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Role of Phosphodiesterases in Adult-Onset Pulmonary Arterial Hypertension

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Phosphodiesterases as Drug Targets

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 204))

Abstract

Pulmonary arterial hypertension (PAH) is characterized by increased mean pulmonary artery pressure (mPAP) due to vasoconstriction and structural changes in the small pulmonary arteries (PAs); proliferation of pulmonary artery smooth muscle cells (PASMCs) contributes to the remodeling. The abnormal pathophysiology in the pulmonary vasculature relates to decreased cyclic nucleotide levels in PASMCs. Phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, thereby PDE inhibitors are effective in vasodilating the PA and decreasing PASMC proliferation. Experimental studies support the use of PDE3, PDE5, and PDE1 inhibitors in PAH. PDE5 inhibitors such as sildenafil are clinically approved to treat different forms of PAH and lower mPAP, increase functional capacity, and decrease right ventricular hypertrophy, without decreasing systemic arterial pressure. New evidence suggests that the combination of PDE inhibitors with other therapies for PAH may be beneficial in treating the disease. Furthermore, inhibiting PDEs in the heart and the inflammatory cells that infiltrate the PA may offer new targets to reduce right ventricular hypertrophy and inhibit inflammation that is associated with and contributes to the development of PAH. This chapter summarizes the advances in the area and the future of PDEs in PAH.

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References

  • Ahn HS, Foster M, Cable M, Pitts BJ, Sybertz EJ (1991) Ca/CaM-stimulated and cGMP-specific phosphodiesterases in vascular and non-vascular tissues. Adv Exp Med Biol 308:191–197

    PubMed  CAS  Google Scholar 

  • Andersen A, Nielsen JM, Peters CD, Schou UK, Sloth E, Nielsen-Kudsk JE (2008) Effects of phosphodiesterase-5 inhibition by sildenafil in the pressure overloaded right heart. Eur J Heart Fail 10:1158–1165

    Article  PubMed  CAS  Google Scholar 

  • Archer SL, Huang JM, Hampl V, Nelson DP, Shultz PJ, Weir EK (1994) Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proc Natl Acad Sci USA 91:7583–7587

    Article  PubMed  CAS  Google Scholar 

  • Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, Torbicki A (2009) Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 54:S55–S66

    Article  PubMed  Google Scholar 

  • Balabanian K, Foussat A, Dorfmuller P, Durand-Gasselin I, Capel F, Bouchet-Delbos L, Portier A, Marfaing-Koka A, Krzysiek R, Rimaniol AC, Simonneau G, Emilie D, Humbert M (2002) CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med 165:1419–1425

    Article  PubMed  Google Scholar 

  • Baliga RS, Zhao L, Madhani M, Lopez-Torondel B, Visintin C, Selwood D, Wilkins MR, MacAllister RJ, Hobbs AJ (2008) Synergy between natriuretic peptides and phosphodiesterase 5 inhibitors ameliorates pulmonary arterial hypertension. Am J Respir Crit Care Med 178:861–869

    Article  PubMed  CAS  Google Scholar 

  • Barman SA, Zhu S, Han G, White RE (2003) cAMP activates BKCa channels in pulmonary arterial smooth muscle via cGMP-dependent protein kinase. Am J Physiol Lung Cell Mol Physiol 284:L1004–L1011

    PubMed  CAS  Google Scholar 

  • Barnes PJ, Liu SF (1995) Regulation of pulmonary vascular tone. Pharmacol Rev 47:87–131

    PubMed  CAS  Google Scholar 

  • Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58:488–520

    Article  PubMed  CAS  Google Scholar 

  • Black SM, Sanchez LS, Mata-Greenwood E, Bekker JM, Steinhorn RH, Fineman JR (2001) sGC and PDE5 are elevated in lambs with increased pulmonary blood flow and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 281:L1051–L1057

    PubMed  CAS  Google Scholar 

  • Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF (2009) The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest 135:794–804

    Article  PubMed  CAS  Google Scholar 

  • Botha P, Parry G, Dark JH, Macgowan GA (2009) Acute hemodynamic effects of intravenous sildenafil citrate in congestive heart failure: comparison of phosphodiesterase type-3 and -5 inhibition. J Heart Lung Transplant 28:676–682

    Article  PubMed  Google Scholar 

  • Chaouat A, Coulet F, Favre C, Simonneau G, Weitzenblum E, Soubrier F, Humbert M (2004) Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax 59:446–448

    Article  PubMed  CAS  Google Scholar 

  • Clarke WR, Uezono S, Chambers A, Doepfner P (1994) The type III phosphodiesterase inhibitor milrinone and type V PDE inhibitor dipyridamole individually and synergistically reduce elevated pulmonary vascular resistance. Pulm Pharmacol 7:81–89

    Article  PubMed  CAS  Google Scholar 

  • Cohen AH, Hanson K, Morris K, Fouty B, McMurty IF, Clarke W, Rodman DM (1996) Inhibition of cyclic 3′-5′-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxic rats. J Clin Invest 97:172–179

    Article  PubMed  CAS  Google Scholar 

  • Corbin JD, Beasley A, Blount MA, Francis SH (2005) High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors. Biochem Biophys Res Commun 334:930–938

    Article  PubMed  CAS  Google Scholar 

  • D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT et al (1991) Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 115:343–349

    PubMed  Google Scholar 

  • Deb B, Bradford K, Pearl RG (2000) Additive effects of inhaled nitric oxide and intravenous milrinone in experimental pulmonary hypertension. Crit Care Med 28:795–799

    Article  PubMed  CAS  Google Scholar 

  • Dempsie Y, Morecroft I, Welsh DJ, MacRitchie NA, Herold N, Loughlin L, Nilsen M, Peacock AJ, Harmar A, Bader M, MacLean MR (2008) Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice. Circulation 117:2928–2937

    Article  PubMed  CAS  Google Scholar 

  • Dent G, Magnussen H, Rabe KF (1994) Cyclic nucleotide phosphodiesterases in the human lung. Lung 172:129–146

    Article  PubMed  CAS  Google Scholar 

  • Dolci S, Belmonte A, Santone R, Giorgi M, Pellegrini M, Carosa E, Piccione E, Lenzi A, Jannini EA (2006) Subcellular localization and regulation of type-1C and type-5 phosphodiesterases. Biochem Biophys Res Commun 341:837–846

    Article  PubMed  CAS  Google Scholar 

  • Dony E, Lai YJ, Dumitrascu R, Pullamsetti SS, Savai R, Ghofrani HA, Weissmann N, Schudt C, Flockerzi D, Seeger W, Grimminger F, Schermuly RT (2008) Partial reversal of experimental pulmonary hypertension by phosphodiesterase-3/4 inhibition. Eur Respir J 31:599–610

    Article  PubMed  CAS  Google Scholar 

  • Dunkerley HA, Tilley DG, Palmer D, Liu H, Jimmo SL, Maurice DH (2002) Reduced phosphodiesterase 3 activity and phosphodiesterase 3A level in synthetic vascular smooth muscle cells: implications for use of phosphodiesterase 3 inhibitors in cardiovascular tissues. Mol Pharmacol 61:1033–1040

    Article  PubMed  CAS  Google Scholar 

  • Eddahibi S, Raffestin B, Monnier L, de Gouville AC, Adnot S (1998) Effect of DMPPO, a phosphodiesterase type 5 inhibitor, on hypoxic pulmonary hypertension in rats. Br J Pharmacol 125:681–688

    Article  PubMed  CAS  Google Scholar 

  • Evgenov OV, Busch CJ, Evgenov NV, Liu R, Petersen B, Falkowski GE, Petho B, Vas A, Bloch KD, Zapol WM, Ichinose F (2006) 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 290:L723–L729

    Article  PubMed  CAS  Google Scholar 

  • Fink TL, Francis SH, Beasley A, Grimes KA, Corbin JD (1999) Expression of an active, monomeric catalytic domain of the cGMP-binding cGMP-specific phosphodiesterase (PDE5). J Biol Chem 274:34613–34620

    Article  PubMed  CAS  Google Scholar 

  • Francis SH, Chu DM, Thomas MK, Beasley A, Grimes K, Busch JL, Turko IV, Haik TL, Corbin JD (1998) Ligand-induced conformational changes in cyclic nucleotide phosphodiesterases and cyclic nucleotide-dependent protein kinases. Methods 14:81–92

    Article  PubMed  CAS  Google Scholar 

  • Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353:2148–2157

    Article  PubMed  CAS  Google Scholar 

  • Galie N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, Shapiro S, White RJ, Chan M, Beardsworth A, Frumkin L, Barst RJ (2009a) Tadalafil therapy for pulmonary arterial hypertension. Circulation 119:2894–2903

    Article  PubMed  CAS  Google Scholar 

  • Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G (2009b) Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 34:1219–1263

    Article  PubMed  CAS  Google Scholar 

  • Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G, Vahanian A, Auricchio A, Bax J, Ceconi C, Dean V, Filippatos G, Funck-Brentano C, Hobbs R, Kearney P, McDonagh T, McGregor K, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas P, Widimsky P, Al Attar N, Andreotti F, Aschermann M, Asteggiano R, Benza R, Berger R, Bonnet D, Delcroix M, Howard L, Kitsiou AN, Lang I, Maggioni A, Nielsen-Kudsk JE, Park M, Perrone-Filardi P, Price S, Domenech MT, Vonk-Noordegraaf A, Zamorano JL (2009c) Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 30:2493–2537

    Article  PubMed  Google Scholar 

  • Gantner F, Schudt C, Wendel A, Hatzelmann A (1999) Characterization of the phosphodiesterase (PDE) pattern of in vitro-generated human dendritic cells (DC) and the influence of PDE inhibitors on DC function. Pulm Pharmacol Ther 12:377–386

    Article  PubMed  CAS  Google Scholar 

  • Ghofrani HA, Wiedemann R, Rose F, Olschewski H, Schermuly RT, Weissmann N, Seeger W, Grimminger F (2002) Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 136:515–522

    PubMed  CAS  Google Scholar 

  • Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Kreckel A, Weissmann N, Ghofrani S, Enke B, Seeger W, Grimminger F (2003) Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 42:158–164

    Article  PubMed  CAS  Google Scholar 

  • Ghofrani HA, Voswinckel R, Reichenberger F, Olschewski H, Haredza P, Karadas B, Schermuly RT, Weissmann N, Seeger W, Grimminger F (2004) Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study. J Am Coll Cardiol 44:1488–1496

    PubMed  CAS  Google Scholar 

  • Giembycz MA, Corrigan CJ, Seybold J, Newton R, Barnes PJ (1996) Identification of cyclic AMP phosphodiesterases 3, 4 and 7 in human CD4+ and CD8+ T-lymphocytes: role in regulating proliferation and the biosynthesis of interleukin-2. Br J Pharmacol 118:1945–1958

    PubMed  CAS  Google Scholar 

  • Goraya TA, Cooper DM (2005) Ca2+ -calmodulin-dependent phosphodiesterase (PDE1): current perspectives. Cell Signal 17:789–797

    Article  PubMed  CAS  Google Scholar 

  • Grandoch M, Roscioni SS, Schmidt M (2010) The role of Epac proteins, novel cAMP mediators, in the regulation of immune, lung and neuronal function. Br J Pharmacol 159:265–284

    Article  PubMed  CAS  Google Scholar 

  • Guilluy C, Sauzeau V, Rolli-Derkinderen M, Guerin P, Sagan C, Pacaud P, Loirand G (2005) Inhibition of RhoA/Rho kinase pathway is involved in the beneficial effect of sildenafil on pulmonary hypertension. Br J Pharmacol 146:1010–1018

    Article  PubMed  CAS  Google Scholar 

  • Hanasato N, Oka M, Muramatsu M, Nishino M, Adachi H, Fukuchi Y (1999) E-4010, a selective phosphodiesterase 5 inhibitor, attenuates hypoxic pulmonary hypertension in rats. Am J Physiol 277:L225–L232

    PubMed  CAS  Google Scholar 

  • Hanson KA, Ziegler JW, Rybalkin SD, Miller JW, Abman SH, Clarke WR (1998) Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity. Am J Physiol 275:L931–L941

    PubMed  CAS  Google Scholar 

  • Hassoun PM, Mouthon L, Barbera JA, Eddahibi S, Flores SC, Grimminger F, Jones PL, Maitland ML, Michelakis ED, Morrell NW, Newman JH, Rabinovitch M, Schermuly R, Stenmark KR, Voelkel NF, Yuan JX, Humbert M (2009) Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 54:S10–S19

    Article  PubMed  CAS  Google Scholar 

  • Hemnes AR, Zaiman A, Champion HC (2008) PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation. Am J Physiol Lung Cell Mol Physiol 294:L24–L33

    Article  PubMed  CAS  Google Scholar 

  • Hentschel T, Yin N, Riad A, Habbazettl H, Weimann J, Koster A, Tschope C, Kuppe H, Kuebler WM (2007) Inhalation of the phosphodiesterase-3 inhibitor milrinone attenuates pulmonary hypertension in a rat model of congestive heart failure. Anesthesiology 106:124–131

    Article  PubMed  CAS  Google Scholar 

  • Hoeper MM, Faulenbach C, Golpon H, Winkler J, Welte T, Niedermeyer J (2004) Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 24:1007–1010

    Article  PubMed  CAS  Google Scholar 

  • Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot-Keros L, Duroux P, Galanaud P, Simonneau G, Emilie D (1995) Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 151:1628–1631

    PubMed  CAS  Google Scholar 

  • Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M (2004) Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43:13S–24S

    Article  PubMed  CAS  Google Scholar 

  • Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Simonneau G (2006) Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 173:1023–1030

    Article  PubMed  Google Scholar 

  • Ichinose F, Adrie C, Hurford WE, Bloch KD, Zapol WM (1998) Selective pulmonary vasodilation induced by aerosolized zaprinast. Anesthesiology 88:410–416

    Article  PubMed  CAS  Google Scholar 

  • Izikki M, Raffestin B, Klar J, Hatzelmann A, Marx D, Tenor H, Zadigue P, Adnot S, Eddahibi S (2009) Effects of roflumilast, a phosphodiesterase-4 inhibitor, on hypoxia- and monocrotaline-induced pulmonary hypertension in rats. J Pharmacol Exp Ther 330:54–62

    Article  PubMed  CAS  Google Scholar 

  • Jeffery TK, Wanstall JC (1998) Phosphodiesterase III and V inhibitors on pulmonary artery from pulmonary hypertensive rats: differences between early and established pulmonary hypertension. J Cardiovasc Pharmacol 32:213–219

    Article  PubMed  CAS  Google Scholar 

  • Jing ZC, Jiang X, Wu BX, Xu XQ, Wu Y, Ma CR, Wang Y, Yang YJ, Pu JL, Gao W (2009) Vardenafil treatment for patients with pulmonary arterial hypertension: a multicentre, open-label study. Heart 95:1531–1536

    Article  PubMed  CAS  Google Scholar 

  • Kemeny V, Molnar S, Andrejkovics M, Makai A, Csiba L (2005) Acute and chronic effects of vinpocetine on cerebral hemodynamics and neuropsychological performance in multi-infarct patients. J Clin Pharmacol 45:1048–1054

    Article  PubMed  CAS  Google Scholar 

  • Keravis T, Thaseldar-Roumie R, Lugnier C (2005) Assessment of phosphodiesterase isozyme contribution in cell and tissue extracts. Methods Mol Biol 307:63–74

    PubMed  CAS  Google Scholar 

  • Kim D, Rybalkin SD, Pi X, Wang Y, Zhang C, Munzel T, Beavo JA, Berk BC, Yan C (2001) Upregulation of phosphodiesterase 1A1 expression is associated with the development of nitrate tolerance. Circulation 104:2338–2343

    Article  PubMed  CAS  Google Scholar 

  • Kim D, Aizawa T, Wei H, Pi X, Rybalkin SD, Berk BC, Yan C (2005) Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: a mechanism by which angiotensin II antagonizes cGMP signaling. J Mol Cell Cardiol 38:175–184

    Article  PubMed  CAS  Google Scholar 

  • Klinger JR, Thaker S, Houtchens J, Preston IR, Hill NS, Farber HW (2006) Pulmonary hemodynamic responses to brain natriuretic peptide and sildenafil in patients with pulmonary arterial hypertension. Chest 129:417–425

    Article  PubMed  CAS  Google Scholar 

  • Kodama K, Adachi H (1999) Improvement of mortality by long-term E4010 treatment in monocrotaline-induced pulmonary hypertensive rats. J Pharmacol Exp Ther 290:748–752

    PubMed  CAS  Google Scholar 

  • Koyama H, Raines EW, Bornfeldt KE, Roberts JM, Ross R (1996) Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of Cdk2 inhibitors. Cell 87:1069–1078

    Article  PubMed  CAS  Google Scholar 

  • Koyama H, Bornfeldt KE, Fukumoto S, Nishizawa Y (2001) Molecular pathways of cyclic nucleotide-induced inhibition of arterial smooth muscle cell proliferation. J Cell Physiol 186:1–10

    Article  PubMed  CAS  Google Scholar 

  • Lamarche Y, Perrault LP, Maltais S, Tetreault K, Lambert J, Denault AY (2007) Preliminary experience with inhaled milrinone in cardiac surgery. Eur J Cardiothorac Surg 31:1081–1087

    Article  PubMed  Google Scholar 

  • Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA 3rd, Loyd JE, Nichols WC, Trembath RC (2000) Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 26:81–84

    Article  PubMed  CAS  Google Scholar 

  • Li M, Sun X, Li Z, Liu Y (2009) Inhibition of cGMP phosphodiesterase 5 suppresses serotonin signalling in pulmonary artery smooth muscles cells. Pharmacol Res 59:312–318

    Article  PubMed  CAS  Google Scholar 

  • Lin CS, Chow S, Lau A, Tu R, Lue TF (2001a) Identification and regulation of human PDE5A gene promoter. Biochem Biophys Res Commun 280:684–692

    Article  PubMed  CAS  Google Scholar 

  • Lin CS, Chow S, Lau A, Tu R, Lue TF (2001b) Regulation of human PDE5A2 intronic promoter by cAMP and cGMP: identification of a critical Sp1-binding site. Biochem Biophys Res Commun 280:693–699

    Article  PubMed  CAS  Google Scholar 

  • Lobato EB, Beaver T, Muehlschlegel J, Kirby DS, Klodell C, Sidi A (2006) Treatment with phosphodiesterase inhibitors type III and V: milrinone and sildenafil is an effective combination during thromboxane-induced acute pulmonary hypertension. Br J Anaesth 96:317–322

    Article  PubMed  CAS  Google Scholar 

  • Long L, Crosby A, Yang X, Southwood M, Upton PD, Kim DK, Morrell NW (2009) Altered bone morphogenetic protein and transforming growth factor-beta signaling in rat models of pulmonary hypertension: potential for activin receptor-like kinase-5 inhibition in prevention and progression of disease. Circulation 119:566–576

    Article  PubMed  CAS  Google Scholar 

  • Lu W, Ran P, Zhang D, Peng G, Li B, Zhong N, Wang J (2010) Sildenafil inhibits chronically hypoxic upregulation of canonical transient receptor potential expression in rat pulmonary arterial smooth muscle. Am J Physiol Cell Physiol 298:C114–C123

    Article  PubMed  CAS  Google Scholar 

  • Machado RD, Pauciulo MW, Thomson JR, Lane KB, Morgan NV, Wheeler L, Phillips JA 3rd, Newman J, Williams D, Galie N, Manes A, McNeil K, Yacoub M, Mikhail G, Rogers P, Corris P, Humbert M, Donnai D, Martensson G, Tranebjaerg L, Loyd JE, Trembath RC, Nichols WC (2001) BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet 68:92–102

    Article  PubMed  CAS  Google Scholar 

  • Machado RD, Eickelberg O, Elliott CG, Geraci MW, Hanaoka M, Loyd JE, Newman JH, Phillips JA 3rd, Soubrier F, Trembath RC, Chung WK (2009) Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 54:S32–S42

    Article  PubMed  CAS  Google Scholar 

  • MacLean MR, Sweeney G, Baird M, McCulloch KM, Houslay M, Morecroft I (1996) 5-Hydroxytryptamine receptors mediating vasoconstriction in pulmonary arteries from control and pulmonary hypertensive rats. Br J Pharmacol 119:917–930

    PubMed  CAS  Google Scholar 

  • Maclean MR, Johnston ED, McCulloch KM, Pooley L, Houslay MD, Sweeney G (1997) Phosphodiesterase isoforms in the pulmonary arterial circulation of the rat: changes in pulmonary hypertension. J Pharmacol Exp Ther 283:619–624

    PubMed  CAS  Google Scholar 

  • Maurice DH (2005) Cyclic nucleotide phosphodiesterase-mediated integration of cGMP and cAMP signaling in cells of the cardiovascular system. Front Biosci 10:1221–1228

    Article  PubMed  CAS  Google Scholar 

  • McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J (2009) ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 53:1573–1619

    Article  PubMed  Google Scholar 

  • Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S (2002) Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 105:2398–2403

    Article  PubMed  CAS  Google Scholar 

  • Millen J, MacLean MR, Houslay MD (2006) Hypoxia-induced remodelling of PDE4 isoform expression and cAMP handling in human pulmonary artery smooth muscle cells. Eur J Cell Biol 85:679–691

    Article  PubMed  CAS  Google Scholar 

  • Miller CL, Oikawa M, Cai Y, Wojtovich AP, Nagel DJ, Xu X, Xu H, Florio V, Rybalkin SD, Beavo JA, Chen YF, Li JD, Blaxall BC, Abe J, Yan C (2009) Role of Ca2+/calmodulin-stimulated cyclic nucleotide phosphodiesterase 1 in mediating cardiomyocyte hypertrophy. Circ Res 105:956–964

    Article  PubMed  CAS  Google Scholar 

  • Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, McMurtry IF, Stenmark KR, Thistlethwaite PA, Weissmann N, Yuan JX, Weir EK (2009) Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 54:S20–S31

    Article  PubMed  CAS  Google Scholar 

  • Mouchaers KT, Schalij I, Versteilen AM, Hadi AM, van Nieuw Amerongen GP, van Hinsbergh VW, Postmus PE, van der Laarse WJ, Vonk-Noordegraaf A (2009) Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 297:H200–H207

    Article  PubMed  CAS  Google Scholar 

  • Mullershausen F, Friebe A, Feil R, Thompson WJ, Hofmann F, Koesling D (2003) Direct activation of PDE5 by cGMP: long-term effects within NO/cGMP signaling. J Cell Biol 160:719–727

    Article  PubMed  CAS  Google Scholar 

  • Murray F, MacLean MR, Pyne NJ (2002) Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension. Br J Pharmacol 137:1187–1194

    Article  PubMed  CAS  Google Scholar 

  • Murray F, MacLean MR, Pyne NJ (2003) An assessment of the role of the inhibitory gamma subunit of the retinal cyclic GMP phosphodiesterase and its effect on the p42/p44 mitogen-activated protein kinase pathway in animal and cellular models of pulmonary hypertension. Br J Pharmacol 138:1313–1319

    Article  PubMed  CAS  Google Scholar 

  • Murray F, Patel HH, Suda RY, Zhang S, Thistlethwaite PA, Yuan JX, Insel PA (2007) 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 292:L294–L303

    Article  PubMed  CAS  Google Scholar 

  • Muzaffar S, Shukla N, Bond M, Sala-Newby GB, Newby AC, Angelini GD, Jeremy JY (2008) Superoxide from NADPH oxidase upregulates type 5 phosphodiesterase in human vascular smooth muscle cells: inhibition with iloprost and NONOate. Br J Pharmacol 155:847–856

    Article  PubMed  CAS  Google Scholar 

  • Nagel DJ, Aizawa T, Jeon KI, Liu W, Mohan A, Wei H, Miano JM, Florio VA, Gao P, Korshunov VA, Berk BC, Yan C (2006) Role of nuclear Ca2+/calmodulin-stimulated phosphodiesterase 1A in vascular smooth muscle cell growth and survival. Circ Res 98:777–784

    Article  PubMed  CAS  Google Scholar 

  • Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, St Aubin C, Webster L, Rebeyka IM, Ross DB, Light PE, Dyck JR, Michelakis ED (2007) Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation 116:238–248

    Article  PubMed  CAS  Google Scholar 

  • Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin LJ, Nikkho S, Speich R, Hoeper MM, Behr J, Winkler J, Sitbon O, Popov W, Ghofrani HA, Manes A, Kiely DG, Ewert R, Meyer A, Corris PA, Delcroix M, Gomez-Sanchez M, Siedentop H, Seeger W (2002) Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 347:322–329

    Article  PubMed  CAS  Google Scholar 

  • Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML et al (1991) Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med 325:1468–1475

    Article  PubMed  CAS  Google Scholar 

  • Palmer D, Maurice DH (2000) Dual expression and differential regulation of phosphodiesterase 3A and phosphodiesterase 3B in human vascular smooth muscle: implications for phosphodiesterase 3 inhibition in human cardiovascular tissues. Mol Pharmacol 58:247–252

    PubMed  CAS  Google Scholar 

  • Paul GA, Gibbs JS, Boobis AR, Abbas A, Wilkins MR (2005) Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol 60:107–112

    Article  PubMed  CAS  Google Scholar 

  • Pauvert O, Bonnet S, Rousseau E, Marthan R, Savineau JP (2004) Sildenafil alters calcium signaling and vascular tone in pulmonary arteries from chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 287:L577–L583

    Article  PubMed  CAS  Google Scholar 

  • Peacock AJ, Murphy NF, McMurray JJ, Caballero L, Stewart S (2007) An epidemiological study of pulmonary arterial hypertension. Eur Respir J 30:104–109

    Article  PubMed  CAS  Google Scholar 

  • Perros F, Dorfmuller P, Souza R, Durand-Gasselin I, Godot V, Capel F, Adnot S, Eddahibi S, Mazmanian M, Fadel E, Herve P, Simonneau G, Emilie D, Humbert M (2007) Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension. Eur Respir J 29:937–943

    Article  PubMed  CAS  Google Scholar 

  • Phillips PG, Long L, Wilkins MR, Morrell NW (2005) cAMP phosphodiesterase inhibitors potentiate effects of prostacyclin analogs in hypoxic pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 288:L103–L115

    Article  PubMed  CAS  Google Scholar 

  • Pyne NJ, Murray F, Tate R, MacLean MR (2007) Molecular determinants in pulmonary hypertension: the role of PDE5. CRC Press, Boca Raton

    Google Scholar 

  • Rabe KF, Tenor H, Dent G, Schudt C, Nakashima M, Magnussen H (1994) Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors. Am J Physiol 266:L536–L543

    PubMed  CAS  Google Scholar 

  • Raymond DR, Wilson LS, Carter RL, Maurice DH (2007) Numerous distinct PKA-, or EPAC-based, signalling complexes allow selective phosphodiesterase 3 and phosphodiesterase 4 coordination of cell adhesion. Cell Signal 19:2507–2518

    Article  PubMed  CAS  Google Scholar 

  • Rybalkin SD, Bornfeldt KE (1999) Cyclic nucleotide phosphodiesterases and human arterial smooth muscle cell proliferation. Thromb Haemost 82:424–434

    PubMed  CAS  Google Scholar 

  • Rybalkin SD, Bornfeldt KE, Sonnenburg WK, Rybalkina IG, Kwak KS, Hanson K, Krebs EG, Beavo JA (1997) Calmodulin-stimulated cyclic nucleotide phosphodiesterase (PDE1C) is induced in human arterial smooth muscle cells of the synthetic, proliferative phenotype. J Clin Invest 100:2611–2621

    Article  PubMed  CAS  Google Scholar 

  • Rybalkin SD, Rybalkina I, Beavo JA, Bornfeldt KE (2002) Cyclic nucleotide phosphodiesterase 1C promotes human arterial smooth muscle cell proliferation. Circ Res 90:151–157

    Article  PubMed  CAS  Google Scholar 

  • Rybalkina IG, Tang XB, Rybalkin SD (2010) Multiple affinity states of cGMP-specific phosphodiesterase for sildenafil inhibition defined by cGMP-dependent and cGMP-independent mechanisms. Mol Pharmacol 77:670–677

    Article  PubMed  CAS  Google Scholar 

  • Schafer S, Ellinghaus P, Janssen W, Kramer F, Lustig K, Milting H, Kast R, Klein M (2009) Chronic inhibition of phosphodiesterase 5 does not prevent pressure-overload-induced right-ventricular remodelling. Cardiovasc Res 82:30–39

    Article  PubMed  CAS  Google Scholar 

  • Schermuly RT, Roehl A, Weissmann N, Ghofrani HA, Leuchte H, Grimminger F, Seeger W, Walmrath D (2001) Combination of nonspecific PDE inhibitors with inhaled prostacyclin in experimental pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 281:L1361–L1368

    PubMed  CAS  Google Scholar 

  • Schermuly RT, Kreisselmeier KP, Ghofrani HA, Samidurai A, Pullamsetti S, Weissmann N, Schudt C, Ermert L, Seeger W, Grimminger F (2004) Antiremodeling effects of iloprost and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in chronic experimental pulmonary hypertension. Circ Res 94:1101–1108

    Article  PubMed  CAS  Google Scholar 

  • Schermuly RT, Inholte C, Ghofrani HA, Gall H, Weissmann N, Weidenbach A, Seeger W, Grimminger F (2005) Lung vasodilatory response to inhaled iloprost in experimental pulmonary hypertension: amplification by different type phosphodiesterase inhibitors. Respir Res 6:76

    Article  PubMed  CAS  Google Scholar 

  • Schermuly RT, Pullamsetti SS, Kwapiszewska G, Dumitrascu R, Tian X, Weissmann N, Ghofrani HA, Kaulen C, Dunkern T, Schudt C, Voswinckel R, Zhou J, Samidurai A, Klepetko W, Paddenberg R, Kummer W, Seeger W, Grimminger F (2007) Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy. Circulation 115:2331–2339

    Article  PubMed  CAS  Google Scholar 

  • Selige J, Tenor H, Hatzelmann A, Dunkern T (2010) Cytokine-dependent balance of mitogenic effects in primary human lung fibroblasts related to cyclic AMP signaling and phosphodiesterase 4 inhibition. J Cell Physiol 223(2):317–326

    PubMed  CAS  Google Scholar 

  • Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R (2009) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 54:S43–S54

    Article  PubMed  Google Scholar 

  • Souness JE, Aldous D, Sargent C (2000) Immunosuppressive and anti-inflammatory effects of cyclic AMP phosphodiesterase (PDE) type 4 inhibitors. Immunopharmacology 47:127–162

    Article  PubMed  CAS  Google Scholar 

  • Stavros F, Kramer WG, Wilkins MR (2010) The effects of sitaxentan on sildenafil pharmacokinetics and pharmacodynamics in healthy subjects. Br J Clin Pharmacol 69:23–26

    Article  PubMed  CAS  Google Scholar 

  • Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF (2009) Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol 297:L1013–L1032

    Article  PubMed  CAS  Google Scholar 

  • Sun CK, Lee FY, Sheu JJ, Yuen CM, Chua S, Chung SY, Chai HT, Chen YT, Kao YH, Chang LT, Yip HK (2009a) Early combined treatment with cilostazol and bone marrow-derived endothelial progenitor cells markedly attenuates pulmonary arterial hypertension in rats. J Pharmacol Exp Ther 330:718–726

    Article  PubMed  CAS  Google Scholar 

  • Sun XZ, Li ZF, Liu Y, Fang P, Li MX (2010) Inhibition of cGMP phosphodiesterase 5 suppresses MMP2 production in pulmonary artery smooth muscles cells. Clin Exp Pharmacol Physiol 37(3):362–367

    Google Scholar 

  • Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA (2005) Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11:214–222

    Article  PubMed  CAS  Google Scholar 

  • Takimoto E, Koitabashi N, Hsu S, Ketner EA, Zhang M, Nagayama T, Bedja D, Gabrielson KL, Blanton R, Siderovski DP, Mendelsohn ME, Kass DA (2009) Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. J Clin Invest 119:408–420

    PubMed  CAS  Google Scholar 

  • Thompson WJ, Brooker G, Appleman MM (1974) Assay of cyclic nucleotide phosphodiesterases with radioactive substrates. Methods Enzymol 38:205–212

    Article  PubMed  CAS  Google Scholar 

  • Thompson PD, Zimet R, Forbes WP, Zhang P (2002) Meta-analysis of results from eight randomized, placebo-controlled trials on the effect of cilostazol on patients with intermittent claudication. Am J Cardiol 90:1314–1319

    Article  PubMed  CAS  Google Scholar 

  • Toque HA, Teixeira CE, Priviero FB, Morganti RP, Antunes E, De Nucci G (2008) Vardenafil, but not sildenafil or tadalafil, has calcium-channel blocking activity in rabbit isolated pulmonary artery and human washed platelets. Br J Pharmacol 154:787–796

    Article  PubMed  CAS  Google Scholar 

  • Trembath RC (2001) Mutations in the TGF-beta type 1 receptor, ALK1, in combined primary pulmonary hypertension and hereditary haemorrhagic telangiectasia, implies pathway specificity. J Heart Lung Transplant 20:175

    Article  PubMed  Google Scholar 

  • Truss MC, Stief CG, Uckert S, Becker AJ, Wefer J, Schultheiss D, Jonas U (2001) Phosphodiesterase 1 inhibition in the treatment of lower urinary tract dysfunction: from bench to bedside. World J Urol 19:344–350

    Article  PubMed  CAS  Google Scholar 

  • Tsai BM, Turrentine MW, Sheridan BC, Wang M, Fiore AC, Brown JW, Meldrum DR (2006) Differential effects of phosphodiesterase-5 inhibitors on hypoxic pulmonary vasoconstriction and pulmonary artery cytokine expression. Ann Thorac Surg 81:272–278

    Article  PubMed  Google Scholar 

  • Tuder RM, Groves B, Badesch DB, Voelkel NF (1994) Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 144:275–285

    PubMed  CAS  Google Scholar 

  • Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite PA, Haworth SG (2009) Development and pathology of pulmonary hypertension. J Am Coll Cardiol 54:S3–S9

    Article  PubMed  CAS  Google Scholar 

  • Wagner RS, Smith CJ, Taylor AM, Rhoades RA (1997) Phosphodiesterase inhibition improves agonist-induced relaxation of hypertensive pulmonary arteries. J Pharmacol Exp Ther 282:1650–1657

    PubMed  CAS  Google Scholar 

  • Wang C, Li JF, Zhao L, Liu J, Wan J, Wang YX, Wang J (2009) Inhibition of SOC/Ca2+/NFAT pathway is involved in the anti-proliferative effect of sildenafil on pulmonary artery smooth muscle cells. Respir Res 10:123

    Article  PubMed  CAS  Google Scholar 

  • Wharton J, Strange JW, Moller GM, Growcott EJ, Ren X, Franklyn AP, Phillips SC, Wilkins MR (2005) Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med 172:105–113

    Article  PubMed  Google Scholar 

  • Wilkens H, Guth A, Konig J, Forestier N, Cremers B, Hennen B, Bohm M, Sybrecht GW (2001) Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 104:1218–1222

    Article  PubMed  CAS  Google Scholar 

  • Yan C, Miller CL, Abe J (2007) Regulation of phosphodiesterase 3 and inducible cAMP early repressor in the heart. Circ Res 100:489–501

    Article  PubMed  CAS  Google Scholar 

  • Zaccolo M, Movsesian MA (2007) cAMP and cGMP signaling cross-talk: role of phosphodiesterases and implications for cardiac pathophysiology. Circ Res 100:1569–1578

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Murray F, Zahno A, Kanter JR, Chou D, Suda R, Fenlon M, Rassenti L, Cottam H, Kipps TJ, Insel PA (2008) Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 105:19532–19537

    Article  PubMed  CAS  Google Scholar 

  • Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A, Mirrakhimov MM, Aldashev A, Wilkins MR (2001) Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 104:424–428

    Article  PubMed  CAS  Google Scholar 

  • Zhu S, White RE, Barman SA (2008) Role of phosphodiesterases in modulation of BKCa channels in hypertensive pulmonary arterial smooth muscle. Ther Adv Respir Dis 2:119–127

    Article  PubMed  Google Scholar 

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Acknowledgment

This work was supported by grants from the National Heart, Lung and Blood Institute of the National Institutes of Health (K99HL091061), the Leukemia & Lymphoma Society (7332-06), and the Ellison Medical Foundation (AG-SS-1662-06).

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Authors and Affiliations

  1. Department of Pharmacology and Department of Medicine, BSB 3073, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093-0636, USA

    F. Murray & P. A. Insel

  2. Institute of Cardiovascular & Medical Sciences College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, Scotland, UK

    M. R. MacLean

  3. University of Glasgow, Glasgow, Scotland, UK

    M. R. MacLean

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  1. F. Murray
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  2. M. R. MacLean
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  3. P. A. Insel
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Editors and Affiliations

  1. School of Medicine, Dept. Molecular Physiology & Biophysics, Vanderbilt University, Light Hall 702, Nashville, 37232-0615, Tennessee, USA

    Sharron H. Francis

  2. HSW 1656, Center for Reproductive Sciences, Parnassus Avenue 513, San Francisco, 94143-0556, California, USA

    Marco Conti

  3. Wolfson Building, University of Glasgow, Glasgow, G12 8QQ, United Kingdom

    Miles D. Houslay

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Murray, F., MacLean, M.R., Insel, P.A. (2011). Role of Phosphodiesterases in Adult-Onset Pulmonary Arterial Hypertension. In: Francis, S., Conti, M., Houslay, M. (eds) Phosphodiesterases as Drug Targets. Handbook of Experimental Pharmacology, vol 204. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-17969-3_12

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