Heymann; R I Clyman
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  American journal of physiology. Regulatory, integrative and comparative physiology     Volume:  278     ISSN:  0363-6119     ISO Abbreviation:  Am. J. Physiol. Regul. Integr. Comp. Physiol.     Publication Date:  2000 Jun 
Date Detail:
Created Date:  2000-07-06     Completed Date:  2000-07-06     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  100901230     Medline TA:  Am J Physiol Regul Integr Comp Physiol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  R1496-505     Citation Subset:  IM    
Affiliation:
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94143-0544, USA.
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MeSH Terms
Descriptor/Qualifier:
6-Ketoprostaglandin F1 alpha / blood
Animals
Cyclooxygenase 1
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors / blood,  pharmacology
Dinoprostone / blood
Ductus Arteriosus / drug effects*,  enzymology*
Epoprostenol / metabolism
Female
Hemodynamics / drug effects,  physiology
Indomethacin / blood,  pharmacology
Isoenzymes / antagonists & inhibitors*,  metabolism,  pharmacology
Nitrobenzenes / pharmacology
Nitroprusside / pharmacology
Oxygen / pharmacology
Pregnancy
Prostaglandin-Endoperoxide Synthases / metabolism,  pharmacology
Pulmonary Artery / drug effects,  physiology
Pyrazoles
Sheep
Sulfonamides / blood,  pharmacology
Vasoconstriction / drug effects*
Vasodilator Agents / pharmacology
Grant Support
ID/Acronym/Agency:
HD32518/HD/NICHD NIH HHS; HL46691/HL/NHLBI NIH HHS; HL56061/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cyclooxygenase 2 Inhibitors; 0/Cyclooxygenase Inhibitors; 0/Isoenzymes; 0/Nitrobenzenes; 0/Pyrazoles; 0/Sulfonamides; 0/Vasodilator Agents; 123653-11-2/N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; 15078-28-1/Nitroprusside; 169590-42-5/celecoxib; 35121-78-9/Epoprostenol; 363-24-6/Dinoprostone; 53-86-1/Indomethacin; 58962-34-8/6-Ketoprostaglandin F1 alpha; 7782-44-7/Oxygen; EC 1.14.99.1/Cyclooxygenase 1; EC 1.14.99.1/Cyclooxygenase 2; EC 1.14.99.1/Prostaglandin-Endoperoxide Synthases

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