doi: 10.1161/CIRCRESAHA.107.162511
© 2007 American Heart Association, Inc.
Review |
Phosphodiesterase Type 5
Expanding Roles in Cardiovascular Regulation
From the Division of Cardiology (D.A.K., H.C.C.), Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Md; and the Department of Pharmacology (J.A.B.), University of Washington, Seattle.
Correspondence to David A. Kass, MD, Ross 835, 720 Rutland Avenue, Johns Hopkins Medical Institutions, Baltimore, MD 21205. E-mail dkass{at}jhmi.edu
This Review is part of a thematic series on Phosphodiesterases, which includes the following articles:
Compartmentation of Cyclic Nucleotide Signaling in the Heart: The Role of Cyclic Nucleotide Phosphodiesterases
Overview of PDEs and their Regulation
Regulation of Phosphodiesterase 3 (PDE3) and Inducible cAMP Early Repressor in the Heart
cAMP Specific Phosphodiesterase-4 Enzymes in the Cardiovascular System: A Molecular Toolbox for Generating
Compartmentalized cAMP Signalling
cAMP and cGMP Signaling Cross-Talk: Role of Phosphodiesterases and Implications for Cardiac Pathophysiology
Phosphodiesterase Type 5: Expanding Roles in Cardiovascular Regulation
David A. Kass Editor
Phosphodiesterase type 5A (PDE5A) selectively hydrolyzes cyclic GMP. Inhibitors of PDE5A such as sildenafil are widely used to treat erectile dysfunction, but growing evidence supports important roles for the enzyme in both the vasculature and heart. In disorders such as cardiac failure, PDE5A upregulation may contribute to a decline in cGMP and protein kinase G signaling, exacerbating dysfunction. PDE5A plays an important role in the pulmonary vasculature where its inhibition benefits patients with pulmonary hypertension. In the heart, PDE5A signaling appears compartmentalized, and its inhibition is cardioprotective against ischemia-reperfusion and antracycline toxicity, blunts acute adrenergic contractile stimulation, and can suppress chronic hypertrophy and dysfunction attributable to pressure-overload. In this review, we discuss the molecular biology, pharmacology, and physiology of PDE5A, mechanisms of vascular and cardiac regulation, and recent evidence supporting the utility of selective PDE5A inhibition for the treatment of cardiovascular disorders.
Key Words: blood vessels • cardiac myocytes • cardiovascular physiology • phosphodiesterase type 5 inhibitor • pressure overload • protein kinase G • reperfusion injury
This article has been cited by other articles:
 |
|
 |
|
  F. S. Menniti, J. Ren, T. M. Coskran, J. Liu, D. Morton, D. K. Sietsma, A. Som, D. T. Stephenson, B. A. Tate, and S. P. Finklestein Phosphodiesterase 5A Inhibitors Improve Functional Recovery after Stroke in Rats: Optimized Dosing Regimen with Implications for Mechanism J. Pharmacol. Exp. Ther., December 1, 2009; 331(3): 842 - 850. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Sartoretto, B. Y. Jin, M. Bauer, F. B. Gertler, R. Liao, and T. Michel Regulation of VASP phosphorylation in cardiac myocytes: differential regulation by cyclic nucleotides and modulation of protein expression in diabetic and hypertrophic heart Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1697 - H1710. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dussault, F. Maingrette, C. Menard, S.-E. Michaud, P. Haddad, J. Groleau, J. Turgeon, G. Perez, and A. Rivard Sildenafil Increases Endothelial Progenitor Cell Function and Improves Ischemia-Induced Neovascularization in Hypercholesterolemic Apolipoprotein E-Deficient Mice Hypertension, November 1, 2009; 54(5): 1043 - 1049. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Vandeput, J. Krall, R. Ockaili, F. N. Salloum, V. Florio, J. D. Corbin, S. H. Francis, R. C. Kukreja, and M. A. Movsesian cGMP-Hydrolytic Activity and Its Inhibition by Sildenafil in Normal and Failing Human and Mouse Myocardium J. Pharmacol. Exp. Ther., September 1, 2009; 330(3): 884 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Melenovsky, H. Al-Hiti, L. Kazdova, A. Jabor, P. Syrovatka, I. Malek, J. Kettner, and J. Kautzner Transpulmonary B-type natriuretic peptide uptake and cyclic guanosine monophosphate release in heart failure and pulmonary hypertension: the effects of sildenafil. J. Am. Coll. Cardiol., August 11, 2009; 54(7): 595 - 600. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Reffelmann and R. A. Kloner Phosphodiesterase 5 inhibitors: are they cardioprotective? Cardiovasc Res, July 15, 2009; 83(2): 204 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ahmad, Y. Wang, A. K. Ali, and M. Ashraf Long-acting phosphodiesterase-5 inhibitor, tadalafil, induces sustained cardioprotection against lethal ischemic injury Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H387 - H391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kuhn Cardiac anti-remodelling effects of phosphodiesterase type 5 inhibitors: afterload-(in)dependent? Cardiovasc Res, April 1, 2009; 82(1): 4 - 6. [Full Text] [PDF]
|
|
|
|
 |
|
 B. Zhu, L. Zhang, M. Alexeyev, D. F. Alvarez, S. J. Strada, and T. Stevens Type 5 phosphodiesterase expression is a critical determinant of the endothelial cell angiogenic phenotype Am J Physiol Lung Cell Mol Physiol, February 1, 2009; 296(2): L220 - L228. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pokreisz, S. Vandenwijngaert, V. Bito, A. Van den Bergh, I. Lenaerts, C. Busch, G. Marsboom, O. Gheysens, P. Vermeersch, L. Biesmans, et al. Ventricular Phosphodiesterase-5 Expression Is Increased in Patients With Advanced Heart Failure and Contributes to Adverse Ventricular Remodeling After Myocardial Infarction in Mice Circulation, January 27, 2009; 119(3): 408 - 416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nagayama, S. Hsu, M. Zhang, N. Koitabashi, D. Bedja, K. L. Gabrielson, E. Takimoto, and D. A. Kass Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload. J. Am. Coll. Cardiol., January 13, 2009; 53(2): 207 - 215. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Guazzi Clinical Use of Phosphodiesterase-5 Inhibitors in Chronic Heart Failure Circ Heart Fail, November 1, 2008; 1(4): 272 - 280. [Full Text] [PDF]
|
|
|
|
|
|
T. Nagayama, M. Zhang, S. Hsu, E. Takimoto, and D. A. Kass Sustained Soluble Guanylate Cyclase Stimulation Offsets Nitric-Oxide Synthase Inhibition to Restore Acute Cardiac Modulation by Sildenafil J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 380 - 387. [Abstract] [Full Text] [PDF]
|
|