dinoprost and Ductus-Arteriosus--Patent

Prostaglandins exert a wide variety of biological actions through specific receptors. The prostaglandins PGE2 and PGF2 alpha have been suggested to affect many physiological processes. There have been four pharmacologically identified receptor subtypes, EP1 through EP4 for PGE2 and a single receptor type, FP for PGF2 alpha. However, it is yet unknown as to which receptor is involved in each process. To make this clear, we investigated the distribution of these receptors in various systems and established mice deficient in each receptor and examined their physiology. Finally, we found that these receptors are involved in several processes associated with reproduction physiology. FP-deficient mice are able to become pregnant, but cannot deliver their pups because of the lack of parturition; luteolysis does not occur normally. EP2-deficient mice are able to become pregnant, but their litter sizes are much reduced, which is due to defects in ovulation and fertilization; cumulus cell function is impaired. EP4-deficient mice die within a few days after birth because of patency of the ductus arteriosus; remodeling of cardiovascular system during birth is impaired. Thus, the E- and F-types of prostaglandins play roles in cumulus function, luteolysis and ductus closure through EP2, FP and EP4, respectively.

Topics: Animals; Dinoprost; Dinoprostone; Ductus Arteriosus, Patent; Female; Gene Deletion; Male; Mice; Pregnancy; Receptors, Prostaglandin; Receptors, Prostaglandin E; Reproduction

Increased oxygen tension at birth regulates physiologic events that are essential to postnatal survival, but the accompanying oxidative stress may also generate isoprostanes. We hypothesized that isoprostanes regulate ductus arteriosus (DA) function during postnatal vascular transition.. Isoprostanes were measured by gas chromatography-mass spectrometry. DA tone was assessed by pressure myography. Gene expression was measured by quantitative PCR.. Oxygen exposure was associated with increased 8-iso-prostaglandin (PG)F2α in newborn mouse lungs. Both 8-iso-PGE2 and 8-iso-PGF2α induced concentration-dependent constriction of the isolated term DA, which was reversed by the thromboxane A2 (TxA2) receptor antagonist SQ29548. SQ29548 pretreatment unmasked an isoprostane-induced DA dilation mediated by the EP4 PG receptor. Exposure of the preterm DA to 8-iso-PGE2 caused unexpected DA relaxation that was reversed by EP4 antagonism. In contrast, exposure to 8-iso-PGF2α caused preterm DA constriction via TxA2 receptor activation. Further investigation revealed the predominance of the TxA2 receptor at term, whereas the EP4 receptor was expressed and functionally active from mid-gestation onward.. This study identifies a novel physiological role for isoprostanes during postnatal vascular transition and provide evidence that oxidative stress may act on membrane lipids to produce vasoactive mediators that stimulate physiological DA closure at birth or induce pathological patency of the preterm DA.

Topics: Analysis of Variance; Animals; Animals, Newborn; Bridged Bicyclo Compounds, Heterocyclic; Dinoprost; Dinoprostone; Ductus Arteriosus; Ductus Arteriosus, Patent; Fatty Acids, Unsaturated; Female; Gas Chromatography-Mass Spectrometry; Gene Expression Profiling; Hydrazines; Isoprostanes; Mice; Myography; Oxidative Stress; Oxygen; Pregnancy; Premature Birth; Receptors, Prostaglandin E, EP4 Subtype; Receptors, Thromboxane A2, Prostaglandin H2; Vasodilation

The use of indomethacin in preterm newborn infants with symptomatic patent ductus arteriosus is associated with compromised renal function. Ibuprofen has been shown to be as effective as indomethacin with fewer renal side effects. We examined the hypothesis that early postnatal ibuprofen has less adverse effects on neonatal rat renal prostanoids, COX-2 expression, and angiotensin II than indomethacin. Newborn rats received IP injections of human therapeutic doses of ibuprofen or indomethacin on the first 3 days of life. Control rats were treated with equivalent volume saline. Kidneys were assessed in suckling and weanling rats for prostanoids, COX-2 expression, and angiotensin II. In suckling rats, indomethacin suppressed PGE(2) and COX-2 expression, and increased PGF(2alpha), whereas ibuprofen increased COX-2 and angiotensin II. Although both NSAIDs suppressed 6-ketoPGF(1alpha) and TxB(2) levels in suckling rats, the effect was sustained in weanling rats with indomethacin. Our findings demonstrate that indomethacin exhibits more potent suppressive effects on renal COX-2 and vasodilator prostanoids which are important regulators of renal development and function. These long-term, sustained effects may explain in part, why indomethacin exerts more severe adverse renal effects than ibuprofen, when administered during early postnatal life.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Animals; Animals, Newborn; Animals, Suckling; Cyclooxygenase 2; Dinoprost; Dinoprostone; Ductus Arteriosus, Patent; Ibuprofen; Indomethacin; Kidney; Prostaglandins; Rats; Rats, Sprague-Dawley; Stimulation, Chemical; Thromboxane B2

The inflammatory process is known to cause preterm delivery. Recently, a cyclooxygenase (COX)-2 inhibitor has been developed as an anti-inflammatory drug with few side-effects. We evaluated the COX-2 inhibitor, Celecoxib, for its tocolytic effects and side-effects on dams and pups using a lipopolysaccharide (LPS)-induced preterm delivery mouse model (preterm delivery rates; 95%). With administration of Celecoxib (50, 10, 1 and 0.3 mg/kg), the preterm labour rate was significantly reduced to 18, 30, 36 and 60% respectively. The prostaglandin F(2alpha)(PGF(2alpha)) and PGE(2) concentrations in murine uterine tissue 4 and 10 h after LPS treatment with Celecoxib (10 and 1 mg/kg) were significantly lower than those in the LPS-treated group without CELECOXIB: With administration of 10 or 100 mg/kg Celecoxib, the fetal ductus arteriosus was constricted significantly in preterm and near-term rats, although constriction rates in preterm rats were significantly lower than those in near-term rats. Reproductive and renal functions in offspring whose mothers were treated with LPS and Celecoxib were normal. These data demonstrate that Celecoxib could be used as a new therapy for preterm labour. However, careful attention to constriction of the fetal ductus arteriosus should be given.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Chorioamnionitis; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Ductus Arteriosus, Patent; Female; Interleukin-1; Interleukin-6; Isoenzymes; Lipopolysaccharides; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Models, Animal; Obstetric Labor, Premature; Pregnancy; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Wistar; Sulfonamides; Time Factors; Tocolysis; Tumor Necrosis Factor-alpha; Uterus

Our objective was to investigate whether maternal administration of prostaglandins PGE2 and PGF2(alpha) is associated with changes in fetal ductus venosus flow velocity waveforms. Second-trimester termination of pregnancy was induced in 11 women (group A) by intra-amniotic instillation of 40 mg PGF2(alpha). In group B, 19 patients received 0.5 mg PGE2 intracervically for preinduction cervical ripening. Doppler flow velocity waveforms were recorded from the fetal ductus venosus immediately before and 40-60 min after prostaglandin administration. The paired t-test was used for statistical analysis of the ductus venosus index (DVI). The mean DVI decreased after PGF2(alpha) administration from 0.62 +/- 0.12 to 0.52 +/- 0.13 (p < 0.01); and from 0.62 +/- 0.10 to 0.58 +/- 0.12 (p < 0.05) after PGE2 administration. Atrial peak velocities were significantly increased after the procedures. No significant changes were found for systolic peak velocity values. The data indicate that major changes in ductus venosus hemodynamics are induced by PGF2(alpha) and PGE2.

Topics: Abortion, Therapeutic; Blood Flow Velocity; Dinoprost; Dinoprostone; Ductus Arteriosus, Patent; Female; Fetal Blood; Hemodynamics; Humans; Injections, Intralesional; Labor, Induced; Oxytocics; Pregnancy; Ultrasonography, Prenatal

During prospective studies of indomethacin treatment of symptomatic patent ductus arteriosus, the question arose whether aminoglycosides alter renal prostaglandin metabolism. Adopting the matched-pair method, we retrospectively analyzed creatinine clearances, urine output and renal PGE2 and PGF2 alpha excretion in preterm infants with and without aminoglycosides. No consistent differences of any of these parameters within the matched pairs could be demonstrated. Indomethacin induced comparable reductions of creatinine clearances in patients with and without aminoglycoside pretreatment. Discrepancies with animal studies and clinical implications of these results are discussed.

Topics: Adult; Aminoglycosides; Anti-Bacterial Agents; Creatinine; Dinoprost; Dinoprostone; Ductus Arteriosus, Patent; Female; Humans; Indomethacin; Infant, Newborn; Infant, Premature; Pregnancy; Premedication; Prostaglandins; Prostaglandins E; Prostaglandins F; Tobramycin

Patency of the ductus arteriosus in preterm infants is mediated by vasodilating prostanoids; however, reliable methods to monitor prostanoid activity or production in preterm infants are lacking. We measured the excretion rates of major and characteristic urinary metabolites of prostacyclin (PGI2), PGE1, and PGE2, 6-keto-PGF1 alpha, and 7 alpha-hydroxy-5,11-diketotetranorprostane-1,16-dioic acid (PGE-M), respectively. Besides these parameters which reflect total body prostanoid turnover and production, the urinary levels of PGE2 and PGF2 alpha, the primary prostaglandins, were measured as an index of renal prostanoid synthesis. There were four study groups. One contained 11 thriving preterm infants; a second, six preterm infants with respiratory distress syndrome (RDS); a third, 30 preterm infants with RDS and patent ductus arteriosus (PDA); and a fourth, nine fullterm infants. All infants with RDS required artificial ventilation. There were no significant differences in PGE-M, PGE2, and PGF2 alpha excretion rates among the various groups; however, a significant increase of the 6-keto-PGF1 alpha excretion rates was observed in the groups of infants with RDS and with and without PDA (P less than 0.01 and P less than 0.02, respectively). Spontaneous (n = 2) or indomethacin-induced (n = 6) closure of PDA was associated with weaning from the respirator and a concomitant drop into the normal and subnormal range of the excretion rates of 6-keto-PGF1 alpha (P less than 0.01) and PGE-M (P less than 0.02).

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Dinoprost; Dinoprostone; Ductus Arteriosus, Patent; Female; Humans; Indomethacin; Infant, Newborn; Male; Prostaglandins E; Prostaglandins F; Prostanoic Acids; Respiration, Artificial; Respiratory Distress Syndrome, Newborn

In order to determine if prostaglandin values correlate with gestational age, birth weight, postnatal age, or respiratory distress syndrome (RDS), we determined plasma prostaglandin F2 alpha (PGF2 alpha) and prostaglandin E2 (PGE2) by specific radioimmunoassay in 34 samples from 27 preterm infants. Neither prostaglandin correlated with gestational age or with birth weight. PGF2 alpha decreased (p less than 0.3) with postnatal age. Values for PGF2 alpha and PGE2 in each sample varied together (p less than .01) but only PGF2 alpha increased (p less than .09) in infants with RDS. The highest PGF2 alpha values occurred in infants with severe RDS, including four infants with patent ductus arteriosus (PDA). In contrast, plasma PGE2 was not elevated in infants with RDS or PDA.

Topics: Age Factors; Birth Weight; Dinoprost; Dinoprostone; Ductus Arteriosus, Patent; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Prostaglandins E; Prostaglandins F; Respiratory Distress Syndrome, Newborn

The distribution of prostaglandin E2 and F2 alpha was examined in the peripheral veins and in several positions of the cardiovascular system before and after the blood had passed through the lungs in 37 infants. Prostaglandin E2 varied from 0.25 +/- 0.09 ng/ml to 0.44 +/- 0.09 ng/ml when measured in the pulmonary artery, the ductus arteriosus, the right atrium, the right ventricle, the left atrium, the left ventricle, the inferior vena cava and the descending aorta. Prostaglandin F2 alpha was much higher in these positions of the cardiovascular system. The range was 0.99 +/- 0.36 ng/ml to greater than 2.0 ng/ml. The vascular tissues produced virtually identical high amounts of prostaglandin E2 and F2 alpha, but there were no significant differences in prostaglandin E2 and F2 alpha, concentrations, in venous blood as well as in systemic arterial blood. The results suggest that prostaglandin E2 is not responsible for the persisting patency of the ductus arteriosus in infants. There is no explanation for the increased prostaglandin F2 alpha concentrations in these patients.

Topics: Aorta, Thoracic; Cardiovascular System; Child; Child, Preschool; Dinoprost; Dinoprostone; Ductus Arteriosus, Patent; Heart Atria; Heart Ventricles; Humans; Infant; Infant, Newborn; Prostaglandins E; Prostaglandins F; Pulmonary Artery; Vena Cava, Inferior