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Phosphodiesterase 5 inhibition in heart failure: mechanisms and clinical implications

Nature Reviews Cardiology volume 6, pages 349–355 (2009)Cite this article

Abstract

Phosphodiesterase 5 (PDE5) selectively hydrolyzes cyclic guanosine monophosphate. Inhibitors of PDE5 were originally developed to treat angina pectoris, and currently have multiple therapeutic indications, including erectile dysfunction and pulmonary hypertension. Several lines of research have provided evidence to support various potential PDE5-dependent cellular mechanisms in the myocardium that are involved in the pathophysiology of heart failure and cardiac dysfunction. In this Review we provide a mechanistic overview of the pharmacological inhibition of PDE5 in the context of heart failure, and evaluate the evidence supporting the use of novel PDE5 inhibitors in the treatment of this condition.

Key Points

  • Phosphodiesterase 5 (PDE5) inhibitors have been used clinically to treat erectile dysfunction and pulmonary hypertension

  • Cyclic guanosine monophosphate concentration rises and PDE5 expression is upregulated in a variety of cardiac disorders, including congestive heart failure and right ventricular hypertrophy

  • The downstream effects of cyclic guanosine monophosphate and PDE5 can be modified by PDE5 inhibition in the presence of enhanced sympathetic stimulation

  • Potential benefits of PDE5 inhibition in patients with heart failure include blunting of cardiac hypertrophy, and beneficial effects on the right ventricle, pulmonary and systemic vasculature, and ischemic preconditioning

  • The clinical benefits of PDE5 inhibitors in patients with heart failure are potentially synergistic with current pharmacologic therapies, although the safety profile of these agents needs to be established

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Figure 1: The second messenger pathway in the cardiomyocyte.

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References

  1. Mullershausen, F. et al. Direct activation of PDE5 by cGMP: long-term effects within NO/cGMP signaling. J. Cell Biol. 160, 719–727 (2003).

    Article  CAS  Google Scholar 

  2. Conti, M. & Beavo, J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu. Rev. Biochem. 76, 481–511 (2007).

    Article  CAS  Google Scholar 

  3. Omori, K. & Kotera, J. Overview of PDEs and their regulation. Circ. Res. 100, 309–327 (2007).

    Article  CAS  Google Scholar 

  4. Martin, W., Furchgott, R. F., Villani, G. M. & Jothianandan, D. Phosphodiesterase inhibitors induce endothelium-dependent relaxation of rat and rabbit aorta by potentiating the effects of spontaneously released endothelium-derived relaxing factor. J. Pharmacol. Exp. Ther. 237, 539–547 (1986).

    CAS  PubMed  Google Scholar 

  5. Pauvert, O. et al. Effect of sildenafil on cyclic nucleotide phosphodiesterase activity, vascular tone and calcium signaling in rat pulmonary artery. Br. J. Pharmacol. 139, 513–522 (2003).

    Article  CAS  Google Scholar 

  6. Lin, C. S., Lin, G., Xin, Z. C. & Lue, T. F. Expression, distribution and regulation of phosphodiesterase 5. Curr. Pharm. Des. 12, 3439–3457 (2006).

    Article  CAS  Google Scholar 

  7. Ghofrani, H. A., Osterloh, I. H. & Grimminger, F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat. Rev. Drug Discov. 5, 689–702 (2006).

    Article  CAS  Google Scholar 

  8. Corbin, J. et al. Sildenafil citrate does not affect cardiac contractility in human or dog heart. Curr. Med. Res. Opin. 19, 747–752 (2003).

    Article  CAS  Google Scholar 

  9. Wallis, R. M., Corbin, J. D., Francis, S. H. & 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. 83, 3C–12C (1999).

    Article  CAS  Google Scholar 

  10. Takimoto, E. et al. cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism. Circ. Res. 96, 100–109 (2005).

    Article  CAS  Google Scholar 

  11. Chen, Y. et al. Effect of PDE5 inhibition on coronary hemodynamics in pacing-induced heart failure. Am. J. Physiol. Heart Circ. Physiol. 284, H1513–H1520 (2003).

    Article  CAS  Google Scholar 

  12. Corbin, J. D., Beasley, A., Blount, M. A. & Francis, S. H. High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors. Biochem. Biophys. Res. Commun. 334, 930–938 (2005).

    Article  CAS  Google Scholar 

  13. Forfia, P. R. et al. Acute phosphodiesterase 5 inhibition mimics hemodynamic effects of B-type natriuretic peptide and potentiates B-type natriuretic peptide effects in failing but not normal canine heart. J. Am. Coll. Cardiol. 49, 1079–1088 (2007).

    Article  CAS  Google Scholar 

  14. Nagendran, J. et al. 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 (2007).

    Article  CAS  Google Scholar 

  15. Rybalkin, S. D., Rybalkina, I. G., Shimizu-Albergine, M., Tang, X. B. & Beavo, J. A. PDE5 is converted to an activated state upon cGMP binding to the GAF A domain. EMBO J. 22, 469–478 (2003).

    Article  CAS  Google Scholar 

  16. Leroy, M. J. et al. Characterization of two recombinant PDE3 (cGMP-inhibited cyclic nucleotide phosphodiesterase) isoforms, RcGIP1 and HcGIP2, expressed in NIH 3006 murine fibroblasts and Sf9 insect cells. Biochemistry 35, 10194–10202 (1996).

    Article  CAS  Google Scholar 

  17. Layland, J., Li, J. M. & Shah, A. M. Role of cyclic GMP-dependent protein kinase in the contractile response to exogenous nitric oxide in rat cardiac myocytes. J. Physiol. 540, 457–467 (2002).

    Article  CAS  Google Scholar 

  18. Lincoln, T. M., Wu, X., Sellak, H., Dey, N. & Choi, C. S. Regulation of vascular smooth muscle cell phenotype by cyclic GMP and cyclic GMP-dependent protein kinase. Front. Biosci. 11, 356–367 (2006).

    Article  CAS  Google Scholar 

  19. Lincoln, T. M., Dey, N. & Sellak, H. Invited review: cGMP-dependent protein kinase signaling mechanisms in smooth muscle: from the regulation of tone to gene expression. J. Appl. Physiol. 91, 1421–1430 (2001).

    Article  CAS  Google Scholar 

  20. Corbin, J. D., Turko, I. V., Beasley, A. & Francis, S. H. Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. Eur. J. Biochem. 267, 2760–2767 (2000).

    Article  CAS  Google Scholar 

  21. Castro, L. R., Verde, I., Cooper, D. M. & Fischmeister, R. Cyclic guanosine monophosphate compartmentation in rat cardiac myocytes. Circulation 113, 2221–2228 (2006).

    Article  CAS  Google Scholar 

  22. Nagayama, T., Zhang, M., Hsu, S., Takimoto, E. & Kass, D. A. Sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil. J. Pharmacol. Exp. Ther. 326, 380–387 (2008).

    Article  CAS  Google Scholar 

  23. Hart, C. Y., Hahn, E. L., Meyer, D. M., Burnett, J. C. Jr & Redfield, M. M. Differential effects of natriuretic peptides and NO on LV function in heart failure and normal dogs. Am. J. Physiol. Heart Circ. Physiol. 281, H146–H154 (2001).

    Article  CAS  Google Scholar 

  24. Takimoto, E. et al. Compartmentalization of cardiac beta-adrenergic inotropy modulation by phosphodiesterase type 5. Circulation 115, 2159–2167 (2007).

    Article  CAS  Google Scholar 

  25. Piggott, L. A. et al. Natriuretic peptides and nitric oxide stimulate cGMP synthesis in different cellular compartments. J. Gen. Physiol. 128, 3–14 (2006).

    Article  CAS  Google Scholar 

  26. Senzaki, H. et al. Cardiac phosphodiesterase 5 (cGMP-specific) modulates beta-adrenergic signaling in vivo and is downregulated in heart failure. FASEB J. 15, 1718–1726 (2001).

    Article  CAS  Google Scholar 

  27. Borlaug, B. A., Melenovsky, V., Marhin, T., Fitzgerald, P. & Kass, D. A. Sildenafil inhibits beta-adrenergic-stimulated cardiac contractility in humans. Circulation 112, 2642–2649 (2005).

    Article  CAS  Google Scholar 

  28. Kukreja, R. C. et al. Pharmacological preconditioning with sildenafil: basic mechanisms and clinical implications. Vascul. Pharmacol. 42, 219–232 (2005).

    Article  CAS  Google Scholar 

  29. Das, A., Xi, L. & Kukreja, R. C. Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. J. Biol. Chem. 280, 12944–12955 (2005).

    Article  CAS  Google Scholar 

  30. Sesti, C., Florio, V., Johnson, E. G. & Kloner, R. A. The phosphodiesterase-5 inhibitor tadalafil reduces myocardial infarct size. Int. J. Impot. Res. 19, 55–61 (2007).

    Article  CAS  Google Scholar 

  31. Salloum, F. N., Ockaili, R. A., Wittkamp, M., Marwaha, V. R. & Kukreja, R. C. 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. 40, 405–411 (2006).

    Article  CAS  Google Scholar 

  32. Kishimoto, I., Rossi, K. & Garbers, D. L. A genetic model provides evidence that the receptor for atrial natriuretic peptide (guanylyl cyclase-A) inhibits cardiac ventricular myocyte hypertrophy. Proc. Natl Acad. Sci. USA 98, 2703–2706 (2001).

    Article  CAS  Google Scholar 

  33. Zahabi, A., Picard, S., Fortin, N., Reudelhuber, T. L. & Deschepper, C. F. Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse hearts. J. Biol. Chem. 278, 47694–47699 (2003).

    Article  CAS  Google Scholar 

  34. Wollert, K. C. et al. Gene transfer of cGMP-dependent protein kinase I enhances the antihypertrophic effects of nitric oxide in cardiomyocytes. Hypertension 39, 87–92 (2002).

    Article  CAS  Google Scholar 

  35. Knowles, J. W. et al. Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. J. Clin. Invest. 107, 975–984 (2001).

    Article  CAS  Google Scholar 

  36. Takimoto, E. et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat. Med. 11, 214–222 (2005).

    Article  CAS  Google Scholar 

  37. Lepore, J. J. et al. Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. Am. J. Cardiol. 90, 677–680 (2002).

    Article  CAS  Google Scholar 

  38. Galie, N. et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N. Engl. J. Med. 353, 2148–2157 (2005).

    Article  CAS  Google Scholar 

  39. Chen, H. H., Huntley, B. K., Schirger, J. A., Cataliotti, A. & Burnett, J. C. Jr Maximizing the renal cyclic 3'-5'-guanosine monophosphate system with type V phosphodiesterase inhibition and exogenous natriuretic peptide: a novel strategy to improve renal function in experimental overt heart failure. J. Am. Soc. Nephrol. 17, 2742–2747 (2006).

    Article  CAS  Google Scholar 

  40. Alaeddini, J. et al. Efficacy and safety of sildenafil in the evaluation of pulmonary hypertension in severe heart failure. Am. J. Cardiol. 94, 1475–1477 (2004).

    Article  CAS  Google Scholar 

  41. Guazzi, M., Tumminello, G., Di Marco, F., Fiorentini, C. & Guazzi, M. D. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J. Am. Coll. Cardiol. 44, 2339–2348 (2004).

    Article  CAS  Google Scholar 

  42. Zakliczynski, M. et al. Effectiveness and safety of treatment with sildenafil for secondary pulmonary hypertension in heart transplant candidates. Transplant. Proc. 39, 2856–2858 (2007).

    Article  CAS  Google Scholar 

  43. Michelakis, E. D. et al. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation 108, 2066–2069 (2003).

    Article  CAS  Google Scholar 

  44. Phillips, B. G. et al. Sympathetic activation by sildenafil. Circulation 102, 3068–3073 (2000).

    Article  CAS  Google Scholar 

  45. Piccirillo, G. et al. Effects of sildenafil citrate (viagra) on cardiac repolarization and on autonomic control in subjects with chronic heart failure. Am. Heart J. 143, 703–710 (2002).

    Article  CAS  Google Scholar 

  46. Al-Hesayen, A., Floras, J. S. & Parker, J. D. The effects of intravenous sildenafil on hemodynamics and cardiac sympathetic activity in chronic human heart failure. Eur. J. Heart Fail. 8, 864–868 (2006).

    Article  CAS  Google Scholar 

  47. Katz, S. D. et al. Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediated vasodilation in patients with chronic heart failure. J. Am. Coll. Cardiol. 36, 845–851 (2000).

    Article  CAS  Google Scholar 

  48. Guazzi, M., Samaja, M., Arena, R., Vicenzi, M. & Guazzi, M. D. Long-term use of sildenafil in the therapeutic management of heart failure. J. Am. Coll. Cardiol. 50, 2136–2144 (2007).

    Article  CAS  Google Scholar 

  49. Guazzi, M., Tumminello, G., Di Marco, F. & Guazzi, M. D. Influences of sildenafil on lung function and hemodynamics in patients with chronic heart failure. Clin. Pharmacol. Ther. 76, 371–378 (2004).

    Article  CAS  Google Scholar 

  50. Hirata, K., Adji, A., Vlachopoulos, C. & O'Rourke, M. F. Effect of sildenafil on cardiac performance in patients with heart failure. Am. J. Cardiol. 96, 1436–1440 (2005).

    Article  CAS  Google Scholar 

  51. Hryniewicz, K. et al. Inhibition of angiotensin-converting enzyme and phosphodiesterase type 5 improves endothelial function in heart failure. Clin. Sci. (Lond.) 108, 331–338 (2005).

    Article  CAS  Google Scholar 

  52. Guazzi, M., Tumminello, G., Di Marco, F., Fiorentini, C. & Guazzi, M. D. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J. Am. Coll. Cardiol. 44, 2339–2348 (2004).

    Article  CAS  Google Scholar 

  53. Lewis, G. D. et al. Sildenafil improves exercise hemodynamics and oxygen uptake in patients with systolic heart failure. Circulation 115, 59–66 (2007).

    Article  CAS  Google Scholar 

  54. Lewis, G. D. et al. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation 116, 1555–1562 (2007).

    Article  CAS  Google Scholar 

  55. Goldsmith, S. R. Type 5 phosphodiesterase inhibition in heart failure: the next step. J. Am. Coll. Cardiol. 50, 2145–2147 (2007).

    Article  CAS  Google Scholar 

  56. Packer, M. et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N. Engl. J. Med. 325, 1468–1475 (1991).

    Article  CAS  Google Scholar 

  57. Kass, D. A., Champion, H. C. & Beavo, J. A. Phosphodiesterase type 5: expanding roles in cardiovascular regulation. Circ. Res. 101, 1084–1095 (2007).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Cleveland Clinic, Cleveland, OH, USA

    Praneet Kumar & W. H. Wilson Tang

  2. University of Minnesota, Minneapolis, MN, USA

    Gary S. Francis

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Correspondence to W. H. Wilson Tang.

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Kumar, P., Francis, G. & Wilson Tang, W. Phosphodiesterase 5 inhibition in heart failure: mechanisms and clinical implications. Nat Rev Cardiol 6, 349–355 (2009). https://doi.org/10.1038/nrcardio.2009.32

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