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Nitric oxide plays a major role in vascular tone control. Increased blood levels of bradykinin (BK), which stimulates nitric oxide biosynthesis, occur at birth. BK effects on ductus arteriosus (DA) tone were investigated in fetal rabbit under fetal (2.5% O2 "low PO2") and neonatal (30% O2 "high PO2") conditions using in vitro isometric tension studies. Intact and endothelium-denuded DA, contracted with norepinephrine (ED75-90), showed a biphasic response to BK, with relaxation at 10(-9) to 10(-7) M BK and contraction at 10(-6) to 10(-5) M BK. BK (10(-6) to 10(-5) M) contracted intact DA from baseline tension, with greater contraction under high PO2. The B2-receptor antagonist D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-BK (Hoe-140, 10(-7) M) abolished relaxation, but not contraction, to BK in intact and denuded DA. The B1-receptor antagonist des-Arg9-[Leu5]-BK (10(-7) M) reduced BK-induced contraction but not relaxation in intact DA only. Nitric oxide synthase inhibitors, N(omega)-nitro-L-arginine methyl ester (10(-4) M) and N(omega)-monomethyl-L-arginine (10(-4) M) partially inhibited relaxation to BK in intact DA, with L-arginine (3 x 10(-4) M) reversing N(omega)-monomethyl-L-arginine inhibition. N(omega)-nitro-L-arginine methyl ester (10(-4) M) caused a small but significant inhibition of relaxation to BK in denuded DA. Indomethacin (2.8 x 10(-6) M), a cyclooxygenase inhibitor, abolished relaxation but not contraction to BK in intact and denuded DA. BK-induced relaxation of the DA acts through B2-receptors, releasing both nitric oxide and prostaglandins, whereas endothelial B1-receptors may mediate contraction. BK action on isolated DA changes from relaxation to contraction as its concentration increases, with greater contraction at neonatal PO2. Thus increased BK levels at birth may aid functional closure of the DA.

Fetal patency of the ductus arteriosus is an active state maintained by the relaxant action of a prostaglandin, most probably prostaglandin E2. This PG mechanism is most active in the immature ductus and decreases toward term. The ductus closes when this prostaglandin effect if withdrawn. Indomethacin may induce closure of the patent ductus arteriosus of prematurity. It is most likely to be successful if given intravenously and early in postnatal life. Prostaglandin E1, to maintain patency of the ductus, is now established in the emergency management of several congenital heart defects causing problems in the newborn.

Pulmonary and systemic vascular effects of three stable prostaglandin (PG) I2 analogs were studied in normoxic and hypoxic conscious newborn lambs. The three agents were : (5E)-6a-carba-PGI2 (analog I); 9-deoxy-9 alpha, 6-nitrilo-PGF1 hydrochloride (analog II); and (2E,5S)-9-deoxy-5,9 alpha-epoxy-13,14-dihydro-delta 1-PGF1 (analog III). Each component was injected into either a branch pulmonary artery or the ascending aorta. Locally induced alterations in pulmonary vascular tone were assessed from changes in the ratio of blood flow to the injected lung over total flow (delta Qinj/Qt). Each compound was a systemic vasodilator, with thresholds from 1 to 3 micrograms/kg. However, analog III was without local pulmonary vasoactivity, and analog I was a pulmonary vasodilator only at the highest dose used (30 micrograms/kg) and in hypoxic lambs. Analog II, in contrast, was a pulmonary vasodilator in both hypoxic (threshold = 3 micrograms/kg) and normoxic (threshold = 10 micrograms/kg) lambs. Moreover, only analog II mimicked PGI2 during hypoxia by decreasing vascular resistance in the injected lung more than systemic resistance. These results demonstrate that PGI2 analogs are vasodilators with variable activity on the pulmonary and systemic circulations of the newborn lamb. Of the three analogs tested, only analog II resembles PGI2 in being more specific for the pulmonary as opposed to the systemic circulation. Analog II, however, is less active than PGI2 in this regard.

The effects of prostaglandins PGD2, PGE1, PGE2, PGF2 alpha, and PGI2 on pulmonary vascular tone were investigated in normoxic and hypoxic unsedated newborn lambs with chronically implanted flow probes around right and left pulmonary arteries. Prostaglandins were injected into only one pulmonary artery, and direct effects of the compounds were determined by comparing the flow changes in the injected vs. the uninjected lung. PGD2 and PGF2 alpha were direct pulmonary vasoconstrictors, whereas PGE1, PGE2 and PGI2 were direct pulmonary dilators. Hypoxia augmented the vasodilation of PGE1 and PGI2 and diminished the constriction of PGD2 and PGF2 alpha; it also lowered the threshold for PGI2-induced dilation. While the E-type prostaglandins and PGI2 were both local dilators, they differed in that the systemic dilatory effects of the E-type agents exceeded their pulmonary effects, whereas the opposite occurred with PGI2. These results demonstrate that prostaglandins can act locally on pulmonary vascular smooth muscle tone in vivo and that the level of oxygenation or base-line vascular tone influences the pulmonary vascular responses to the PGs. Among the dilator prostaglandins, PGI2 appears to be more effective on the pulmonary rather than the systemic vascular bed under hypoxic conditions.

Prostaglandin (PG) I2 and its stable metabolite, 6-keto-PGF1alpha, were tested on the isolated ductus arteriosus from mature fetal lambs. PGI2 relaxed the ductus in high doses (threshold 10(-6)M) and its activity disappeared on standing at room temperature for 30 minutes. 6-keto-PGF1alpha was inactive at all doses. By contrast, PGE2 produced a dose-dependent relaxation over a range between 10(-10) and 10(-6)M. These findings confirm that PGE2 is the most potent ductal relaxant among the known derivatives of arachidonic acid. PGE2 probably maintains ductus patency in the fetus and, together with PGE1, remains the compound of choice in the management of newborns requiring a viable ductus for survival.

We compared oxygen-related prostaglandin synthesis in fetal lamb ductus arteriosus (DA) pulmonary artery (PA) and aorta endothelial and smooth muscle cells. We measured basal synthesis of 6-keto-PGF1 alpha and PGE2, the response to calcium ionophore (A23187), a nonspecific stimulus of prostaglandin production, as well as the response to oxygen, a perinatal stimulus, monitoring both the effects of hyperoxia (95% O2) and hypoxia (2% O2). In addition, we established whether differences observed in fetal lamb PA cells related to oxygen tension were also observed in newborn central and microvessel PA cells. Our results indicate that DA endothelial cells increase 6-keto-PGF1 alpha in response to ionophore (p less than 0.05). With hyperoxia, DA endothelial cells increase PGE2 synthesis and DA smooth muscle cells increase 6-keto-PGF1 alpha (p less than 0.05 and 0.02, respectively). Aorta smooth muscle cells increase 6-keto-PGF1 alpha in response to ionophore and hyperoxia (p less than 0.003 and 0.05, respectively). PA endothelial and smooth muscle cells have higher levels of basal prostaglandin synthesis when compared with DA and aorta. In response to ionophore, increased 6-keto-PGF1 alpha is observed in both PA endothelial and smooth muscle cells (p less than 0.02 and 0.0004, respectively), and PGE2 is increased in PA smooth muscle cells (p less than 0.003). Hypoxia, however, decreases PA smooth muscle production of both 6-keto-PGF1 alpha and PGE2 (p less than 0.02 and 0.01, respectively). Similar observations were made in newborn lamb central and microvessel PA cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Several lines of evidence implicate E-type PGs in the maintenance of patency of the foetal ductus arteriosus. The PGE mechanism is functional in man, sheep, rat and rabbit, but it is seemingly absent in guinea pig. The role of the PGs in the closure of the vessel at birth is uncertain. Work with different species suggests that as PO2 rises at birth the relaxant effect of PGEs on the ductal muscle decreases. This decreased sensitivity may facilitate the oxygen triggered contraction. The calf ductus is an exception and its closure may be mediated by PGF2alpha. An important fact emerging from this review is that species may differ with regard to the occurrence and possible function of the PGs in the ductus arteriosus. The significance of these differences to the function of the oxygen-sensing mechanism remains a major question for future research.

Research in the past few years has established that prostaglandins, specially prostaglandin (PG) E2, are responsible for keeping the ductus arteriosus patent in the fetus. Another prostaglandin, PGI2, is likely involved in the pulmonary vasodilation occurring at birth. This knowledge has afford a new approach in the management of several pathological conditions of the newborn. PGE2 and structurally related PGE1 are currently in newborns with congenital heart lesions required patency of the ductus to maintain the pulmonary or systemic circulation. Conversely, inhibitors of prostaglandin synthesis are used for closing a patent ductus in the premature infant. Preliminary experience indicates that PGI2 can be useful in the treatment of pulmonary hypertensive disorders of the neonate.

Prostaglandin (PG) E2, the PG endoperoxides PGG2 and PGH2, and enzymatically generated PGI2 and thromboxane A2 (TXA2) were tested in vitro on circular strips of ductus arteriosus from mature fetal lambs. Both PGE2 and the PG endoperoxides produced a dose-dependent relaxation of the ductus at low PO2 (7-11 torr), and their action was reduced or abolished at high PO2 (410-660 torr). PGE2, however, was more potent than the endoperoxides. The reaction mixture containing PGI2 relaxed the hypoxic ductus, but this response was not due to PGI2 but to two, more stable and as yet unidentified, compounds, one of which is most certainly PGE2. TXA2 was inactive on the vessel at low and high PO2. These results confirm that PGE2 is the most effective PG acting on the ductus and provide further support to the hypothesis that this PG is responsible for patency of the vessel during fetal life. PGE2 action, however, may be complemented by that of another endoperoxide derivative formed in the PGI2 synthetic reaction which remains to be identified.