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Effects of phosphodiesterase 5 inhibitor on pulmonary vascular reactivity in the fetal lamb
S132 SMFM Abstracts 456
CHANGES IN AQUAPORIN 1 EXPRESSION AFFECT AMNIOTIC FLUID VOLUME STEPHANIE MANN1, NATALIA DVORAK2, ROBERT TAYLOR2, 1Phoenix Integrated Residency in Ob/Gyn, Obstetrics and Gynecology, Phoenix, Arizona, 2 University of California, San Francisco, Obstetrics, Gynecology and Reproductive Sciences, San Francisco, California OBJECTIVE: Recent work from our laboratory has demonstrated the presence of aquaporin (AQP) water channels in fetal membranes from pregnancies with normal amniotic fluid (AF) volume. The objective of this study was to investigate changes in AQP 1 mRNA expression from fetal membranes of pregnancies with polyhydramnios and oligohydramnios. STUDY DESIGN: Placentas from term pregnancies (37-40 wks) were collected from women who presented with intact membranes and one of the following: (1) idiopathic oligohydramnios (AFI !5.0 cm); (2) polyhydramnios (AFI >24.0 cm); and (3) normal amount AF (AFI >5.0 cm and !24.0 cm). The membranes (amnion and chorion) directly overlying the placenta and the free floating reflected membranes were sampled (total of four samples from each placenta). RNA was isolated from the amnion and chorion of each region. Quantitative RT-PCR was used to compare expression of AQP1 mRNA in the membranes collected from the above pregnancies. Statistical analysis was performed with a t test. P ! .05 was considered signficant. RESULTS: As shown in the figure, AQP1 mRNA expression is increased in the reflected amnion from pregnancies with idiopathic polyhydramnios and decreased in the reflected amnion and chorion from pregnancies with oligohydramnios. CONCLUSION: The expression of the water channel AQP1 is altered in the reflected fetal membranes. These results suggests that there is an adaptive response by the fetal membranes in situations of either decreased or increased AF volume to prevent excessive loss or accumulation of fluid, respectively. We speculate that therapies focused on regulating AQP1 expression may be useful for treating oligohydramnios and polyhydramnios.
458
PERINATAL GLUCOSE TOLERANCE AFTER INTRAUTERINE GROWTH RESTRICTION IN THE LATE-GESTATION OVINE FETUS PHILIPPE DERUELLE1, IVA GUEORGUIEVA2, BERENGERE SICOT DE JENLIS3, SOPHIE JAILLARD4, JACQUES WEILL2, VERONIQUE DEBARGE4, LAURENT STORME4, 1CHRU de Lille, Lille, France, 2 CHRU de Lille, Pediatric endocrinology unit, Lille, France, 3CHRU de Lille, Department of perinatology, Lille, France, 4CHRU de Lille, France, Department of perinatology, Lille, France OBJECTIVE: Newborns with Intrauterine-Growth Restriction (IUGR) are at increased risk to develop a metabolic syndrome later in life, namely obesity, cardiovascular disease, impaired glucose tolerance. Whereas these facts have been largely studied during childhood or adult life, little is known about the consequences of IUGR on glucose tolerance during the perinatal period. The purpose of this study was to determine whether chronic placental embolization in the late gestation ovine fetus induce insulin resistance during the perinatal period. STUDY DESIGN: IUGR was induced by umbilico-placental embolization during late gestation in chronically catheterized sheep. Umbilico-placental embolization was performed between 130 and 140 d of gestation (terme = 147 d) during which fetuses were hypoxemic relative to controls. Euglycemic, hyperinsulinemic glucose clamp experiments were performed in utero and during the first three weeks after birth in order to measure the effect of fetal insulin concentration on fetal glucose uptake at a constant glucose concentration. Fetal coricotropin, cortisol and catecholamines concentrations were measured daily. RESULTS: Chronic placental embolization produced asymmetrically IUGR fetuses and increased vascular resistance in umbilical artery (P ! .05). The exogenous glucose infusion rate necessary to maintain constant glycemia was significantly lower in IUGR relative to control fetuses at 140 d of gestation (IUGR vs. control, 2.5 G .5 mg/kg/min and 5.0 G 0.5 mg/kg/min, P ! .05) and 7 days after birth (IUGR vs. control, 3.5 G .7 mg/kg/min and 5.7 G 1.4 mg/kg/ min, P ! .05). Glucose clamps were similar between groups at 2 and 3 weeks after birth. Cortisol levels were similar between the two groups. In response to chronic fetal hypoxemia, there was a progressive increased in baseline fetal plasma epinephrine, norepinephrine and dopamine concentrations (P ! .01). CONCLUSION: We concluded that chronic fetal hypoxemia induces insulin resistance during the perinatal period. We speculate that this change could be related to an increase in fetal catecholamines levels.
457
EFFECTS OF PHOSPHODIESTERASE 5 INHIBITOR ON PULMONARY VASCULAR REACTIVITY IN THE FETAL LAMB PHILIPPE DERUELLE1, BENOIT LARRUE1, THAMEUR RAKZAH1, SOPHIE JAILLARD1, GHAZWAN BUTROUS2, LAURENT STORME1, 1 CHRU de Lille, France, Department of Perinatology, Lille, France, 2Sandwich Laboratories, Pfizer Limited, Sandwich, Kent, United Kingdom OBJECTIVE: Nitric oxide (NO) released by pulmonary vascular endothelium is a potent vasodilator related to increased cGMP content. Hydrolysis of cGMP is achieved predominately by cGMP-specific phosphodiesterases (PDEs). Sildenafil (SILD) is a selective phosphodieste´rase-5 (PDE-5) inhibitor. The purpose of the study is to assess the effects of sildenafil on pulmonary vascular circulation during the perinatal period. STUDY DESIGN: 12 pregnant ewes were operated on between 128 and 130 days gestation (term = 145 d). Catheters were placed into the ascending aorta, superior vena cava, main pulmonary artery and left atrium. An ultrasonic flow transducer was placed around left pulmonary artery (LPA). An inflatable vascular occluder was placed around ductus arteriosus (DA). Fetal lambs were divided in two groups: (1) a SILD group infused continuously by SILD at 0.3 mg/kg/h (n = 6) and; 2/control group (CONT) infused with saline (n = 6). After 24 hrs of infusion, we compared the response of PA hemodynamic to: (1) to increased fetal PaO2, and (2) to increased in vascular shear-stress. RESULTS: PAP, Q and PVR were similar in both groups before and after 24 h of infusion. Despite similar baseline values, PVR during maternal O2 inhalation was lower in SILD than in CONT group (0.23 G 0.01 vs 0.27 G 0.01 mm Hg/ mL.min respectively) (P ! .01). Furthermore, drop in PVR during acute DA compression was greater in the SILD group (from 0.54 G 0.03 to 0.26 G 0.02 mm Hg/mL.min) than in the CONT group (from 0.55 G 0.04 to 0.39 G 0.02 mm Hg/mL.min) (P ! .01). CONCLUSION: Although no difference was found in the basal pulmonary vascular tone, sildenafil increases PVR in the ovine fetus. These data suggest that PDE-5 is involved in the regulation of pulmonary vascular reactivity during the perinatal period. We further speculate that specific inhibitor of PDE-5 may potentiate birth related pulmonary vasodilator stimuli and could improve conditions associated with failure to circulatory adaptation at birth.
459
WITHDRAWN
CHANGES IN AQUAPORIN 1 EXPRESSION AFFECT AMNIOTIC FLUID VOLUME STEPHANIE MANN1, NATALIA DVORAK2, ROBERT TAYLOR2, 1Phoenix Integrated Residency in Ob/Gyn, Obstetrics and Gynecology, Phoenix, Arizona, 2 University of California, San Francisco, Obstetrics, Gynecology and Reproductive Sciences, San Francisco, California OBJECTIVE: Recent work from our laboratory has demonstrated the presence of aquaporin (AQP) water channels in fetal membranes from pregnancies with normal amniotic fluid (AF) volume. The objective of this study was to investigate changes in AQP 1 mRNA expression from fetal membranes of pregnancies with polyhydramnios and oligohydramnios. STUDY DESIGN: Placentas from term pregnancies (37-40 wks) were collected from women who presented with intact membranes and one of the following: (1) idiopathic oligohydramnios (AFI !5.0 cm); (2) polyhydramnios (AFI >24.0 cm); and (3) normal amount AF (AFI >5.0 cm and !24.0 cm). The membranes (amnion and chorion) directly overlying the placenta and the free floating reflected membranes were sampled (total of four samples from each placenta). RNA was isolated from the amnion and chorion of each region. Quantitative RT-PCR was used to compare expression of AQP1 mRNA in the membranes collected from the above pregnancies. Statistical analysis was performed with a t test. P ! .05 was considered signficant. RESULTS: As shown in the figure, AQP1 mRNA expression is increased in the reflected amnion from pregnancies with idiopathic polyhydramnios and decreased in the reflected amnion and chorion from pregnancies with oligohydramnios. CONCLUSION: The expression of the water channel AQP1 is altered in the reflected fetal membranes. These results suggests that there is an adaptive response by the fetal membranes in situations of either decreased or increased AF volume to prevent excessive loss or accumulation of fluid, respectively. We speculate that therapies focused on regulating AQP1 expression may be useful for treating oligohydramnios and polyhydramnios.
458
PERINATAL GLUCOSE TOLERANCE AFTER INTRAUTERINE GROWTH RESTRICTION IN THE LATE-GESTATION OVINE FETUS PHILIPPE DERUELLE1, IVA GUEORGUIEVA2, BERENGERE SICOT DE JENLIS3, SOPHIE JAILLARD4, JACQUES WEILL2, VERONIQUE DEBARGE4, LAURENT STORME4, 1CHRU de Lille, Lille, France, 2 CHRU de Lille, Pediatric endocrinology unit, Lille, France, 3CHRU de Lille, Department of perinatology, Lille, France, 4CHRU de Lille, France, Department of perinatology, Lille, France OBJECTIVE: Newborns with Intrauterine-Growth Restriction (IUGR) are at increased risk to develop a metabolic syndrome later in life, namely obesity, cardiovascular disease, impaired glucose tolerance. Whereas these facts have been largely studied during childhood or adult life, little is known about the consequences of IUGR on glucose tolerance during the perinatal period. The purpose of this study was to determine whether chronic placental embolization in the late gestation ovine fetus induce insulin resistance during the perinatal period. STUDY DESIGN: IUGR was induced by umbilico-placental embolization during late gestation in chronically catheterized sheep. Umbilico-placental embolization was performed between 130 and 140 d of gestation (terme = 147 d) during which fetuses were hypoxemic relative to controls. Euglycemic, hyperinsulinemic glucose clamp experiments were performed in utero and during the first three weeks after birth in order to measure the effect of fetal insulin concentration on fetal glucose uptake at a constant glucose concentration. Fetal coricotropin, cortisol and catecholamines concentrations were measured daily. RESULTS: Chronic placental embolization produced asymmetrically IUGR fetuses and increased vascular resistance in umbilical artery (P ! .05). The exogenous glucose infusion rate necessary to maintain constant glycemia was significantly lower in IUGR relative to control fetuses at 140 d of gestation (IUGR vs. control, 2.5 G .5 mg/kg/min and 5.0 G 0.5 mg/kg/min, P ! .05) and 7 days after birth (IUGR vs. control, 3.5 G .7 mg/kg/min and 5.7 G 1.4 mg/kg/ min, P ! .05). Glucose clamps were similar between groups at 2 and 3 weeks after birth. Cortisol levels were similar between the two groups. In response to chronic fetal hypoxemia, there was a progressive increased in baseline fetal plasma epinephrine, norepinephrine and dopamine concentrations (P ! .01). CONCLUSION: We concluded that chronic fetal hypoxemia induces insulin resistance during the perinatal period. We speculate that this change could be related to an increase in fetal catecholamines levels.
457
EFFECTS OF PHOSPHODIESTERASE 5 INHIBITOR ON PULMONARY VASCULAR REACTIVITY IN THE FETAL LAMB PHILIPPE DERUELLE1, BENOIT LARRUE1, THAMEUR RAKZAH1, SOPHIE JAILLARD1, GHAZWAN BUTROUS2, LAURENT STORME1, 1 CHRU de Lille, France, Department of Perinatology, Lille, France, 2Sandwich Laboratories, Pfizer Limited, Sandwich, Kent, United Kingdom OBJECTIVE: Nitric oxide (NO) released by pulmonary vascular endothelium is a potent vasodilator related to increased cGMP content. Hydrolysis of cGMP is achieved predominately by cGMP-specific phosphodiesterases (PDEs). Sildenafil (SILD) is a selective phosphodieste´rase-5 (PDE-5) inhibitor. The purpose of the study is to assess the effects of sildenafil on pulmonary vascular circulation during the perinatal period. STUDY DESIGN: 12 pregnant ewes were operated on between 128 and 130 days gestation (term = 145 d). Catheters were placed into the ascending aorta, superior vena cava, main pulmonary artery and left atrium. An ultrasonic flow transducer was placed around left pulmonary artery (LPA). An inflatable vascular occluder was placed around ductus arteriosus (DA). Fetal lambs were divided in two groups: (1) a SILD group infused continuously by SILD at 0.3 mg/kg/h (n = 6) and; 2/control group (CONT) infused with saline (n = 6). After 24 hrs of infusion, we compared the response of PA hemodynamic to: (1) to increased fetal PaO2, and (2) to increased in vascular shear-stress. RESULTS: PAP, Q and PVR were similar in both groups before and after 24 h of infusion. Despite similar baseline values, PVR during maternal O2 inhalation was lower in SILD than in CONT group (0.23 G 0.01 vs 0.27 G 0.01 mm Hg/ mL.min respectively) (P ! .01). Furthermore, drop in PVR during acute DA compression was greater in the SILD group (from 0.54 G 0.03 to 0.26 G 0.02 mm Hg/mL.min) than in the CONT group (from 0.55 G 0.04 to 0.39 G 0.02 mm Hg/mL.min) (P ! .01). CONCLUSION: Although no difference was found in the basal pulmonary vascular tone, sildenafil increases PVR in the ovine fetus. These data suggest that PDE-5 is involved in the regulation of pulmonary vascular reactivity during the perinatal period. We further speculate that specific inhibitor of PDE-5 may potentiate birth related pulmonary vasodilator stimuli and could improve conditions associated with failure to circulatory adaptation at birth.
459
WITHDRAWN