Endothelin‐induced constriction of the ductus venosus in fetal sheep: developmental aspects and possible interaction with vasodilatory prostaglandin

The ductus venosus is actively regulated in the fetus, but questions remain on the presence of a functional sphincter at its inlet. Using fetal sheep (0.6–0.7 gestation onwards), we have examined the morphology of the vessel and have also determined whether endothelin‐1 (ET‐1) qualifies as a natural constrictor being modulated by prostaglandins (PGs). Masson's staining and α‐actin immunohistochemistry showed a muscular, sphincter‐like formation at the ductus inlet and a muscle layer within the wall of the vessel proper. This muscle cell component increased with age. ET‐1 contracted dose‐dependently isolated sphincter and extrasphincter preparations of the ductus from term fetus. This ET‐1 effect also occurred in the premature, but its threshold was higher. BQ123 (1 μM) caused a rightward shift in the ET‐1 dose–response curve, while indomethacin at a threshold concentration (28 nM) tended to have an opposite effect. Big ET‐1 also contracted the ductus sphincter but differed from ET‐1 for its lesser potency and inhibition by phosphoramidon (50 μM). The ductus sphincter (term and preterm) and extrasphincter (term) released 6‐keto‐PGF1α (hence PGI2) and, to a lesser degree, PGE2 at rest and their release increased dose‐dependently upon ET‐1 treatment. Both basal and stimulated release was curtailed by endothelium removal. BQ123 and phosphoramidon reduced slightly the contraction of ductus sphincter to indomethacin (2.8 μM). We conclude that the ductus contains a contractile mechanism in the sphincter and extrasphincter regions. ET‐1 lends itself to a role in the generation of contractile tone and its action may be modulated by prostaglandins. British Journal of Pharmacology (2004) 142, 727–736. doi:10.1038/sj.bjp.0705849