Abstract

Review Article

Sildenafil citrate in healthy and diseased hearts

Seriki Samuel Adinoyi*

Published: 23 April, 2021 | Volume 6 - Issue 1 | Pages: 033-039

Sildenafil citrate is one of the frontline drugs used to manage erectile dysfunction (ED). Chemically, it is described as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H –pyrazolo [4,3-d]pyrimidin-5-yl)-4 ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate (C22H30N6O4 S). It is a highly selective inhibitor of cyclic guanine monophosphate-specific phosphodiesterase type-5. There had been heightened concerns following reports that sildenafil citrate may increase the risk of cardiovascular events, particularly fatal arrhythmias, in patients with cardiovascular disease. So the cardiac electrophysiological effects of sildenafil citrate have been investigated extensively in both animal and clinical studies. This article ties up the various outcomes of the investigations with a view to guiding physicians and patients that use sildenafil citrate to manage erectile dysfunction, especially as it concerns its effect on their cardiovascular function in health and in disease. Sildenafil citrate could impact negatively on ailing hearts, but on a healthy heart, there may not be any such impact, rather, it improves on heart performance as it lowers the blood pressure.

Read Full Article HTML DOI: 10.29328/journal.jccm.1001115 Cite this Article Read Full Article PDF

Keywords:

Sildenafil citrate; Erectile dysfunction; Cardiovascular function; Nitrate oxide; Myocardial infarction

References

  1. Chew KK, Earle CM, Stuckey BG, Jamrozik K, Keogh EJ. Erectile dysfunction in general medicine practice: prevalence and clinical correlates. Int J Impotence Res. 2000; 12: 41-45. PubMed: https://pubmed.ncbi.nlm.nih.gov/10982311/
  2. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. J Am Med Assoc. 1999; 281: 537-544. PubMed: https://pubmed.ncbi.nlm.nih.gov/10022110/
  3. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. 1994; 151: 54-61. PubMed: https://pubmed.ncbi.nlm.nih.gov/8254833/
  4. Kloner RA. Cardiovascular risk and sildenafil. Am J Cardiol. 2000; 86: 57F-61F. PubMed: https://pubmed.ncbi.nlm.nih.gov/10899281/
  5. Greenstein A, Chen J, Miller H, Matzkin H, Villa Y, et al. Does severity of ischemic coronary disease correlate with erectile function? Int J Impotence Res.1997; 9: 123-126.
  6. Israilov S, Baniel J, Shmueli J, Niv E, Engelstein D, et al. Treatment program for erectile dysfunction in patients with cardiovascular diseases. Am J Cardiol. 2004; 93: 689-693.
  7. Khan MA, Ledda A, Mikhailidis DP, Rosano G, Vale J, et al. Second Consensus Conference on Cardiovascular Risk Factors and Erectile Dysfunction. Curr Med Res Opinion. 2002; 18: 33-35.
  8. Lue TF. Erectile dysfunction. New Engl J Med. 2000; 342: 1802-1813. PubMed: https://pubmed.ncbi.nlm.nih.gov/10853004/
  9. Kloner RA, Jarow JP. Erectile dysfunction and sildenafil citrate and cardiologists. Am J Cardiol. 1999; 83: 576-582. PubMed: https://pubmed.ncbi.nlm.nih.gov/10073864/
  10. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, et al. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. New Engl J Med. 1998; 338: 1397-1404. PubMed: https://pubmed.ncbi.nlm.nih.gov/9580646/
  11. Shakir SA, Wilton LV, Boshier A, Layton D, Heeley E. Cardiovascular events in users of sildenafil: results from first phase of prescription event monitoring in England. Bri Med J. 2001; 322: 651-652.
  12. DeBusk R, Drory Y, Goldstein I. Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel. Am J Cardiol. 2000; 86: 62F-68F. PubMed: https://pubmed.ncbi.nlm.nih.gov/10899282/
  13. Webb DJ, Freestone S, Allen MJ, Muirhead GJ. Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am J Cardiol. 1999; 83: 21C–28C. PubMed: https://pubmed.ncbi.nlm.nih.gov/10078539/
  14. Francis SH, Busch JL, Corbin JD, Sibley D. cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev. 2010; 62: 525 563. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964902/
  15. Viagra Clinical Pharmacology. 2008. RxList.com
  16. Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev. 1995; 75: 725-748. PubMed: https://pubmed.ncbi.nlm.nih.gov/7480160/
  17. Wallis RM, Corbin JD, Francis SH, Ellis P. Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol. 1999; 83: 3C-12C. PubMed: https://pubmed.ncbi.nlm.nih.gov/10078537/
  18. Arora RR, Timoney M, Melilli L. Acute myocardial infarction after the use of sildenafil. New Engl J Med.1999; 341: 700.
  19. Mittleman MA, Glasser DB, Orazem J. Clinical trials of sildenafil citrate (Viagra) demonstrate no increase in risk of myocardial infarction and cardiovascular death compared with placebo. Int J Clin Pract. 2003; 57: 597-600. PubMed: https://pubmed.ncbi.nlm.nih.gov/14529061/
  20. Manfroi WC, Caramori PR, Zago AJ, Melchior R, Zen V, et al. Hemodynamic effects of sildenafil in patients with stable ischemic heart disease. Int J Cardiol. 2003: 90: 153-157.
  21. Cheitlin MD, Hutter Jr AM, Brindis RG, Ganz P, Kaul S, et al. Use of sildenafil (Viagra) in patients with cardiovascular disease. Technology and Practice Executive Committee. Circulation.1999; 99: 168-177. PubMed: https://pubmed.ncbi.nlm.nih.gov/9884398/
  22. Cheitlin MD, Hutter Jr AM, Brindis RG, Ganz P, Kaul S, et al. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am College Cardiol. 1999; 33: 273-282. PubMed: https://pubmed.ncbi.nlm.nih.gov/9935041/
  23. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The Promise Study Research Group. New Engl J Med. 1991; 325: 1468-1475. PubMed: https://pubmed.ncbi.nlm.nih.gov/1944425/
  24. Degerman E, Belfrage P, Manganiello VC. Structure, localization, and regulation of cGMP-inhibited phosphodiesterase (PDE3). J Biol Chem. 1997; 272: 6823-6826. PubMed: https://pubmed.ncbi.nlm.nih.gov/9102399/
  25. Nony P, Boissel JP, Lievre M, Leizorovicz A, Haugh MC, et al. Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients. A meta-analysis. Eur J Clin Pharmacol. 1994; 46: 191-196. PubMed: https://pubmed.ncbi.nlm.nih.gov/8070498/
  26. Corbin J, Rannels S, Neal D, Chang P, Grimes K, et al. Sildenafil citrate does not affect cardiac contractility in human or dog heart. Curr Med Res Opinion. 2003; 19: 747-752.
  27. Herrmann HC, Chang G, Klugherz BD, Mahoney PD. Hemodynamic effects of sildenafil in men with severe coronary artery disease. New Engl J Med. 2000; 342: 1622-1626. PubMed: https://pubmed.ncbi.nlm.nih.gov/10833207/
  28. Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ. Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. New Eng J Med. 1992; 326: 90-94. PubMed: https://pubmed.ncbi.nlm.nih.gov/1309211/
  29. Sebkhi A, Strange JW, Phillips SC, Wharton J, Wilkins MR. Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension. Circulation. 2003; 107: 3230-3235. PubMed: https://pubmed.ncbi.nlm.nih.gov/12796132/
  30. Stiebellehner L, Petkov V, Vonbank K, Funk G, Schenk P, et al. Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension. Chest. 2003; 123: 1293-1295. PubMed: https://pubmed.ncbi.nlm.nih.gov/12684325/
  31. Wilkens H, Guth A, Konig J, Forestier N, Cremers B, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation. 2001; 104: 1218-1222. PubMed: https://pubmed.ncbi.nlm.nih.gov/11551870/
  32. Kanthapillai P, Lasserson T, Walters E. Sildenafil for pulmonary hypertension. Cochrane Database of Syst Rev. 2004; CD003562. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396057/
  33. Geelen P, Drolet B, Rail J, Berube J, Daleau P, et al. Sildenafil (Viagra) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current. Circulation. 2002; 102: 275-277.
  34. Swissa M, Ohara T, Lee MH, Kaul S, Shah PK, et al. Sildenafil-nitric oxide donor combination promotes ventricular tachyarrhythmias in the swine right ventricle. Am J Physiol. 2002; 282: H1787-H1792.
  35. Vardi Y, Bulus M, Reisner S, Nassar S, Aboud L, et al. Effects of sildenafil citrate (Viagra) on hemodynamic parameters during exercise testing and occurrence of ventricular arrhythmias in patients with erectile dysfunction and cardiovascular disease. Eur Urol. 2003; 43: 544-551.
  36. Chiang CE, Luk HN, Wang TM, Ding PY. Effects of sildenafil on cardiac repolarization. Cardiovasc Res. 2002; 55: 290-299.
  37. Kaya D, Guler C, Esen AM, Barutcu I, Dincel C. Sildenafil citrate does not alter ventricular repolarization properties: novel evidence from dynamic QT analysis. Ann Noninvasive Electrocardiol. 2004; 9: 228-233. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932561/
  38. Nagy O, Hajnal A, Parratt JR, Vegh A. Sildenafil (Viagra) reduces arrhythmia severity during ischaemia 24h after oral administration in dogs. Br J Pharmacol. 2004; 141: 549-551. PubMed: https://pubmed.ncbi.nlm.nih.gov/14744808/
  39. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986; 74: 1124-1136. PubMed: https://pubmed.ncbi.nlm.nih.gov/3769170/
  40. Salloum F, Yin C, Xi L, Kukreja RC. Sildenafil induces delayed preconditioning through inducible nitric oxide synthase-dependent pathway in mouse heart. Circulat Res. 2003; 92: 595-597. PubMed: https://pubmed.ncbi.nlm.nih.gov/12637371/
  41. Das S, Maulik N, Das DK, Kadowitz PJ, Bivalacqua TJ. Cardioprotection with sildenafil, a selective inhibitor of cyclic 3',5'-monophosphate-specific phosphodiesterase 5. Drugs under Experimen Clin Res. 2002; 28: 213-219. PubMed: https://pubmed.ncbi.nlm.nih.gov/12776574/
  42. Reffelmann T, Kloner RA. Effects of sildenafil on myocardial infarct size, microvascular function, and acute ischemic left ventricular dilation. Cardiovasc Res. 2003; 59: 441-449. PubMed: https://pubmed.ncbi.nlm.nih.gov/12909327/
  43. Ockaili R, Salloum F, Hawkins J, Kukreja RC. Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial K(ATP) channels in rabbits. Am J Physiol. 2002; 283: H1263-H1269. PubMed: https://pubmed.ncbi.nlm.nih.gov/12181158/
  44. Wallis RM. The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. Nippon Yakurigaku Zasshi. Japanese J Pharmacol. 1999; 114: 22P-26P.
  45. Zhao TC, Kukreja RC. Late preconditioning elicited by activation of adenosine A(3) receptor in heart: role of NF-kappa B, iNOS and mitochondrial K(ATP) channel. J Mole Cell Cardiol. 2002; 34: 263-277.
  46. Gross GJ. The role of mitochondrial KATP channels in cardioprotection. Basic Res Cardiol. 2000; 95: 280-284.
  47. Das A, Ockaili R, Salloum F, Kukreja RC. Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits. Am J Physiol. 2004; 286: H1455-H1460. PubMed: https://pubmed.ncbi.nlm.nih.gov/15020304/

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