Platinum Priority – EditorialReferring to the article published on pp. 948–955 of this issue

NO Problem: Arterial and Venous Endothelial Function and

Erectile Dysfunction

Anthony S. Wierzbicki a,*, Graham Jackson b

a Guy’s & St Thomas Hospitals, London, UKb London Bridge Hospital, London, UK

E U R O P E A N U R O L O G Y 5 9 ( 2 0 1 1 ) 9 5 6 – 9 5 8

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journal homepage: www.europeanurology.com

Erectile dysfunction (ED) is a common and increasing

problem with a still-significant social stigma [1,2]. Over

the last decade ED has been increasingly recognised as an

atherosclerotic problem showing clear associations with

many cardiovascular disease (CVD) risk factors including

age, smoking, diabetes, hypercholesterolaemia, and

hypertension. It is known to be associated with coronary

atheroma burden, physiologic cardiac dysfunction, and

increased risk of subsequent CVD events and to be predictive

beyond classical risk scores. Yet, only the minority of

clinicians ask about its occurrence, despite the Sexual Health

Inventory for Men (SHIM) score being easy to determine.

The physiology of arterial dysfunction in the penile

arteries has been clarified with the identification of

nitridergic (nitric oxide (NO)–producing) nerves acting on

the arterial endothelium to produce arterial vasodilation

and venous smooth muscle to produce venoconstriction.

NO is produced from arginine, whereas the cobalamin-

dependent one carbon pool pathways lead to arginine

methylation and the production of both asymmetric

dimethyl arginine (ADMA) and symmetric dimethyl argi-

nine (SDMA). ADMA is a competitive inhibitor of NO, like

the commonly experimentally used inhibitor of NO function

L-nitro-arginine methyl ester (L-NAME) but unlike ADMA’s

regio-isomer, SDMA [3]. Thus NO dilates whereas ADMA

constricts arteries. As in many biological systems, sensitivity

of control is increased by having two mutually opposed

regulators. This yin–yang hypothesis is a general guide to

how to interpret ADMA–NO interactions but can break down

when viewed in detail, as both ADMA and SDMA can have

other direct actions on the vasculature. ADMA is an easily

measured stable molecule and an independent CVD risk

DOI of original article: 10.1016/j.eururo.2011.02.008* Corresponding author. St. Thomas’ Hospital, Lambeth Palace Road, LondonE-mail address: Anthony.Wierzbicki@kcl.ac.uk (A.S. Wierzbicki).

0302-2838/$ – see back matter # 2011 European Association of Urology. Publis

factor, and levels are associated with poorer prognosis in a

number of epidemiologic studies. Some studies show

increased precision of CVD risk prediction when ADMA

levels are expressed as a ratio to SDMA, but the latter is more

often used as a marker of renal function. Because ED is often

associated with peripheral arterial disease, and thus renal

atherosclerosis, an association of SDMA with ED would be

predictable in epidemiologic studies, even though SDMA has

no direct effect on penile arteries.

Both peripheral (brachial) and coronary endothelial

dysfunction are associated with penile NO dysfunction

and ED. Because endothelial dysfunction is often general-

ised within the vasculature, markers of total NO turnover

should correlate with the degree of ED. This has been shown

for urinary nitrate excretion, but studies investigating the

role of ADMA have not shown a clear correlation with SHIM

scores, although they correlate with the degree of CVD risk

factor burden [4]. However, these studies were limited by

the poor sensitivity of the measures used (eg, SHIM score).

In this issue, Ioakeimidis and colleagues [5] demonstrate in

a study of 104 individuals that arterial insufficiency

measured by penile Doppler ultrasound is associated with

ADMA, age, glucose, and baseline pressure, whereas venous

insufficiency is associated with high-density lipoprotein

cholesterol (HDL-C) and glucose and is not significantly

associated with ADMA levels. The data are adjusted for prior

use of statins and angiotensin I–converting enzyme

inhibitors (ACE-Is), which have mostly but not universally

beneficial effects on the extent of ED. The data accords well

with the epidemiology of ED in the Massachusetts Male

Aging Study for arterial risk factors but also hints that

venous dysfunction plays a significant part in ED.

SE1 7EH, UK. Tel.: +44 207 188 1256; Fax: +44 207 928 4226.

hed by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2011.02.019

E U R O P E A N U R O L O G Y 5 9 ( 2 0 1 1 ) 9 5 6 – 9 5 8 957

NO made by the NO-synthase enzymes is a vasodilator,

but if endothelial NO synthase (eNOS) is released from its

membrane binding site, it can be donated to hydroxyl

radicals to form the vasoconstrictor peroxynitrite. Inflam-

mation allied to hypercholesterolaemia are two of the

processes responsible for releasing eNOS from its binding

sites. Many drug treatments affecting endothelial function

act by recoupling eNOS. Optimisation of blood pressure and

glycaemic control of diabetes improve endothelial dysfunc-

tion and ED. The greatest benefit for antihypertensive drugs

has been shown with renin-angiotensin agents including

ACE-Is and angiotensin-2 type 1 receptor blockers (ARBs),

which directly affect vascular eNOS coupling, in contrast

with diuretics, which can increase insulin resistance, have

no effect on eNOS, and are associated with increased rates of

ED [6]. Despite improvements in ED with ARB therapy in

small, specific studies, no effect of either ACE-Is or ARBs was

seen on ED in the large ONTARGET trial using SHIM scores as

an end point [7]. Statins generally improve ED, acting again

through eNOS coupling, although their neuropathic side

effects can exacerbate it. The mainstay of treatment of ED

relies on inhibition of the degradation of NO by phospho-

diesterase type 5 (PDE5) by drugs such as sildenafil. These

drugs act over and above CVD risk factor control, although

their efficacy depends on the degree of CVD risk factor

control such that patients with poorly controlled risk

factors will show reduced or absent response to PDE5

inhibitors [8]. In the small study by Ioakeimidis et al [5],

only a dichotomous correction was made for use of renin-

angiotensin drugs or statin usage so subtler dose-related or

efficacy effects on penile Doppler flow would not be

detected.

The suggestion that venous endothelial dysfunction may

contribute to the thromboembolic process is now increas-

ingly recognised and likely operates through similar

mechanisms allied to endothelial cell activation and

expression of intercellular adhesion molecules combined

with leukocyte-platelet coactivation. Its role in ED is

unclear. The CVD epidemiology of venous thromboembo-

lism (VTE) is slowly being clarified. This issue has been

relatively neglected, despite the long-known associations of

VTE with age, gender, obesity, smoking, and diabetes.

Recent studies have identified low HDL-C elevated trigly-

cerides (probably acting via plasminogen-activator inhibi-

tor-1) as risk factors for VTE. A post hoc analysis of the

JUPITER study of rosuvastatin in moderate-risk primary

prevention showed a significant 43% reduction in VTE

episodes with statin therapy, suggesting that alterations in

venous lipid levels and/or changes in venous-plasma

lipoprotein–endothelial interactions may reduce embolus

generation [9]. The finding that venous insufficiency and

endothelial dysfunction in patients with ED correlates with

HDL-C and glucose [5] is entirely consistent with a

suggested venous endothelial physiology and an extended

role for plasma risk factors for ED on venous vasoconstric-

tion. What are the therapeutic implications? Warfarin

therapy is known to be associated with a 1.7-fold increased

rate of ED, but it does not affect leukocyte-platelet

coactivation or endothelial dysfunction. There are no

studies of aspirin, thienopyridines (eg, clopidogrel), or

direct thrombin inhibitors (eg, dabigatran). Thienopyridines

potentially may have other actions in the ED pathways,

given their action on ADP purinergic receptors, but there

have been no analyses of ED rates in any of the large

clopidogrel trials, and none contained an ED substudy.

Similarly, none of the trials of direct thrombin inhibitors in

elderly populations with atrial fibrillation or as prophylaxis

for VTE prior to (usually) orthopaedic surgery has been

analysed for ED, although the prevalence is likely to be high,

given the recruitment characteristics of these trials.

Endothelial function correlates with ED and end organ

damage. It is becoming clearer that plasma risk factors are

associated with both arterial and venous endothelial

dysfunction. As ED is associated with both, maybe the

measurement of biomarkers such as ADMA may play a role

in identifying patients at high risk of developing ED and

thus CVD events. It is increasingly recognised that

standard CVD risk calculation techniques are nonspecific

and oversensitive in moderate-risk (10–20%) populations.

In addition, the mathematical estimates of CVD risk are

subject to large confidence intervals due to the large

number of individual factors in the equation and the

substantial biological variation in each. The archetypes of

many risk algorithms also do not include many risk factors

that are viewed as desirable to identify small but

significantly higher risk groups, such as patients with a

family history of CVD or with an ethnicity-associated risk

or, indeed, with ED [2]. Many guidelines groups are

looking to add independent additional measures to

restratify risk within the 10–25% CVD risk range. These

measures include markers of inflammation (eg, C-reactive

protein), cardiac function, or damage (N-terminal pro-B-

type natriuretic peptide; ultra-low levels of troponins);

physiologic vascular function (eg, endothelial function or

pulse wave analysis); and atheroma imaging (carotid

intima-media thickness and coronary calcium scores)

[10]. Although these measures are being investigated in

general risk prediction, some may have higher utility

with specific subgroups. Considering the relationship of

ADMA to penile artery dysfunction, this may be an

interesting candidate to pursue in epidemiologic studies

as a screening tool for ED.

Conflicts of interest: The authors have nothing to disclose.

References

[1] Jackson G, Boon N, Eardley I, et al. Erectile dysfunction and coronary

artery disease prediction: evidence-based guidance and consensus.

Int J Clin Pract 2010;64:848–57.

[2] Billups KL, Miner MM, Wierzbicki AS, Jackson G. Gender-based

cardiometabolic risk evaluation in minority and non-minority

men grading the evidence of non-traditional determinants of car-

diovascular risk. Int J Clin Pract 2011;65:134–47.

[3] Mangoni AA. The emerging role of symmetric dimethylarginine in

vascular disease. Adv Clin Chem 2009;48:73–94.

[4] Wierzbicki AS, Solomon H, Lumb PJ, Lyttle K, Lambert-Hammill M,

Jackson G. Asymmetric dimethyl arginine levels correlate with

E U R O P E A N U R O L O G Y 5 9 ( 2 0 1 1 ) 9 5 6 – 9 5 8958

cardiovascular risk factors in patients with erectile dysfunction.

Atherosclerosis 2006;185:421–5.

[5] Ioakeimidis N, Vlachopoulos C, Rokkas K, et al. Relationship of

asymmetric dimethylarginine with penile Doppler ultrasound

parameters in men with vasculogenic erectile dysfunction. Eur Urol

2011;59:948–55.

[6] Bank AJ, Kelly AS, Kaiser DR, et al. The effects of quinapril and

atorvastatin on the responsiveness to sildenafil in men with erectile

dysfunction. Vasc Med 2006;11:251–7.

[7] Bohm M, Baumhakel M, Teo K, et al. Erectile dysfunction predicts

cardiovascular events in high-risk patients receiving telmisartan,

ramipril, or both: the Ongoing Telmisartan Alone and in Combination

With Ramipril Global Endpoint Trial/Telmisartan Randomized As-

sessment Study in ACE Intolerant Subjects With Cardiovascular

Disease (ONTARGET/TRANSCEND) trials. Circulation 2010;121:

1439–46.

[8] Solomon H, Wierzbicki AS, Lumb PJ, Lambert-Hammill M,

Jackson G. Cardiovascular risk factors determine erectile and

arterial function response to sildenafil. Am J Hypertens 2006;

19:915–9.

[9] Glynn RJ, Danielson E, Fonseca FA, et al. A randomized trial of

rosuvastatin in the prevention of venous thromboembolism. N Engl

J Med 2009;360:1851–61.

[10] Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for

assessment of cardiovascular risk in asymptomatic adults: execu-

tive summary: a report of the American College of Cardiology

Foundation/American Heart Association Task Force on Practice

Guidelines. J Am Coll Cardiol 2010;56:2182–99.