Download PDF
Horm Metab Res 2012; 44(10): 766-775
DOI: 10.1055/s-0032-1321870
Review
© Georg Thieme Verlag KG Stuttgart · New York

Cardiac Cyclic Nucleotide Phosphodiesterases: Function, Regulation, and Therapeutic Prospects

W. E. Knight
1   Department of Pharmacology and Physiology, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
2   Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
,
C. Yan
2   Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
› Author Affiliations
Further Information

Publication History

received 26 December 2011

accepted 27 June 2012

Publication Date:
05 September 2012 (online)

Also available at
    Permissions and Reprints

Abstract

The second messengers cAMP and cGMP exist in multiple discrete compartments and regulate a variety of biological processes in the heart. The cyclic nucleotide phosphodiesterases, by catalyzing the hydrolysis of cAMP and cGMP, play crucial roles in controlling the amplitude, duration, and compartmentalization of cyclic nucleotide signaling. Over 60 phosphodiesterase isoforms, grouped into 11 families, have been discovered to date. In the heart, both cAMP- and cGMP-hydrolyzing phosphodiesterases play important roles in physiology and pathology. At least 7 of the 11 phosphodiesterase family members appear to be expressed in the myocardium, and evidence supports phosphodiesterase involvement in regulation of many processes important for normal cardiac function including pacemaking and contractility, as well as many pathological processes including remodeling and myocyte apoptosis. Pharmacological inhibitors for a number of phosphodiesterase families have also been used clinically or preclinically to treat several types of cardiovascular disease. In addition, phosphodiesterase inhibitors are also being considered for treatment of many forms of disease outside the cardiovascular system, raising the possibility of cardiovascular side effects of such agents. This review will discuss the roles of phosphodiesterases in the heart, in terms of expression patterns, regulation, and involvement in physiological and pathological functions. Additionally, the cardiac effects of various phosphodiesterase inhibitors, both potentially beneficial and detrimental, will be discussed.

Key words

cAMP - cGMP - PDE - heart
 

  • References

  • 1 Ding B, Abe J, Wei H, Xu H, Che W, Aizawa T, Liu W, Molina CA, Sadoshima J, Blaxall BC, Berk BC, Yan C. A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis. Proc Natl Acad Sci USA 2005; 102: 14771-14776
    CrossrefPubMedGoogle Scholar
  • 2 Zhang M, Kass DA. Phosphodiesterases and cardiac cGMP: evolving roles and controversies. Trends Pharmacol Sci 2011; 32: 360-365
    CrossrefPubMedGoogle Scholar
  • 3 Feldman RD, Gros R. New insights into the regulation of cAMP synthesis beyond GPCR/G protein activation: Implications in cardiovascular regulation. Life Sci 2007; 81: 267-271
    CrossrefPubMedGoogle Scholar
  • 4 Chen J, Levin LR, Buck J. Role of Soluble Adenylyl Cyclase in the Heart. Am J Physiol Heart Circul Physiol 2012; 302: H-538-H-543
    PubMedGoogle Scholar
  • 5 Iancu RV, Ramamurthy G, Harvey RD. Spatial and temporal aspects of cAMP signalling in cardiac myocytes. Clin Exp Pharmacol Physiol 2008; 35: 1343-1348
    CrossrefPubMedGoogle Scholar
  • 6 Halls ML, Cooper DMF. Sub-picomolar relaxin signalling by a pre-assembled RXFP1, AKAP79, AC2, β-arrestin 2, PDE4D3 complex. EMBO J 2010; 29: 2772-2787
    CrossrefPubMedGoogle Scholar
  • 7 Zaccolo M. cAMP signal transduction in the heart: understanding spatial control for the development of novel therapeutic strategies. Br J Pharmacol 2009; 158: 50-60
    CrossrefPubMedGoogle Scholar
  • 8 Métrich M, Berthouze M, Morel E, Crozatier B, Gomez AM, Lezoualc’h F. Role of the cAMP-binding protein Epac in cardiovascular physiology and pathophysiology. Pflügers Archiv Eur J Physiol 2009; 459: 535-546
    PubMedGoogle Scholar
  • 9 Tsai EJ, Kass DA. Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics. Pharmacol Ther 2009; 122: 216-238
    CrossrefPubMedGoogle Scholar
  • 10 Castro LRV, Verde I, Cooper DM, Fischmeister R. Cyclic guanosine monophosphate compartmentation in rat cardiac myocytes. Circulation 2006; 113: 2221-2228
    CrossrefPubMedGoogle Scholar
  • 11 Bender AT, Beavo JA. Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use. Pharmacol Rev 2006; 58: 488-520
    CrossrefPubMedGoogle Scholar
  • 12 Conti M, Beavo J. Biochemistry and Physiology of Cyclic Nucleotide Phosphodiesterases: Essential Components in Cyclic Nucleotide Signaling. Annu Rev Biochem 2007; 76: 481-511
    Google Scholar
  • 13 Miller CL, Yan C. Targeting cyclic nucleotide phosphodiesterase in the heart: therapeutic implications. J Cardiovasc Transl Res 2010; 3: 507-515
    CrossrefPubMedGoogle Scholar
  • 14 Sonnenburg WK, Seger D, Beavo JA. Molecular cloning of a cDNA encoding the “61-kDa” calmodulin-stimulated cyclic nucleotide phosphodiesterase. Tissue-specific expression of structurally related isoforms. J Biol Chem 1993; 268: 645-652
    PubMedGoogle Scholar
  • 15 Yan C, Zhao AZ, Bentley JK, Beavo JA. The Calmodulin-dependent Phosphodiesterase Gene PDE1C Encodes Several Functionally Different Splice Variants in a Tissue-specific Manner. J Biol Chem 1996; 271: 25699-25706
    CrossrefPubMedGoogle Scholar
  • 16 Yan C, Kim D, Aizawa T, Berk BC. Functional Interplay Between Angiotensin II and Nitric Oxide. Arterioscler Thromb Vasc Biol 2003; 23: 26-36
    CrossrefPubMedGoogle Scholar
  • 17 Miller CL, Oikawa M, Cai Y, Wojtovich AP, Nagel DJ, Xu X, Xu H, Florio V, Rybalkin SD, Beavo JA, Chen Y-F, Li J-D, Blaxall BC, Abe J, Yan C. Role of Ca2+/Calmodulin-Stimulated Cyclic Nucleotide Phosphodiesterase 1 in Mediating Cardiomyocyte Hypertrophy. Circ Res 2009; 105: 956-964
    CrossrefPubMedGoogle Scholar
  • 18 Nagel DJ, Aizawa T, Jeon K-I, Liu W, Mohan A, Wei H, Miano JM, Florio VA, Gao P, Korshunov VA, Berk BC, Yan C. Role of Nuclear Ca2+/­Calmodulin-Stimulated Phosphodiesterase 1A in Vascular Smooth Muscle Cell Growth and Survival. Circ Res 2006; 98: 777-784
    CrossrefPubMedGoogle Scholar
  • 19 Miller CL, Cai Y, Oikawa M, Thomas T, Dostmann WR, Zaccolo M, Fujiwara K, Yan C. Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart. Basic Res Cardiol 2011; 106: 1023-1039
    CrossrefPubMedGoogle Scholar
  • 20 Bender AT, Beavo JA. PDE1B2 regulates cGMP and a subset of the phenotypic characteristics acquired upon macrophage differentiation from a monocyte. Proc Natl Acad Sci USA 2006; 103: 460-465
    CrossrefPubMedGoogle Scholar
  • 21 Reed TM, Repaske DR, Snyder GL, Greengard P, Vorhees CV. Phosphodiesterase 1B Knock-Out Mice Exhibit Exaggerated Locomotor Hyperactivity and DARPP-32 Phosphorylation in Response to Dopamine Agonists and Display Impaired Spatial Learning. J Neurosci 2002; 22: 5188-5197
    PubMedGoogle Scholar
  • 22 Kanda N, Watanabe S. Regulatory roles of adenylate cyclase and cyclic nucleotide phosphodiesterases 1 and 4 in interleukin-13 production by activated human T cells. Biochem Pharmacol 2001; 62: 495-507
    CrossrefPubMedGoogle Scholar
  • 23 Rybalkin SD, Rybalkina I, Beavo JA, Bornfeldt KE. Cyclic nucleotide phosphodiesterase 1C promotes human arterial smooth muscle cell proliferation. Circ Res 2002; 90: 151-157
    CrossrefPubMedGoogle Scholar
  • 24 Han P, Werber J, Surana M, Fleischer N, Michaeli T. The calcium/calmodulin-dependent phosphodiesterase PDE1C down-regulates glucose-induced insulin secretion. J Biol Chem 1999; 274: 22337-22344
    CrossrefPubMedGoogle Scholar
  • 25 Dunkern TR, Hatzelmann A. Characterization of inhibitors of phosphodiesterase 1C on a human cellular system. FEBS J 2007; 274: 4812-4824
    CrossrefPubMedGoogle Scholar
  • 26 Wallis RM, Corbin JD, Francis SH, Ellis P. Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol 1999; 83: 3-12
    PubMedGoogle Scholar
  • 27 Vandeput F, Wolda SL, Krall J, Hambleton R, Uher L, McCaw KN, Radwanski PB, Florio V, Movsesian MA. Cyclic Nucleotide Phosphodiesterase PDE1C1 in Human Cardiac Myocytes. J Biol Chem 2007; 282: 32749-32757
    CrossrefPubMedGoogle Scholar
  • 28 Loughney K, Martins TJ, Harris EAS, Sadhu K, Hicks JB, Sonnenburg WK, Beavo JA, Ferguson K. Isolation and Characterization of cDNAs Corresponding to Two Human Calcium, Calmodulin-regulated, 3′,5′-Cyclic Nucleotide Phosphodiesterases. J Biol Chem 1996; 271: 796-806
    CrossrefPubMedGoogle Scholar
  • 29 Beavo JA, Francis SH, Houslay MD. Cyclic nucleotide phosphodiesterases in health and disease. Boca Raton, Florida: CRC Press; 2006
    CrossrefGoogle Scholar
  • 30 Mongillo M, McSorley T, Evellin S, Sood A, Lissandron V, Terrin A, Huston E, Hannawacker A, Lohse MJ, Pozzan T, Houslay MD, Zaccolo M. Fluorescence Resonance Energy Transfer-Based Analysis of cAMP Dynamics in Live Neonatal Rat Cardiac Myocytes Reveals Distinct Functions of Compartmentalized Phosphodiesterases. Circ Res 2004; 95: 67-75
    CrossrefPubMedGoogle Scholar
  • 31 Sun B, Li H, Shakur Y, Hensley J, Hockman S, Kambayashi J, Manganiello VC, Liu Y. Role of phosphodiesterase type 3A and 3B in regulating platelet and cardiac function using subtype-selective knockout mice. Cell Signal 2007; 19: 1765-1771
    CrossrefPubMedGoogle Scholar
  • 32 Moberg E, Enoksson S, Hagström-Toft E. Importance of phosphodiesterase 3 for the lipolytic response in adipose tissue during insulin-induced hypoglycemia in normal man. Horm Metab Res 1998; 30: 684-688
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Choi YH, Ekholm D, Krall J, Ahmad F, Degerman E, Manganiello VC, Movsesian MA. Identification of a novel isoform of the cyclic-nucleotide phosphodiesterase PDE3A expressed in vascular smooth-muscle myocytes. Biochem J 2001; 353: 41-50
    CrossrefPubMedGoogle Scholar
  • 34 Shakur Y, Holst LS, Landstrom TR, Movsesian M, Degerman E, Manganiello V. Regulation and function of the cyclic nucleotide phosphodiesterase (PDE3) gene family. Prog Nucleic Acid Res Mol Biol 2001; 66: 241-277
    PubMedGoogle Scholar
  • 35 Kostic MM, Erdogan S, Rena G, Borchert G, Hoch B, Bartel S, Scotland G, Huston E, Houslay MD, Krause E-G. Altered Expression of PDE1 and PDE4 Cyclic Nucleotide Phosphodiesterase Isoforms in 7-oxo-prostacyclin-preconditioned Rat Heart. J Mol Cell Cardiol 1997; 29: 3135-3146
    CrossrefPubMedGoogle Scholar
  • 36 Mokni W, Keravis T, Etienne-Selloum N, Walter A, Kane MO, Schini-Kerth VB, Lugnier C. Concerted Regulation of cGMP and cAMP Phosphodiesterases in Early Cardiac Hypertrophy Induced by Angiotensin II. PLoS One 2010; 5: e14227
    CrossrefPubMedGoogle Scholar
  • 37 Richter W, Xie M, Scheitrum C, Krall J, Movsesian MA, Conti M. Conserved expression and functions of PDE4 in rodent and human heart. Basic Res Cardiol 2011; 106: 249-262
    CrossrefPubMedGoogle Scholar
  • 38 Leroy J, Richter W, Mika D, Castro LRV, Abi-Gerges A, Xie M, Scheitrum C, Lefebvre F, Schittl J, Mateo P, Westenbroek R, Catterall WA, Charpentier F, Conti M, Fischmeister R, Vandecasteele G. Phosphodiesterase 4B in the cardiac L-type Ca2+ channel complex regulates Ca2+ current and protects against ventricular arrhythmias in mice. J Clin Invest 2011; 121: 2651-2661
    CrossrefPubMedGoogle Scholar
  • 39 Kotera J, Fujishige K, Imai Y, Kawai E, Michibata H, Akatsuka H, Yanaka N, Omori K. Genomic origin and transcriptional regulation of two variants of cGMP binding cGMP specific phosphodiesterases. Eur J Biochem 1999; 262: 866-873
    CrossrefPubMedGoogle Scholar
  • 40 Pokreisz P, Vandenwijngaert S, Bito V, Van den Bergh A, Lenaerts I, Busch C, Marsboom G, Gheysens O, Vermeersch P, Biesmans L, Liu X, Gillijns H, Pellens M, Van Lommel A, Buys E, Schoonjans L, Vanhaecke J, Verbeken E, Sipido K, Herijgers P, Bloch KD, Janssens SP. Ventricular Phosphodiesterase-5 Expression Is Increased in Patients With Advanced Heart Failure and Contributes to Adverse Ventricular Remodeling After Myocardial Infarction in Mice. Circulation 2009; 119: 408-416
    CrossrefPubMedGoogle Scholar
  • 41 Corbin J, Rannels S, Neal D, Chang P, Grimes K, Beasley A, Francis S. Sildenafil citrate does not affect cardiac contractility in human or dog heart. Curr Med Res Opin 2003; 19: 747-752
    CrossrefPubMedGoogle Scholar
  • 42 Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, St Aubin C, Webster L, Rebeyka IM, Ross DB, Light PE, Dyck JRB, Michelakis ED. Phosphodiesterase Type 5 Is Highly Expressed in the Hypertrophied Human Right Ventricle, and Acute Inhibition of Phosphodiesterase Type 5 Improves Contractility. Circulation 2007; 116: 238-248
    CrossrefPubMedGoogle Scholar
  • 43 Kass DA, Takimoto E, Nagayama T, Champion HC. Phosphodiesterase regulation of nitric oxide signaling. Cardiovasc Res 2007; 75: 303-314
    CrossrefPubMedGoogle Scholar
  • 44 Zhang M, Koitabashi N, Nagayama T, Rambaran R, Feng N, Takimoto E, Koenke T, O’Rourke B, Champion HC, Crow MT, Kass DA. Expression, Activity, and Pro-Hypertrophic Effects of PDE5A in Cardiac Myocytes. Cell Signal 2008; 20: 2231-2236
    CrossrefPubMedGoogle Scholar
  • 45 Lukowski R, Rybalkin SD, Loga F, Leiss V, Beavo JA, Hofmann F. Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes. Proc Natl Acad Sci USA 2010; 107: 5646-5651
    CrossrefPubMedGoogle Scholar
  • 46 Patrucco E, Albergine MS, Santana LF, Beavo JA. Phosphodiesterase 8A (PDE8A) regulates excitation-contraction coupling in ventricular myocytes. J Mol Cell Cardiol 2010; 49: 330-333
    CrossrefPubMedGoogle Scholar
  • 47 Rentero C, Monfort A, Puigdomènech P. Identification and distribution of different mRNA variants produced by differential splicing in the human phosphodiesterase 9A gene. Biochem Biophys Res Commun 2003; 301: 686-692
    CrossrefPubMedGoogle Scholar
  • 48 Galindo-Tovar A, Vargas ML, Kaumann AJ. Phosphodiesterases PDE3 and PDE4 jointly control the inotropic effects but not chronotropic effects of ( − )-CGP12177 despite PDE4-evoked sinoatrial bradycardia in rat atrium. Naunyn-Schmied Arch Pharmacol 2008; 379: 379-384
    PubMedGoogle Scholar
  • 49 Kaumann AJ. Phosphodiesterases reduce spontaneous sinoatrial beating but not the “fight or flight” tachycardia elicited by agonists through Gs-protein-coupled receptors. Trends Pharmacol Sci 2011; 32: 377-383
    CrossrefPubMedGoogle Scholar
  • 50 DiFrancesco D, Tortora P. Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature 1991; 351: 145-147
    CrossrefPubMedGoogle Scholar
  • 51 Alig J, Marger L, Mesirca P, Ehmke H, Mangoni ME, Isbrandt D. Control of heart rate by cAMP sensitivity of HCN channels. Proc Natl Acad Sci USA 2009; 106: 12189-12194
    CrossrefPubMedGoogle Scholar
  • 52 Galindo Tovar A, Kaumann AJ. Phosphodiesterase 4 blunts inotropism and arrhythmias but not sinoatrial tachycardia of (–)-adrenaline mediated through mouse cardiac β1adrenoceptors. Br J Pharmacol 2008; 153: 710-720
    CrossrefPubMedGoogle Scholar
  • 53 Galindo-Tovar A, Vargas ML, Kaumann AJ. Function of cardiac [beta]1- and [beta]2-adrenoceptors of newborn piglets: Role of phosphodiesterases PDE3 and PDE4. Eur J Pharmacol 2010; 638: 99-107
    CrossrefPubMedGoogle Scholar
  • 54 Christ T, Galindo-Tovar A, Thoms M, Ravens U, Kaumann AJ. Inotropy and L-type Ca2+ current, activated by β1- and β2-adrenoceptors, are differently controlled by phosphodiesterases 3 and 4 in rat heart. Br J Pharmacol 2009; 156: 62-83
    CrossrefPubMedGoogle Scholar
  • 55 Yan C, Miller CL, Abe J. Regulation of Phosphodiesterase 3 and Inducible cAMP Early Repressor in the Heart. Circ Res 2007; 100: 489-501
    CrossrefPubMedGoogle Scholar
  • 56 Matthew AM. PDE3 inhibition in dilated cardiomyopathy: reasons to reconsider. J Card Fail 2003; 9: 475-480
    CrossrefPubMedGoogle Scholar
  • 57 Singh A, Redden JM, Kapiloff MS, Dodge-Kafka KL. The Large Isoforms of A-Kinase Anchoring Protein 18 Mediate the Phosphorylation of Inhibitor-1 by Protein Kinase A and the Inhibition of Protein Phosphatase 1 Activity. Mol Pharmacol 2011; 79: 533-540
    CrossrefPubMedGoogle Scholar
  • 58 Layland J, Li J-M, Shah AM. Role of cyclic GMP-dependent protein kinase in the contractile response to exogenous nitric oxide in rat cardiac myocytes. J Physiol 2002; 540: 457-467
    CrossrefPubMedGoogle Scholar
  • 59 Yang L, Liu G, Zakharov SI, Bellinger AM, Mongillo M, Marx SO. Protein kinase G phosphorylates Cav1.2 alpha1c and beta2 subunits. Circ Res 2007; 101: 465-474
    CrossrefPubMedGoogle Scholar
  • 60 Dittrich M, Jurevicius J, Georget M, Rochais F, Fleischmann B, Hescheler J, Fischmeister R. Local response of L-type Ca(2+) current to nitric oxide in frog ventricular myocytes. J Physiol (Lond) 2001; 534: 109-121
    CrossrefPubMedGoogle Scholar
  • 61 Rivet-Bastide M, Vandecasteele G, Hatem S, Verde I, Bénardeau A, Mercadier JJ, Fischmeister R. cGMP-stimulated cyclic nucleotide phosphodiesterase regulates the basal calcium current in human atrial myocytes. J Clin Invest 1997; 99: 2710-2718
    CrossrefPubMedGoogle Scholar
  • 62 Méry PF, Lohmann SM, Walter U, Fischmeister R. Ca2+ current is regulated by cyclic GMP-dependent protein kinase in mammalian cardiac myocytes. Proc Natl Acad Sci USA 1991; 88: 1197-1201
    CrossrefPubMedGoogle Scholar
  • 63 Fischmeister R, Castro L, Abi-Gerges A, Rochais F, Vandecasteele G. Species- and tissue-dependent effects of NO and cyclic GMP on cardiac ion channels. Comp Biochem Physiol Part A: Mol Integ Physiol 2005; 142: 136-143
    PubMedGoogle Scholar
  • 64 Vandecasteele G, Verde I, Rücker-Martin C, Donzeau-Gouge P, Fischmeister R. Cyclic GMP regulation of the L-type Ca2+ channel current in human atrial myocytes. J Physiol 2001; 533: 329-340
    CrossrefPubMedGoogle Scholar
  • 65 Mongillo M, Tocchetti CG, Terrin A, Lissandron V, Cheung Y-F, Dostmann WR, Pozzan T, Kass DA, Paolocci N, Houslay MD, Zaccolo M. Compartmentalized phosphodiesterase-2 activity blunts beta-adrenergic cardiac inotropy via an NO/cGMP-dependent pathway. Circ Res 2006; 98: 226-234
    CrossrefPubMedGoogle Scholar
  • 66 Kerfant B-G, Zhao D, Lorenzen-Schmidt I, Wilson LS, Cai S, Chen SRW, Maurice DH, Backx PH. PI3Kγ Is Required for PDE4, not PDE3, Activity in Subcellular Microdomains Containing the Sarcoplasmic Reticular Calcium ATPase in Cardiomyocytes. Circ Res 2007; 101: 400-408
    CrossrefPubMedGoogle Scholar
  • 67 Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med 1991; 325: 1468-1475
    CrossrefPubMedGoogle Scholar
  • 68 Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin SD, Silengo L, Altruda F, Wetzker R, Wymann MP, Lembo G, Hirsch E. PI3K[gamma] Modulates the Cardiac Response to Chronic Pressure Overload by Distinct Kinase-Dependent and -Independent Effects. Cell 2004; 118: 375-387
    CrossrefPubMedGoogle Scholar
  • 69 De Arcangelis V, Liu R, Soto D, Xiang Y. Differential association of phosphodiesterase 4D isoforms with beta2-adrenoceptor in cardiac myocytes. J Biol Chem 2009; 284: 33824-33832
    CrossrefPubMedGoogle Scholar
  • 70 Baillie GS, Sood A, McPhee I, Gall I, Perry SJ, Lefkowitz RJ, Houslay MD. beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi. Proc Natl Acad Sci USA 2003; 100: 940-945
    CrossrefPubMedGoogle Scholar
  • 71 Richter W, Day P, Agrawal R, Bruss MD, Granier S, Wang YL, Rasmussen SGF, Horner K, Wang P, Lei T, Patterson AJ, Kobilka B, Conti M. Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4. EMBO J 2008; 27: 384-393
    CrossrefPubMedGoogle Scholar
  • 72 Lehnart SE, Wehrens XHT, Reiken S, Warrier S, Belevych AE, Harvey RD, Richter W, Jin S-LC, Conti M, Marks AR. Phosphodiesterase 4D Deficiency in the Ryanodine-Receptor Complex Promotes Heart Failure and Arrhythmias. Cell 2005; 123: 25-35
    CrossrefPubMedGoogle Scholar
  • 73 Beca S, Helli PB, Simpson JA, Zhao D, Farman GP, Jones P, Tian X, Wilson LS, Ahmad F, Chen SRW, Movsesian MA, Manganiello V, Maurice DH, Conti M, Backx PH. Phosphodiesterase 4D Regulates Baseline Sarcoplasmic Reticulum Ca2+ Release and Cardiac Contractility, Independently of L-Type Ca2+ Current. Circ Res 2011; 109: 1024-1030
    CrossrefPubMedGoogle Scholar
  • 74 Takimoto E, Belardi D, Tocchetti CG, Vahebi S, Cormaci G, Ketner EA, Moens AL, Champion HC, Kass DA. Compartmentalization of Cardiac β-Adrenergic Inotropy Modulation by Phosphodiesterase Type 5. Circulation 2007; 115: 2159-2167
    CrossrefPubMedGoogle Scholar
  • 75 Borlaug BA, Melenovsky V, Marhin T, Fitzgerald P, Kass DA. Sildenafil Inhibits β-Adrenergic-Stimulated Cardiac Contractility in Humans. Circulation 2005; 112: 2642-2649
    CrossrefPubMedGoogle Scholar
  • 76 Takimoto E, Champion HC, Belardi D, Moslehi J, Mongillo M, Mergia E, Montrose DC, Isoda T, Aufiero K, Zaccolo M, Dostmann WR, Smith CJ, Kass DA. cGMP Catabolism by Phosphodiesterase 5A Regulates Cardiac Adrenergic Stimulation by NOS3-Dependent Mechanism. Circ Res 2005; 96: 100-109
    PubMedGoogle Scholar
  • 77 Ding B, Abe J, Wei H, Huang Q, Walsh RA, Molina CA, Zhao A, Sadoshima J, Blaxall BC, Berk BC, Yan C. Functional role of phosphodiesterase 3 in cardiomyocyte apoptosis: implication in heart failure. Circulation 2005; 111: 2469-2476
    CrossrefPubMedGoogle Scholar
  • 78 Francis SH, Blount MA, Corbin JD. Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions. Physiol Rev 2011; 91: 651-690
    Google Scholar
  • 79 Yan C, Ding B, Shishido T, Woo C-H, Itoh S, Jeon K-I, Liu W, Xu H, McClain C, Molina CA, Blaxall BC, Abe J. Activation of Extracellular Signal-Regulated Kinase 5 Reduces Cardiac Apoptosis and Dysfunction via Inhibition of a Phosphodiesterase 3A/Inducible cAMP Early Repressor Feedback Loop. Circ Res 2007; 100: 510-519
    CrossrefPubMedGoogle Scholar
  • 80 Abi-Gerges A, Richter W, Lefebvre F, Mateo P, Varin A, Heymes C, Samuel J-L, Lugnier C, Conti M, Fischmeister R, Vandecasteele G. Decreased Expression and Activity of cAMP Phosphodiesterases in Cardiac Hypertrophy and Its Impact on β-Adrenergic cAMP Signals. Circ Res 2009; 105: 784-792
    CrossrefPubMedGoogle Scholar
  • 81 Ma D, Fu L, Shen J, Zhou P, Gao Y, Xie R, Li Y, Han Y, Wang Y, Wang F. Interventional effect of valsartan on expression of inducible cAMP early repressor and phosphodiesterase 3A in rats after myocardial infarction. Eur J Pharmacol 2009; 602: 348-354
    CrossrefPubMedGoogle Scholar
  • 82 Holbrook M, Coker SJ. Effects of zaprinast and rolipram on platelet aggregation and arrhythmias following myocardial ischaemia and reperfusion in anaesthetized rabbits. Br J Pharmacol 1991; 103: 1973-1979
    CrossrefPubMedGoogle Scholar
  • 83 Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 2000; 101: 365-376
    CrossrefPubMedGoogle Scholar
  • 84 Wehrens XHT, Lehnart SE, Huang F, Vest JA, Reiken SR, Mohler PJ, Sun J, Guatimosim S, Song L-S, Rosemblit N, D’Armiento JM, Napolitano C, Memmi M, Priori SG, Lederer WJ, Marks AR. FKBP12.6 Deficiency and Defective Calcium Release Channel (Ryanodine Receptor) Function Linked to Exercise-Induced Sudden Cardiac Death. Cell 2003; 113: 829-840
    CrossrefPubMedGoogle Scholar
  • 85 Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR. PKA Phosphorylation Dissociates FKBP12.6 from the Calcium Release Channel (Ryanodine Receptor): Defective Regulation in Failing Hearts. Cell 2000; 101: 365-376
    CrossrefPubMedGoogle Scholar
  • 86 Molina CE, Leroy J, Richter W, Xie M, Scheitrum C, Lee I-O, Maack C, Rucker-Martin C, Donzeau-Gouge P, Verde I, Llach A, Hove-Madsen L, Conti M, Vandecasteele G, Fischmeister R. Cyclic Adenosine Monophosphate Phosphodiesterase Type 4 Protects Against Atrial Arrhythmias. J Am Coll Cardiol 2012; 59: 2182-2190
    CrossrefPubMedGoogle Scholar
  • 87 Vandeput F, Krall J, Ockaili R, Salloum FN, Florio V, Corbin JD, Francis SH, Kukreja RC, Movsesian MA. cGMP-Hydrolytic Activity and Its Inhibition by Sildenafil in Normal and Failing Human and Mouse Myocardium. J Pharmacol Exp Therap 2009; 330: 884-891
    CrossrefPubMedGoogle Scholar
  • 88 Kukreja RC, Ockaili R, Salloum F, Yin C, Hawkins J, Das A, Xi L. Cardioprotection with phosphodiesterase-5 inhibition – a novel preconditioning strategy. J Mol Cell Cardiol 2004; 36: 165-173
    CrossrefPubMedGoogle Scholar
  • 89 Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC. Phosphodiesterase-5 Inhibition With Sildenafil Attenuates Cardiomyocyte Apoptosis and Left Ventricular Dysfunction in a Chronic Model of Doxorubicin Cardiotoxicity. Circulation 2005; 111: 1601-1610
    CrossrefPubMedGoogle Scholar
  • 90 Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 2005; 11: 214-222
    CrossrefPubMedGoogle Scholar
  • 91 Das A, Xi L, Kukreja RC. Phosphodiesterase-5 Inhibitor Sildenafil Preconditions Adult Cardiac Myocytes against Necrosis and Apoptosis. J Biol Chem 2005; 280: 12944-12955
    CrossrefPubMedGoogle Scholar
  • 92 Koitabashi N, Aiba T, Hesketh GG, Rowell J, Zhang M, Takimoto E, Tomaselli GF, Kass DA. Cyclic GMP/PKG-dependent inhibition of TRPC6 channel activity and expression negatively regulates cardiomyocyte NFAT activation Novel mechanism of cardiac stress modulation by PDE5 inhibition. J Mol Cell Cardiol 2010; 48: 713-724
    CrossrefPubMedGoogle Scholar
  • 93 Redondo J, Bishop JE, Wilkins MR. Effect of atrial natriuretic peptide and cyclic GMP phosphodiesterase inhibition on collagen synthesis by adult cardiac fibroblasts. Br J Pharmacol 1998; 124: 1455-1462
    CrossrefPubMedGoogle Scholar
  • 94 Zhang M, Takimoto E, Hsu S, Lee DI, Nagayama T, Danner T, Koitabashi N, Barth AS, Bedja D, Gabrielson KL, Wang Y, Kass DA. Myocardial Remodeling Is Controlled by Myocyte-Targeted Gene Regulation of Phosphodiesterase Type 5. J Am Coll Cardiol 2010; 56: 2021-2030
    CrossrefPubMedGoogle Scholar
  • 95 Das A, Xi L, Kukreja RC. Protein Kinase G-dependent Cardioprotective Mechanism of Phosphodiesterase-5 Inhibition Involves Phosphorylation of ERK and GSK3β. J Biol Chem 2008; 283: 29572-29585
    CrossrefPubMedGoogle Scholar
  • 96 Takimoto E, Koitabashi N, Hsu S, Ketner EA, Zhang M, Nagayama T, Bedja D, Gabrielson KL, Blanton R, Siderovski DP, Mendelsohn ME, Kass DA. Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. J Clin Invest 2009; 119: 408-420
    PubMedGoogle Scholar
  • 97 Chakir K, Zhu W, Tsang S, Woo AY-H, Yang D, Wang X, Zeng X, Rhee M-H, Mende U, Koitabashi N, Takimoto E, Blumer KJ, Lakatta EG, Kass DA, Xiao R-P. RGS2 is a primary terminator of [beta]2-adrenergic receptor-mediated Gi signaling. J Mol Cell Cardiol 2011; 50: 1000-1007
    CrossrefPubMedGoogle Scholar
  • 98 Frantz S, Klaiber M, Baba HA, Oberwinkler H, Völker K, Gaβner B, Bayer B, Abeβer M, Schuh K, Feil R, Hofmann F, Kuhn M. Stress-Dependent Dilated Cardiomyopathy in Mice with Cardiomyocyte-Restricted Inactivation of Cyclic GMP-Dependent Protein Kinase I. Eur Heart J Dec 2011; [Epub ahead of print]. Available from: http://eurheartj.oxfordjournals.org/content/early/2011/12/23/eurheartj.ehr445
    PubMedGoogle Scholar
  • 99 Baim DS, McDowell AV, Cherniles J, Monrad ES, Parker JA, Edelson J, Braunwald E, Grossman W. Evaluation of a new bipyridine inotropic agent – milrinone – in patients with severe congestive heart failure. N Engl J Med 1983; 309: 748-756
    CrossrefPubMedGoogle Scholar
  • 100 Jaski BE, Fifer MA, Wright RF, Braunwald E, Colucci WS. Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside. J Clin Invest 1985; 75: 643-649
    CrossrefPubMedGoogle Scholar
  • 101 Amsallem E, Kasparian C, Haddour G, Boissel J-P, Nony P. Phosphodiesterase III inhibitors for heart failure. In: The Cochrane Collaboration. Nony P. (ed.). Cochrane Database of Systematic Reviews. Chichester, UK: Wiley; 2005
    Google Scholar
  • 102 Movsesian MA, Alharethi R. Inhibitors of cyclic nucleotide phosphodiesterase PDE3 as adjunct therapy for dilated cardiomyopathy. Expert Opin Investig Drugs 2002; 11: 1529-1536
    CrossrefPubMedGoogle Scholar
  • 103 Cuffe MS, Califf RM, Adams KF, Benza R, Bourge R, Colucci WS, Massie BM, O’Connor CM, Pina I, Quigg R, Silver MA, Gheorghiade M. Short-Term Intravenous Milrinone for Acute Exacerbation of Chronic Heart Failure A Randomized Controlled Trial. JAMA 2002; 287: 1541-1547
    CrossrefPubMedGoogle Scholar
  • 104 Assad-Kottner C, Chen D, Jahanyar J, Cordova F, Summers N, Loebe M, Merla R, Youker K, Torre-Amione G. The Use of Continuous Milrinone Therapy as Bridge to Transplant Is Safe in Patients With Short Waiting Times. J Card Fail 2008; 14: 839-843
    CrossrefPubMedGoogle Scholar
  • 105 Canver CC, Chanda J. Milrinone for long-term pharmacologic support of the status 1 heart transplant candidates. Ann Thor Surg 2000; 69: 1823-1826
    CrossrefPubMedGoogle Scholar
  • 106 Chapman TM, Goa KL. Cilostazol: a review of its use in intermittent claudication. Am J Cardiovasc Drugs 2003; 3: 117-138
    CrossrefPubMedGoogle Scholar
  • 107 Sun B, Le SN, Lin S, Fong M, Guertin M, Liu Y, Tandon NN, Yoshitake M, Kambayashi J-I. New mechanism of action for cilostazol: interplay between adenosine and cilostazol in inhibiting platelet activation. J Cardiovasc Pharmacol 2002; 40: 577-585
    CrossrefPubMedGoogle Scholar
  • 108 Wang S, Cone J, Fong M, Yoshitake M, Kambayashi Ji, Liu Y. Interplay between inhibition of adenosine uptake and phosphodiesterase type 3 on cardiac function by cilostazol, an agent to treat intermittent claudication. J Cardiovasc Pharmacol 2001; 38: 775-783
    CrossrefPubMedGoogle Scholar
  • 109 Shakur Y, Fong M, Hensley J, Cone J, Movsesian MA, Kambayashi J-I, Yoshitake M, Liu Y. Comparison of the effects of cilostazol and milrinone on cAMP-PDE activity, intracellular cAMP and calcium in the heart. Cardiovasc Drugs Ther 2002; 16: 417-427
    CrossrefPubMedGoogle Scholar
  • 110 Kass DA, Champion HC, Beavo JA. Phosphodiesterase type 5: expanding roles in cardiovascular regulation. Circ Res 2007; 101: 1084-1095
    CrossrefPubMedGoogle Scholar
  • 111 Bergot E, Magnier R, Zalcman G. Phosphodiesterase Inhibitors for Pulmonary Hypertension. N Eng J Med 2010; 362: 559-560
    CrossrefPubMedGoogle Scholar
  • 112 Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 Inhibition With Sildenafil Improves Left Ventricular Diastolic Function, Cardiac Geometry, and Clinical Status in Patients With Stable Systolic Heart Failure/Clinical Perspective. Circulation: Heart Fail 2011; 4: 8-17
    PubMedGoogle Scholar
  • 113 Giannetta E, Isidori AM, Galea N, Carbone I, Mandosi E, Vizza CD, Naro F, Morano S, Fedele F, Lenzi A. Chronic Inhibition of Cyclic GMP Phosphodiesterase 5A Improves Diabetic Cardiomyopathy: A Randomized, Controlled Clinical Trial Using Magnetic Resonance Imaging with Myocardial Tagging. Circulation 2012; 125: 2323-2333
    CrossrefPubMedGoogle Scholar
  • 114 Herrmann HC, Chang G, Klugherz BD, Mahoney PD. Hemodynamic effects of sildenafil in men with severe coronary artery disease. N Engl J Med 2000; 342: 1622-1626
    CrossrefPubMedGoogle Scholar
  • 115 Denardo SJ, Wen X, Handberg EM, Bairey Merz CN, Sopko GS, Cooper-Dehoff RM, Pepine CJ. Effect of Phosphodiesterase Type 5 Inhibition on Microvascular Coronary Dysfunction in Women: A Women’s Ischemia Syndrome Evaluation (WISE) Ancillary Study. Clin Cardiol 2011; 34: 483-487
    CrossrefPubMedGoogle Scholar