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Phosphodiesterase type 5 inhibition in cardiovascular disease: experimental models and potential clinical applications

G. Jackson*

Cardiac Department, Guy's and St. Thomas' Hospital, London, U.K.

* Correspondence: Graham Jackson, MD, Cardiac Department, St. Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, U.K.

Abstract

Inhibition of phosphodiesterase type 5, with amplification of the nitric oxide-cyclic nucleotide signalling pathway, and smooth muscle relaxation within erectile tissues and the penile vasculature, is the mechanism underlying the pro-erectile effects of sildenafil citrate. However, this enzyme is also expressed in other vascular beds, and preliminary findings have suggested that phosphodiesterase type 5 inhibition represents a promising treatment strategy for a range of cardiovascular conditions, including hypertension and chronic heart failure. Administered either alone or in concert with an inhaled prostacyclin analogue, sildenafil exhibited beneficial vasodilator effects in patients with pulmonary hypertension, reducing pulmonary arterial pressure and pulmonary vascular resistance, as well as prolonging exercise time and enhancing quality of life. Among patients with heart failure, sildenafil also significantly increased brachial artery diameter (versus placebo) in a flow-mediated vasodilatation paradigm and augmented the blood pressure lowering effects of a calcium channel blocker in men with essential hypertension. Sildenafil was also well tolerated and/or increased the ischaemic threshold during exercise testing in men with stable coronary heart disease. Concomitant therapy with sildenafil and nitrates or nitric oxide donors can cause profound hypotension (and other adverse effects), and is thus absolutely contraindicated.

Key Words: Coronary heart disease • heart failure • pulmonary hypertension • sildenafil citrate

References

  1. 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, neurotransmission. N Engl J Med. 1992;326:90–94[Abstract]
  2. Stasch JP, Becker EM, Alonso--Alija C, et al. NO-independent regulatory site on soluble guanylate cyclase. Nature. 2001;410:212–215[CrossRef][Medline]
  3. Carvajal JA, Germain AM, Huidobro-Toro JP, Weiner CP. Molecular mechanism of cGMP-mediated smooth muscle relaxation. J Cell Physiol. 2000;184:409–420[CrossRef][ISI][Medline]
  4. Sáenz de Tejada I. Molecular mechanisms for the regulation of penile smooth muscle contractility. Int J Impot Res. 2000;12(suppl 4):S34–S38
  5. 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[ISI][Medline]
  6. Rybalkin SD, Bornfeldt KE, Sonnenburg WK, et al. Calmodulin-stimulated cyclic nucleotide phosphodiesterase (PDE1C) is induced in human arterial smooth muscle cells of the synthetic, proliferative phenotype. J Clin Invest. 1997;100:2611–2621[ISI][Medline]
  7. Katz SD, Balidemaj K, Homma S, et al. Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediated vasodilation in patients with chronic heart failure. J Am Coll Cardiol. 2000;36:845–851[Abstract/Free Full Text]
  8. 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[ISI][Medline]
  9. Zhao L, Mason NA, Morrell NW, et al. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation. 2001;104:424–428[Abstract/Free Full Text]
  10. Lepore JJ, Pereira N, Maroo A, et al. Sildenafil is a pulmonary vasodilator which augments and prolongs vasodilatation by inhaled nitric oxide in patients with pulmonary hypertension. [abstract 1247]Circulation. 1999;100(suppl I):I–240 18
  11. Atz AM, Wessel DL. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology. 1999;91:307–310[CrossRef][ISI][Medline]
  12. Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart. 2000;84:E4
  13. Wilkens H, Guth A, Konig J, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation. 2001;104:1218–1222[Abstract/Free Full Text]
  14. Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension. [letter]N Engl J Med. 2000;343:1342[Free Full Text]
  15. Jackson G, Chambers J. Sildenafil for primary pulmonary hypertension: short and long-term symptomatic benefit. Int J Clin Pract. 2002;56:397–398[ISI][Medline]
  16. Jackson G. Phosphodiesterase 5 inhibition: effects on the coronary vasculature. Int J Clin Pract. 2001;55:183–188[ISI][Medline]
  17. 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[Abstract/Free Full Text]
  18. Jackson G, Benjamin N, Jackson N, Allen MJ. Effects of sildenafil citrate on human hemodynamics. Am J Cardiol. 1999;83:13C–20C[ISI][Medline]
  19. Arruda-Olson AM, Mahoney DW, Nehra A, Leckel M, Pellikka PA. Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized crossover trial. JAMA. 2002;287:719–725[Abstract/Free Full Text]
  20. Rosano GMC, Leonardo F, Pagnotta P, et al. Effects of phosphodiesterase-inhibition on myocardial ischemia in patients with chronic stable angina in therapy with ß-blockers. [abstract]Eur Heart J. 1999;20:541[Abstract/Free Full Text]
  21. Fox KM, Thadani U, Ma PTS, Nash SD, Keltai M. Time to limiting angina during treadmill exercise in men with erectile dysfunction and stable chronic angina: effect of sildenafil citrate. [abstract 2846]Circulation. 2001;104(suppl II):II-601–II-602 17
  22. Jackson G, Keltai M, Gillies H, Czorniak M, Keating Z. Viagra is well tolerated by subjects with stable angina and erectile dysfunction during incremental treadmill exercise. [abstract 596]Presented at the XVIIth congress of the European Association of Urology. February 23–26 2002. Birmingham, U.K.
  23. 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[ISI][Medline]
  24. Cheitlin MD, Hutter AM Jr., Brindis RG, et al. Use of sildenafil (Viagra) in patients with cardiovascular disease. Technology and Practice Executive Committee. Circulation. 1999;99:168–177[Free Full Text]
  25. Sildenafil citrate (Viagra®) prescribing information. New York: Pfizer; 1999.

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