Therapeutic Potentials of Phosphodiesterase-5 Inhibitors in Cardiovascular Disease

Reviews in Cardiovascular Medicine

Volumn 15, Issue 2, 2014, Pages 158-167

  Nguyen, Ha ^a,b   Amanullah, Aman M ^a,b,c  

^a EINSTEIN MEDICAL CENTER   (United States)

^b Department of Medicine ^*  (United States)

^c THOMAS JEFFERSON UNIVERSITY   (United States)

Author keywords

Cardiovascular disease; Phosphodiesterase 5 inhibitors; Pulmonary arterial hypertension; Sildenafil; Tadalafil; Vardenafil

Indexed keywords

ACETYLSALICYLIC ACID; BOSENTAN; CYCLIC GMP; CYCLIC GMP DEPENDENT PROTEIN KINASE; DOXORUBICIN; ILOPROST; NITRIC OXIDE; PHOSPHODIESTERASE V; PHOSPHODIESTERASE V INHIBITOR; PROSTACYCLIN; SILDENAFIL; TADALAFIL; VARDENAFIL; CARDIOVASCULAR AGENT;

ANTIPROLIFERATIVE ACTIVITY; APOPTOSIS; BRAIN BLOOD FLOW; BRAIN HYPOXIA; BREAST CANCER; CARDIOMYOPATHY; CARDIOTOXICITY; CARDIOVASCULAR DISEASE; CONGESTIVE HEART FAILURE; DOXORUBICIN CARDIOMYOPATHY; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG TOLERABILITY; DYSPEPSIA; ERECTILE DYSFUNCTION; GASTROINTESTINAL SYMPTOM; HEADACHE; HEART PROTECTION; HODGKIN DISEASE; HUMAN; HYPOTENSION; ISCHEMIC HEART DISEASE; LEUKEMIA; LOW DRUG DOSE; MYALGIA; NONHODGKIN LYMPHOMA; NONHUMAN; PERIPHERAL OCCLUSIVE ARTERY DISEASE; PERIPHERAL VASCULAR DISEASE; PLACENTA INSUFFICIENCY; PREECLAMPSIA; PROSTATE HYPERTROPHY; PULMONARY HYPERTENSION; RAYNAUD PHENOMENON; REVIEW; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; THROMBOCYTE AGGREGATION INHIBITION; VASODILATATION; ANIMAL; DRUG EFFECT; ENZYMOLOGY; METABOLISM; TREATMENT OUTCOME;

ANIMALS; CARDIOVASCULAR AGENTS; CARDIOVASCULAR DISEASES; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 5; HUMANS; PHOSPHODIESTERASE 5 INHIBITORS; SIGNAL TRANSDUCTION; TREATMENT OUTCOME;

EID: 84906321869     PISSN: 15306550     EISSN: None     Source Type: Journal    
DOI: 10.3909/ricm0679     Document Type: Review

References (80)

1. Sutherland EW, Rall TW. Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles. J Biol Chem. 1958;232:1077-1091.
2. Ashman DF, Lipton R, Melicow MM, Price TD. Isolation of adenosine 3′, 5′-monophosphate and guanosine 3′, 5′-monophosphate from rat urine. Biochem Biophys Res Commun.1963;11:330-334.
3. White RE, Lee AB, Shcherbatko AD, et al. Potassium channel stimulation by natriuretic peptides through cGMP-dependent dephosphorylation. Nature. 1993; 361:263-266. (Pubitemid 23034477)
4. Hall SK, Armstrong DL. Conditional and unconditional inhibition of calcium-activated potassium channels by reversible protein phosphorylation. J Biol Chem. 2000;275:3749-3754. (Pubitemid 30094594)
5. Raeymaekers L, Hofmann F, Casteels R. Cyclic GMP-dependent protein kinase phosphorylates phospholamban in isolated sarcoplasmic reticulum from cardiac and smooth muscle. Biochem J. 1988;252:269-273.
6. Schlossmann J, Ammendola A, Ashman K, et al. Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Ibeta. Nature. 2000;404:197-201. (Pubitemid 30154489)
7. Hofmann F. The biology of cyclic GMP-dependent protein kinases. J Biol Chem. 2005;280:1-4. (Pubitemid 40164957)
8. Remillard CV, Yuan JX. Activation of K+ channels: an essential pathway in programmed cell death. Am J Physiol Lung Cell Mol Physiol. 2004;286:L49-L67. (Pubitemid 38055858)
9. Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006;58:488-520. (Pubitemid 44394910)
10. McAllister-Lucas LM, Haik TL, Colbran JL, et al. An essential aspartic acid at each of two allosteric cGM-Pbinding sites of a cGMP-specific phosphodiesterase. J Biol Chem. 1995;270:30671-30679. (Pubitemid 26005132)
11. Loughney K, Hill TR, Florio VA, et al. Isolation and characterization of CDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3′,5′- cyclic nucleotide phosphodiesterase. Gene. 1998;216:139-147. (Pubitemid 28389111)
12. Salloum FN, Ockaili RA, Wittkamp M, et al. Vardenafil: a novel type 5 phosphodiesterase inhibitor reduces myocardial infarct size following ischemia/reperfusion injury via opening of mitochondrial K(ATP) channels in rabbits. J Mol Cell Cardiol. 2006;40:405-411. (Pubitemid 43277842)
13. Kukreja RC, Salloum FN, Das A, et al. Emerging new uses of phosphodiesterase-5 inhibitors in cardiovascular diseases. Exp Clin Cardiol. 2011;16:e30-e35.
14. Wang X, Fisher P, Xi L, Kukreja RC. Activation of mitochondrial calcium-activated and ATP sensitive potassium channels is essential for sildenafil-induced cardioprotection. J Mol Cell Cardiol. 2008;44:105-113.
15. Das A, Xi L, Kukreja RC. Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. J Biol Chem. 2005;280:12944-12955.
16. Salloum FN, Chau VQ, Hoke NN, et al. Phosphodiesterase-5 inhibitor, tadalafil, protects against myocardial ischemia/reperfusion through protein-kinase G dependent generation of hydrogen sulfide. Circulation. 2009;120(11 suppl):S31-S36.
17. Elrod JW, Greer JJ, Lefer DJ. Sildenafil-mediated acute cardioprotection is independent of the NO/cGMP pathway. Am J Physiol Heart Circ Physiol. 2007;292:H342-H347. (Pubitemid 46105196)
18. du Toit EF, Rossouw E, Salie R, et al. Effect of sildenafil on reperfusion function, infarct size, and cyclic nucleotide levels in the isolated rat heart model. Cardiovasc Drugs Ther. 2005;19:23-31. (Pubitemid 40767769)
19. Sesti C, Florio V, Johnson EG, Kloner RA. The phosphodiesterase-5 inhibitor tadalafil reduces myocardial infarct size. Int J Impot Res. 2007;19:55-61. (Pubitemid 46067349)
20. Ahmad N, Wang Y, Ali AK, Ashraf M. Long-acting phosphodiesterase-5 inhibitor, tadalafil, induces sustained cardioprotection against lethal ischemic injury. Am J Physiol Heart Circ Physiol. 2009;297:H387-H391.
21. Maas O, Donat U, Frenzel M, et al. Vardenafil protects isolated rat hearts at reperfusion dependent on GC and PKG. Br J Pharmacol. 2008;154:25-31. (Pubitemid 351620400)
22. Nagy O, Hajnal A, Parratt JR, Végh A. Sildenafil (Viagra) reduces arrhythmia severity during ischemia 24 h after oral administration in dogs. Br J Pharmacol. 2004;141:549-551. (Pubitemid 38453246)
23. Przyklenk K, Kloner RA. Sildenafil citrate (Viagra) does not exacerbate myocardial ischemia in canine models of coronary artery stenosis. J Am Coll Cardiol. 2001;37:286-292. (Pubitemid 32051752)
24. 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. (Pubitemid 30341530)
25. Arruda-Olson AM, Mahoney DW, Nehra A, et al. Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease. JAMA. 2002;287:719-725. (Pubitemid 34250457)
26. Thadani U, Smith W, Nash S, et al. The effect of vardenafil, a potent and highly selective phosphodiesterase-5 inhibitor for the treatment of erectile dys-function, on the cardiovascular response to exercise in patients with coronary artery disease. J Am Coll Cardiol. 2002;40:2006-2012. (Pubitemid 35425369)
27. Patterson D, McDonald TM, Effron MB, et al. Tadalafil does not affect time to ischemia during exercise stress testing in patients with coronary artery disease. Int J Impot Res. 2002;14(suppl 3):S102.
28. Berkels R, Klotz T, Sticht G, et al. Modulation of human platelet aggregation by the phosphodiesterase type 5 inhibitor sildenafil. J Cardiovasc Pharmacol. 2001;37:413-421. (Pubitemid 32240423)
29. Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling-concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol. 2000;35:569-582. (Pubitemid 30167013)
30. Kim KH, Kim YJ, Ohn JH, et al. Long-term effects of sildenafil in a rat model of chronic mitral regurgitation: benefits of ventricular remodeling and exercise capacity. Circulation. 2012;125:1390-1401.
31. Takimoto E, Champion HC, Li M, et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 2005;11:214-222. (Pubitemid 40321358)
32. Lindman BR, Zajarias A, Madrazo JA, et al. Effects of phosphodiesterase type 5 inhibition on systemic and pulmonary hemodynamics and ventricular function in patients with severe symptomatic aortic stenosis. Circulation. 2012;125:2353-2362.
33. Lewis GD, Lachmann J, Camuso J, et al. Sildenafil improves exercise hemodynamics and oxygen uptake in patients with systolic heart failure. Circulation. 2007;115:59-66. (Pubitemid 46058612)
34. Lewis GD, Shah R, Shahzad K, et al. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation. 2007;116:1555-1562. (Pubitemid 47511419)
35. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation. 2011;124:164-174.
36. Guazzi M, Casali M, Berti F, et al. Endothelium-mediated modulation of ergoreflex and improvement in exercise ventilation by acute sildenafil in heart failure patients. Clin Pharmacol Ther. 2008;83:336-341.
37. Behling A, Rohde LE, Colombo FC, et al. Effects of 5′- phosphodiesterase four-week long inhibition with sildenafil in patients with chronic heart failure: a double-blind, placebo-controlled clinical trial. J Card Fail. 2008;14:189-197. (Pubitemid 351444866)
38. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation. 1990;81:1161-1172. (Pubitemid 20119612)
39. Salloum FN, Abbate A, Das A, et al. Sildenafil (Viagra) attenuates ischemic cardiomyopathy and improves left ventricular function in mice. Am J Physiol Heart Circ Physiol. 2008;294:H1398-H1406. (Pubitemid 351468739)
40. Powis G. Free radical formation by antitumor quinones. Free Radic Biol Med.1989;6:63-101. (Pubitemid 19032733)
41. Doroshow JH. Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res. 1983;43:460-472. (Pubitemid 13193830)
42. Olson RD, Mushlin PS. Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J. 1990;4:3076-3086.
43. Doroshow JH, Davies KJ. Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical. J Biol Chem. 1986;261:3068-3074. (Pubitemid 17204910)
44. Rabkin SW, Sunga P. The effect of doxorubicin (adriamycin) on cytoplasmic microtubule system in cardiac cells. J Mol Cell Cardiol. 1987;19:1073-1083. (Pubitemid 18029096)
45. Myers CE, McGuire WP, Liss RH, et al. Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science. 1977;197:165-167. (Pubitemid 8140036)
46. Doroshow JH, Locker GY, Myers CE. Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin. J Clin Invest. 1980;65:128-135. (Pubitemid 10214339)
47. Arola OJ, Saraste A, Pulkki K, et al. Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res. 2000;60:1789-1792. (Pubitemid 30207630)
48. Nakamura T, Ueda Y, Juan Y, et al. Fas-mediated apoptosis in adriamycin-induced cardiomyopathy in rats: in vivo study. Circulation. 2000;102:572-578. (Pubitemid 30639976)
49. Fisher PW, Salloum F, Das A, et al. Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation. 2005;111:1601-1610. (Pubitemid 40525159)
50. Kukreja RC, Salloum F, Das A, et al. Pharmacological preconditioning with sildenafil: basic mechanisms and clinical implications. Vascul Pharmacol. 2005;42:219-232. (Pubitemid 40726325)
51. Koka S, Kukreja RC. Attenuation of doxorubicin-induced cardiotoxicity by tadalafil: a long acting phosphodiesterase-5 inhibitor. Mol Cell Pharmacol. 2010;2:173-178.
52. Koka S, Das A, Zhu SG, et al. Long-acting phosphodiesterase-5 inhibitor tadalafil attenuates doxo-rubicin-induced cardiomyopathy without interfering with chemotherapeutic effect. J Pharmacol Exp Ther. 2010;334:1023-1030.
53. McLaughlin VV, Archer SL, Badesch DB, et al. 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. 2009;53:1573-1619.
54. Archer SL, Michelakis ED. Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. N Engl J Med. 2009;361:1864-1871.
55. Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992;327:70-75.
56. Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:13S-24S. (Pubitemid 38759713)
57. Michelakis ED. Spatio-temporal diversity of apoptosis within the vascular wall in pulmonary arterial hypertension: heterogeneous BMP signaling may have therapeutic implications. Circ Res. 2006;98:172-175.
58. Murray F, MacLean MR, Pyne NJ. Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension. Br J Pharmacol. 2002;137:1187-1194. (Pubitemid 36071735)
59. Nagendran J, Archer SL, Soliman D, et al. 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. (Pubitemid 47196559)
60. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995;333:214-221.
61. Wharton J, Strange JW, Møller GM, et al. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med. 2005;172:105-113. (Pubitemid 40923321)
62. Galiè N, Ghofrani HA, Torbicki A, et al Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148-2157. (Pubitemid 41653106)
63. Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension: comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2000;161:487-492. (Pubitemid 30129457)
64. Wilkins MR, Paul GA, Strange JW, et al. Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) Study. Am J Respir Crit Care Med. 2005;171:1292-1297. (Pubitemid 40740738)
65. Galiè N, Brundage BH, Ghofrani HA, et al Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension Circulation. 2009;119:2894-2903.
66. Frost AE, Langleben D, Oudiz R, et al. The 6-min walk test (6MW) as an efficacy endpoint in pulmonary arterial hypertension clinical trials: demonstration of a ceiling effect. Vascul Pharmacol. 2005;43:36-39. (Pubitemid 40828831)
67. Simonneau G, Rubin LJ, Galiè N, et al PACES Study Group. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension. Ann Intern Med. 2008;149:521-530.
68. Ghofrani HA, Voswinckel R, Reichenberger F, et al. 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. 2004;44:1488-1496. (Pubitemid 39303954)
69. Fries R, Shariat K, von Wilmowsky H, Böhm M. Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy. Circulation. 2005;112:2980-2985. (Pubitemid 41612301)
70. Caglayan E, Huntgeburth M, Karasch T, et al. Phosphodiesterase type 5 inhibition is a novel therapeutic option in Raynaud disease. Arch Intern Med. 2006;166:231-233. (Pubitemid 43144949)
71. Schiopu E, Hsu VM, Impens AJ, et al. Randomized placebo-controlled crossover trial of tadalafil in Raynaud's phenomenon secondary to systemic sclerosis. J Rheumatol. 2009;36:2264-2268.
72. Wareing M, Myers JE, O'Hara M, Baker PN. Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction. J Clin Endocrinol Metab. 2005;90:2550-2555. (Pubitemid 40686290)
73. Downing JW, Ramasubramanian R, Johnson RF, et al. Hypothesis: selective phosphodiesterase-5 inhibition improves outcome in preeclampsia. Med Hypotheses. 2004;63:1057-1064. (Pubitemid 39422408)
74. Sahara M, Sata M, Morita T, et al. A phosphodiesterase-5 inhibitor vardenafil enhances angiogenesis through a protein kinase G-dependent hypoxia-inducible factor-1/vascular endothelial growth factor pathway. Arterioscler Thromb Vasc Biol. 2010;30:1315-1324.
75. Senthilkumar A, Smith RD, Khitha J, et al. Sildenafil promotes ischemia-induced angiogenesis through a PKG-dependent pathway. Arterioscler Thromb Vasc Biol. 2007;27:1947-1954. (Pubitemid 47312303)
76. Chan CW, Hoar H, Pattinson K, et al Birmingham Medical Research Expeditionary Society. Effect of sildenafil and acclimatization on cerebral oxygenation at altitude. Clin Sci (Lond). 2005;109:319-324. (Pubitemid 41337137)
77. Rosengarten B, Schermuly RT, Voswinckel R, et al. Sildenafil improves dynamic vascular function in the brain: studies in patients with pulmonary hypertension. Cerebrovasc Dis. 2006;21:194-200.
78. Zhang R, Zhang L, Zhang Z, et al. A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats. Ann Neurol. 2001;50:602-611. (Pubitemid 33021918)
79. Zhang R, Wang Y, Zhang L, et al. Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke. 2002;33:2675-2680. (Pubitemid 35266440)
80. Al-Amran FG, Zwain AA, Hadi NR, Al-Mudhaffer AM. Autonomic cerebral vascular response to sildenafil in diabetic patient. Diabetol Metab Syndr. 2012;4:2.