Effects of Phosphodiesterase 5 Inhibitor on Pulmonary Vascular Reactivity in the Fetal Lamb

Jaillard, Sophie; Larrue, Benoît; Deruelle, Philippe; Delelis, Anne; Rakza, Thameur; Butrous, Ghazwan; Storme, Laurent

doi:10.1016/j.athoracsur.2005.09.022

Cited by 20 publications

(18 citation statements)

References 26 publications

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“…This haemodynamic effect of SC is apparently maintained over time, as evidenced by the lower DV indices associated with increased fetal, placental and liver weight gain in the third trimester. This vasodilatation effect has also been reported in fetal rats and sheep 32 . Fetal liver enlargement may be species–specific, as previously suggested 30 .…”

Section: Discussionsupporting

confidence: 81%

Haemodynamic effects of long-term administration of sildenafil in normotensive pregnant and non-pregnant rats

Pellicer

Herraiz

Cauli

et al. 2011

BJOG: An International Journal of Obstetrics &Amp; Gynaecology

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Objective To determine the effects of chronic administration of sildenafil citrateon healthy pregnant rats.Design In vivo animal experimental study.Setting Fundació n IVI-Instituto Universitario IVI, Valencia, Spain.Sample Pregnant and non-pregnant Wistarrats exposed to chronic administration of sildenafil.Methods Placental cross-barrier and feto-maternal relationship levels, maternal blood pressure, and haemodymamic effects on uterine arteries were evaluated. The effect of growth on weight and fetal tissues, and on perinatal outcome, was investigated.Main outcome measures Maternal blood pressure, blood viscosity, vascular indices of uterine arteries and fetal ductus venosus, plasmatic levels of sildenafil, embryo/fetal and litter weights, perinatal/postnatal survival rates.Results Sildenafil citrate crossed the placenta. The maternal and fetal levels of sildenafil, and its metabolite desmethyl-sildenafil, demonstrated a positive linear correlation in treated pregnant animals versus controls; a selective maternal hypotensive effect without changes in uterine vascular resistance was noted on days E8 and E11 (embryonic day). The lower pulsatility index of the ductus venosus on day E18 suggests fetal overflow at the end of the pregnancy. Effects on offspring were placental and liver enlargement, and increased fetal weight gain in the second half of pregnancy (irrespective of liver enlargement) and at birth. Perinatal and postnatal survival rates in the sildenafil group remained unaltered. No haemodynamic effects were evident in non-pregnant animals.Conclusions In normotensive rats, sildenafil appears to have a selective effect at the onset of pregnancy, implying increased fetal blood supply, and increased fetal weight, and placental and liver enlargement, but no increased perinatal mortality.

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Section: Discussionsupporting

confidence: 81%

Haemodynamic effects of long-term administration of sildenafil in normotensive pregnant and non-pregnant rats

Pellicer

Herraiz

Cauli

et al. 2011

BJOG: An International Journal of Obstetrics &Amp; Gynaecology

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“…The effect is blocked by inhibition of NO synthase (158). When treated with sildenafil, a specific PDE5 inhibitor, PVR of term fetal lambs is lower during maternal oxygen inhalation compared with air-breathing ewes (298).…”

Section: Pdesmentioning

confidence: 99%

Regulation of the Pulmonary Circulation in the Fetus and Newborn

Gao

Raj

2010

Physiological Reviews

298

267

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During the development of the pulmonary vasculature in the fetus, many structural and functional changes occur to prepare the lung for the transition to air breathing. The development of the pulmonary circulation is genetically controlled by an array of mitogenic factors in a temporo-spatial order. With advancing gestation, pulmonary vessels acquire increased vasoreactivity. The fetal pulmonary vasculature is exposed to a low oxygen tension environment that promotes high intrinsic myogenic tone and high vasocontractility. At birth, a dramatic reduction in pulmonary arterial pressure and resistance occurs with an increase in oxygen tension and blood flow. The striking hemodynamic differences in the pulmonary circulation of the fetus and newborn are regulated by various factors and vasoactive agents. Among them, nitric oxide, endothelin-1, and prostaglandin I(2) are mainly derived from endothelial cells and exert their effects via cGMP, cAMP, and Rho kinase signaling pathways. Alterations in these signaling pathways may lead to vascular remodeling, high vasocontractility, and persistent pulmonary hypertension of the newborn.

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“…This hypothesis is further supported by the observation that sildenafil significantly reduces pulmonary vascular resistance in normal and ductus arteriosus-ligated fetal sheep in response to birth-related stimuli such as oxygen and shear stress. 58,59 The sildenafil dose chosen for the pregnant rats was 100 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 on the basis of previous studies that examined the pharmacokinetics of sildenafil in rodents. 23 In long-term in vivo studies in rats, this dose yielded mean free plasma concentrations comparable to levels obtained in humans at doses of 1 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 .…”

Section: Discussionmentioning

confidence: 99%

Antenatal Sildenafil Treatment Attenuates Pulmonary Hypertension in Experimental Congenital Diaphragmatic Hernia

et al. 2011

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Background-Lung hypoplasia and persistent pulmonary hypertension of the newborn limit survival in congenital diaphragmatic hernia (CDH). Unlike other diseases resulting in persistent pulmonary hypertension of the newborn, infants with CDH are refractory to inhaled nitric oxide (NO). Nitric oxide mediates pulmonary vasodilatation at birth in part via cyclic GMP production. Phosphodiesterase type 5 (PDE5) limits the effects of NO by inactivation of cyclic GMP. Because of the limited success in postnatal management of CDH, we hypothesized that antenatal PDE5 inhibition would attenuate pulmonary artery remodeling in experimental nitrofen-induced CDH. Methods and Results-Nitrofen administered at embryonic day 9.5 to pregnant rats resulted in a 60% incidence of CDH in the offspring and recapitulated features seen in human CDH, including structural abnormalities (lung hypoplasia, decreased pulmonary vascular density, pulmonary artery remodeling, right ventricular hypertrophy), and functional abnormalities (decreased pulmonary artery relaxation in response to the NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide). Antenatal sildenafil administered to the pregnant rat from embryonic day 11.5 to embryonic day 20.5 crossed the placenta, increased fetal lung cyclic GMP and decreased active PDE5 expression. Antenatal sildenafil improved lung structure, increased pulmonary vessel density, reduced right ventricular hypertrophy, and improved postnatal NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide-induced pulmonary artery relaxation. This was associated with increased lung endothelial NO synthase and vascular endothelial growth factor protein expression. Antenatal sildenafil had no adverse effect on retinal structure/function and brain development. Conclusions-Antenatal sildenafil improves pathological features of persistent pulmonary hypertension of the newborn in experimental CDH and does not alter the development of other PDE5-expressing organs. Given the high mortality/ morbidity of CDH, the potential benefit of prenatal PDE5 inhibition in improving the outcome for infants with CDH warrants further studies. (Circulation. 2011;123:2120-2131.)

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Effects of Phosphodiesterase 5 Inhibitor on Pulmonary Vascular Reactivity in the Fetal Lamb

Cited by 20 publications

References 26 publications

Haemodynamic effects of long-term administration of sildenafil in normotensive pregnant and non-pregnant rats

Haemodynamic effects of long-term administration of sildenafil in normotensive pregnant and non-pregnant rats

Regulation of the Pulmonary Circulation in the Fetus and Newborn

Antenatal Sildenafil Treatment Attenuates Pulmonary Hypertension in Experimental Congenital Diaphragmatic Hernia

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