The cGMP-specific phosphodiesterase inhibitor E4021 dilates the pulmonary circulation

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 p renatal ligation of the ductus arteriosus. E4021 alone significantly relaxe d 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 hyperten sive lambs. Pretreatment with E4021 (10(-7) M) significantly enhanced relax ations to the NO donor S-nitrosyl-acetyl-penicilamine (SNAP) in arteries fr om both control and hypertensive lambs. In control, fully instrumented feta l lambs, infusions of E4021 (31 mu g/min) selectively dilated the pulmonary circulation, an effect again blocked after inhibition of NO synthase. Furt her 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 mu g/kg/min) decreased pulmonary artery pressure (Ppa) in a dose-de pendent fashion, and had minimal effect on systemic pressure. At the highes t dose (100 mu g/kg/min), the dilation was selective for the pulmonary circ ulation. In subsequent protocols, E4021 (10 mu g/kg/min) significantly decr eased Ppa and pulmonary vascular resistance (PVR), but these pulmonary vasc ular effects were not enhanced after NO inhalation at 0.5 or 5 ppm. We spec ulate that the lack of enhancement was due to the dramatic effects of E4021 alone. Potent, specific phosphodiesterase inhibitors such as E4021 may pro ve to be useful in the treatment of PPHN.