The cGMP-specific phosphodiesterase inhibitor E4021 dilates the pulmonary circulation

Robert C. Dukarm, James A. Russell, Frederick C. Morin, Bryan J. Perry, Robin H Steinhorn

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

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 μg/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 μg/kg/min) decreased pulmonary artery pressure (Ppa) in a dose-dependent fashion, and had minimal effect on systemic pressure. At the highest dose (100 μg/kg/min), the dilation was selective for the pulmonary circulation. In subsequent protocols, E4021 (10 μg/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.

Original languageEnglish (US)
Pages (from-to)858-865
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume160
Issue number3
StatePublished - 1999
Externally publishedYes

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Pulmonary Circulation
Phosphodiesterase Inhibitors
Pulmonary Hypertension
Pulmonary Artery
Blood Vessels
Nitric Oxide Synthase
E 4021
Ductus Arteriosus
Pressure
Lung
Phosphoric Diester Hydrolases
Vascular Resistance
Inhalation
Ligation
Dilatation
Arteries
Pregnancy

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Dukarm, R. C., Russell, J. A., Morin, F. C., Perry, B. J., & Steinhorn, R. H. (1999). The cGMP-specific phosphodiesterase inhibitor E4021 dilates the pulmonary circulation. American Journal of Respiratory and Critical Care Medicine, 160(3), 858-865.

The cGMP-specific phosphodiesterase inhibitor E4021 dilates the pulmonary circulation. / Dukarm, Robert C.; Russell, James A.; Morin, Frederick C.; Perry, Bryan J.; Steinhorn, Robin H.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 160, No. 3, 1999, p. 858-865.

Research output: Contribution to journalArticle

Dukarm, RC, Russell, JA, Morin, FC, Perry, BJ & Steinhorn, RH 1999, 'The cGMP-specific phosphodiesterase inhibitor E4021 dilates the pulmonary circulation', American Journal of Respiratory and Critical Care Medicine, vol. 160, no. 3, pp. 858-865.
Dukarm, Robert C. ; Russell, James A. ; Morin, Frederick C. ; Perry, Bryan J. ; Steinhorn, Robin H. / The cGMP-specific phosphodiesterase inhibitor E4021 dilates the pulmonary circulation. In: American Journal of Respiratory and Critical Care Medicine. 1999 ; Vol. 160, No. 3. pp. 858-865.
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