Over a decade ago, sildenafil, the first phosphodiesterase type 5 (PDE5) inhibitor, became available and revolutionized the treatment of erectile dysfunction (ED). Ever since, several other agents, such as vardenafil and tadalafil, have enriched the spectrum of therapy offering therapeutic flexibility. The fascinating background of PDE5 inhibitors is that they were initially developed for cardiovascular treatment, and this aspect has lately attracted increasing attention. Both type 2 diabetes mellitus (T2DM) and ED are associated with endothelial dysfunction and an increased risk for cardiovascular disease (CVD). While sudden drops in blood pressure from PDE5 inhibitor use may trigger sympathetic activation with potential negative effects on a damaged cardiovascular system, a growing body of literature suggests that PDE5 inhibitors restore endothelial function, thus representing a potential cardiovascular therapy.
This article discusses current use, safety profile and future therapeutic developments of this class of dugs.
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References
1.
BoolellM., AllenM.J., BallardS.A., Gepi-AtteeS., MuirheadG.J., NaylorA.M., et al.Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res, 1996; 8:47–52.
KlonerR.A.Cardiovascular effects of the 3 phosphodiesterase-5 inhibitors approved for the treatment of erectile dysfunction. Circulation, 2004; 110:3149–3155.
4.
DeBuskR.F., PepineC.J., GlasserD.B., ShpilskyA., DeRiesthalH., SweeneyM.Efficacy and safety of sildenafil citrate in men with erectile dysfunction and stable coronary artery disease. Am J Cardiol, 2004; 93:147–153.
5.
JacksonG.Hemodynamic and exercise effects of phosphodiesterase 5 inhibitors. Am J Cardiol, 2005; 96:32M–36M.
6.
RosenR.C., RileyA., WagnerG., OsterlohI.H., KirkpatrickJ., MishraA.The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology, 1997; 49:822–830.
7.
PalumboP.J.Metabolic risk factors, endothelial dysfunction, and erectile dysfunction in men with diabetes. Am J Med Sci, 2007; 334:466–480.
8.
EspositoK., GiuglianoF., MartediE., FeolaG., MarfellaR., D’ArmientoM., et al.High proportions of erectile dysfunction in men with the metabolic syndrome. Diabetes Care, 2005; 28:1201–1203.
9.
JacksonG., RosenR.C., KlonerR.A., KostisJ.B.The second Princeton consensus on sexual dysfunction and cardiac risk: new guidelines for sexual medicine. J Sex Med, 2006; 3:28–36.
10.
GuayA.T.Relation of endothelial cell function to erectile dysfunction: implications for treatment. Am J Cardiol, 2005; 96:52M–56M.
11.
NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA, 1993; 270:83–90.
12.
MazoE., GamidovS., IremashviliV., GasanovR.Pathogenetic aspects of erectile dysfunction in patients with the metabolic syndrome. J Mens Health, 2008; 5:42–47.
13.
KamenovZ., ChristovV., YankovaT.Erectile dysfunction in diabetic men is linked more to microangiopathic complications and neuropathy than to macroangiopathic disturbances. J Mens Health Gend, 2007; 4:64–73.
14.
RosenR.C., CappelleriJ.C., SmithM.D., LipskyJ., PenaB.M.Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res, 1999; 11:319–326.
15.
CelermajerD.S.Endothelial dysfunction: does it matter? Is it reversible?. J Am Coll Cardiol, 1997; 30:325–333.
16.
WeverR.M., LuscherT.F., CosentinoF., RabelinkT.J.Atherosclerosis and the two faces of endothelial nitric oxide synthase. Circulation, 1998; 97:108–112.
17.
WallisR.M., CorbinJ.D., FrancisS.H., EllisP.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.
18.
NagendranJ., ArcherS.L., SolimanD., GurtuV., MoudgilR., HaromyA., et al.Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation, 2007; 116:238–248.
GhofraniH.A., OsterlohI.H., GrimmingerF.Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov, 2006; 5:689–702.
HryniewiczK., DimayugaC., HudaihedA., AndroneA.S., ZhengH., JankowskiK., et al.Inhibition of angiotensin-converting enzyme and phosphodiesterase type 5 improves endothelial function in heart failure. Clin Sci (Lond), 2005; 108:331–338.
25.
KatzS.D., BalidemajK., HommaS., WuH., WangJ., MaybaumS.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.
26.
HalcoxJ.P., NourK.R., ZalosG., MincemoyerR.A., WaclawiwM., RiveraC.E., et al.The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia. J Am Coll Cardiol, 2002; 40:1232–1240.
27.
DesouzaC., ParulkarA., LumpkinD., AkersD., FonsecaV.A.Acute and prolonged effects of sildenafil on brachial artery flow-mediated dilatation in type 2 diabetes. Diabetes Care, 2002; 25:1336–1339.
28.
RosanoG.M., AversaA., VitaleC., FabbriA., FiniM., SperaG.Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk. Eur Urol, 2005; 47:214–220.
29.
ForestaC., FerlinA., De ToniL., LanaA., VinanziC., GalanA., et al.Circulating endothelial progenitor cells and endothelial function after chronic tadalafil treatment in subjects with erectile dysfunction. Int J Impot Res, 2006; 18:484–488.
30.
AversaA., GrecoE., BruzzichesR., PiliM., RosanoG., SperaG.Relationship between chronic tadalafil administration and improvement of endothelial function in men with erectile dysfunction: a pilot study. Int J Impot Res, 2007; 19:200–207.
31.
MazoE., GamidovS., IremashviliV.The effect of vardenafil on endothelial function of brachial and cavernous arteries. Int J Impot Res, 2006; 18:464–469.
32.
MazoE.B., GamidovS.I., IremashviliV.V.Does the clinical efficacy of vardenafil correlate with its effect on the endothelial function of cavernosal arteries? A pilot study. BJU Int, 2006; 98:1054–1058.
33.
DishyV., SofoworaG., HarrisP.A., KandcerM., ZhanF., WoodA.J., et al.The effect of sildenafil on nitric oxide-mediated vasodilation in healthy men. Clin Pharmacol Ther, 2001; 70:270–279.
34.
DishyV., HarrisP.A., PierceR., PrasadH.C., SofoworaG., BonarH.L., et al.Sildenafil does not improve nitric oxide-mediated endothelium-dependent vascular responses in smokers. Br J Clin Pharmacol, 2004; 57:209–212.
35.
RobinsonS.D., LudlamC.A., BoonN.A., NewbyD.E.Phosphodiesterase type 5 inhibition does not reverse endothelial dysfunction in patients with coronary heart disease. Heart, 2005; 92:170–176.
U.S. Food and Drug Administration (Center for Drug Evaluation and Reseach). Summary of Death Reports in Viagra Received from Marketing (late March) through June 1998. Washington, DC: U.S. FDA; 1998.
39.
AroraR.R., TimoneyM., MelilliL.Acute myocardial infarction after the use of sildenafil. N Engl J Med, 1999; 341:700.
40.
HerrmannH.C., ChangG., KlugherzB.D., MahoneyP.D.Hemodynamic effects of sildenafil in men with severe coronary artery disease. N Engl J Med, 2000; 342:1622–1626.
41.
MahmudA., HennessyM., FeelyJ.Effect of sildenafil on blood pressure and arterial wave reflection in treated hypertensive men. J Hum Hypertens, 2001; 15:707–713.
42.
PomaraG., MorelliG., PomaraS., TaddeiS., GhiadoniL., DinelliN., et al.Cardiovascular parameter changes in patients with erectile dysfunction using PDE-5 inhibitors: a study with sildenafil and vardenafil. J Androl, 2004; 25:625–629.
43.
PiccirilloG., NoccoM., LionettiM., MoisèA., NasoC., MariglianoV., et al.Effects of sildenafil citrate (viagra) on cardiac repolarization and on autonomic control in subjects with chronic heart failure. Am Heart J, 2002; 143:703–710.
44.
PhillipsB.G., KatoM., PesekC.A., WinnickiM., NarkiewiczK., DavisonD., et al.Sympathetic activation by sildenafil. Circulation, 2000; 102:3068–3073.
45.
AgelinkM.W., SchmitzT., RembrinkK., BeckerlingD., Muck-WeymannM., MercikD., et al.Cardiovascular effects of sildenafil citrate (Viagra): a naturalistic cross-over study. Eur J Med Res, 2001; 6:459–464.
46.
ZusmanR.M., PrisantL.M., BrownM.J.Effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication. Sildenafil Study Group. J Hypertens, 2000; 18:1865–1869.
47.
ContiC.R., PepineC.J., SweeneyM.Efficacy and safety of sildenafil citrate in the treatment of erectile dysfunction in patients with ischemic heart disease. Am J Cardiol, 1999; 83:29C–34C.
48.
StirbanA., LaudeD., ElghoziJ.L., SanderD., AgelinkM.W., HilzM.J., et al.Acute effects of sildenafil on flow mediated dilatation and cardiovascular autonomic nerve function in type 2 diabetic patients. Diabetes Metab Res Rev, 2009; 25:136–143.
49.
GoriT., SicuroS., DragoniS., DonatiG., ForconiS., ParkerJ.D.Sildenafil prevents endothelial dysfunction induced by ischemia and reperfusion via opening of adenosine triphosphate-sensitive potassium channels: a human in vivo study. Circulation, 2005; 111:742–746.
50.
HeitzerT., SchlinzigT., KrohnK., MeinertzT., MunzelT.Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation, 2001; 104:2673–2678.
51.
KatzS.D., HryniewiczK., HriljacI., BalidemajK., DimayugaC., HudaihedA., et al.Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation, 2005; 111:310–314.
52.
SchofieldR.S., EdwardsD.G., SchulerB.T., EstradaJ., ArandaJ.M., PaulyD.F., et al.Vascular effects of sildenafil in hypertensive cardiac transplant recipients. Am J Hypertens, 2003; 16:874–877.
53.
KhaodhiarL., VevesA.Acute and prolonged effects of sildenafil on brachial artery flow-mediated dilatation in type 2 diabetes. Diabetes Care, 2003; 26:962–963.
54.
DietzU., TriesH.P., MerkleW., Jaursch-HanckeC., LambertzH.[Sildenafil does not change coronary flow reserve in diabetics with erectile dysfunction]. Dtsch Med Wochenschr, 2003; 128:190–195.
55.
FonsecaV., JawaA.Endothelial and erectile dysfunction, diabetes mellitus, and the metabolic syndrome: common pathways and treatments?. Am J Cardiol, 2005; 96:13M–18M.
56.
AversaA., VitaleC., VolterraniM., FabbriA., SperaG., FiniM., et al.Chronic administration of sildenafil improves markers of endothelial function in men with type 2 diabetes. Diabet Med, 2008; 25:37–44.
57.
MazoE., GamidovS., AnranovichS., IremashviliV.Testing endothelial function of brachial and cavernous arteries in patients with erectile dysfunction. J Sex Med, 2006; 3:323–330.
58.
PeggeN.C., TwomeyA.M., VaughtonK., GravenorM.B., RamseyM.W., PriceD.E.The role of endothelial dysfunction in the pathophysiology of erectile dysfunction in diabetes and in determining response to treatment. Diabet Med, 2006; 23:873–878.
59.
ForestaC., LanaA., CabrelleA., FerigoM., CarettaN., GarollaA., et al.PDE-5 inhibitor, vardenafil, increases circulating progenitor cells in humans. Int J Impot Res, 2005; 17:377–380.
60.
ForestaC., CarettaN., LanaA., De ToniL., BiagioliA., VinanziC., et al.Relationship between vascular damage degrees and endothelial progenitor cells in patients with erectile dysfunction: effect of vardenafil administration and PDE5 expression in the bone marrow. Eur Urol, 2006; 51:1411–1417.
61.
DaiZ.K., TanM.S., ChaiC.Y., ChouS.H., LinP.C., YehJ.L., et al.Effects of sildenafil on pulmonary hypertension and levels of ET-1, eNOS, and cGMP in aorta-banded rats. Exp Biol Med (Maywood), 2006; 231:942–947.
62.
MoranoS., MandosiE., FallarinoM., GattiA., TibertiC., SensiM., et al.Antioxidant treatment associated with sildenafil reduces monocyte activation and markers of endothelial damage in patients with diabetic erectile dysfunction: a double-blind, placebo-controlled study. Eur Urol, 2007; 52:1768–1774.
63.
KatzS.D.Potential role of type 5 phosphodiesterase inhibition in the treatment of congestive heart failure. Congest Heart Fail, 2003; 9:9–15.
64.
CremersB., BohmM.Non erectile dysfunction application of sildenafil. Herz, 2003; 28:325–333.
65.
FinkelM.S., OddisC.V., JacobT.D., WatkinsS.C., HattlerB.G., SimmonsR.L.Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science, 1992; 257:387–389.
66.
HareJ.M., LohE., CreagerM.A., ColucciW.S.Nitric oxide inhibits the positive inotropic response to beta-adrenergic stimulation in humans with left ventricular dysfunction. Circulation, 1995; 92:2198–2203.
67.
KumarA., BrarR., WangP., DeeL., SkorupaG., KhadourF., et al.Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility. Am J Physiol, 1999; 276:R265–R276.
68.
SemigranM.J.Type 5 phosphodiesterase inhibition: the focus shifts to the heart. Circulation, 2005; 112:2589–2591.
WooK.S., ChookP., LolinY.I., SandersonJ.E., MetreweliC., CelermajerD.S.Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. J Am Coll Cardiol, 1999; 34:2002–2006.
72.
StirbanA., NegreanM., StratmannB., GawlowskiT., HorstmannT., GottingC., et al.Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care, 2006; 29:2064–2071.
73.
LingL., ZhaoS.P., GaoM., ZhouQ.C., LiY.L., XiaB.Vitamin C preserves endothelial function in patients with coronary heart disease after a high-fat meal. Clin Cardiol, 2002; 25:219–224.
74.
MaierW., CosentinoF., LutolfR.B., FleischM., SeilerC., HessO.M., et al.Tetrahydrobiopterin improves endothelial function in patients with coronary artery disease. J Cardiovasc Pharmacol, 2000; 35:173–178.
75.
CerielloA., TabogaC., TonuttiL., QuagliaroL., PiconiL., BaisB., et al.Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment. Circulation, 2002; 106:1211–1218.
76.
O’DriscollG., GreenD., MaioranaA., StantonK., ColreavyF., TaylorR.Improvement in endothelial function by angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. J Am Coll Cardiol, 1999; 33:1506–1511.
