Function of cyclo-oxygenase-1 and cyclo-oxygenase-2 in the ductus arteriosus from foetal lamb: differential development and change by oxygen and endotoxin
F. Coceani et al., Function of cyclo-oxygenase-1 and cyclo-oxygenase-2 in the ductus arteriosus from foetal lamb: differential development and change by oxygen and endotoxin, BR J PHARM, 132(1), 2001, pp. 241-251
1 Prenatal patency of the ductus arteriosus is maintained mainly by prostag
landin(PG) E-2. Here we have examined the relative importance of cyclo-oxyg
enase-1 (COX1) and cyclo-oxygenase-2 (COX2) for PGE(2) formation in the foe
tal lamb ductus (0.65 gestation onwards).
2 Using fluorescence microscopy and immunogold staining, COX1 appeared more
abundant than COX2 in endothelial and smooth muscle cells, and this differ
ence was greater before-term. Inside muscle cells, COX1 and COX2 immunoreac
tivity was located primarily in the perinuclear region. Endotoxin, given to
the lamb in utero (similar to 0.1 mug kg(-1)), caused COX2 upregulation, w
hile an opposite effect with disappearance of the enzyme followed endotoxin
treatment in vitro (100 ng ml(-1)). COX1 immunoreactivity remained virtual
ly unchanged with either treatment; however, this isoform as well as any in
duced COX2 migrated towards the outer cytoplasm.
3 The COX2 inhibitor L-745,337 (1-10 muM) contracted the isolated ductus at
term, the response being almost as high as that to indomethacin (dual COX1
/COX2 inhibitor) over the same dose-range. Conversely, L-745,337 was relati
vely less effective in the premature.
4 Pretreatment of the premature in vivo with endotoxin enhanced the contrac
tion of the ductus to L-745,337, while in vitro endotoxin had a variable ef
fect.
5 The premature ductus exhibited a stronger contraction to L-745,337 follow
ing exposure to oxygen. On the other hand, the oxygen contraction, which is
modest before-term, was enhanced by L-745,337.
6 We conclude that COX1 and COX2 develop unevenly in the ductus. While both
enzymes contribute to PGE2 formation at term, COX1 is the major isoform in
the premature. COX2, however, may acquire greater importance before-term f
ollowing physiological and pathophysiological stimuli.