PtwscaahDrmcc

E

Vcoipsm(

d

Td

0d

Hemodynamic and Exercise Effects of Phosphodiesterase 5Inhibitors

Graham Jackson, MD

Phosphodiesterase 5 (PDE5) inhibitors have modest nitrate-like hemodynamic ef-fects, lowering wedge pressure, pulmonary artery pressure, and systolic and diastolicarterial pressure. At rest, decreases in arterial pressure averaging 9/8 mm Hg mayincrease to 12/5 mm Hg as a result of the vasodilatory response, but no clinicaladverse effects have been reported. On the background of increased vasoconstrictionrelated to elevation of angiotensin II, a greater decrease may occur and be relevant tocardiovascular therapy, particularly if angiotensin II antagonists are coprescribed.Exercise studies in patients with ischemia identified no adverse event potential forsildenafil, vardenafil, and tadalafil. Another study showed sildenafil had an anti-ischemic effect, increasing time to limiting angina. Evidence supports the safety ofthese agents in patients with chronic stable coronary artery disease (CAD). Withaccumulating evidence of benefits on endothelial function and clinical improvementsin pulmonary hypertension and heart failure, the hemodynamic and exercise effectsof PDE5 inhibitors suggest an important therapeutic cardiovascular role, reinforcingtheir safety in the patient with CAD and erectile dysfunction. © 2005 Elsevier Inc.

All rights reserved. (Am J Cardiol 2005;96[suppl]:32M–36M)

getaitdatPP

T

Pvnv

estarpNa5lc

hosphodiesterase 5 (PDE5) inhibitors have transformedhe treatment of erectile dysfunction (ED).1 Sildenafil citrateas the first agent developed, and its oral acceptability and

uccess rate rapidly moved it into the treatment of firsthoice for most men with ED. Sildenafil began as a potentiallternative agent to oral nitrates for the treatment of stablengina pectoris, but its short half-life and modest nitrate-likeemodynamic effects were not seen as a clinical advance.uring chronic dosing studies, improved erections were

eported, and this led to sildenafil development as a treat-ent for ED. However, it is worth remembering the original

ardiac concept and looking at the hemodynamic and exer-ise effects of PDE5 inhibitors afresh.2

rectile Dysfunction and Endothelial Dysfunction

ascular endothelium provides the link between ED andardiovascular disease. It plays a vital role in the regulationf circulation, and it is now recognized that vascular diseases the major cause of ED.3 The shared risk factors of hy-ertension, hypercholesterolemia, diabetes mellitus, andmoking suggest that ED in an otherwise asymptomatic manay be the first manifestation of vascular disease elsewhere

Figure 1).4 The smaller penile arteries will be affected to a

Cardiothoracic Centre, St. Thomas’ Hospital, London, United King-om.

Address for reprints: Graham Jackson, MD, Cardiothoracic Centre, St.homas’ Hospital, Lambeth Palace Road, London, SE1 7EH, United King-om.

tE-mail address: gjcardiol@talk21.com.

002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2005.07.009

reater degree by plaque than the larger coronary or periph-ral arteries where asymptomatic lesions may be vulnerableo rupture, if lipid rich.5 Therefore, it is important to see EDs a marker for cardiovascular disease, especially because its correlated with disease severity. This gives us the oppor-unity to look at cardiovascular risk reduction to reduceisease progression using modern medical strategies, suchs lipid-lowering therapy and lifestyle advice.6,7 Becausehe vascular endothelium is the common denominator andDE5 is present throughout the vascular tree, inhibition ofDE5 may have effects beyond the penile arteries.

issue Distribution of Phosphodiesterase 5

DE5 is found in skeletal muscle, visceral smooth muscle,ascular smooth muscle, and the corpus cavernosum. It isot found in the myocardium but is present in coronaryascular smooth muscle tissue.8

When we consider the role of PDE5 inhibitors in penilerection (Figure 2), we can envisage the potential formooth muscle relaxation elsewhere.9 Under normal condi-ions, the vascular endothelium releases nitric oxide (NO)nd prostacyclin, which prevent platelet adhesion. NO iseleased continually from healthy endothelial cells andlays a major role in the pathophysiology of atherosclerosis.O diffuses from the endothelium (there are no receptors)

nd activates guanylate cyclase, which converts guanosine-=-triphosphate to cyclic guanosine monophosphate, whicheads to smooth muscle relaxation generally and, specifi-ally, to relaxation in the cavernosal smooth muscle, which

hen leads to erection. Cyclic guanosine monophosphate is

www.AJConline.org

dda

teTcbPmrafcmt

ctpdpv

H

Dwctni

FN

33MJackson/Hemodynamic and Exercise Effects of Phosphodiesterase 5 Inhibitors

egraded by PDE5, leading to penile flaccidity; this degra-ation is inhibited by PDE5 inhibitors, such as sildenafil,nd the newer agents tadalafil and vardenafil.

From our knowledge of the tissue distribution of PDE5 andhe physiologic effects of its presence and inhibition, we canxpect general hemodynamic effects from PDE5 inhibitors.here are, however, potential differences, depending on theardiovascular status of the individual. PDE5 may be enhancedy angiotensin II secondary to a vasoconstrictive process.DE5 inhibition combined with angiotension II antagonismay, in this situation, have a greater effect on smooth muscle

elaxation (Figure 3).10 The observation that valsartan haslmost no adverse effect and even a potential benefit on sexualunction in men with hypertension reinforces the concept of alose relation between PDE5 and angiotensin II.11 Further-ore, in clinical situations where PDE5 may be increased,

Figure 1. Endothelial link between cardio

igure 2. The role of phosphodiesterase 5 (PDE5) inhibition in penile erecO � nitric oxde.

here could be a therapeutic role for PDE5 inhibition—the g

linical benefit in pulmonary hypertension already realized buthe potential benefit in systemic hypertension not fully ex-lored.12 Because 17% of men with hypertension have someegree of ED before any drug therapy, the attraction of aotential blood pressure–lowering ED–correcting agent is ob-ious.

emodynamic Studies

ata from hemodynamic studies in volunteers and in thoseith coronary artery disease (CAD) support the original con-

ept of PDE5 inhibition being nitrate-like and therefore poten-ially beneficial to the patient with ischemia (silent or recog-ized).13 Sildenafil, being soluble, was studied using anntravenous protocol in 8 men with stable angina and angio-

r disease and erectile dysfunction (ED).

MP � cyclic guanosine monophosphate; GTP � guanosine triphosphate;

vascula

tion. cG

raphically proved CAD. Intravenous sildenafil at a cumula-

t2wpprohw

nppun

rcde

ertbwdwti

Fio

34M The American Journal of Cardiology (www.AJConline.org) Vol 96 (12B) December 26, 2005

ive dose of 40 mg was administered over 60 minutes betweensupine bicycle exercise tests. All antianginal medicationsere uneventfully withdrawn for 48 hours before the study. Aulmonary artery catheter and arterial line were inserted forressure monitoring. After baseline hemodynamic readings atest, sildenafil was infused during 4 15-minute periods at dosesf 5, 5, 10, and 20 mg. After the final dose, at-rest and exerciseemodynamics data were recorded. Sildenafil plasma levelsere similar to oral doses of 100 to 200 mg.As expected, sildenafil behaved in the same manner as a

itrate (Table 1). At rest, there was a small decrease in wedgeressure, pulmonary artery pressure, and systolic and diastolicressure. Heart rate and thermodilution cardiac output werenchanged. On exercise, the decreases in wedge and pulmo-

igure 3. (A) Interaction of angiotensin II and phosphodiesterase 5 (PDE5).nhibitors; 2 � angiotensin II antagonists; AII � angiotensin II; cGMP �xde.

ary artery pressure increased as a result of the vasodilatory �

esponse, and arterial pressure decreased by 12/5 mm Hgompared with 9/8 mm Hg at rest. Thus, there was a modestecrease in central arterial pressure, with a reduction in periph-ral resistance in keeping with mixed vasodilatory properties.

Studies in healthy volunteers identified no dose-responseffect on cardiovascular variables, with the mean maximumeduction in supine blood pressure (8/6 mm Hg) occurring 1o 2 hours after oral dosing. Blood pressure returned toaseline after 5 hours. In patients with hypertension, thereas a blood pressure–lowering effect, which may be depen-ent on the baseline blood pressure control. When sildenafilas added to background therapy for hypertension in pa-

ients whose condition was not fully controlled, a decreasen pressure of 24 � 10 mm Hg versus 6 � 8 mm Hg (p

ential benefits of angiotensin II antagonists and PDE5 inhibitors. 1� PDE5guanosine monophosphate; GTP � guanosine triphosphate; NO � nitric

(B) Potcyclic

0.05) in systolic and 8 � 5 mm Hg versus 3 � 2 mm Hg

(twc

hhtde

twvd

E

Woesaa

awcawlsscce

a

pi1ttdltcfis

bssposns

ordatdts

h1trwrc

TE

P

PPRSDCH

s

35MJackson/Hemodynamic and Exercise Effects of Phosphodiesterase 5 Inhibitors

p �0.05) in diastolic pressure was recorded in comparisono placebo.14 In a similar study, a decrease of 15/10 mm Hgas recorded, which are levels that might be expected from

onventional hypotensive agents.2

Tadalafil differs from sildenafil and vardenafil in that itas a longer half-life (17 hours vs 6 hours, respectively).9 Inemodynamic terms, this longer half-life may be therapeu-ically advantageous if PDE5 inhibitors become cardiacrugs in their own right, or disadvantageous when consid-ring the duration of the nitrate–PDE5 inhibitor interaction.

Because all 3 PDE5 inhibitors share the same fundamen-al mechanism of action, they should be viewed similarly,ith only the half-life and onset of action (sildenafil andardenafil, 30 to 60 minutes; tadalafil, 1 to 2 hours) beingifferent.9

xercise Studies

ith these nitrate-like properties, a neutral or beneficial effectn exercise performance in patients with ischemia would bexpected. This is reinforced from the safety perspective by thetudies showing improved coronary artery endothelial functionnd prolonged brachial artery flow–mediated vasodilation incute and chronic dosing protocols.15,16

Using exercise echocardiography, Arruda-Olson etl17 assessed sildenafil in men with known CAD or whoere at high risk for CAD. In a double-blind placebo-

ontrolled crossover study of 105 men with ED (meange, 66 years), 50-mg and 100-mg doses were comparedith placebo. The results were neutral, with no adverse

eft ventricular wall motion score developing and withimilar hemodynamics regarding heart rate, blood pres-ure, double product, and exercise capacity. They con-luded that sildenafil taken 1 hour before maximal exer-ise testing was well tolerated with no adverse ischemicffects.

In a multicenter study of sildenafil in 108 men with ED

able 1ffects of sildenafil on mean hemodynamic parameters at rest and during

arameter

At Rest

Baseline (n � 7)Silden

AOP (mm Hg) 8.1 � 5.1AP (mm Hg) 16.7 � 4.0AP (mm Hg) 5.7 � 3.7ystolic SAP (mm Hg) 150 � 12iastolic SAP (mm Hg) 74 � 8ardiac output (L/min) 5.6 � 0.9eart rate (beats per min) 67 � 11

Values represent the mean � 2D.IV, intravenous; NR, not recorded; PAOP, pulmonary arterial occlude

ystemic arterial pressure.

nd stable angina, sildenafil 100 mg was compared with v

lacebo in a parallel-group study.18 All had reproducibleschemia at baseline and underwent exercise on a treadmillhour after sildenafil or placebo. The primary end point was

ime to limiting angina, and secondary end points includedime to angina, time to ST-segment depression, and exerciseuration. Sildenafil significantly increased time to onset ofimiting angina, time to onset of angina, and exercise dura-ion compared with placebo (p �0.05). It did not signifi-antly affect time to ST depression; however, the trend wasavorable (Figure 4). Sildenafil was not associated withncreased adverse events and was generally beneficial in thistable population.

Halcox et al15 compared sildenafil 100 mg with isosor-ide dinitrate 10 mg versus placebo in 24 patients withtable CAD in a double-blind randomized study. Resultshowed no difference in exercise time or rate-pressureroduct for all 3 treatments, but ST depression was lessn the nitrate at peak exercise (p �0.05). Once more,ildenafil had a favorable trend that failed to reach sig-ificance, probably because of the small numbers ofubjects in the study.

Vardenafil has been evaluated in a double-blind, cross-ver, single-dose multicenter study of 41 men with stableeproducible angina.19 In comparison with placebo, var-enafil 10 mg did not alter treadmill exercise time or time tongina, but it did significantly prolong time to ischemichreshold (p � 0.0004). Blood pressure, heart rate, andouble product were unchanged from placebo. Vardenafil,herefore, did not adversely affect exercise parameters intable patients with CAD.

Tadalafil demonstrates similar hemodynamic effects inealthy subjects when compared with sildenafil in studies of0-mg or 20-mg doses (mean systolic blood pressure reduc-ion, �4.3 mm Hg).20 In patients with CAD, similar smalleductions were seen, but greater decreases were seen in thoseith higher baseline readings. No symptomatic effects were

ecorded. Tadalafil has been studied in exercise testing proto-ols, but no formal publications are available. However, re-

e in patients with stable ischemic heart disease

After 4-Min Exercise Test

mg, IV)) Baseline (n � 8)

Sildenafil (40 mg, IV)(n � 8)

4.3 36.0 � 13.7 27.8 � 15.33.9 39.4 � 12.9 31.7 � 13.23.7 NR NR16 200 � 37 188 � 3010 85 � 10 80 � 91.1 11.5 � 2.4 10.2 � 3.512 102 � 12 99 � 20

ure; PAP, pulmonary arterial pressure; RAP, right atrial pressure; SAP,

exercis

afil (40(n � 8

6.5 �12.1 �4.1 �141 �66 �5.2 �57 �

d press

iews of cardiovascular safety identify no increased risk.21

PE

Eftnaepcli

C

HveactEmied

1

1

1

1

1

1

1

1

1

1

2

2

2

xercise

36M The American Journal of Cardiology (www.AJConline.org) Vol 96 (12B) December 26, 2005

hosphodiesterase 5 Inhibitors—Looking Beyondrectile Dysfunction

vidence is accumulating for beneficial hemodynamic ef-ects in pulmonary hypertension and cardiac failure, withhe possibility of clinical improvements in Raynaud phe-omenon.16,21 Formal studies in hypertension are needed,nd with documented improvements in arterial stiffness andndothelial function, long-term PDE5 therapy may haverognostic implications.22 Adverse events in a particularontext are not necessarily adverse in another context—aesson learned from sildenafil. The nitrate–PDE5 inhibitornteraction could be used in resistant hypertension.

onclusion

emodynamically, PDE5 inhibitors are balanced, nitrate-likeasodilators and have well-established safety profiles in prop-rly assessed and advised patients with CAD. Their potentials cardiovascular drugs is now being realized. Sildenafil hasome full circle from cardiac, to ED, and then back to cardiacherapy. As vardenafil and tadalafil bring therapeutic options toD therapy, and with tadalafil’s long half-life, daily therapyay provide both ED and cardiovascular benefits recondition-

ng the endothelium. For now, we can be assured of clinicalfficacy combined with safety, providing we avoid the unpre-ictable nitrate–PDE5 inhibitor interaction.22

1. DeBusk RF, Pepine CJ, Glasser DB, Shpilsky A, DeRiesthal H,Sweeney M. Efficacy and safety of sildenafil citrate in men witherectile dysfunction and stable coronary artery disease. Am J Cardiol2004;93:147–153.

2. Gillies HC, Roblin D, Jackson G. Coronary and systemic haemodynamiceffects of sildenafil citrate: from basic science to clinical studies in patientswith cardiovascular disease. Int J Cardiol 2002;86:131–141.

3. Sullivan ME, Thompson CS, Dashwood MR, Khan MA, Jeremy JY,Morgan RJ, Mikhailidis DP. Nitric oxide and penile erection: is erec-tile dysfunction another manifestation of vascular disease? CardiovascRes 1999;43:658–665.

4. O’Kane PD, Jackson G. Erectile dysfunction: is there silent obstructivecoronary artery disease? Int J Clin Pract 2001;55:210–230.

5. Montorsi P, Montorsi F, Schulman C. Is erectile dysfunction the tip of theiceberg of a systemic vascular disorder? Eur Urol 2003;44:352–354.

6. Jackson G. Erectile dysfunction: a window of opportunity for prevent-

Figure 4. Phosphodiesterase 5 inhibition: effects on e

ing vascular disease [editorial]? Int J Clin Pract 2003;57:747.

7. Cheitlin MD. Erectile dysfunction: the earliest sign of generalizedvascular disease? J Am Coll Cardiol 2004;43:185–186.

8. Corbin JD, Francis SH. Pharmacology of phosphodiesterase-5 inhibi-tors. Int J Clin Pract 2002;56:453–459.

9. Giuliano F. Phosphodiesterase type 5 inhibition in erectile dysfunc-tion: an overview. Eur Heart J Suppl 2002;4:H7–H12.

0. Katz S. Potential role of type 5 phosphodiesterase inhibition in thetreatment of congestive heart failure. Congest Heart Fail 2003;9:9–15.

1. Fogari R, Zoppi A, Poletti L, Marasi G, Mugellini A, Corradi L.Sexual activity in hypertensive men treated with valsartan or carve-dilol: a crossover study. Am J Hypertens 2001;14:27–31.

2. Mikhail GW, Prasad SK, Li W, Rogers P, Chester AH, Bayne S,Stephens D, Khan M, Gibbs JSR, Evans TW, et al. Clinical andhaemodynamic effects of sildenafil in pulmonary hypertension: acuteand mid term effects. Eur Heart J 2004;25:431–436.

3. Jackson G, Benjamin B, Jackson N, Allen MJ. Effects of sildenafil citrateon human hemodynamics. Am J Cardiol 1999;83(suppl):13C–20C.

4. Mahmud A, Hennessy M, Feely J. Effect of sildenafil on blood pres-sure and arterial wave reflection in treated hypertensive men. J HumHypertens 2001;15:707–713.

5. Halcox JP, Nour KR, Zalos G, Mincemoyer RA, Waclawiw M, RiveraCE, Willie G, Ellahham S, Quyyumi AA. The effect of sildenafil onhuman vascular function, platelet activation and myocardial ischemia.J Am Coll Cardiol 2003;40:1232–1240.

6. Reffelmann T, Kloner RA. Therapeutic potential of phosphodiesteraseinhibition for cardiovascular disease. Circulation 2003;108:239–244.

7. Arruda-Olson AM, Mahoney DW, Nehra A, Leckel M, Pellikka PA.Cardiovascular effects of sildenafil during exercise in men with knownor probable coronary artery disease: a randomized crossover trial.JAMA 2002;287:719–725.

8. Fox KM, Thadanib U, Mac PTS, Nashd SD, Keatinge Z, CzorniakfMA, Gilliese H, Keltaig M, for the Clinical American and EuropeanStudies of Angina and Revascularization I (CAESAR I) Investigators.Sildenafil citrate does not reduce exercise tolerance in men witherectile dysfunction and chronic stable angina. Eur Heart J 2002;24:2206–2212.

9. Thadani U, Smith W, Nash S, Bittar N, Glasser S, Narayan P, SteinRA, Larkin S, Mazzu A, Tota R, Pomerantz K, Sundaresan P. Theeffect of vardenafil, a potent and highly selective phosphodiesterase-5inhibitor for the treatment of erectile dysfunction, on cardiovascularresponse to exercise in patients with coronary artery disease. J Am CollCardiol 2002;40:2006–2012.

0. Kloner RA, Mitchell M, Emmick JT. Cardiovascular effects oftadalafil. Am J Cardiol 2003;92(suppl):37M–46M.

1. Jackson G, Kloner RA, Costigan TM, Warner MR, Emmick JT.Update on the clinical trials of tadalafil demonstrates no increasedrisk of cardiovascular adverse events. J Sex Med 2004;1:161–167.

2. Jackson G. PDE-5 inhibitors: looking beyond ED. Int J Clin Pract

parameters. p �0.05. (Adapted from Eur Heart J.18)

2003;57:159–160.