Responsiveness of the lamb ductus arteriosus to prostaglandins and their metabolites

The relative potencies of the prostaglandins A1, A2, E1, E2, F2alpha and their 15-keto-, 15-keto-13,14-dihydro-, and 13,14-dihydro-metabolites were investigated on isolated lamb ductus arteriosus preparations contracted by exposure to elevated PO2. All the prostaglandins (except PGF2alpha and its 15-keto-metabolites) relaxed the tissue. However, only PGE1, E2, and their 13,14-dihydro-metabolites, were effective at concentrations below 10(-8) M. Therefore, events that alter metabolism of circulating PGs in the perinatal period may have significant effects on the relative patency or closure of the ductus arteriosus.     

Responsiveness of the lamb ductus arteriosus to prostaglandins and their metabolites

The relative potencies of the prostaglandins A₁, A₂, E₁, E₂, F_2α and their 15-keto-, 15-keto-13,14-dihydro-, and 13,14-dihydro-metabolites were investigated on isolated lamb ductus arteriosus preparations contracted by exposure to elevated PO₂. All the prostaglandins (except PGF_2α and its 15-keto-metabolites) relaxed the tissue. However, only PGE₁, E₂, and their 13,14-dihydro-metabolites, were effective at concentrations below 10⁻⁸ M. Therefore, events that alter metabolism of circulating PGs in the perinatal period may have significant effects on the relative patency or closure of the ductus arteriosus.     

Synthesis of prostaglandins by the ductus arteriosus of the bovine fetus

Previous studies demonstrated that prostaglandins are local or tissue hormones which can be released from blood vessel walls. In the present study, we investigated the capacity of bovine ductus arteriosus to synthetize prostaglandins in vitro. After incubation of slices of ductus arteriosus in Krebs' solution with (1-14C) arachidonic acid for 3 hours, more than 40% of the radiolabeled material recovered from the incubating medium were metabolites of arachidonic acid. The major product was indistinguishable from 6 keto-PGF1alpha as determined by its chromatographic motility and resistance to alkaline conversion to PGB. The PGI2 synthetic capacity of the ductus arteriosus, as revealed by the predominance of its major metabolite 6 keto-PGF1alpha, suggests that this metabolic pathway of arachidonic acid may contribute to the hemodynamic changes occurring during fetal life and at birth.     

Synthesis of prostaglandins by the ductus arteriosus of the bovine fetus

Previous studies demonstrated that prostaglandins are local or tissue hormones which can be released from blood vessel walls. In the present study, we investigated the capacity of bovine ductus arteriosus to synthetize prostaglandins . After incubation of slices of ductus arteriousus in Krebs' solution with (1-¹⁴C) arachidonic acid for 3 hours, more than 40% of the radiolabeled material recovered from the incubating medium were metabolites of arachidonic acid. The major product was indistinguisable from 6 keto-PGF_1α as determined by its chromatographic mobility and resistance to alkaline conversion to PGB.The PGI₂ synthetic capacity of the ductus arteriosus, as revealed by the predominance of its major metabolite 6 keto-PGF_1α, suggests that this metabolic pathway of arachidonic acid may contribute to the hemodynamic changes occurring during fetal life and at birth.     

Percutaneous closure of an adult patent ductus arteriosus

A 23-year-old asymptomatic male was referred to our outpatient clinic because of an incidentally discovered grade III continuous machinery murmur at the third intercostal space on the left sternal edge. The echocardiography showed the presence of a patent ductus arteriosus (PDA).     

DuctOcclud--implant for transcatheter closure of patent ductus arteriosus.

The DuctOcclud implant is a metal coil device designed for transcatheter closure of small to moderate size patent ductus arteriosus, a Congenital Heart Disease in which a vessel-like communication between the aorta and the pulmonary artery persists after birth. The paper describes the design of the device, its delivery system, and the implant procedure. It also reviews and reports the experimental and the clinical experiences accumulated utilizing the device for occlusion of patent ductus arteriosus.     

Anatomical closure of the ductus arteriosus in the dog (Canis familiaris).

The ductus arteriosus was studied in 138 dogs (80 female and 58 male) aged from 6 h to 21 days. This experiment led us to conclude that the anatomical closure of the d. arteriosus starts within 96 h and is obliterated after 6 days in 100% of the animals studied. We have also evidenced that the closure starts in the medial part of the d. arteriosus and progresses to the pulmonary artery and aorta.     

Differential temporal and spatial progerin expression during closure of the ductus arteriosus in neonates

Closure of the ductus arteriosus (DA) at birth is essential for the transition from fetal to postnatal life. Before birth the DA bypasses the uninflated lungs by shunting blood from the pulmonary trunk into the systemic circulation. The molecular mechanism underlying DA closure and degeneration has not been fully elucidated, but is associated with apoptosis and cytolytic necrosis in the inner media and intima. We detected features of histology during DA degeneration that are comparable to Hutchinson Gilford Progeria syndrome and ageing. Immunohistochemistry on human fetal and neonatal DA, and aorta showed that lamin A/C was expressed in all layers of the vessel wall. As a novel finding we report that progerin, a splicing variant of lamin A/C was expressed almost selectively in the normal closing neonatal DA, from which we hypothesized that progerin is involved in DA closure. Progerin was detected in 16.2%±7.2 cells of the DA. Progerin-expressing cells were predominantly located in intima and inner media where cytolytic necrosis accompanied by apoptosis will develop. Concomitantly we found loss of α-smooth muscle actin as well as reduced lamin A/C expression compared to the fetal and non-closing DA. In cells of the adjacent aorta, that remains patent, progerin expression was only sporadically detected in 2.5%±1.5 of the cells. Data were substantiated by the detection of mRNA of progerin in the neonatal DA but not in the aorta, by PCR and sequencing analysis. The fetal DA and the non-closing persistent DA did not present with progerin expressing cells. Our analysis revealed that the spatiotemporal expression of lamin A/C and progerin in the neonatal DA was mutually exclusive. We suggest that activation of LMNA alternative splicing is involved in vascular remodeling in the circulatory system during normal neonatal DA closure.     

Effect of the administration of prostaglandins (PGE2) in the early postnatal period on closure of the ductus arteriosus in the laboratory rat

Maintenance of a patent ductus arteriosus by means of prostaglandins enables the surgical correction of a congenital heart defect in infants to be postponed until a phase of development when the operation hazards are smaller. We investigated the pathophysiological consequences of this therapeutic measure in an experimental model in which E2 prostaglandin was administered to newborn laboratory rats. It was found that, physiologically, the ductus arteriosus (DA) closed progressively within 180 min after birth. The repeated administration of PGE2 (subcutaneously, 15 micrograms.kg-1 every 30 min from the 5th min after birth) blocked closure of the DA, which was still fully patent 300 min after birth. Histological tests showed no significant differences in the structure of the tunica media of the physiologically patent and the PGE2-treated DA. The results show that PGE2 also inhibit physiological closure of the DA in newborn rats. Long-term study of this pathophysiological process is at present impeded by the need for the continuous administration of prostaglandins.     

Studies on closure of the ductus arteriosus. X. effect of prostaglandin

The effect of prostaglandins F_2∝, E₁ and of 7-oxa-13-prostynoic acid on the newborn rat and rabbit ductus can be studied using the whole-body freezing technique. PGF_2∝ and PGE₁ were able to re-open the closing ductus arteriosus in adequately oxygenated animals. PGF_2∝ administration was accompanied by a strong physical reaction in the rat but less in the rabbit. PGF₁ had sedative effects in both animals. A prostaglandin antagonist, 7-oxa-13-prostynoic acid had no effect on normal ductal closure nor did it counteract the effects of PGF_2∝ and PGE₁. The role of prostaglandins in homeostasis during the fetal and newborn period may be to modify ductal tone.     

Studies on closure of the ductus arteriosus. XI. Ductal closure by a prostaglandin synthetase inhibitor

Intrauterine contraction of the ductus arteriosus in fetuses followed a single oral dose of 15 mg/kg indomethacin to pregnant rats 12 or 18 h prior to delivery. This ductal contraction studied by the whole-body freezing technique was markedly pronounced up to 30 min after delivery. Blood gas measurements showed a low pH at 30 min which returned to normal at 120 min. Cyanosis was persistant in the indomethacin groups. Intrauterine ductal closure may be a danger to the fetus and subsequent postnatal adjustment. The present results need confirmation in other species to predict a similar risk in the human fetus.     

The effects of prostaglandins, prostaglandin inhibitors, and oxygen on the closure of the ductus arteriosus, pulmonary arteries and umbilical vessels in vitro

Three prostaglandins (PGF₂α and PGE₁, PGE₂) have been found in maternal and fetal circulation during labour. Two of these prostaglandins (PGF₂α and PGE₂) are present in elevated levels in maternal circulation during labour and their presence in fetal vessels has been shown.These three prostaglandins have been tested for their effects on fetal vessels in vitro (umbilical artery and vein, ductus arteriosus, and smaller pulmonary artery). These vessels were selected as being crucial in the conversion from fetal to extra-uterine circulation in mammalian species. Responses of these vessels to the prostaglandins under varying oxygen regimes have been examined as well as their responses to prostaglandin inhibitors. Activity of vessels of varying gestational ages exposed to PGF₂α was also examined. The following results were obtained:

1. All vessels, with the exception of pulmonary arteries, contracted in the presence of oxygen over the range 20–100mmHg pO₂. At a pO₂ of < 20mmHg the ductus arteriosus remained inactive or dilated. Pulmonary arteries dilated at high pO₂.

2. All vessels contracted in response to exogenous PGF₂α with the exception of the pulmonary arteries which dilated. In the presence of PGF₂α, the umbilical veins dilated under low (< 20mmHg) pO₂ and contracted at higher levels. Contraction also occurred at lower levels after a period of time.

3. Although PGF₂α was capable of causing contraction in the ductus arteriosus at near zero pO₂, oxygen, (or possibly the products of oxygenation), appear to be required for continued contraction in the presence of PGF₂α. A synergistic relationship between oxygen and PGF₂α responses was found as oxygen tensions increased. A synergistic response between PGF₂α and oxygen with umbilical arteries which did not increase with increased pO₂ was also found. Oxygen tension appeared to have little effect on the response of other vessels to PGF₂α.

4. PGE₁ caused dilations in all vessels examined. Such dilations appearing to be independent of the oxygen regime prevailing. However, an increase in oxygen during experiments reversed any dilation caused by the prostaglandins.

5. PGE₂ caused contractions in umbilical vessels which were independent of oxygen. PGE₂ caused contraction of pulmonary arteries. However, in the ductus arteriosus, PGE₂ caused an initial contraction followed by a strong dilation. This dilation became weaker as pO₂ increased.

6. Additions of prostaglandin inhibitors (Naproxen and Indomethacin) to the bathing solution in which the ductus arteriosus and umbilical arteries were contracting (in response to PGF₂α, or oxygen alone) caused a decrease in contractions, and sometimes a slight decrease when the vessel had been pretreated with PGF₂α suggesting a possible need for endogenously synthesised prostaglandins for the maintenance of oxygen mediated contractions (in vivo).

7. Vessels responsed to PGF₂α at an early gestational age. A role for prostaglandins and oxygen in the closure of fetal vessels is discussed.

     

Evidence for an effector role of endothelin in closure of the ductus arteriosus at birth.

The ductus arteriosus is a special muscular shunt that in the fetus allows blood to bypass the unexpanded lungs. It closes rapidly after birth and this event is initiated by the physiologic rise in blood oxygen tension. Endothelin-1 has been proposed by us as a local mediator for oxygen after demonstrating that it is formed within the ductus and is a potent ductus constrictor. To confirm this possibility, we have now measured the release of endothelin-1 from the isolated ductus of near-term fetal lambs at different oxygen concentrations of the medium. In addition, using the same preparation, we have examined the effect on contractile tone of compounds interfering with the synthesis (phosphoramidon, 50 microM) and action (BQ123, 1 microM) of endothelin-1. We report that release of endothelin-1 from the ductus tends to increase with the oxygen concentration up to a value mimicking the neonatal condition. Phosphoramidon and, to a greater degree, BQ123 inhibit the contraction of the vessel to oxygen. These results implicate endothelin-1 as the effector agent for oxygen in the ductus and, by extension, assign to this peptide a critical role in the closure of the vessel at birth.