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

doi:10.1016/j.athoracsur.2005.09.022

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Original article: Cardiovascular

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

Sophie Jaillard, MD, PhD^a^,
e^,
_*, Benoît Larrue, MD^b, Philippe Deruelle, MD^c^,
e, Anne Delelis, MD^c, Thameur Rakza, MD^c, Ghazwan Butrous, MD^d, Laurent Storme, MD^c^,
e

^a Department of Surgery, Polyclinique du Bois, Lille, France
^b Department of Cardiac Surgery, CHRU de Lille, Lille, France
^c Department of Perinatology, CHRU de Lille, Lille, France
^d Pfizer Laboratories, Sandwich, Great Britain
^e EA1049, Department of Biophysics, CHRU de Lille, Lille, France

Accepted for publication September 9, 2005.

^_* Address correspondence to Dr Jaillard, Department of Surgery, Polyclinique du Bois, Ave Marx Dormoy, 59000 Lille, France (Email: sjaillard{at}wanadoo.fr).

BACKGROUND: Nitric oxide released by pulmonary vascular endothelium is apotent vasodilator related to increased cyclic guanosine monophosphate(cGMP) content. Hydrolysis of cGMP is achieved predominatelyby cGMP-specific phosphodiesterases. Sildenafil is a selectivephosphodiesterase-5 (PDE5) inhibitor. The purpose of the studyis to assess the effects of sildenafil on pulmonary vascularcirculation during the perinatal period.

METHODS: Thirty-two pregnant ewes were operated on at the end of gestation,and fetal lambs were prepared with catheters placed into theaorta, vena cava, pulmonary artery, and left atrium. An ultrasonicflow transducer and an inflatable vascular occluder were placedrespectively around the left pulmonary artery and the ductusarteriosus. Fetal lambs were randomly divided into two groups:(1) sildenafil group, infused continuously with sildenafil for24 hours at a rate of 1 mg/h; or (2) control group, infusedwith saline for 24 hours. After 24 hours of infusion, we comparedbasal pulmonary vascular resistance and the pulmonary vascularresponses to increase in fetal PaO₂ and to acute ductus arteriosuscompression causing "shear stress."

RESULTS: Sildenafil infusion did not change mean aortic and pulmonaryartery pressures, increased mean left pulmonary blood flow by160%, and decreased pulmonary vascular resistance by 60% (p< 0.05). However, both mean flow (Q) and pulmonary vascularresistance returned to baseline values after 2 hours of sildenafilinfusion. Despite similar baseline values, pulmonary vascularresistance during maternal O₂ inhalation was lower in the sildenafilgroup than in the control group (0.21 ± 0.03 versus 0.33± 0.03 mm Hg · mL^–1 · min^–1,respectively; p < 0.01). Furthermore, drop in pulmonary vascularresistance during acute ductus arteriosus compression was greaterin the sildenafil group (from 0.56 ± 0.06 to 0.26 ±0.04 mm Hg · mL^–1 · min^–1) thanin the control group (from 0.55 ± 0.05 to 0.39 ±0.03 mm Hg · mL^–1 · min^–1; p <0.01).

CONCLUSIONS: Although sildenafil induces a transient pulmonary vasodilation,it mediates a sustained change in vascular reactivity, especiallyto birth-related stimuli in the ovine fetal lung. These datasuggest that PDE5 is involved in the regulation of pulmonaryvascular reactivity during the perinatal period and may potentiatebirth-related pulmonary vasodilator stimuli.

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