| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Clinical Pharmacology, Imperial College, London, Middlesex, United Kingdom
2 Department of Medicine, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom
* To whom correspondence should be addressed. E-mail: nwm23{at}cam.ac.uk.
We investigated the effects of prostacyclin analogues and isoform-selective phosphodiesterase (PDE) inhibitors, alone and in combination, on pulmonary vascular remodeling in vitro and in vivo. Vascular smooth muscle cells (VSMCs) isolated from the pulmonary (proximal and distal) and systemic circulations demonstrated subtle variations in the expression of PDE isoform mRNA. However, using biochemical assays, PDE3 and PDE4 isoforms were found to be responsible for the majority of cAMP hydrolysis in all VSMCs. In growth assays, the prostacyclin analogues cicaprost and iloprost inhibited mitogen-induced proliferation of VSMCs in a cAMPdependent manner. In addition, isoform selective antagonists of PDEs 1, 3 or 4 inhibited VSMC proliferation, an effect which synergized with the effect of prostacyclin analogues. The inhibitory effects were greater in cells isolated from the pulmonary circulation. In an in situ perfused rat lung preparation, the administration of prostacyclin analogues or the PDE inhibitors vinpocetine (PDE1), cilostamide (PDE3) or rolipram (PDE4), but not EHNA (PDE2), attenuated acute hypoxic vasoconstriction (HPV), Combinations of agents led to a greater reduction in HPV. Furthermore, during exposure to hypoxia for 13 days, Wistar rats were treated with iloprost, rolipram, cilostamide, or combinations of these agents. Compared to normoxic controls, hypoxic animals developed pulmonary hypertension and distal pulmonary artery muscularization. These parameters were attenuated by iloprost+cilostamide, iloprost+rolipram and cilostamide+rolipram, but were not significantly affected by single agents. Taken together, these findings provide a greater understanding of the role of cAMP PDEs in VSMC proliferation and provide a rationale for the combined use of prostacylcin analogues plus PDE3/4 inhibitors in the treatment of pulmonary vascular remodelling.
This article has been cited by other articles:
|
|
 |
|
  M. S. Hanson, A. H. Stephenson, E. A. Bowles, M. Sridharan, S. Adderley, and R. S. Sprague Phosphodiesterase 3 is present in rabbit and human erythrocytes and its inhibition potentiates iloprost-induced increases in cAMP Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H786 - H793. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Wilkins, J. Wharton, F. Grimminger, and H. A. Ghofrani Phosphodiesterase inhibitors for the treatment of pulmonary hypertension Eur. Respir. J., July 1, 2008; 32(1): 198 - 209. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Huang and M. Peters-Golden Eicosanoid Lipid Mediators in Fibrotic Lung Diseases: Ready for Prime Time? Chest, June 1, 2008; 133(6): 1442 - 1450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. De Franceschi, O. S. Platt, G. Malpeli, A. Janin, A. Scarpa, C. Leboeuf, Y. Beuzard, E. Payen, and C. Brugnara Protective effects of phosphodiesterase-4 (PDE-4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice FASEB J, June 1, 2008; 22(6): 1849 - 1860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. R. Bauer, T. M. Moore, and I. F. McMurtry Rodent models of PAH: are we there yet? Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L580 - L582. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ito, T. Okada, J. Mimuro, H. Miyashita, R. Uchibori, M. Urabe, H. Mizukami, A. Kume, M. Takahashi, U. Ikeda, et al. Adenoassociated Virus Mediated Prostacyclin Synthase Expression Prevents Pulmonary Arterial Hypertension in Rats Hypertension, September 1, 2007; 50(3): 531 - 536. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Murray, H. H. Patel, R. Y. S. Suda, S. Zhang, P. A. Thistlethwaite, J. X.-J. Yuan, and P. A. Insel Expression and activity of cAMP phosphodiesterase isoforms in pulmonary artery smooth muscle cells from patients with pulmonary hypertension: role for PDE1 Am J Physiol Lung Cell Mol Physiol, January 1, 2007; 292(1): L294 - L303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. I. Said Mediators and modulators of pulmonary arterial hypertension Am J Physiol Lung Cell Mol Physiol, October 1, 2006; 291(4): L547 - L558. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Kim, K.S. Prabhu, F. J. Gonzalez, and J. M. Peters Inhibition of chemically induced skin carcinogenesis by sulindac is independent of peroxisome proliferator-activated receptor-{beta}/{delta} (PPAR{beta}/{delta}) Carcinogenesis, May 1, 2006; 27(5): 1105 - 1112. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Busch, H. Liu, A. R. Graveline, and K. D. Bloch Nitric oxide induces phosphodiesterase 4B expression in rat pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, April 1, 2006; 290(4): L747 - L753. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. V. Evgenov, C. J. Busch, N. V. Evgenov, R. Liu, B. Petersen, G. E. Falkowski, B. Petho, A. Vas, K. D. Bloch, W. M. Zapol, et al. Inhibition of phosphodiesterase 1 augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs with acute pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, April 1, 2006; 290(4): L723 - L729. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Hoeper and L. J. Rubin Update in pulmonary hypertension 2005. Am. J. Respir. Crit. Care Med., March 1, 2006; 173(5): 499 - 505. [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Tsai, M. W. Turrentine, B. C. Sheridan, M. Wang, A. C. Fiore, J. W. Brown, and D. R. Meldrum Differential Effects of Phosphodiesterase-5 Inhibitors on Hypoxic Pulmonary Vasoconstriction and Pulmonary Artery Cytokine Expression Ann. Thorac. Surg., January 1, 2006; 81(1): 272 - 278. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
