Endogenous retinoic acid may play a role in inducing smooth muscle differentiation in the fetal ductus arteriosus. Maternal administration of retinoic acid may accelerate the process. This study was designed to investigate the effect of vitamin A on developmental changes in the contractile system of the ductus. Vitamin A was injected into pregnant rats and the ductus was isolated from the fetus at 19, 20, or 21 d of gestation. The fetus at 19 d of gestation served as a model of the preterm fetus. The force of contraction and [Ca] i were measured. Membrane depolarization caused by high KCl induced ductal contraction in all age groups studied. In the 19-d fetus, O 2 did not cause significant contraction or changes in [Ca] i in the control group, but it did induce a significant contraction and increases in [Ca] i in the vitamin A-treated group. In the 20-and 21-d fetuses, 5% O 2 -induced contraction in the vitamin A-treated group was significantly greater than in the control group. In the 19-d fetus, noradrenaline-induced contraction and increases in [Ca] i , indicators of the size of the intracellular Ca pool, were observed and they were similar in the control group and in the vitamin Atreated group. These data suggest that 1) in the preterm fetus, the contractile system, including membrane depolarization, [Ca]i increase, and its activation of contractile proteins, is already functioning, but the O 2 -sensing mechanism is underdeveloped, 2) vitamin A accelerates the development of the O 2 -sensing mechanism of the ductus arteriosus. The ductus arteriosus (DA) normally closes after birth. Increases in arterial PO 2 , decreases in endogenous dilator prostaglandins and nitric oxide, and/or production of endothelin-1 may be responsible for the ductal closure (1-4).Failure of the DA to close after birth is more frequent in premature than in mature infants. In full-term neonates, closure of the DA occurs in two phases after birth: 1) initial muscular constriction, and 2) neointimal thickening after mechanical closure. Both muscular constriction and neointimal thickening may be inadequate in premature neonates (5). Indomethacin, a prostaglandin synthetase inhibitor, has been used clinically to induce ductal closure, but its effect is minimal before 24 wk of gestation in humans (6, 7). In an in situ morphometric analysis in rats, showed that maternal administration of indomethacin caused only mild DA constriction at 19 d of gestation and strong constriction in the near-term fetus at 21 d of gestation. The precise mechanisms by which the DA in premature infants or animals is resistant to vasoconstrictive stimulation remain unclear. Kim et al. (11) have shown in near-term fetal rabbits that the expression of the adult type isoform of smooth muscle myosin heavy chain in the DA was more prominent than in other arteries. They suggested that vascular smooth muscle cells might be more differentiated in the DA than in other arteries. Colbert et al. (12) showed that endogenous retinoic acid signaling colocalized with advance...

The role of endothelin in oxygen-induced contraction remains controversial. The present study was designed to investigate the role of endothelin in O2-induced contraction in the isolated ductal preparation of rabbit and rat, using the endothelin receptor antagonists, bosentan (antagonist for both ET-A and ET-B receptors) and BQ 485 (an ET-A selective antagonist). The ductus was isolated from fetal rabbits at 30 days of gestation (term 31 days) and fetal rats at 21 days of gestation (term 22 days). In the rabbit ductus with intact endothelium, 13% of the O2-induced contraction was inhibited by bosentan and 14% by BQ 485. In the rabbit ductus without endothelium, bosentan did not cause significant inhibition of the oxygen-induced contraction. In the rat ductus with intact endothelium, about 44% of the O2-induced contraction was inhibited by bosentan. In the rat ductus without endothelium, O2-induced contraction was 20% less than that in the ductus with intact endothelium. In the rat ductus without endothelium, bosentan further decreased the oxygen-induced contraction by about 24%. These data suggest that (1) endothelin plays a significant role in O2-induced contraction in the isolated ductus arteriosus, (2) there is a species difference in the degree of contribution of endothelin to the O2-induced ductal contraction, and (3) there is a species difference in the degree of contribution of the endothelium and vascular smooth muscle cells to the release of endothelin from the ductus arteriosus.