Phosphodiesterase-5 Inhibitors as Therapeutics for Cardiovascular Diseases: A Brief Review
-
Milena Corbic
,
Jasmina Sretenovic
,
Vladimir Zivkovic
,
Vladimir Jakovljevic
,
Tamara Nikolic Turnic
Abstract
Background: Three selective and most used inhibitors of PDE-5- sildenafil, vardenafil and tadalafil- have been successfully used for the treatment of erectile dysfunction. Erectile dysfunction and cardiovascular diseases might be considered as two dissimilar clinical signs of the identical systemic disease. PDE-5 inhibitors can through different models and mechanisms induce vasodilation, decrease apoptosis and cell proliferation, and they are widely present in various tissues that make them promising targets in a range of cardiovascular diseases. Methods: PubMed was explored to identify papers published from 1990-2019, presenting data for the most used PDE-5 inhibitors (sildenafil, tadalafil or vardenafil) in treatment of cardiovascular diseases. Results: This article analyses the therapeutic potentials of PDE-5 inhibitors in cardiovascular diseases and discusses mechanisms, possible risks and limitations. Comparable to earlier studies, newer studies suggest cardioprotective effects of PDE-5 inhibitors, which include different models and mechanisms and do not indicate an increased rate of significant cardiovascular adverse reactions. Dissimilarity in the pharmacokinetics and pharmacodynamics of PDE-5 inhibitors are significant to their risk- benefit profile and clinical use. Some of the studies suggesting infarct size reduction after PDE-5 inhibition described the especially close dose-effect relation, other studies dosage adaptation in drug- drug interactions.Conclusion: PDE-5 inhibitors indicate the encouraging useful effects by ischemia/reperfusion injury, myocardial infarction, cardiac hypertrophy, cardiomyopathy and systolic and diastolic congestive heart failure. Therefore, this and similar reviews can help for additional clinical targeting in the therapy of cardiovascular diseases.
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3. Corbin JD, Francis SH (2002). Pharmacology of phosphodiesterase-5 inhibitors. Int J Clin Pract, 56(6):453-9.
4. Al-Nema MY, Gaurav A (2019). Protein-Protein In-teractions of Phosphodiesterases. Curr Top Med Chem,19(7):555-564.
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6. Cai Z, Zhang J, Li H (2019). Two Birds with One Stone: Regular Use of PDE5 Inhibitors for Treat-ing Male Patients with Erectile Dysfunction and Cardiovascular Diseases. Cardiovasc Drugs Ther, 33(1):119-128.
7. Andersson DP, Trolle Lagerros Y, Grotta A, et al (2017). Association between treatment for erectile dysfunction and death or cardiovascularoutcomes after myocardial infarction. Heart,103(16):1264-1270.
8. Yellon DM, Hausenloy DJ, (2007). Myocardial reper-fusion injury. N Engl J Med, 357:1121–1135.
9. Ockaili R, Salloum F, Hawkins J, et al (2002). Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial K(ATP) channels in rabbits. Am J Physiol Heart Circ Physiol,283(3):H1263-9.
10. Das S, Maulik N, Das DK, et al (2002). Cardiopro-tection with sildenafil, a selective inhibitor of cyclic 3′,5′-monophosphate-specific phosphodiesterase 5. Drugs Exp Clin Res, 28(6):213-9.
11. Nagy O, Hajnal A, Parratt JR, et al (2004). Sildenafil (Viagra) reduces arrhythmia severity during is-chaemia 24 h after oral administration in dogs. Br J Pharmacol, 141(4):549–51
12. du Toit EF, Rossouw E, Salie R, et al (2005). Effect of sildenafil on reperfusion function, infarct size, and cyclic nucleotide levels in the isolated rat heart model. Cardiovasc Drugs Ther, 19(1):23-31.
13. Elrod JW, Greer JJ, Lefer DJ (2007). Sildenafil-mediated acute cardioprotection is independent of the NO/cGMP pathway. Am J Physiol Heart Circ Physiol,292(1):H342–7.
14. Salloum FN, Takenoshita Y, Ockaili RA, et al (2007). Sildenafil and vardenafil but not nitroglycerin limit myocardial infarction through opening of mito-chondrial K(ATP) channels when administered at reperfusion following ischemia in rabbits. J Mol Cell Cardiol, 42(2): 453–458.
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19. Rosanio S, Ye Y, Atar S, et al (2006). Enhanced car-dioprotection against ischemia-reperfusion injury with combining sildenafil with low-dose atorvas-tatin. Cardiovasc Drugs Ther, 20(1):27-36.
20. Elrod JW, Calvert JW, Morrison J, et al (2007). Hy-drogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochon-drial function. Proc Natl Acad Sci USA, 104(39):15560–5.
21. Das A, Ockaili R, Salloum F, et al (2004). Protein ki-nase C plays an essential role in sildenafil-induced cardioprotection in rabbits. Am J Physiol Heart Circ Physiol, 286(4):H1455-60.
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28. Salloum F, Yin C, Xi L, et al (2003). Sildenafil induces delayed preconditioning through inducible nitric oxide synthase-dependent pathway in mouse heart. Circ Res, 92(6):595-7.
29. Das A, Xi L, Kukreja RC (2005). Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essen-tial role of nitric oxide signaling. J Biol Chem, 280(13):12944-55.
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37. Koka S, Kukreja RC (2010). Attenuation of doxoru-bicin-induced cardiotoxicity by tadalafil: A long act-ing phosphodiesterase-5 inhibitor. Mol Cell Phar-macol, 2(5):173-178.
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39. S Greco,A Salgado Somoza,Y Devaux, et al (2017). Long noncoding RNAs and cardiac disease. An-tioxid Redox Signal, 29(9):880-901.
40. Xiang Zhou, Wei Zhang, Mengchao Jin, et al (2017). lncRNA MIAT functions as a competing endog-enous RNA to upregulate DAPK2 by sponging miR-22-3p in diabetic cardiomyopathy. Cell Death & Disease, 8(7): e2929.
41. Mengyao Zhang, Huimin Gu, Weiting Xu, et al (2016). Down-regulation of lncRNA MALAT1 reduces cardiomyocyte apoptosis and improves left ventricular function in diabetic rats. Int J Cardiol, 203:214–6.
42. Bacci L, Barbati SA, Colussi C,et al (2018). Sildenafil normalizes MALAT1 level in diabetic cardiomy-opathy. Endocrine, 62(1):259-262.
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52. Halcox JP, Nour KR, Zalos G, et al (2002). The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia. J Am Coll Car-diol, 40(7):1232-40.
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2. Bender AT, Beavo JA (2006). Cyclic nucleotide phosphodiesterases: molecular regulation to clini-cal use. Pharmacol Rev,58:488–520.
3. Corbin JD, Francis SH (2002). Pharmacology of phosphodiesterase-5 inhibitors. Int J Clin Pract, 56(6):453-9.
4. Al-Nema MY, Gaurav A (2019). Protein-Protein In-teractions of Phosphodiesterases. Curr Top Med Chem,19(7):555-564.
5. Kukreja RC, Salloum FN, et al (2011). Emerging new uses of phosphodiesterase-5 inhibitors in cardio-vascular diseases. Exp Clin Cardiol,16(4): e30-5.
6. Cai Z, Zhang J, Li H (2019). Two Birds with One Stone: Regular Use of PDE5 Inhibitors for Treat-ing Male Patients with Erectile Dysfunction and Cardiovascular Diseases. Cardiovasc Drugs Ther, 33(1):119-128.
7. Andersson DP, Trolle Lagerros Y, Grotta A, et al (2017). Association between treatment for erectile dysfunction and death or cardiovascularoutcomes after myocardial infarction. Heart,103(16):1264-1270.
8. Yellon DM, Hausenloy DJ, (2007). Myocardial reper-fusion injury. N Engl J Med, 357:1121–1135.
9. Ockaili R, Salloum F, Hawkins J, et al (2002). Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial K(ATP) channels in rabbits. Am J Physiol Heart Circ Physiol,283(3):H1263-9.
10. Das S, Maulik N, Das DK, et al (2002). Cardiopro-tection with sildenafil, a selective inhibitor of cyclic 3′,5′-monophosphate-specific phosphodiesterase 5. Drugs Exp Clin Res, 28(6):213-9.
11. Nagy O, Hajnal A, Parratt JR, et al (2004). Sildenafil (Viagra) reduces arrhythmia severity during is-chaemia 24 h after oral administration in dogs. Br J Pharmacol, 141(4):549–51
12. du Toit EF, Rossouw E, Salie R, et al (2005). Effect of sildenafil on reperfusion function, infarct size, and cyclic nucleotide levels in the isolated rat heart model. Cardiovasc Drugs Ther, 19(1):23-31.
13. Elrod JW, Greer JJ, Lefer DJ (2007). Sildenafil-mediated acute cardioprotection is independent of the NO/cGMP pathway. Am J Physiol Heart Circ Physiol,292(1):H342–7.
14. Salloum FN, Takenoshita Y, Ockaili RA, et al (2007). Sildenafil and vardenafil but not nitroglycerin limit myocardial infarction through opening of mito-chondrial K(ATP) channels when administered at reperfusion following ischemia in rabbits. J Mol Cell Cardiol, 42(2): 453–458.
15. Salloum FN, Chau VQ, Hoke NN, et al (2009). Phosphodiesterase-5 inhibitor, tadalafil, protects against myocardial ischemia/reperfusion through protein-kinase G dependent generation of hy-drogen sulfide. Circulation, 120(11 0): S31–S36..
16. Kloner RA, Rezkalla SH (2006). Preconditioning, postconditioning and their application to clinical cardiology. Cardiovasc Res,70(2):297-307.
17. Behmenburg F, Dorsch M, Huhn R, et al (2015). Impact of Mitochondrial Ca2+-Sensitive Potassi-um (mBKCa) Channels in Sildenafil-Induced Cardioprotection in rats. PLoS One, 10(12): e0144737.
18. Skyschally A, van CP, Iliodromitis EK, et al (2009). Is-chemic postconditioning: experimental models and protocol algorithms. Basic Res Cardiol, 104(5):469–83.
19. Rosanio S, Ye Y, Atar S, et al (2006). Enhanced car-dioprotection against ischemia-reperfusion injury with combining sildenafil with low-dose atorvas-tatin. Cardiovasc Drugs Ther, 20(1):27-36.
20. Elrod JW, Calvert JW, Morrison J, et al (2007). Hy-drogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochon-drial function. Proc Natl Acad Sci USA, 104(39):15560–5.
21. Das A, Ockaili R, Salloum F, et al (2004). Protein ki-nase C plays an essential role in sildenafil-induced cardioprotection in rabbits. Am J Physiol Heart Circ Physiol, 286(4):H1455-60.
22. Carden DL, Granger DN (2000). Pathophysiology of ischaemia-reperfusion injury. J Pathol, 190(3):255–266.
23. Vinten-Johansen J (2004). Involvement of neutro-phils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc Res, 61(3):481–97.
24. Heusch G, Boengler K, Schulz R (2008). Cardiopro-tection: nitric oxide, protein kinases, and mito-chondria. Circulation, 118(19):1915-9.
25. McAlindon E, Bucciarelli-Ducci C, Suleiman MS, et al (2015). Infarct size reduction in acute myocardial infarction. Heart, 101:155–160.
26. Halestrap AP, Clarke SJ, Javadov SA (2004). Mito-chondrial permeability tran sition pore opening during myocardial reperfusion—a target for car-dio- protection. Cardiovasc Res, 61(3):372-85.
27. Das A, Xi L, Kukreja RC (2008). Protein kinase G-dependent cardioprotective mechanism of phos-phodiesterase-5 inhibition involves phosphoryla-tion of ERK and GSK3b. J Biol Chem, 283(43):29572-85.
28. Salloum F, Yin C, Xi L, et al (2003). Sildenafil induces delayed preconditioning through inducible nitric oxide synthase-dependent pathway in mouse heart. Circ Res, 92(6):595-7.
29. Das A, Xi L, Kukreja RC (2005). Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essen-tial role of nitric oxide signaling. J Biol Chem, 280(13):12944-55.
30. Kukreja RC, Salloum F, Das A, et al (2005). Pharma-cological preconditioning with sildenafil: basic mechanisms and clinical implications. Vascul Pharmacol, 42(5-6):219-32.
31. Koneru S, Varma Penumathsa S, Thirunavukkarasu M, et al (2008). Sildenafil-mediated neovasculariza-tion and protection against myocardial ischaemi-areperfusion injury in rats: role of VEGF/angiopoietin-1. J Cell Mol Med, 12(6b): 2651–2664.
32. Lux A, Pokreisz P, Swinnen M, et al (2016). Con-comitant Phosphodiesterase 5 Inhibition En-hances Myocardial Protection by Inhaled Nitric Oxide in Ischemia-Reperfusion Injury. J Pharmacol Exp Ther, 356(2):284-92.
33. Fisher PW, Salloum F, Das A, et al (2005). Phos-phodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dys-function in a chronic model of doxorubicin car-diotoxicity. Circulation, 111(13):1601-10.
34. Li F, Jiang Q, Shi KJ, et al (2013). RhoA modulates functional and physical interaction between ROCK1 and Erk1/2 in selenite-induced apopto-sis of leukaemia cells. Cell Death Dis, 4(7):e708.
35. Prysyazhna O, Burgoyne JR, Scotcher J, et al (2016). Phosphodiesterase 5 Inhibition Limits Doxoru-bicin-induced Heart Failure by Attenuating Protein Kinase G Iα Oxidation. J Biol Chem, 291(33):17427-36.
36. Koka S, Das A, Zhu SG, et al (2010). Long-acting phosphodiesterase-5 inhibitor tadalafil attenuates doxorubicin-induced cardiomyopathy without in-terfering with chemotherapeutic effect. J Pharmacol Exp Ther, 334(3):1023-30.
37. Koka S, Kukreja RC (2010). Attenuation of doxoru-bicin-induced cardiotoxicity by tadalafil: A long act-ing phosphodiesterase-5 inhibitor. Mol Cell Phar-macol, 2(5):173-178.
38. Di Luigi L, Corinaldesi C, Colletti M, et al (2016). Phosphodiesterase Type 5 inhibitor sildenafil de-creases the proinflammatory chemokine CXCL10 in human cardiomyocytes and in sub-jects with diabetic cardiomyopathy. Inflammation, 39(3):1238–52.
39. S Greco,A Salgado Somoza,Y Devaux, et al (2017). Long noncoding RNAs and cardiac disease. An-tioxid Redox Signal, 29(9):880-901.
40. Xiang Zhou, Wei Zhang, Mengchao Jin, et al (2017). lncRNA MIAT functions as a competing endog-enous RNA to upregulate DAPK2 by sponging miR-22-3p in diabetic cardiomyopathy. Cell Death & Disease, 8(7): e2929.
41. Mengyao Zhang, Huimin Gu, Weiting Xu, et al (2016). Down-regulation of lncRNA MALAT1 reduces cardiomyocyte apoptosis and improves left ventricular function in diabetic rats. Int J Cardiol, 203:214–6.
42. Bacci L, Barbati SA, Colussi C,et al (2018). Sildenafil normalizes MALAT1 level in diabetic cardiomy-opathy. Endocrine, 62(1):259-262.
43. Wang X, Fisher P, Xi L, et al (2008). Activation of mi-tochondrial calcium-activated and ATP-sensitive potassium channels is essential for sildenafil-induced cardioprotection. J Mol Cell Cardiol, 44:105–13.
44. Giannetta E, Isidori AM, Galea N, et al (2012). Chronic Inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a ran-domized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circu-lation, 125(19):2323–33.
45. Hadi HA, Carr CS, Al Suwaidi J (2005). Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag, 1(3):183-98.
46. Cayatte AJ, Palacino JJ, Horten K, et al (1994). Chron-ic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits. Arterio-scler Thromb, 14(5):753-9.
47. Widlansky ME, Gokce N, Keaney JF Jr, et al (2003). The clinical impli- cations of endothelial dysfunc-tion. J Am Coll Cardiol, 42(7):1149-60.
48. Ganz P, Vita JA (2003). Testing endothelial vasomo-tor function: nitric oxide, a multipotent molecule. Circulation, 108(17):2049-53.
49. Vasquez EC, Gava AL, Graceli JB, et al (2016). Novel Therapeutic Targets for Phosphodiesterase 5 In-hibitors: current state-of-the-art on systemic arterial hypertension and atherosclerosis. Curr Pharm Bio-technol, 17(4):347-64.
50. Lerman A, Zeiher AM (2005). Endothelial function: cardiac events. Circulation, 111(3):363-8.
51. Katz SD, Balidemaj K, Homma S, et al (2000). Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediated vasodilation in patients with chronic heart failure. J Am Coll Cardiol, 36(3):845-51.
52. Halcox JP, Nour KR, Zalos G, et al (2002). The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia. J Am Coll Car-diol, 40(7):1232-40.
53. Gori T, Sicuro S, Dragoni S, et al (2005). Sildenafil prevents endothelial dysfunction induced by is-chemia and reperfusion via opening of adenosine triphosphate-sensitive potassium channels: A human in vivo study. Circulation, 111)6):742–6.
54. Dias AT, Leal MAS, Zanardo TC, et al (2018). Bene-ficial Morphofunctional Changes Promoted by Sildenafil in Resistance Vessels in the Angiotensin II-Induced Hypertension Model. Curr Pharm Bio-technol, 19(6):483-494.
55. Takimoto E, Champion HC, Li M, et al (2005). Chronic inhibition of cyclic GMP phos-phodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med, 11(2):214–22.
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| Files | ||
| Issue | Vol 52 No 5 (2023) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v52i5.12704 | |
| Keywords | ||
| Cardiovascular disease Cardioprotective effects Phosphodiesterase-5 inhibitors | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Corbic M, Sretenovic J, Zivkovic V, Jakovljevic V, Nikolic Turnic T. Phosphodiesterase-5 Inhibitors as Therapeutics for Cardiovascular Diseases: A Brief Review. Iran J Public Health. 2023;52(5):870-879.
