Abstract
The availability of selective inhibitors of the cyclic guanosine monophosphate (cGMP)-specific type 5 phosphodiesterase (PDE5) has created increasing interest in unlocking the therapeutic potential of PDE5 inhibition in cardiovascular diseases that are marked by dysfunction of nitric oxide (NO)-cGMP signaling. Pulmonary arterial hypertension (PAH) and heart failure (HF) are characterized by pulmonary arterial vasoconstriction that is thought to be caused by relative deficiencies of vasodilators such as NO and exaggerated production of vasoconstrictors such as endothelin. PDE5 is abundant in the pulmonary vasculature where it catabolizes cGMP, the second messenger of NO. Inhibition of PDE5 has been shown to lower pulmonary vascular resistance in PAH and HF by augmenting local cGMP. This review outlines the therapeutic potential of PDE5 inhibition for the treatment of PAH and HF.
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References and Recommended Reading
Beavo JA: Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 1995, 75:725–748.
Wallis RM, Corbin JD, Francis SH, et al.: Tissue distribution of phosphodiesterase families and the effect 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. Wallis et al. identified phosphodiesterase isoenzymes by substrate specificity and phosphodiesterase antibodies. This study delineates the tissue distribution of PDE5 and concludes that PDE5 is present in various vascular beds, and in platelets but not in human cardiac ventricles.
Maurice DH, Palmer D, Tilley DG, et al.: Cyclic nucleotide phosphodiesterase activity, expression, and targeting in cells of the cardiovascular system. Mol Pharmacol 2003, 64:533–546.
Reffelmann T, Kloner RA: Therapeutic potential of phosphodiesterase 5 inhibition for cardiovascular disease. Circulation 2003, 108:239–244.
Butcher RW, Sutherland EW: Adenosine 3’5’-phosphate in biological materials. J Biol Chem 1962, 237:1244–1250.
Gresser U, Gleiter CH: Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil: review of the literature. Eur J Med Res 2002, 7:435–446.
Rubin LJ: Primary pulmonary hypertension. N Engl J Med 1997, 336:111–117.
Lincoln TM, 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 2001, 91:1421–1430.
Steudel W, Hurford WE, Zapol WM: Inhaled nitric oxide: basic biology and clinical applications. Anesthesiology 1999, 91:1090–1121.
Rabe KF, Tenor H, Dent G, et al.: Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors. Am J Physiol 1994, 266:L536-L543.
Thomas MK, Francis SH, Corbin JD: Characterisation of a purified bovine lung cGMP-binding cGMP phosphodiesterase. J Biol Chem 1990, 265:14964–14970.
Sebkhi A, Strange JW, Phillips SC, et al.: Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension. Circulation 2003, 107:3230–3235.
MacLean MR, Johnston ED, McCulloch KM, et al.: Phosphodiesterase isoforms in the pulmonary arterial circulation of the rat. J Pharmacol Exp Ther 1997, 283:619–624.
Hanson KA, Ziegler JW, Rybalkin SD, et al.: Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity. Am J Physiol 1998, 275:L931-L941.
Zhao L, Mason NW, Morrell NW, et al.: Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 2001, 104:424–428.
Schermuly RT, Kreisselmeier KP, Ghofrani HY, et al.: Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats. Am J Resp Crit Care Med 2004, 169:39–45.
Ichinose F, Erana-Garcia J, Hromi J, et al.: Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med 2001, 29:1000–1005.
Lepore JJ, Maroo A, Pereira NL, et al.: Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. Am J Cardiol 2002, 90:677–680. This study demonstrates that sildenafil improves cardiac performance and augments and prolongs the hemodynamic effects of inhaled NO in patients with PAH.
Michelakis ED, Tymchak W, Noga M, et al.: Long term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation 2003, 108:2066–2069. This small but carefully done study demonstrates that chronic administration of sildenafil to patients with PAH (n = 5) results in improvement in exercise capacity and PVR, while inducing regression of RV hypertrophy. If these results can be duplicated in large randomized trials of PDE5 inhibitors for the treatment of PAH, it will represent a significant advance in the therapy for this devastating disease.
Sastry BK, Narasimhan C, Reddy NK, et al.: Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004, 43:1149–1153.
Ghofrani HA, Wiedemann R, Rose F, et al.: Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomized controlled trial. Lancet 2002, 360:895–900.
Lewis GD, Bloch KD, Semigran MJ: Pulmonary embolism superimposed on congenital VSD: sildenafil to the rescue. Cardiol Rev 2004, 12:188–190.
Atz AM, Lefler AK, Fairbrother DL, et al.: Sildenafil augments the effect of inhaled nitric oxide for postoperative pulmonary hypertensive crises. J Thorac Cardiovasc Surg 2002, 124:628–629.
Mychaskiw G, Sachdev V, Heath BJ: Sildenafil facilitates weaning of inhaled nitric oxide following placement of a biventricular-assist device. J Clin Anesth 2001, 13:218–220.
Wilkins 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.
Di SalvoTG, Mathier M, Semigran MJ, et al.: Preserved right ventricular ejection fraction predicts exercise capacity and survival in advanced heart failure. J Am Coll Cardiol 1995, 25:1143–1153.
Franciosa JA, Baker BJ, Seth L: Pulmonary versus systemic hemodynamics in determining exercise capacity of patients with chronic left ventricular failure. Am Heart J 1985, 110:807–813.
Moraes DL, Colucci WS, Givertz MM: Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management. Circulation 2000, 102:1718–1723.
Kiowski W, Sutsch G, Hunziker P, et al.: Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet 1995, 346:732–736.
Givertz MM, Colucci WS, Lejemtel TH, et al.: Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. Circulation 2000, 101:2922–2927.
Loh E, Stamler JS, Hare JM, et al.: Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction. Circulation 1994, 90:2780–2785.
Semigran MJ, Cockrill BA, Kacmarek R, et al.: Hemodynamic effects of inhaled nitric oxide in heart failure. J Am Coll Cardiol 1994, 24:982–988.
Koelling TM, Kirmse M, Di Salvo TG, et al.: Inhaled nitric oxide improves exercise capacity in patients with severe heart failure and right ventricular dysfunction. Am J Cardiol 1998, 81:1494–1497.
Rabe KF, Tenor H, Dent G, et al.: Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors. Am J Physiol 1994, 266:L536-L543.
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.
Lepore JJ, Maroo A, PereiraNL, et al.:Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide.Chest 2004, In press.
Lachman J, Camuso J, Lewis G, et al.: Sildenafil improves hemodynamics and exercise tolerance in patients with advanced heart failure [abstract]. Circulation 2002, 106(Suppl):II-469.
Bocchi EA, Guimaraes G, Mocelin A, et al.: Sildenafil effects on exercise, neurohormonal activation, and erectile dysfunction in congestive heart failure: a double-blind, placebo-controlled, randomized study followed by a prospective treatment for erectile dysfunction. Circulation 2002, 106:1097–1103.
Webster LJ, Michelakis ED, Davis T, Archer SL: Use of sildenafil for safe improvement of erectile function and quality of life in men with New York Heart Association classes II and III congestive heart failure: a prospective, placebo-controlled, double-blind crossover trial. Arch Intern Med 2004, 164:514–520.
Cockrill BA, Kacmarek RM, Fifer MA, et al.: Comparison of the effects of nitric oxide, nitroprusside, and nifedipine on hemodynamics and right ventricular contractility in patients with chronic pulmonary hypertension. Chest 2001, 119:128–136.
Colucci WS, Jaski BE, Fifer MA, et al.: Milrinone: a positive inotropic vasodilator. Trans Assoc Am Physicians 1984, 97:124–133.
Burstein S, Semigran MJ, Dec GW, et al.: Positive inotropic and lusitropic effects of intravenous flosequinan in patients with heart failure. J Am Coll Cardiol 1992, 20:822–829.
Kotera J, Fujishige K, Akatsuka H, et al.: Novel alternative splice variants of cGMP-binding cGMP-specific phosphodiesterase. J Biol Chem 1998, 273:26982–26990.
Yanaka N, Kotera J, Ohtsuka A, et al.: Expression, structure and chromosomal localization of the human cGMP-binding cGMP-specific phosphodiesterase PDE5A gene. Eur J Biochem 1998, 255:391–399.
Corbin J, Rannels S, Neal D, et al.: Sildenafil citrate does not effect cardiac contractility in human or dog heart. Curr Med Res Opin 2003, 19:747–752.
Senzaki H, Smith CJ, Juang GJ, et al.: Cardiac phosphodiesterase 5 (cGMP-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure. FASEB J 2001, 15:1718–1726. These authors report evidence of PDE5A activity in canine cardiomyocytes, which remains controversial. PDE5A inhibition was observed to markedly attenuate β-adrenergic responsiveness in normal canine hearts but not in dogs with HF induced by tachypacing. These findings suggest that PDE5 modulates β-adrenergic responsiveness and that reduction of PDE5 activity in the failing heart may contribute to the characteristic reduced β-adrenergic responsiveness that is observed in HF.
Hare JM, Givertz MM, Creager MA, Colucci WS: Increased sensitivity to nitric oxide synthase inhibition in patients with heart failure: potentiation of beta-adrenergic inotropic responsiveness. Circulation 1998, 97:161–166.
Hare JM, Lofthouse RA, Juang GJ, et al.: Contribution of caveolin protein abundance to augmented nitric oxide signaling in conscious dogs with pacing-induced heart failure. Circ Res 2000, 86:1085–1092.
Chen HH, Burnett JC: The natriuretic peptides in heart failure: diagnostic and therapeutic potentials. Proc Assoc Am Physicians 1999, 111:406–416.
Hare JM, Loh E, Creager MA, Colucci WS: Nitric oxide inhibits the positive inotropic response to beta-adrenergic stimulation in humans with left ventricular dysfunction. Circulation 1995, 92:2198–2203.
Stief CG, Ückert S, Becker AJ, et al.: Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and cardiac tissue. Urology 2000, 55:146–150.
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.
Morales A, Gingell C, Collins M, et al.: Clinical safety of oral sildenafil citrate (Viagra) in the treatment of erectile dysfunction. Int J Impot Res 1998, 10:69–74.
Melvin D, Cheitlin MD, Hutter AM, et al.: ACC/AHA expert consensus document: use of sildenafil (Viagra) in patients with cardiovascular disease. Circulation 1999, 99:168–177.
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Lewis, G.D., Semigran, M.J. Type 5 phosphodiesterase inhibition in heart failure and pulmonary hypertension. Curr Heart Fail Rep 1, 183–189 (2004). https://doi.org/10.1007/s11897-004-0007-6
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DOI: https://doi.org/10.1007/s11897-004-0007-6