Am. J. Respir. Crit. Care Med., Volume 160, Number 3, September 1999, 858-865

The cGMP-specific Phosphodiesterase Inhibitor E4021 Dilates the Pulmonary Circulation

ROBERT C. DUKARM, JAMES A. RUSSELL, FREDERICK C. MORIN III, BRYAN J. PERRY, and ROBIN H. STEINHORN

School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York

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 (10⁷ 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.

This article has been cited by other articles:

				K. N. Farrow, B. S. Groh, P. T. Schumacker, S. Lakshminrusimha, L. Czech, S. F. Gugino, J. A. Russell, and R. H. Steinhorn Hyperoxia Increases Phosphodiesterase 5 Expression and Activity in Ovine Fetal Pulmonary Artery Smooth Muscle Cells Circ. Res., February 1, 2008; 102(2): 226 - 233. [Abstract] [Full Text] [PDF]

				S. Jaillard, B. Larrue, P. Deruelle, A. Delelis, T. Rakza, G. Butrous, and L. Storme Effects of Phosphodiesterase 5 Inhibitor on Pulmonary Vascular Reactivity in the Fetal Lamb Ann. Thorac. Surg., March 1, 2006; 81(3): 935 - 942. [Abstract] [Full Text] [PDF]

				R. C. Dukarm, R. H. Steinhorn, J. A. Russell, S. Lakshminrusimha, D. Swartz, and J. J. Cummings Selective type 5 phosphodiesterase inhibition alters pulmonary hemodynamics and lung liquid production in near-term fetal lambs J Appl Physiol, December 1, 2005; 99(6): 2331 - 2336. [Abstract] [Full Text] [PDF]

				B. Larrue, S. Jaillard, M. Lorthioir, X. Roubliova, G. Butrous, T. Rakza, H. Warembourg, and L. Storme Pulmonary vascular effects of sildenafil on the development of chronic pulmonary hypertension in the ovine fetus Am J Physiol Lung Cell Mol Physiol, June 1, 2005; 288(6): L1193 - L1200. [Abstract] [Full Text] [PDF]

				P. M. Hassoun, G. Filippov, M. Fogel, C. Donaldson, U. S. Kayyali, L. A. Shimoda, and K. D. Bloch Hypoxia Decreases Expression of Soluble Guanylate Cyclase in Cultured Rat Pulmonary Artery Smooth Muscle Cells Am. J. Respir. Cell Mol. Biol., June 1, 2004; 30(6): 908 - 913. [Abstract] [Full Text] [PDF]

				L. Zhao, N. A. Mason, J. W. Strange, H. Walker, and M. R. Wilkins Beneficial Effects of Phosphodiesterase 5 Inhibition in Pulmonary Hypertension Are Influenced by Natriuretic Peptide Activity Circulation, January 21, 2003; 107(2): 234 - 237. [Abstract] [Full Text] [PDF]

				L. S. Shekerdemian, H. B. Ravn, and D. J. Penny Intravenous Sildenafil Lowers Pulmonary Vascular Resistance in a Model of Neonatal Pulmonary Hypertension Am. J. Respir. Crit. Care Med., April 15, 2002; 165(8): 1098 - 1102. [Abstract] [Full Text] [PDF]

				J. J. Haddad, S. C. Land, W. O. Tarnow-Mordi, M. Zembala, D. Kowalczyk, and R. Lauterbach Immunopharmacological Potential of Selective Phosphodiesterase Inhibition. I. Differential Regulation of Lipopolysaccharide-Mediated Proinflammatory Cytokine (Interleukin-6 and Tumor Necrosis Factor-alpha ) Biosynthesis in Alveolar Epithelial Cells J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 559 - 566. [Abstract] [Full Text] [PDF]

				S. M. Black, L. S. Sanchez, E. Mata-Greenwood, J. M. Bekker, R. H. Steinhorn, and J. R. Fineman sGC and PDE5 are elevated in lambs with increased pulmonary blood flow and pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, November 1, 2001; 281(5): L1051 - L1057. [Abstract] [Full Text] [PDF]

				R. H. STEINHORN, G. ALBERT, D. D. SWARTZ, J. A. RUSSELL, C. R. LEVINE, and J. M. DAVIS Recombinant Human Superoxide Dismutase Enhances the Effect of Inhaled Nitric Oxide in Persistent Pulmonary Hypertension Am. J. Respir. Crit. Care Med., September 1, 2001; 164(5): 834 - 839. [Abstract] [Full Text] [PDF]

				L. Zhao, N. A. Mason, N. W. Morrell, B. Kojonazarov, A. Sadykov, A. Maripov, M. M. Mirrakhimov, A. Aldashev, and M. R. Wilkins Sildenafil Inhibits Hypoxia-Induced Pulmonary Hypertension Circulation, July 24, 2001; 104(4): 424 - 428. [Abstract] [Full Text] [PDF]

				R. H. Steinhorn, J. A. Russell, S. Lakshminrusimha, S. F. Gugino, S. M. Black, and J. R. Fineman Altered endothelium-dependent relaxations in lambs with high pulmonary blood flow and pulmonary hypertension Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H311 - H317. [Abstract] [Full Text] [PDF]