Effects of phosphodiesterase 5 inhibitor on pulmonary vascular reactivity in the fetal lamb.
BACKGROUND
Nitric oxide released by pulmonary vascular endothelium is a potent vasodilator related to increased cyclic guanosine monophosphate (cGMP) content. Hydrolysis of cGMP is achieved predominately by cGMP-specific phosphodiesterases. Sildenafil is a selective phosphodiesterase-5 (PDE5) inhibitor. The purpose of the study is to assess the effects of sildenafil on pulmonary vascular circulation 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 the aorta, vena cava, pulmonary artery, and left atrium. An ultrasonic flow transducer and an inflatable vascular occluder were placed respectively around the left pulmonary artery and the ductus arteriosus. Fetal lambs were randomly divided into two groups: (1) sildenafil group, infused continuously with sildenafil for 24 hours at a rate of 1 mg/h; or (2) control group, infused with saline for 24 hours. After 24 hours of infusion, we compared basal pulmonary vascular resistance and the pulmonary vascular responses to increase in fetal PaO2 and to acute ductus arteriosus compression causing "shear stress."


RESULTS
Sildenafil infusion did not change mean aortic and pulmonary artery pressures, increased mean left pulmonary blood flow by 160%, and decreased pulmonary vascular resistance by 60% (p < 0.05). However, both mean flow (Q) and pulmonary vascular resistance returned to baseline values after 2 hours of sildenafil infusion. Despite similar baseline values, pulmonary vascular resistance during maternal O2 inhalation was lower in the sildenafil group 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 vascular resistance during acute ductus arteriosus compression was greater in the sildenafil group (from 0.56 +/- 0.06 to 0.26 +/- 0.04 mm Hg.mL(-1).min(-1)) than in 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, especially to birth-related stimuli in the ovine fetal lung. These data suggest that PDE5 is involved in the regulation of pulmonary vascular reactivity during the perinatal period and may potentiate birth-related pulmonary vasodilator stimuli.
Jaillard
Sophie
S
Department of Surgery, Polyclinique du Bois, Lille, France. sjaillard@wanadoo.fr
Larrue
Benoît
B
Deruelle
Philippe
P
Delelis
Anne
A
Rakza
Thameur
T
Butrous
Ghazwan
G
Storme
Laurent
L
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000009:adverse effects*; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004373:Ductus Arteriosus / Q000187:drug effects / Q000196:embryology; D005260:Female; D005333:Fetus; D005552:Forelimb / Q000098:blood supply / Q000196:embryology; D007839:Functional Laterality; D006439:Hemodynamics / Q000187:drug effects; D023421:Models, Animal; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D011247:Pregnancy; D011651:Pulmonary Artery / Q000187:drug effects / Q000196:embryology / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects*; D011687:Purines; D012756:Sheep; D000068677:Sildenafil Citrate; D013450:Sulfones; D014664:Vasodilation / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5