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Effects of various prostaglandin types on strips of lamb ductus arteriosus were investigated under anaerobic and aerobic conditions. Prostaglandins E1 and E2 relaxed markedly the anoxic ductus over a dose range from 10−9 to 10−5 M whereas they had little or no effect on the tissue after exposure to oxygen. This is in contrast to papaverine which relaxed the ductus to a similar degree before and after exposure to oxygen. An additional finding was that prostaglandins E1 and E2 are less active on the anoxic tissue depolarized by excess potassium. The greater effectiveness of prostaglandins on the anoxic ductus suggests a role for these compounds in the regulation of the vessel tone during fetal life.

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A method was developed for recording isometric tension from isolated small arteries (mean internal diameter, 169 microns) and veins (mean internal diameter, 273 microns) of the term fetal lung and was then applied to the study of the mechanisms controlling perinatal pulmonary hemodynamics. The specific purpose was to determine whether the activity of the prostaglandin synthetic system in vessels is conditioned by the oxygen tension and the mode of action of endothelin-1. Both preparations appeared structurally intact and, after normalizing their lumen diameter to either the transmural pressure in vivo (artery) or the contractile capacity of the vessel in vitro (vein), generated force to the activating solution (5 mM Ca2+ in K+ Krebs' solution) in excess of the expected performance under physiological conditions. Treatment with indomethacin (2.8 microM) had no effect on arteries preequilibrated at low PO2 (21 +/- 1 mm Hg); however, the same treatment contracted (approximately 45% of the response to activating solution) arteries at either an intermediate (40 +/- 0.8 mm Hg) or high (70 +/- 0.9 mm Hg) PO2. Endothelin-1 contracted both arteries and veins in a concentration-dependent manner, the threshold being lower with veins (1-10 versus 10-100 pM). Endothelin-1 constriction was also seen in arteries whose tone had been raised with a thromboxane A2 analogue, whereas in thromboxane-treated veins constriction was preceded by a modest relaxation over the range of 1-1,000 pM. The findings with indomethacin lead us to infer that small pulmonary arteries are endowed with a prostaglandin-relaxing mechanism that becomes functional on raising the PO2 from fetal to neonatal levels. Endothelin-1 is a constrictor regardless of the level of intrinsic tone, suggesting a possible role of the peptide in maintaining elevated pulmonary vascular tone in the fetus.

In vitro and in vivo techniques were developed with genetically modified mice to determine whether endothelin-1 (ET-1) functions as an O(2) mediator in closure of the ductus arteriosus (DA) at birth. Wild-type CD-1 and 129/SvEv mice with ET(A) receptor -/-, +/-, and +/+ genotypes were used. Isolated DA from term ET(A) +/+ fetuses contracted to O(2) (5-95%) and a thromboxane A(2) analog (ONO-11113, 0.1 microM). Instead, ET-1 elicited a dual response with weak relaxation (0.1 nM) preceding contraction (1-100 nM). Indomethacin (2.8 microM) was also a constrictor. ET(A) -/- DA, unlike ET(A) +/+ DA, contracted marginally to O(2) and ET-1 but responded to ONO-11113. O(2) contraction was also reduced in ET(A) +/- DA. In vivo, DA constricted equally in tracheotomized ET(A) -/- and ET(A) +/+ newborns. Conversely, no DA constriction was seen in hyperoxic ET(A) -/- fetuses in utero, although it occurred in ET(A) +/+ and +/- littermates. We conclude that ET-1 mediates the DA constrictor response to O(2). Without ET-1, however, the vessel still closes postnatally, conceivably caused by the withdrawal of relaxing influence(s).