We investigated the pulmonary vascular effects of
E4021, a potent inhibitor of cGMP-specific
phosphodiesterase, in control late-gestation fetal lambs, and in newborn lambs with persistent
pulmonary hypertension (PPHN) after prenatal
ligation of the ductus arteriosus.
E4021 alone significantly relaxed fifth-generation pulmonary arteries isolated from control fetal lambs, an effect completely blocked after inhibition of
nitric oxide synthase (NOS). In contrast,
E4021 did not relax pulmonary arteries isolated from hypertensive lambs. Pretreatment with
E4021 (10(-7) M) significantly enhanced relaxations to the NO donor S-nitrosyl-acetyl-penicilamine (SNAP) in arteries from both control and hypertensive lambs. In control, fully instrumented fetal lambs, infusions of
E4021 (31 microgram/min) selectively dilated the pulmonary circulation, an effect again blocked after inhibition of
NO synthase. Further studies were performed in newborn lambs with PPHN to study the vascular effects of
E4021 alone, and in combination with inhaled NO.
E4021 alone (1 to 100 microgram/kg/min) decreased pulmonary artery pressure (Ppa) in a dose-dependent fashion, and had minimal effect on systemic pressure. At the highest dose (100 microgram/kg/min), the dilation was selective for the pulmonary circulation. In subsequent protocols,
E4021 (10 microgram/kg/min) significantly decreased Ppa and pulmonary vascular resistance (PVR), but these pulmonary vascular effects were not enhanced after NO inhalation at 0.5 or 5 ppm. We speculate that the lack of enhancement was due to the dramatic effects of
E4021 alone. Potent, specific
phosphodiesterase inhibitors such as
E4021 may prove to be useful in the treatment of PPHN.