Patofisiologi Erectile Disfunc

Vascular Medicine
http://vmj.sagepub.com/ The pathophysiology of erectile dysfunction related to endothelial dysfunction and mediators of vascular function
Renke Maas, Edzard Schwedhelm, Jennifer Albsmeier and Rainer H Bger Vasc Med 2002 7: 213 DOI: 10.1191/1358863x02vm429ra The online version of this article can be found at: http://vmj.sagepub.com/content/7/3/213
Published by:
http://www.sagepublications.com
On behalf of:
Society for Vascular Medicine
Additional services and information for Vascular Medicine can be found at: Email Alerts: http://vmj.sagepub.com/cgi/alerts Subscriptions: http://vmj.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://vmj.sagepub.com/content/7/3/213.refs.html
>> Version of Record - Aug 1, 2002 What is This?
Downloaded from vmj.sagepub.com by guest on March 8, 2012
Vascular Medicine 2002; 7: 213225
The pathophysiology of erectile dysfunction related to endothelial dysfunction and mediators of vascular function
Renke Maas, Edzard Schwedhelm, Jennifer Albsmeier and Rainer H Bo ger Abstract: The incidence of erectile dysfunction increases with diabetes, hypertension, hypercholesterolaemia, cardiovascular disease and renal failure. All these conditions are associated with endothelial dysfunction. This review addresses the pathophysiology of erectile dysfunction with a special focus on new insights into nitric oxide (NO)-mediated pathways, oxidative stress and parallels to endothelial dysfunction. NO appears to be the key mediator promoting endothelium-derived vasodilation and penile erection. The possibility is discussed that elevated plasma concentrations of asymmetrical dimethylarginine (ADMA), an endogenous NO synthase inhibitor, may provide an additional pathomechanism for various forms of erectile dysfunction associated with cardiovascular risk factors and disease. Likewise, the role of endotheliumderived factors mediating NO-independent pathways is evaluated. Key words: asymmetrical dimethylarginine; endothelial dysfunction; endothelin; erectile dysfunction; nitric oxide; nitric oxide synthase; oxidative stress; prostaglandin
Introduction
In western countries, at least one in ten men is affected by erectile dysfunction, which is de ned as the inability to maintain an erection suf cient to permit satisfactory sexual intercourse.1 It has been estimated that about 30 million men in the USA or half a million men in the UK have partial or complete erectile dysfunction.1 ,2 Based on data from a predominantly white population, the estimated worldwide incidence of erectile dysfunction will increase from roughly 152 million men in 1995 to 322 million men by the year 2025.3 However, due to social, ethnic and cultural factors leading to differences in the perception and reporting of erectile dysfunction, precise estimates of the worldwide incidence and prevalence of erectile dysfunction are dif cult to obtain. Erectile dysfunction is commonly classi ed as organic, psychogenic or mixed organic and psychogenic, with organic erectile dysfunction being the most common form.1 Organic erectile dysfunction, if not traumatic, is usually caused by abnormal function and responsiveness of the penile vasculature attributed to aging4 6 or underlying diseases.7 ,8 Moreover, there is accumulating evidence that erectile dysfunction may be just another manifestation of cardiovascular disease.9 ,1 0 In addition, a considerable number of patients may suffer from drug-induced erectile dysfunction.1 1 ,1 2 The risk of erectile dysfunction increases with diabetes,1 3 1 6 hypercholesterolaemia,1 5 ,1 7 ,1 8 hypertension,6 ,1 5 atherosclerosis1 2 ,1 5 and renal failure.1 9 2 1 All of these disInstitut fu r Experimentelle und Klinische Pharmakologie und Toxikologie, Universita tsklinikum Hamburg-Eppendorf, Hamburg, Germany Address for correspondence: Dr Renke Maas, Institut fu r Experimentelle und Klinische Pharmakologie und Toxikologie, Universita tsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. E-mail: maas@uke.uni-hamburg.de
eases and conditions are also known to be associated with endothelial dysfunction.2 2 3 8 Dysfunction of the endothelium may be interpreted as the ruin of the homeostasis between constricting and relaxing factors.3 9 The pathogenesis of endothelial dysfunction is as multi-factorial as clinical interventions are.4 0 ,4 1 Nevertheless, one mediator of smooth muscle relaxation seems to be a key gure in endothelial function and dysfunction: endothelium-derived nitric oxide (NO). 4 2 ,4 3 This provides a strong link to the physiology and pathophysiology of penile erection where NO-mediated relaxation of smooth muscles also plays a decisive role.4 4 Impaired NO formation may therefore be considered a key pathomechanism in both endothelial4 5 ,4 6 and erectile dysfunction.4 7 ,4 8 It has to be emphasized that the involvement of the endothelium in the regulation of penile tone is rather complex and that important contributions may come from NO-independent pathways. Prostaglandin,4 9 ,5 0 endothelin,5 1 angiotensin,5 2 bradykinin5 2 or endothelium-derived hyperpolarizing factor-mediated5 3 pathways may provide additional mechanisms for the regulation of penile tone. In the following review, we address the pathophysiology of erectile dysfunction with a special focus on new insights into NO-mediated pathways, oxidative stress and parallels to endothelial dysfunction. Based on these data an outlook is given on potential targets for restoring impaired endothelium-dependent relaxation in penile erection.
NO-mediated pathways and mechanisms of impaired NO synthesis

NO, synthesized from l-arginine (Figure 1), is the key mediator of endothelium-dependent smooth muscle relaxation,5 4 5 6 and likewise it is the key mediator of penile erection4 7 ,5 7 ,5 8 (a simpli ed summary of the most important
10.1191/1358863x02vm429ra
Arnold 2002
214 R Maas et al
Figure 1 NO synthases (NOS) oxidize l-arginine to NO and citrulline. NO is a free radical and easily reacts with other free radicals such as superoxide anions (O2 ) to form peroxynitrite (ONOO ). l-Arginine, the substrate for NOS, is transported into the cell via speci c transporters such as y+ . Inside the cell NOS competes with arginases for l-arginine. NOS expression is regulated by various endogenous and exogenous factors. Synthesis of NO is dependent on availability of the substrate l-arginine, calmodulin/Ca2 + and additional co-factors such as tetrahydrobiopterin (TBH), nicotinamide adenine dinucleotide phosphate (NADPH), avin-adenine-mononucleotide (FMN) and avin-adenine-dinucleotide (FAD). NOS can be inhibited by endogenous compounds such as asymmetrical dimethylarginine (ADMA). ADMA is degraded by dimethylarginine dimethylaminohydrolase (DDAH).
pathways governing smooth muscle relaxation in penile erection is given in Figure 2). NO can be synthesized and released from non-adrenergic, non-cholinergic nerve endings by speci c neuronal synthases (nNOS) and from the
endothelium by endothelial NO synthases (eNOS). 4 4 As detailed below, NOS may be up/down-regulated, inhibited or activated. Upon sexual stimulation NO is released directly from nerve endings or from endothelial cells stimu-
Figure 2 A simpli ed scheme of neuronal and endothelium-mediated relaxation and contraction of penile smooth muscle. (a1 , a1 receptor; a2 , a2 -receptor; M3, M3-receptor; ETA , endothelin receptor type A; ETB , endothelin receptor type B; G, G-protein; Gq , Gqprotein; Gs , Gs -protein; NO, nitric oxide; eNOS, endothelial NO synthase; nNOS, neuronal NO synthase; PDE, phosphodiesterase; PGHS, prostaglandin H2 synthase; PGE-S, prostaglandin E2 synthase; PGF-S, prostaglandin F2 a synthase; EP, EP prostaglandin receptor; FP, FP prostaglandin receptor; IP3 , inositol-1,4,5-trisphosphate; AA, arachidonic acid; PLC, phospholipase C; PGE 2 , prostaglandin E2 ; PGF2 a , prostaglandin F2 .)
Erectile dysfunction in relation to endothelial dysfunction and vascular function 215
lated by acetylcholine released from cholinergic nerve endings.7 Even though involvement of both endothelial and neuronal NO synthesis in penile erection has been proposed from early on,4 7 the relative importance of both pathways has been subject to considerable debate. Inhibition of neuronal NO synthesis attenuated erectile responses.5 9 But surprisingly, mice lacking nNOS showed no overt signs of erectile dysfunction.6 0 ,6 1 This has been attributed to splicing variants of nNOS or to additional expression of a penisspeci c NOS (PnNOS) in nNOS knock-out mice.6 2 Erectile function was also found to be preserved in mice lacking eNOS.6 3 However, intracavernosal pressure during erection was signi cantly decreased in eNOS-de cient mice and, over all, NO synthase activity was only 60% of the activity observed in wild-type mice. Thus, it is very likely that physiologic penile erection is mediated by both nNOS and eNOS. Even though inducible NO synthases have been described in the penis, too, their role in penile erection or erectile dysfunction has not been de ned yet.6 4 NO activates a soluble guanylyl cyclase that forms cyclic guanosine monophosphate (cGMP).6 5 Reports of erectile dysfunction in cGMP-dependent kinase-I (cGKI)-de cient mice suggest that cGMP is indeed the principal second messenger in erectile dysfunction.6 6 These ndings are strongly supported by data on the clinical ef cacy of the phosphodiesterase type 5 inhibitor sildena l, which prevents the degradation of cGMP.6 7 Furthermore, the study in cGKI-de cient mice demonstrated that cAMP-mediated pathways cannot compensate de cient cGMP-dependent signalling in vivo.6 6 In humans the situation might be different, however. Prostaglandin E1 and its derivative alprostadil, which induce relaxation predominantly via the cAMP pathway, were found to be highly effective in the treatment of erectile dysfunction.5 0 ,6 8 cGKI appears to regulate myosin light chain phosphatases causing subsequent relaxation of smooth muscle.6 9 These ndings open an unexpected link to noradrenergic and Rho-kinase mediated contraction of penile musculature that counteract the NO-mediated relaxation.7 0 Rho-kinase phosphorylates (and thus inhibits) smooth muscle myosin phosphatases. This in turn results in sensitization of myo laments to Ca2 + and enhances contraction. The Rho-kinase antagonist Y-27632 stimulates penile erection in the rat independently of the NO pathway.7 1 Thus, antagonism of Rho-kinases provides an interesting new target for pharmacologic therapies that completely circumvent the NO pathway. The relative importance of other pathways beyond cGMP which lead to a reduced Ca2 + in ux and subsequent relaxation of the penile smooth muscle is yet unknown. Whatever the principal molecular mechanisms may be, the nal result of relaxation of small arteries and arterioles supplying erectile tissues and the relaxation of trabecular smooth muscles is rapid lling and expansion of the erectile tissue.7 The haemodynamic changes leading to an erection are reversed during detumescence; i.e. the return to the normal accid state.7 2 During a transition phase with increased sympathetic activity causing contraction of the trabecular smooth muscle and increasing the tone of the helicine arteries, arterial ow resumes at a low level. The following detumescense is characterized by a decline of intracavernous pressure, reopening of the venous out ow and a decrease of arterial ow to its prestimulation level.
Availability of the substrate l-arginine

Several principal pathomechanisms may account for reduced availability of NO in both endothelial and erectile dysfunction. NO synthesis is dependent on availability of the substrate l-arginine, calmodulin/Ca2 + and additional cofactors like tetrahydrobiopterin, nicotinamide adenine dinucleotide phosphate (NADPH), avin-adenine-mononucleotide (FMN) and avin-adenine-dinucleotide (FAD). 7 3 For NO synthesis the substrate l-arginine is transported into mammalian cells by at least four different carrier systems (y+ , y+ L, b0 , + and B0 , + ).7 4 The regulation of these carriers is complex and not yet fully understood, but it is of interest to note that the l-arginine transport via the y+ carrier can be inhibited by endogenous l-arginine analogues such as asymmetrical dimethylarginine (ADMA). 7 5 As detailed below, elevated plasma ADMA concentrations are found in many conditions associated with erectile dysfunction (see Table 2). l-Arginine transport may also be inhibited non-competitively by uraemic levels of urea.7 6 In the cell, NO synthases have to compete with other enzymes like arginases for the substrate l-arginine. Inhibition of arginase activity by 2(S)-amino-6-boronohexanoic acid (ABH) has been shown to cause signi cant enhancement of non-adrenergic, non-cholinergic nerve-mediated relaxation of penile corpus cavernosum smooth muscle, suggesting that arginase inhibition sustains l-arginine concentrations for NO. 7 7 Moreover, a recent study demonstrated that diabetic corpus cavernosum from humans with erectile dysfunction had higher levels of arginase II protein, gene expression and enzyme activity than normal human cavernosal tissue.7 8 The impaired ability of diabetic tissue to synthesize NO was reversed by the selective inhibition of arginase activity by ABH. Increased expression of arginase II in diabetic cavernosal tissue may therefore contribute to the erectile dysfunction associated with diabetes.
NOS expression and a link to the eicosanoid pathway

Expression of NOS may be inducible (iNOS) or constitutive.7 9 Under physiological conditions eNOS and nNOS are constitutively expressed in the endothelium and penile nerve endings, respectively.8 0 8 2 But this expression is not entirely constitutive. Expression of eNOS and nNOS is subject to rather complex regulatory mechanisms (for further details please refer to comprehensive reviews7 3 ,8 3 ). Selected factors affecting the expression of eNOS are summarized in Table 1. Data on the role of most of these factors in erectile dysfunction are rather limited and sometimes conicting, however. Reduced androgen concentrations, as found in elderly individuals, may result in impaired expression of penile NO synthases (eNOS and nNOS).9 6 On the other hand, an aging-related increase in expression of iNOS has been described.1 1 0 And, conversely, in rabbit cavernosal tissue, eNOS appeared to be up-regulated with increasing age.1 0 2 However, NO synthesis was found to be impaired in elderly rabbits. Likewise, in animal models of uraemia, nNOS expression and protein levels were found to be elevated while NO production was decreased.1 0 0 ,1 0 1 The same inves-
216 R Maas et al
Table 1 Factors regulating expression of endothelial nitric oxide synthase (eNOS).
Up-regulation
eNOS
Down-regulation
Shear stress8 4 Hypertension8 5 Low salt intake8 6 High salt intake8 7 Low concentration of oxidized High concentration of oxidized LDL8 8 LDL8 9 HMG-CoA-reductase Glucocorticoids9 1 inhibitors9 0 Angiotensin II8 6 Tumour necrosis factor-a9 2 Increase in cGMP9 3 Increase in cAMP9 4 High glucose9 5 Low androgens9 6 Calcium channel blockers9 7 ,9 8 PGE1 9 9 Uraemia1 0 0,10 1 Old age1 0 2 Lysophosphatidylcholine1 0 3 Hyperthyroidism1 0 4 b1-adrenoceptor blocker1 0 5 Exercise training: divergent data for up-regulation1 0 6 and unchanged expression1 0 7 Hypoxia: divergent data for up-1 0 8 and down-regulation1 0 9
tigators found eNOS mRNA content unchanged but eNOS protein levels raised.1 0 1 Also of interest may be the inhibitory effects of atherogenic lipids/lipoproteins on eNOS expression8 9 and endothelial function as a whole (reviewed by Adams et al, 20001 1 1 ). Among their pleiotropic effects on endothelial function, HMG-CoA-reductase inhibitors were found to increase expression of eNOS.9 0 NO activates prostaglandin synthesis.1 1 2 ,1 1 3 Constitutive prostaglandin H2 synthase (PGHS)-1 is expressed in tandem with prostacyclin synthase in endothelial cells.1 1 4 The resulting prostacyclin together with NO released after nNOS and eNOS stimulation ensures relaxation of smooth muscle cells. Under pathophysiologic conditions the situation changes. In in ammation, iNOS is induced by cytokines in the vessel wall. iNOS is co-expressed with the inducible form of PGHS, i.e. PGHS-2.1 1 5 ,1 1 6 Interestingly, PGHS-2 and prostacyclin synthase were not found to be co-localized in endothelial cells.1 1 4 Moreover, after IL1b stimulation prostacyclin synthase was inactivated.1 1 7 Hence, a shift from vasodilatory prostaglandins and prostacyclin to vasoconstrictory eicosanoids is likely. Expression of eNOS is down-regulated after induction of in ammatory cytokines.1 1 8 ,1 1 9 Even though additional NO is provided from iNOS (probably to combat vasoconstrictory eicosanoids), NO from nNOS and eNOS after neuronal stimulation may no longer suf ce for smooth muscle relaxation. Erectile dysfunction would be the consequence. A chronic in ammatory process such as atherosclerosis1 2 0 may be suf cient to induce this scenario.
Oxidative stress and impaired NO availability

With accumulating evidence for oxidative stress playing a causative role in atherosclerosis1 2 1 and endothelial dysfunction,1 1 9 ,1 2 1 ,1 2 2 suspicions are rising that oxidative stress might also contribute to erectile dysfunction.1 2 3 The precise
contribution of oxidative stress to erectile dysfunction has not been evaluated in detail yet, but some mechanisms described for endothelial dysfunction are very likely to have parallels in erectile dysfunction. By reacting with NO itself or by interfering with NO-mediated pathways, highly reactive oxygen species (ROS) could possibly contribute to erectile dysfunction.1 2 4 These mechanisms might deserve some attention since it could be demonstrated that infusion of the antioxidant ascorbic acid restored vascular responses to acetylcholine in patients with endothelial dysfunction.1 2 2 ,1 2 5 Some authors have proposed that nascent NO can be quenched immediately after its synthesis. This uncoupling phenomenon was suggested for nNOS and eNOS unsaturated with the substrate l-arginine or co-factors.1 2 6 ,1 2 7 Nitric oxide synthases depend on tetrahydrobiopterin as a co-factor.7 3 Endothelial dysfunction associated with tetrahydrobiopterin depletion could be reversed by tetrahydrobiopterin supplementation.1 2 8 1 3 0 In the rabbit corpus cavernosum, tetrahydrobiopterin increased NOS activity by 30%.1 3 1 Ascorbic acid was able to potentiate NO synthesis via chemical stabilization of tetrahydrobiopterin.1 3 2 Depletion of tetrahydrobiopterin has been associated with states of increased free radical burden (e.g. oxidative stress).1 2 9 Responsible 133 for the NO quench are ROS-like superoxide anions (O2 ). The reaction between NO and O2 is likely since the two radicals combine extremely fast to the ugly peroxynitrite (ONOO - ).1 3 4 Peroxynitrite reacts with proteins by nitrating tyrosyl residues. This leads to enzyme inactivation (e.g. inactivation of prostacyclin synthase or superoxide dismutase).1 3 5 ,1 3 6 Diminished bioavailability of NO has been implicated with atherosclerosis and cardiovascular disease. One independent risk factor of atherosclerosis and cardiovascular disease is hyperhomocyst(e)inaemia.1 3 7 ,1 3 8 Homocysteine also reduces endothelium-dependent relaxation of the corpus cavernosum, probably due to generation 139 of OAlthough ONOO 2 resulting in ONOO formation. relaxes cavernosal smooth muscle cells via cGMP formation, it is less potent than the NO from which it was formed and may therefore contribute to erectile dysfunction.1 4 0 Superoxide anion is an intermediate product of incomplete oxygen reduction by cytochrome C oxidase from the respiratory chain. Several other sources of O2 , such as NAD(P)H oxidases or xanthin oxidase, and their role in cardiovascular biology have recently been reviewed.1 4 1 ,1 4 2 Aerobic life has evoked an enzymatic defence by superoxide dismutases (SOD). The three isoforms MnSOD, CuZnSOD and extracellular (ec)SOD are found in the mitochondria, cytosol and extracellular uids, respectively.1 4 3 The ecSOD is located between the endothelium and vascular smooth muscle cells and prevents degradation of NO 1 4 4 ,1 4 5 by scavenging OThe expression and secretion of 2. ecSOD is up-regulated after vasoconstriction with vasopressin, endothelin-1 or angiotensin II.1 4 6 ,1 4 7 On the other hand, endothelial NO stimulates ecSOD, too.1 0 6 The effects probably show the key role of ecSOD in maintaining homeostasis of vascular tone.1 4 5 In accordance, in young hypercholesterolaemic individuals, activity of ecSOD is high1 4 8 while in patients with manifested endothelial dysfunction (i.e. coronary artery disease) ecSOD activity is diminished, probably due to a progressed pathophysiologic process.1 4 8 It is not only hypercholesterolaemia that impairs endothelium-dependent relaxation in the corpus cav-
ernosum.1 4 9 Diabetes mellitus is also associated with impaired endothelium-mediated relaxation of penile smooth muscle.1 5 0 In the rabbit, diabetes-related reduction of NOmediated relaxation of cavernosal tissue could be reversed by SOD.1 5 1 ,1 5 2 Further studies have found that glycosylated human haemoglobin impaired smooth muscle relaxation.1 5 3 This effect has been in part attributed to the generation of O2 and extracellular inactivation of NO since the impairment of cavernosal smooth muscle relaxation related to glycosylated haemoglobin could be reversed by exogenous SOD.
Inhibition of NOS
As detailed above, the incidence of erectile dysfunction increases with atherosclerosis,1 5 ,1 8 diabetes,1 3 1 5 hypertension,6 ,1 5 hypercholesterolaemia1 5 ,1 7 and renal failure.1 9 2 1 All of these conditions are associated with an altered endothelial NO production. In addition, impaired NO production has been proposed as the common link between vascular disease and erectile dysfunction.9 Some conditions might be attributed to an altered NOS expression (see Table 1), but more and more studies suggest that impaired NOS function rather than NOS expression may be the cause of insufcient NO production.1 0 1 This draws the attention to a long list of NO inhibitors commonly employed to study the NO-l-arginine pathway in erectile dysfunction.5 7 ,1 5 4 ,1 5 5 Analogues of l-arginine such as NG -monomethyl-l-arginine (l-NMMA), NG -nitrol-arginine (l-NNA) and NG -nitro-l-arginine methyl ester (l-NAME) effectively inhibit the relaxation of cavernous tissue.4 7 ,4 8 ,1 5 6 1 5 8 The inhibitory effect is counteracted by exogenous l-arginine.4 7 ,4 8 Their ef cacy in provoking erectile dysfunction under various in vitro and in vivo conditions highlights the potential importance of NOS inhibitors in erectile dysfunction. Yet, none of the NOS inhibitors preferentially studied in erectile dysfunction reaches physiologically relevant concentrations in vivo.1 5 9 Surprisingly, one NOS inhibitor has received only little attention in erectile dysfunction so far: ADMA. Many conditions associated with erectile dysfunction are known to be associated with elevated plasma levels of ADMA3 7 ,1 6 0 1 6 8 (summarized in Table 2). ADMA is a selective, endogenous NOS-inhibitor,1 6 4 formed by the hydrolysis of proteins containing methylated arginine residues.1 7 6 ,1 7 7 Elevated ADMA plasma levels were rst described in patients with chronic renal failure by Vallance et al in 19921 6 4 and linked to impaired NO synthesis. Since then plasma ADMA levels were shown to be positively correlated with age, mean arterial pressure, glucose tolerance and extent of atherosclerosis.1 6 2 ,1 6 3 ,1 6 9 ,1 7 0 In healthy subjects, the mean plasma ADMA concentration ranges from 0.5 to 1 mM.1 6 4 ,1 7 1 In patients with cardiovascular risk factors, the plasma level is typically increased two fold.3 8 Furthermore, in patients with clinical atherosclerotic disease or end-stage renal disease, plasma ADMA concentrations are even increased further, up to 3.5-fold and 10.4-fold, respectively.3 7 ,1 6 4 ,1 6 6 ,1 6 7 ,1 6 9 It was shown that in diabetic patients with otherwise normal ADMA levels typical (western) high fat meals were associated with an acute 2.5-fold increase of plasma ADMA levels and profound endothelial dysfunction.1 7 8 While elevated ADMA levels in patients with renal
failure could be attributed at least in part to reduced renal excretion, the precise cause of elevated ADMA levels in other diseases has not been identi ed yet. One cause could be a reduced activity of dimethylarginine dimethylaminohydrolase (DDAH), which degrades ADMA. DDAH activity may be inhibited by elevated concentrations of homocysteine or cholesterol.1 7 9 ,1 8 0 Several groups, including our own, could demonstrate that elevated plasma ADMA levels are associated with impaired endothelium-dependent vasodilation and reduced urinary nitrate excretion.3 8 ,1 8 1 Intra-arterial infusion of ADMA (8 and 16 mmol/min) in healthy volunteers caused a signi cant, dose-dependent reduction in forearm blood ow.1 8 2 Since this effect was attenuated by infusion of excess l-arginine it was attributed to impairment of NOS activity by ADMA. This nding strengthens the point that ADMA is not only a marker but also a cause of endothelial dysfunction. Similar results on vascular tone could be obtained in vitro from human cerebral arteries.1 8 3 Rising ADMA concentrations from 1 mmol/l to 10 mmol/l were shown to cause moderate contractions of cerebral vessels in situ.1 5 9 In cerebral tissues, the IC5 0 value of ADMA for inhibition of NO production has been calculated to be between 1.5 and 2.3 mmol/l,1 5 9 ,1 8 4 i.e. within the (patho-) physiological concentration range. Under pathological conditions ADMA reaches tissue concentrations likely to be suf cient to inhibit NO synthesis.1 5 9 ,1 8 3 ,1 8 4 The parallels between cardiovascular risk factors, endothelial dysfunction, erectile dysfunction and elevated ADMA concentration are striking (Table 2). Since ADMA concentrations found in diabetes, hyperlipoproteinaemia, renal failure and cardiovascular disease are high enough to interfere with endothelial NO synthesis and to cause endothelial dysfunction, we hypothesize that elevated ADMA levels can also interfere with penile NO synthesis and smooth muscle function. Thus, ADMA may provide an additional pathomechanism for erectile dysfunction shared by many conditions associated with both endothelial and erectile dysfunction. In several clinical trials endothelial dysfunction associated with elevated ADMA levels was restored by supplementation of l-arginine.3 2 ,1 8 5 ,1 8 6 In a rabbit model of chronic cavernosal ischaemia, impaired smooth muscle relaxation was found not to be related to the ability of erectile tissue to relax to NO.1 8 7 Rather, it appeared to be related to an impaired NO production by the endothelium. In the same study, endothelium-dependent relaxation impaired by hypercholesterolaemia could be completely restored by l-arginine. In animals with chronic cavernosal ischaemia, l-arginine could only partially restore endothelium-dependent relaxation. This suggests that in chronic ischaemia further steps in the NO-mediated pathway may be involved. Results from clinical trials in patients with erectile dysfunction have been controversial.1 8 8 ,1 8 9 Only patients with an initially reduced nitrate excretion (as a marker of impaired NO production) reported an improvement.1 8 8 Today, l-arginine plays only a marginal role in the treatment of erectile dysfunction. Elevated ADMA concentrations offer a possible explanation for conicting data and may encourage a second look at l-arginine treatments in erectile dysfunction: l-arginine has been shown to restore NO synthesis impaired by methylated larginine analogues,4 7 ,4 8 including ADMA.1 6 4 ,1 9 0 Patients with elevated plasma ADMA levels and decreased NO pro-
218 R Maas et al
Table 2
Plasma ADMA concentrations and risk of erectile dysfunction in conditions associated with endothelial dysfunction.
Condition associated with endothelial dysfunction
Plasma ADMA concentration " 5 elevation versus control
Incidence of erectile dysfunction " 5 elevated risk versus control
Atherosclerosis2 2 ,2 3 Hypertension2 4 ,2 5 Diabetes2 6 ,2 7 Renal failure2 8 ,2 9 Hypercholesterolaemia2 6 ,3 0 32 Smoking3 3 ,3 4 Old age3 1 ,3 5,36
" 2.13.533 7 ,1 62 Correlates with extent of disease1 6 9 Correlates with prognosis of disease1 7 0 " 2.22.331 6 1,16 3 Correlates with arterial pressure1 6 2 " 2.331 7 1 Correlates with index of blood glucose1 6 2 " 210.431 6 4 16 7 Correlates with prognosis of disease1 7 2 " 2.231 6 8 Correlation not seen in all collectives with hypercholesterolaemia1 6 2 No data available " Increases with age1 6 2
" 2.631 5 ,1 8 " 1.41.636 ,1 5 " 1.74.631 3 1 5 5082% of patients affected1 9 2 1 " 1.61.831 5 ,1 7 Correlates with total cholesterol1 7 " 1.42.531 5 ,1 73 1 7 5 Increasing with age (up to 103)4 ,5
duction should be more likely than others to bene t from treatment with l-arginine. It has to be emphasized, however, that an association of a factor with a disease does not necessarily imply causality.1 9 1 To pursue this issue we initiated a clinical trial to investigate the role of ADMA in erectile dysfunction.
NO-independent mechanisms involved in endothelial and erectile dysfunction

Prostaglandins Eicosanoids are synthesized in the blood vessels as modulators of vascular tone by PGHS and subsequent conversion to prostaglandin (PG) E2 , PGF2 a , PGD2 , prostacyclin (PGI 2 ) or thromboxane (TxB2 ) by PGE synthase, PGF synthase, PGD synthase, PGI synthase, or thromboxane synthase, respectively (reviewed in1 9 2 ,1 9 3 ). Both isoforms of PGHS, i.e. PGHS-1 and PGHS-2, are expressed in endothelial cells and smooth muscle cells constitutively or inducibly, respectively.1 9 4 ,1 9 5 The regulation of expression in the vasculature has been discussed in detail elsewhere.1 9 6 PGI synthase is predominantly located in the vascular endothelium and smooth muscle.1 9 7 Rate-limiting for eicosanoid release is not only the expression of PGHS and PGI synthase but also the availability of the precursor arachidonic acid. Arachidonic acid is released from phospholipids by phospholipase A2 , which is inducible by interleukins together with PGHS-2, PGE synthase and PGI synthase, leading to a vast amount of vasodilatory prostanoids in human endothelial cells in sepsis and in ammation.1 9 8 2 0 1 In addition, phospholipase A2 may be activated by endothelin-1, which provides a crosslink to the endothelin-mediated effects discussed further below. Human corpus cavernosum has the ability to synthesize all the eicosanoids mentioned above.2 0 2 ,2 0 3 PGI2 formed in the penile tissue dilates blood vessels and inhibits platelet adhesion and aggregation.2 0 4 ,2 0 5 But only PGE 2 and its derivative PGE1 were found to relax the corpus cavernosum and spongiosum.2 0 6 The relaxant effects of PGE2 and PGE1 are likely to be mediated via activation of adenylyl cyclase
and subsequent elevation of intracellular cAMP in the human corpus cavernosum.2 0 7 This effect was mediated via stimulation of prostanoid receptors. The established clinical ef cacy of PGE1 and its derivative alprostadil highlight the role of eicosanoids in penile function.5 0 ,6 8 In diabetic men, PGE 1 receptors are down-regulated.2 0 8 Moreover, in animal models of diabetes mellitus, prostacyclin formation is diminished.2 0 9 ,2 1 0 Both mechanisms may contribute to an imbalance the penile eicosanoid homeostasis. The resulting vasoconstriction of penile blood vessels and contraction of corpus cavernosum provides a further pathomechanism to explain the high incidence of erectile dysfunction in diabetes mellitus. Recent data suggest that upon stimulation by acetylcholine, endothelial cells in the penis do not only release vasodilatory NO but also vasoconstrictory prostanoids.2 1 1 Under physiological conditions NO-mediated relaxation stimulated by acetylcholine outweighs the effects of constrictory eicosanoids, including prostanoids and thromboxane. But in conditions of impaired NO release, the co-release of vasoconstrictory eicosanoids may signi cantly impair acetylcholine-mediated relaxation. These ndings may also be interesting in the light of data from in vitro studies,1 8 7 suggesting that inhibition of constrictory eicosanoids by drugs such as indomethacin can improve the ability of cavernosal tissue to relax. However, the effectiveness of these drugs in erectile dysfunction has not yet been demonstrated in vivo. Angiotensin and kinins The angiotensin system and kinins may provide further mechanisms regulating both vascular and penile tone. Angiotensin- and bradykinin-receptors have been characterized both in the systemic vasculature and in erectile tissues.2 12 216 Bradykinin was able to elicit dose-dependent relaxation of norepinephrine-induced tension in isolated corpus cavernosum strips, whereas angiotensin II caused dose-dependent contraction.5 2 Furthermore, in dogs, intracavernosal angiotensin II terminated spontaneous erections while an intercavernosal angiotensin II antagonist increased intracavernosal blood pressure. In the stage of penile detu-
mescence, a transient increase of the angiotensin II concentration in the corpus cavernosum was observed in healthy volunteers.5 2 When compared with healthy volunteers, both local angiotensin II concentrations in the corpus cavernosum and systemic concentrations were elevated in patients with organic erectile dysfunction.2 1 7 In addition to a possible systemic origin of angiotensin and kinins, there is emerging evidence that the endothelial and smooth muscle cells in the human corpus cavernosum form a local angiotensin II-producing paracrine system. In human volunteers the concentrations of angiotensin II in the corpus cavernosum were found to be higher than those in samples taken from the cubital vein in all stages of penile erection and detumescence.5 2 ,2 1 7 Given the very short plasma halflife of angiotensin II, local production is the most likely source in this case. While inhibition of the angiotensin-converting enzyme decreases the concentration of angiotensin II by preventing the formation of angiotensin II from angiotensin I, inhibition of the angiotensin-converting enzyme increases the concentration of bradykinin by inhibiting its degradation. Thus, it has been suggested that inhibition of the angiotensin-converting enzyme might have some direct bene cial effects in erectile dysfunction since it increases the concentration of bradykinin and decreases the concentration of angiotensin II. Endothelins Endothelin-1, 2 and 3 are mainly known as peptides with potent vasoconstrictor activity.2 1 8 ,2 1 9 Endothelin-1 is the primary endothelium-derived endothelin. Two types of endothelin receptors (ETA and ETB ) have been described. The vascular effects of endothelins and the corresponding second messenger pathways are complex and not yet fully understood. Endothelins act on the endothelium (mainly ETB ) and on smooth muscle (ETA and ETB ). Activation of ETA receptors predominantly causes contraction of vascular smooth muscle, whereas activation of ETB receptors on endothelial cells results in release of NO and prostacyclin and may mediate smooth muscle relaxation. In most vascular beds endothelin-1 causes an initial vasodilation followed by a vasoconstriction. It has been shown that ETA and ETB receptors can couple to overlapping sets of G-proteins. A common pathway is the subsequent activation of phospholipase Cb which increases inositol-1,4,5-trisphosphate and nally results in elevation of Ca2 + .2 1 8 However, additional phospholipases and subsequent pathways are likely to be involved in endothelin-dependent signalling.2 2 0 In addition it has been demonstrated that at physiological concentrations endothelin-1 may enhance the contractile effects of other mediators such as PGF2 a or 5-hydroxytryptamine.2 2 1 2 2 3 Smooth muscle sensitization to Ca2 + may be one possible mechanism. Two distinct pathways seem to be involved in these effects:2 2 4 a Ca2 + -sensitive protein kinase C (PKC)-mediated pathway not involving tyrosine phosphorylation or activation of mitogen-activated protein kinase (MAPK) and a Ca2 + -insensitive PKC-mediated pathway involving tyrosine phosphorylation and activation of MAPK.2 2 4 In summary, endothelin-1 may be an interesting target for mediating the net effect of vasoconstrictor substances. Both endothelin and endothelin receptors type A and B have been identi ed in erectile tissues and in cultured endothelial cells from human corpus cavernosum.5 1
In the penile vasculature the effects of endothelin-1 seem to be dose-dependent.2 2 5 Low doses have a vasodilator effect whereas high doses have a vasoconstrictor effect. The vasodilator effect may be mediated by stimulation of endothelial NO production. Endothelin-3 appears to have a predominantly vasodilatator effect on penile vasculature.2 2 5 Yet at higher doses all three endothelins were shown to elicit cavernosal smooth muscle contraction.2 2 6 However, endothelin levels in systemic and cavernosal blood did not change from accidity to erection and detumescence in healthy males2 2 7 or in patients with erectile dysfunction.2 2 8 In a recently published pilot study of the endothelin-A receptor antagonist BMS-1938,8 4 this drug caused dosedependent relaxation of cavernosal tissue strips in vitro but failed to improve erectile function in men with mild to moderate erectile dysfunction in vivo.2 2 6 Endothelium-derived hyperpolarizing factor There is accumulating evidence for involvement of endothelium-derived hyperpolarizing factors in vasorelaxation.2 2 9 An endothelium-derived hyperpolarizing factor (EDHF) that promotes endothelium-dependent vasodilation independently of NO and prostacyclin has recently been characterized in wild-type and eNOS knock-out mice.2 3 0 EDHF-mediated relaxation was found to be sensitive to speci c K+ -channel blockade by charybdotoxin and apamin but resistant NOS or PGHS inhibition. This suggests that gap-junctions and Ca2 + -dependent K+ -channels are likely to mediate EDHF-dependent relaxation. Futhermore, the relative contribution of EDHF to relaxation was rather signi cant. The nature of EDHF and whether EDHF-like effects in different tissues are mediated by one or by several distinct factors is not yet known.2 2 9 It has still been suggested that EDHF may provide an alternative or back-up pathway for acetylcholine-mediated vasorelaxation. Finally, acetylcholine-induced endothelium-dependent relaxation, sensitive to blockade of small conductance calcium channels but insensitive to NOS or PGHS blockade, has been identi ed in canine corpus cavernosum as well.5 3 Again, the clinical signi cance of these observations remains to be established.
Conclusion
Endothelial and erectile dysfunction are both multifactorial but share fundamental risk factors and pathomechanisms. This opens the door for new therapeutic and preventive approaches. Control of cardiovascular risk factors and treatments that restore normal endothelial function in cardiovascular disease are also likely to be bene cial in the prevention and treatment of erectile dysfunction. Future issues to be addressed in erectile dysfunction are the role of endogenous NOS inhibitors, the impact of oxidative stress and the role of EDHF. New arginase inhibitors and speci c Rho-kinase inhibitors may offer additional therapeutic approaches.
References
1 NIH consensus development panel on impotence. NIH consensus conference: impotence. JAMA 1993; 270: 8390. 2 Green JS, Holden ST, Ingram P, Bose P, St George DP, Bowsher
220 R Maas et al
6 7 8
10 11 12
13 14
15
16 17
18
19 20
21
22
23
24
25
WG. An investigation of erectile dysfunction in Gwent, Wales. BJU Int 2001; 88: 55153. Ayta IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999; 84: 5056. Moreira ED Jr, Abdo CH, Torres EB, Lobo CF, Fittipaldi JA. Prevalence and correlates of erectile dysfunction: results of the Brazilian study of sexual behavior. Urology 2001; 58: 58388. Rosas SE, Joffe M, Franklin E et al. Prevalence and determinants of erectile dysfunction in hemodialysis patients. Kidney Int 2001; 59: 225966. Parazzini F, Menchini Fabris F et al. Frequency and determinants of erectile dysfunction in Italy. Eur Urol 2000; 37: 4349. Lue TF. Erectile dysfunction. N Engl J Med 2000; 342: 180213. Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman KP, McKinlay JB. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachussetts male aging study. J Urol 2000; 163: 46063. Sullivan ME, Thompson CS, Dashwood MR et al. Nitric oxide and penile erection: is erectile dysfunction another manifestation of vascular disease? Cardiovasc Res 1999; 43: 65865. Sullivan ME, Keoghane SR, Miller MA. Vascular risk factors and erectile dysfunction. BJU Int 2001; 87: 83845. Brock GB, Lue TF. Drug-induced male sexual dysfunction. An update. Drug Saf 1993; 8: 41426. Jensen J, Lendorf A, Stimpel H, Frost J, Ibsen H, Rosenkilde P. The prevalence and etiology of impotence in 101 male hypertensive outpatients. Am J Hypertens 1999; 12: 27175. Fedele D, Coscelli C, Cucinotta D et al. Incidence of erectile dysfunction in Italian men with diabetes. J Urol 2001; 166: 136871. Siu SC, Lo SK, Wong KW, Ip KM, Wong YS. Prevalence of and risk factors for erectile dysfunction in Hong Kong diabetic patients. Diabet Med 2001; 18: 73238. Martin-Morales A, Sanchez-Cruz JJ, Saenz de Tejada I, RodriguezVela L, Jimenez-Cruz JF, Burgos-Rodriguez R. Prevalence and independent risk factors for erectile dysfunction in Spain: results of the Epidemiologia de la Disfuncion Erectil Masculina study. J Urol 2001; 166: 56974. McCulloch DK, Campbell IW, Wu FC, Prescott RJ, Clarke BF. The prevalence of diabetic impotence. Diabetologia 1980; 18: 27983. Wei M, Macera CA, Davis DR, Hornung CA, Nankin HR, Blair SN. Total cholesterol and high density lipoprotein cholesterol as important predictors of erectile dysfunction. Am J Epidemiol 1994; 140: 93037. Virag R, Bouilly P, Frydman D. Is impotence an arterial disorder? A study of arterial risk factors in 440 impotent men. Lancet 1985; i: 18184. Palmer BF. Sexual dysfunction in uraemia. J Am Soc Nephrol 1999; 10: 138188. Procci WR, Goldstein DA, Adelstein J, Massry SG. Sexual dysfunction in the male patient with uraemia: a reappraisal. Kidney Int 1981; 19: 31723. Tu rk S, Karalezli G, Tonbul HZ et al. Erectile dysfunction and the effects of sildena l treatment in patients on haemodialysis and continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 2001; 16: 181822. Kuvin JT, Patel AR, Sliney KA et al. Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease. J Am Coll Cardiol 2001; 38: 184349. Hashimoto M, Kozaki K, Eto M et al. Association of coronary risk factors and endotheliumdependent ow-mediated dilatation of the brachial artery. Hypertens Res 2000; 23: 23338. Egashira K, Inou T, Hirooka Y et al. Impaired coronary blood ow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest 1993; 91: 2937. Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endotheliumdependent vascular relaxation of patients with essential hypertension. Circulation 1993; 87: 146874.
26 Thorne S, Mullen MJ, Clarkson P, Donald AE, Dean eld JE. Early endothelial dysfunction in adults at risk from atherosclerosis: different responses to l-arginine. J Am Coll Cardiol 1998; 32: 11016. 27 Preik M, Kelm M, Rosen P, Tscho pe D, Strauer BE. Additive effect of coexistent type 2 diabetes and arterial hypertension on endothelial dysfunction in resistance arteries of human forearm vasculature. Angiology 2000; 51: 54554. 28 Van Guldener C, Janssen MJ, Lambert J, Steyn M, Donker AJ, Stehouwer CD. Endothelium-dependent vasodilatation is impaired in peritoneal dialysis patients. Nephrol Dial Transplant 1998; 13: 178286. 29 Morris ST, McMurray JJ, Spiers A, Jardine AG. Impaired endothelial function in isolated human uremic resistance arteries. Kidney Int 2001; 60: 107782. 30 Kaufmann PA, Gnecchi-Ruscone T, Scha fers KP, Lu scher TF, Camici PG. Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolaemia. J Am Coll Cardiol 2000; 36: 103109. 31 Zeiher AM, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood ow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest 1993; 92: 65262. 32 Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by l-arginine. Lancet 1991; 338: 154650. 33 Celermajer DS, Adams MR, Clarkson P et al. Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N Engl J Med 1996; 334: 15054. 34 Poredos P, Orehek M, Tratnik E. Smoking is associated with doserelated increase of intima-media thickness and endothelial dysfunction. Angiology 1999; 50: 201208. 35 Andrawis N, Jones DS, Abernethy DR. Aging is associated with endothelial dysfunction in human forearm vasculature. J Am Geriatr Soc 2000; 48: 19398. 36 Egashira K, Inou T, Hirooka Y et al. Effects of age on endotheliumdependent vasodilation of resistance coronary artery by acetylcholine in humans. Circulation 1993; 88: 7781. 37 Bo ger RH, Bode-Bo ger SM, Thiele W, Junker W, Alexander K, Fro lich JC. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation 1997; 95: 206874. 38 Bo ger RH, Bode-Bo ger SM, Szuba A et al. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction. Its role in hypercholesterolemia. Circulation 1998; 98: 184247. 39 Rubanyi GM. The role of the endothelium in cardiovascular homeostasis and disease. J Cardiovasc Pharmacol 1993; 22 (suppl): S1S4. 40 De Meyer GR, Herman AG. Vascular endothelial dysfunction. Prog Cardiovasc Dis 1997; 39: 325432. 41 Drexler H. Endothelial dysfunction: clinical implications. Prog Cardiovasc Dis 1997; 39: 287324. 42 Moncada S. Nitric oxide in the vasculature: physiology and pathophysiology. Ann NY Acad Sci 1997; 881: 6069. 43 Goligorsky MS, Noiri E, Tsukahara H, Budzikowski AS, Li H. A pivotal role of nitric oxide in endothelial cell dysfunction. Acta Physiol Scand 2000; 168: 3340. 44 Burnett AL. Nitric oxide in the penis: physiology and pathology. J Urol 1997; 157: 32024. 45 Moncada S, Higgs A. The l-arginine-nitric oxide pathway. N Engl J Med 1993; 329: 200212. 46 Kelm M, Rath J. Endothelial dysfunction in human coronary circulation: relevance of the l-arginine-NO pathway. Basic Res Cardiol 2001; 96: 10727. 47 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, noncholinergic neurotransmission. N Engl J Med 1992; 326: 9094. 48 Kim N, Azadzoi KM, Goldstein I, Saenz de Tejada I. A nitric oxidelike factor mediates nonadrenergic-noncholinergic neurogenic relax-
49 50 51
52
53
54 55
56
57
58 59
60
61
62
63
64
65
66
67
68
69
70
ation of penile corpus cavernosum smooth muscle. J Clin Invest 1991; 88: 11218. Minhas S, Cartledge J, Eardley I. The role of prostaglandins in penile erection. Prostaglandins Leukot Essent Fatty Acids 2000; 62: 13746. Porst H. The rationale for prostaglandin E1 in erectile failure: a survey of worldwide experience. J Urol 1996; 155: 80215. Saenz de Tejada I, Carson MP, de las Morenas A, Goldstein I, Traish AM. Endothelin: localization, synthesis, activity, and receptor types in human penile corpus cavernosum. Am J Physiol 1991; 261: H107885. ckert S, Stief CG et al. Possible role of bradykinin and Becker AJ, U angiotensin II in the regulation of penile erection and detumenescence. Urology 2001; 57: 19398. Ayajiki K, Fujioka H, Okamura T. Mechanisms underlying endothelium-dependent, nitric oxide/prostacyclin-independent, acetylcholine-induced relaxation in canine corpus cavernosum. Naunyn Schmiedebergs Arch Pharmacol 2000; 362: 44851. Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from l-arginine. Nature 1988; 333: 66466. Palmer RM, Rees DD, Ashton DS, Moncada S. l-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun 1988; 153: 125156. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of the endothelium derived-relaxing factor. Nature 1987; 327: 52426. Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, Snyder SH. Nitric oxide: a physiologic mediator of penile erection. Science 1992; 257: 401403. Gonzalez-Cadavid NF, Ignarro LJ, Rajfer J. Nitric oxide and the cyclic GMP system in the penis. Mol Urol 1999; 3: 5159. Ignarro LJ, Bush PA, Buga GM, Wood KS, Fukuto JM, Rajfer J. Nitric oxide and cyclic GMP formation upon electrical eld stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Commun 1990; 170: 84350. Huang PL, Dawson TM, Bredt DS, Snyder SH, Fishman MC. Targeted disruption of the neuronal nitric oxide synthase gene. Cell 1993; 75: 127386. Burnett AL, Nelson RJ, Calvin DC et al. Nitric oxide-dependent penile erection in mice lacking neuronal nitric oxide synthase. Mol Med 1996; 2: 28896. Gonzalez-Cadavid NF, Burnett AL, Magee TR et al. Expression of penile neuronal nitric oxide synthase variants in the rat and mouse penile nerves. Biol Reprod 2000; 63: 70414. Burnett AL, Chang AG, Crone JK, Huang PL, Sezen SE. Noncholinergic penile erection in mice lacking the gene for endothelial nitric oxide synthase. J Androl 2002; 23: 9297. Escrig A, Marin R, Abreu P, Luis Gonzalez-Mora J, Mas M. Changes in mating behavior, erectile function, and nitric oxide levels in penile corpora cavernosa in streptozotocin-diabetic rats. Biol Reprod 2002; 66: 18589. Arnold WP, Mittal CK, Katsuki S, Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3:59-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci U S A 1977; 74: 3203207. Hedlund P, Aszodi A, Pfeifer A et al. Erectile dysfunction in cyclic GMP-dependent kinase I-de cient mice. Proc Natl Acad Sci U S A 2000; 97: 234954. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildena l in the treatment of erectile dysfunction. Sildena l Study Group. N Engl J Med 1998; 338: 1397404. Padma-Nathan H, Hellstrom WJ, Kaiser FE et al. Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med 1997; 336: 17. Surks HK, Mochizuki N, Kasai Y et al. Regulation of myosin phosphatase by a speci c interaction with cGMP dependent protein kinase Ia. Science 1999; 286: 158387. Rees RW, Ralph DJ, Royle M, Moncada S, Cellek S. Y-27632, an
71
72 73 74
75
76
77
78
79 80
81
82
83
84
85
86
87 88
89
90
91
92
inhibitor of Rho-kinase, antagonizes noradrenergic contraction in the rabbit and human penile corpus cavernosum. Br J Pharmacol 2001; 133: 45558. Chitaley K, Wingard CJ, Webb RC et al. Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. Nat Med 2001; 7: 11922. Andersson KE, Wagner G. Physiology of penile erection. Physiol Rev 1995; 75: 191236. Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J 2001; 357: 593615. Deves R, Boyd CA. Transporters for cationic amino acids in animal cells: discovery, structure, and function. Physiol Rev 1998; 78: 487545. Closs EI, Basha FZ, Habermeier A, Fo rstermann U. Interference of l-arginine analogues with l-arginine transport mediated by the y+ carrier hCAT-2B. Nitric Oxide 1997; 1: 6573. Xiao S, Wagner L, Mahaney J, Baylis C. Uremic levels of urea inhibit l-arginine transport in cultured endothelial cells. Am J Physiol Renal Physiol 2001; 280: F98995. Cox JD, Kim NN, Traish AM, Christianson DW. Arginase-boronic acid complex highlights a physiological role in erectile function. Nat Struct Biol 1999; 6: 104347. Bivalacqua TJ, Hellstrom WJ, Kadowitz PJ, Champion HC. Increased expression of arginase II in human diabetic corpus cavernosum: in diabetic-associated erectile dysfunction. Biochem Biophys Res Commun 2001; 283: 92327. Michel T, Feron O. Nitric oxide synthases: which, where, how, and why? J Clin Invest 1997; 100: 214652. Hedlund P, Ny L, Alm P, Andersson KE. Cholinergic nerves in human corpus cavernosum and spongiosum contain nitric oxide synthase and heme oxygenase. J Urol 2000; 164: 86875. Bloch W, Klotz T, Sedlaczek P, Zumbe J, Engelmann U, Addicks K. Evidence for the involvement of endothelial nitric oxide synthase from smooth muscle cells in the erectile function of the human corpus cavernosum. Urol Res 1998; 26: 12935. Dail WG, Barba V, Leyba L, Galindo R. Neural and endothelial nitric oxide synthase activity in rat penile erectile tissue. Cell Tissue Res 1995; 282: 10916. Fo rstermann U, Boissel JP, Kleinert H. Expressional control of the constitutive isoforms of nitric oxide synthase (NOS I and NOS III). FASEB J 1998; 12: 77390. Xiao Z, Zhang Z, Diamond SL. Shear stress induction of the endothelial nitric oxide synthase gene is calcium-dependent but not calcium-activated. J Cell Physiol 1997; 171: 20511. Crabos M, Coste P, Paccalin M et al. Reduced basal NO-mediated dilation and decreased endothelial NO-synthase expression in coronary vessels of spontaneously hypertensive rats. J Mol Cell Cardiol 1997; 29: 5565. Tojo A, Kimoto M, Wilcox CS. Renal expression of constitutive NOS and DDAH: separate effects of salt intake and angiotensin. Kidney Int 2000; 58: 207583. Ni Z, Vaziri ND. Effect of salt loading on nitric oxide synthase expression in normotensive rats. Am J Hypertens 2001; 14: 15563. Hirata K, Miki N, Kuroda Y, Sakoda T, Kawashima S, Yokoyama M. Low concentration of oxidized low-density lipoprotein and lysophosphatidylcholine upregulate constitutive nitric oxide synthase mRNA expression in bovine aortic endothelial cells. Circ Res 1995; 76: 95862. Liao JK, Shin WS, Lee WY, Clark SL. Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem 1995; 270: 31924. Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998; 97: 112935. Wallerath T, Witte K, Scha fer SC et al. Down-regulation of the expression of endothelial NO synthase is likely to contribute to glucocorticoid-mediated hypertension. Proc Natl Acad Sci U S A 1999; 96: 13 35762. Yoshizumi M, Perrella MA, Burnett JC, Lee ME. Tumor necrosis
222 R Maas et al
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
factor downregulates an endothelial nitric oxide synthase messenger RNA by shortening its half-life. Circ Res 1993; 73: 20509. Alonso J, Sanchez de Miguel L, Monton M, Casado S, Ravichandran LV, Johns RA. Up-regulation of endothelial nitric oxide synthase expression by cyclic guanosine 39,59-monophosphate. FEBS Lett 1995; 374: 29598. Belhassen L, Kelly RA, Smith TW, Balligand JL. Nitric oxide synthase (NOS3) and contractile responsiveness to adrenergic and cholinergic agonists in the heart. Regulation of NOS3 transcription in vitro and in vivo by cyclic adenosine monophosphate in rat cardiac myocytes. J Clin Invest 1996; 97: 190815. Cosentino F, Hishikawa K, Katusic ZS, Lu scher TF. High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation 1997; 96: 2528. Marin R, Escrig A, Abreu P, Mas M. Androgen-dependent nitric oxide release in rat penis correlates with levels of constitutive NOS isoenzymes. Biol Reprod 1999; 61: 101218. Yamashita T, Kawashima S, Ozaki M et al. A calcium channel blocker, benidipine, inhibits intimal thickening in the carotid artery of mice by increasing nitric oxide production. J Hypertens 2001; 19: 45158. Kobayashi N, Yanaka H, Tojo A, Kobayashi K, Matsuoka H. Effects of amlodipine on nitric oxide synthase mRNA expression and coronary microcirculation in prolonged nitric oxide blockade-induced hypertensive rats. J Cardiovasc Pharmacol 1999; 34: 17381. Escrig A, Marin R, Mas M. Repeated PGE1 treatment enhances nitric oxide and erection responses to nerve stimulation in the rat penis by upregulating constitutive NOS isoforms. J Urol 1999; 162: 220510. Abdel-Gawad M, Huynh H, Brock GB. Experimental chronic renal failure-associated erectile dysfunction: molecular alterations in nitric oxide synthase pathway and IGF-I system. Mol Urol 1999; 3: 11725. Abdel-Gawad M, Huynh H, Brock GB. The impact of chronic renal failure on nitric oxide synthase isoforms gene expression in the penis and pelvic ganglia of rats. J Urol 1999; 162: 147379. Haas CA, Seftel AD, Razmjouei K, Ganz MB, Hampel N, Ferguson K. Erectile dysfunction in aging: upregulation of endothelial nitric oxide synthase. Urology 1998; 51: 51622. Zembowicz A, Tang JL, Wu KK. Transcriptional induction of endothelial nitric oxide synthase type III by lysophosphatidylcholine. J Biol Chem 1995; 270: 17 00610. Colin IM, Kopp P, Zbaren J, Haberli A, Grizzle WE, Jameson JL. Expression of nitric oxide synthase III in human thyroid follicular cells: evidence for increased expression in hyperthyroidism. Eur J Endocrinol 1997; 136: 64955. Kobayashi N, Mori Y, Nakano S, Tsubokou Y, Shirataki H, Matsuoka H. Celiprolol stimulates endothelial nitric oxide synthase expression and improves myocardial remodeling in deoxycorticosterone acetate-salt hypertensive rats. J Hypertens 2001; 19: 795801. Fukai T, Siegfried MR, Ushio-Fukai M, Cheng Y, Kojda G, Harrison DG. Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. J Clin Invest 2000; 105: 163139. Ennezat PV, Malendowicz SL, Testa M et al. Physical training in patients with chronic heart failure enhances the expression of genes encoding antioxidative enzymes. J Am Coll Cardiol 2001; 38: 19498. Arnet UA, McMillan A, Dinerman JL, Ballermann B, Lowenstein CJ. Regulation of endothelial nitric-oxide synthase during hypoxia. J Biol Chem 1996; 271: 15 06973. Phelan MW, Faller DV. Hypoxia decreases constitutive nitric oxide synthase transcript and protein in cultured endothelial cells. J Cell Physiol 1996; 167: 46976. Ferrini M, Magee TR, Vernet D, Rajfer J, Gonzalez-Cadavid NF. Aging-related expression of inducible nitric oxide synthase and markers of tissue damage in the rat penis. Biol Reprod 2001; 64: 97482. Adams MR, Kinlay S, Blake GJ, Orford JL, Ganz P, Selwyn AP. Atherogenic lipids and endothelial dysfunction: mechanisms in the genesis of ischemic syndromes. Annu Rev Med 2000; 51: 14967. Davidge ST, Baker PN, McLaughlin MK, Roberts JM. Nitric oxide
113
114
115
116
117
118
119 120 121 122 123 124
125
126
127
128
129
130
131
132
133
produced by endothelial cells increases production of eicosanoids through activation of prostaglandin H synthase. Circ Res 1995; 77: 27483. Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P. Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci U S A 1993; 90: 724044. Liou JY, Shyue SK, Tsai MJ, Chung CL, Chu KY, Wu KK. Colocalization of prostacyclin synthase with prostaglandin H synthase-1 (PGHS-1) but not phorbol ester-induced PGHS-2 in cultured endothelial cells. J Biol Chem 2000; 275: 1531420. Vane JR, Mitchell JA, Appleton I et al. Inducible isoforms of cyclooxygenase and nitric-oxide synthase in in ammation. Proc Natl Acad Sci U S A 1994; 91: 204650. Swierkosz TA, Mitchell JA, Warner TD, Botting RM, Vane JR. Coinduction of nitric oxide synthase and cyclooxygenase: interactions between nitric oxide and prostanoids. Br J Pharmacol 1995; 114: 133542. Camacho M, Lopez-Belmonte J, Vila L. Rate of vasoconstrictor prostanoids released by endothelial cells depends on cyclooxygenase-2 expression and prostaglandin I synthase activity. Circ Res 1998; 83: 35365. Arriero MM, Rodriguez-Feo JA, Celdran A et al. Expression of endothelial nitric oxide synthase in human peritoneal tissue: regulation by Escherichia coli lipopolysaccharide. J Am Soc Nephrol 2000; 11: 184856. Harrison DG. Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest 1997; 100: 215357. Ross R. Atherosclerosis an in ammatory disease. N Engl J Med 1999; 340: 11525. Maytin M, Leopold J, Loscalzo J. Oxidant stress in the vasculature. Curr Atheroscler Rep 1999; 1: 15664. Heitzer T, Just H, Mu nzel T. Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. Circulation 1996; 94: 69. Jeremy JY, Angelini GD, Khan M et al. Platelets, oxidant stress and erectile dysfunction: an hypothesis. Cardiovasc Res 2000; 46: 5054. Murohara T, Kugiyama K, Ohgushi M, Sugiyama S, Yasue H. Cigarette smoke extract contracts isolated porcine coronary arteries by superoxide anion-mediated degradation of EDRF. Am J Physiol 1994; 266: H87480. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Mu nzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001; 104: 2673 78. Pou S, Pou WS, Bredt DS, Snyder SH, Rosen GM. Generation of superoxide by puri ed brain nitric oxide synthase. J Biol Chem 1992; 267: 2417376. Vasquez-Vivar J, Kalyanaraman B, Martasek P et al. Superoxide generation by endothelial nitric oxide synthase: the in uence of co-factors. Proc Natl Acad Sci U S A 1998; 95: 922025. Stroes E, Kastelein J, Cosentino F et al. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest 1997; 99: 4146. Heitzer T, Brockhoff C, Mayer B et al. Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers: evidence for a dysfunctional nitric oxide synthase. Circ Res 2000; 86: E3641. Tiefenbacher CP, Bleeke T, Vahl C, Amann K, Vogt A, Ku bler W. Endothelial dysfunction of coronary resistance arteries is improved by tetrahydrobiopterin in atherosclerosis. Circulation 2000; 102: 217279. Bush PA, Gonzalez NE, Ignarro LJ. Biosynthesis of nitric oxide and citrulline from l-arginine by constitutive nitric oxide synthase present in rabbit corpus cavernosum. Biochem Biophys Res Commun 1992; 186: 30814. Heller R, Unbehaun A, Schellenberg B, Mayer B, Werner-Felmayer G, Werner ER. l-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem 2001; 276: 4047. Gryglewski RJ, Palmer RM, Moncada S. Superoxide anion is
134
135
136
137
138 139
140
141 142 143
144
145 146
147
148
149
150
151
152
153
154
155
involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 1986; 320: 45456. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am J Physiol Cell Physiol 1996; 271: C142437. Zou M, Martin C, Ullrich V. Tyrosine nitration as a mechanism of selective inactivation of prostacyclin synthase by peroxynitrite. Biol Chem 1997; 378: 70713. MacMillan-Crow LA, Crow JP, Kerby JD, Beckman JS, Thompson JA. Nitration and inactivation of manganese superoxide dismutase in chronic rejection of human renal allografts. Proc Natl Acad Sci U S A 1996; 93: 1185358. Sydow K, Bo ger RH. Homocyst(e)ine, endothelial dysfunction and cardivascular risk. Pathomechanisms and therapeutical options. Z Kardiol 2001; 90: 111. McDowell IF, Lang D. Homocysteine and endothelial dysfunction: a link with cardiovascular disease. J Nutr 2000; 130: 369S72S. Khan MA, Thompson CS, Emsley AM et al. The interaction of homocysteine and copper markedly inhibits the relaxation of rabbit corpus cavernosum: new risk factors for angiopathic erectile dysfunction? BJU Int 1999; 84: 72024. Khan MA, Thompson CS, Mumtaz FH et al. The effect of nitric oxide and peroxynitrite on rabbit cavernosal smooth muscle relaxation. World J Urol 2001; 19: 22024. Cai A, Harrison DG. Endothelial dysfunction in cardiovascular disease. The role of oxidant stress. Circ Res 2000; 87: 84044. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase. Role in cardiovascular biology and disease. Circ Res 2000; 86: 494501. Mates JM, Sanchez-Jimenez F. Antioxidant enzymes and their implications in pathophysiologic processes. Front Biosci 1999; 4: D33945. Stralin P, Karlsson K, Johansson BO, Marklund SL. The interstitium of the human arterial wall contains very large amounts of extracellular superoxide dismutase. Arterioscler Thromb Vasc Biol 1995; 15: 203236. Oury TD, Day BJ, Crapo JD. Extracellular superoxide dismutase: a regulator of nitric oxide bioavailability. Lab Invest 1996; 75: 61736. Stralin P, Marklund SL. Vasoactive factors and growth factors alter vascular smooth muscle cell ECSOD expression. Am J Physiol Heart Circ Physiol 2001; 281: H162129. Fukai T, Siegfried MR, Ushio-Fukai M, Griendling KK, Harrison DG. Modulation of extracellular superoxide dismutase expression by angiotensin II and hypertension. Circ Res 1999; 85: 2328. Landmesser U, Merten R, Spiekermann S, Bu ttner K, Drexler H, Hornig B. Vascular extracellular superoxide dismutase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation. Circulation 2000; 101: 226470. Azadzoi KM, Saenz de Tejada I. Hypercholesterolemia impairs endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle. J Urol 1991; 146: 23840. Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989; 320: 102530. Azadzoi KM, Saenz de Tejada I. Diabetes mellitus impairs neurogenic and endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle. J Urol 1992; 148: 158791. Khan MA, Thompson CS, Jeremy JY, Mumtaz FH, Mikhailidis P, Morgan RJ. The effect of superoxide dismutase on nitric oxidemediated and electrical eld-stimulated diabetic rabbit cavernosal smooth muscle relaxation. BJU Int 2001; 87: 98103. Cartledge JJ, Eardley I, Morrison JF. Impairment of corpus cavernosal smooth muscle relaxation by glycosylated human haemoglobin. BJU Int 2000; 85: 73541. Trigo-Rocha F, Aronson WJ, Hohenfellner M, Ignarro LJ, Rajfer J, Lue TF. Nitric oxide and cGMP: mediators of pelvic nerve stimulated erection in dogs. Am J Physiol 1993; 264: H41922. Bush PA, Aronson WJ, Buga GM, Rajfer J, Ignarro LJ. Nitric oxide
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175 176
177
is a potent relaxant of human and rabbit corpus cavernosum. J Urol 1992; 147: 165065. Pickard RS, Powell PH, Zar MA. The effect of inhibitors of nitric oxide biosynthesis and cyclic GMP formation on nerve-evoked relaxation of human cavernosal smooth muscle. Br J Pharmacol 1991; 104: 75559. Holmquist F, Steif CG, Jonas U, Andersson KE. Effects of the nitric oxide synthase inhibitor NG-nitro-l-arginine on the erectile response to cavernous nerve stimulation in the rabbit. Acta Physiol Scand 1991; 143: 299304. Holmquist F, Hedlund H, Andersson KE. l-NG -nitroarginine inhibits non-adrenergic, non-cholinergic relaxation of human isolated corpus cavernosum. Acta Physiol Scand 1991; 141: 44142. Faraci FM, Brian JE, Heistad DD. Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase. Am J Physiol 1995; 269: H152227. Cooke JP, Dzau VJ. Derangements of the nitric oxide synthase pathway, l-arginine, and cardiovascular diseases. Circulation 1997; 96: 37982. Surdacki A, Nowicki M, Sandmann J et al. Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension. J Cardiovasc Pharmacol 1999; 33: 65358. Miyazaki H, Matsuoka H, Cooke JP et al. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation 1999; 99: 114166. Goonasekera CD, Rees DD, Woolard P, Frend A, Shah V, Dillon MJ. Nitric oxide synthase inhibitors and hypertension in children and adolescents. J Hypertens 1997; 15: 901909. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992; 339: 57275. MacAllister RJ, Rambausek MH, Vallance P, Williams D, Hoffmann KH, Ritz E. Concentration of dimethyl-l-arginine in the plasma of patients with end-stage renal failure. Nephrol Dial Transplant 1996; 11: 244952. Al Banchaabouchi M, Marescau B, Possemiers I, DHooge R, Levillain O, De Deyn DP. NG,NG-dimethylarginine and NG ,N9G -dimethylarginine in renal insuf ciency. P ugers Arch 2000; 439: 52431. Schmidt RJ, Domico J, Samsell LS et al. Indices of activity of the nitric oxide system in hemodialysis patients. Am J Kidney Dis 1999; 34: 22834. Bo ger RH, Bode-Bo ger-SM. Asymmetric dimethylarginine, derangements of the endothelial nitric oxide synthase pathway, and cardiovascular diseases. Semin Thromb Hemost 2000; 26: 53945. Zoccali C, Benedetto FA, Maas R et al. Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in endstage renal disease. J Am Soc Nephrol 2002; 13: 49096. Valkonen VP, Pavia H, Salonen JT et al. Risk of acute coronary events and serum concentrations of asymmetrical dimethylarginine. Lancet 2001; 358: 212728. Abbasi F, Asagmi T, Cooke JP et al. Plasma concentrations of asymmetric dimethylarginine are increased in patients with type 2 diabetes mellitus. Am J Cardiol 2001; 88: 1201203. Zoccali C, Bode-Bo ger S, Mallamaci F et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with endstage renal disease: a prospective study. Lancet 2001; 358: 211317. Bortolotti A, Fedele D, Chatenoud L et al. Cigarette smoking: a risk factor for erectile dysfunction in diabetics. Eur Urol 2001; 40: 39296. Feldman HA, Johannes CB, Derby CA et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study. Prev Med 2000; 30: 32838. McVary KT, Carrier S, Wessells H. Smoking and erectile dysfunction: evidence based analysis. J Urol 2001; 166: 162432. Leiper J, Vallance P. Biological signi cance of endogenous methylarginines that inhibit nitric oxide synthases. Cardiovasc Res 1999; 43: 54248. Bo ger RH, Sydow K, Borlak J et al. LDL cholesterol upregulates
224 R Maas et al
178
179
180
181
182
183 184
185 186
187
188
189
190
191 192 193 194
195
196 197
198
synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res 2000; 87: 99105. Fard A, Tuck CH, Donis JA et al. Acute elevations of plasma asymmetric dimethylarginine and impaired endothelial function in response to a high-fat meal in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol 2000; 20: 203944. Stru hlinger MC, Tsao PS, Jeng-Horng H, Kimoto M, Balint RF, Cooke JP. Homocysteine impairs the nitric oxide synthase pathway. Role of asymmetric dimethylarginine. Circulation 2001; 104: 256975. Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 1999; 99: 309295. Gardiner SM, Kemp PA, Bennett T, Palmer RMJ, Moncada S. Regional and cardiac haemodynamic effects of NG ,NG dimethyl-larginine and their reversibility by vasodilators in conscious rats. Br J Pharmacol 1993; 110: 145764. Calver A, Collier J, Leone A, Moncada S, Vallance P. Effect of local intra-arterial asymmetric dimethylarginine (ADMA) on the forearm arteriolar bed of healthy volunteers. J Hum Hypertens 1993; 7: 19394. Segarra G, Medina P, Ballester RM et al. Effects of some guanidino compounds on human cerebral arteries. Stroke 1999; 30: 220611. Tsikas D, Bo ger RH, Sandman J, Bode-Bo ger S, Fro lich J. Endogenous nitric oxide synthase inhibitors are responsible for the l-arginine paradox. FEBS Lett 2000; 478: 13. Bo ger RH, Bode-Bo ger SM. The clinical pharmacology of l-arginine. Annu Rev Pharmacol Toxicol 2001; 41: 7999. Clarkson P, Adams MR, Powe AJ et al. Oral l-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest 1996; 97: 198994. Azadzoi KM, Goldstein I, Siroky MB, Traish AM, Krane RJ, Saenz de Tejada I. Mechanisms of ischemia-induced cavernosal smooth muscle relaxation impairment in a rabbit model of vasculogenic erectile dysfunction. J Urol 1998; 160: 221622. Chen J, Wollman Y, Chernichovsky T, Laina A, Sofer M, Matzkin H. Effect of oral administration of high dose nitric oxide donor larginine in men with organic erectile dysfunction: results of a double blind, randomized, placebo controlled study. BJU Int 1999; 83: 26773. Klotz T, Mahers MJ, Braun M, Bloch W, Engelmann U. Effectiveness of oral l-arginine in rst-line treatment of erectile dysfunction in a controlled crossover study. Urol Int 1999; 63: 22023. Azuma H, Sato J, Hamasaki H, Sugimoto A, Isotani E, Obayashi S. Accumulation of endogenous inhibitors for nitric oxide synthesis and decreased content of l-arginine in regenerated endothelial cells. Br J Pharmacol 1995; 115: 10011004. Edelman ER. On causes: Hippocrates, Aristotle, Robert Koch, and the Dread Pirate Roberts. Circulation 2001; 104: 250912. Smith WL, Marnett LJ. Prostaglandin endoperoxide synthase: structure and catalysis. Biochim Biophys Acta 1991; 1083: 117. Urade Y, Watanabe K, Hayaishi O. Prostaglandin D, E, and F synthases. J Lipid Mediat Cell Signal 1995; 12: 25773. Wang LH, Hajibeigi A, Xu XM, Loose-Mitchell D, Wu KK. Characterization of the promoter of human prostaglandin H synthase-1 gene. Biochem Biophys Res Commun 1993; 190: 40611. Hirai K, Ezumi Y, Nishida E, Uchiyama T, Takayama H. Comparative study of vanadate- and phorbol ester-induced cyclooxygenase-2 expression in human endothelial cells. Thromb Haemost 1999; 82: 154552. Davidge ST. Prostaglandin H synthase and vascular function. Circ Res 2001; 89: 65060. Smith WL. Prostaglandin biosynthesis and its compartmentation in vascular smooth muscle and endothelial cells. Annu Rev Physiol 1986; 48: 25162. Toratani A, Sawada S, Kono Y et al. Interleukin-1a stimulated prostacyclin release by increasing gene transcription of prostaglandin H
199
200
201
202
203
204
205 206
207
208
209
210
211
212
213
214
215 216
217
218
219
synthase and phospholipase A2 in human vascular endothelial cells. J Cardiovasc Pharmacol 1999; 33: 84351. Wort SJ, Evans TW. The role of the endothelium in modulating vascular control in sepsis and related conditions. Br Med Bull 1999; 55: 3048. Houliston RA, Wheeler-Jones CP. sPLA2 cooperates with cPLA2a to regulate prostacyclin synthesis in human endothelial cells. Biochem Biophys Res Commun 2001; 287: 88187. Caughey GE, Cleland LG, Penglis PS, Gamble JR, James MJ. Roles of cyclooxygenase (COX)-1 and COX-2 in prostanoid production by human endothelial cells: selective upregulation of prostacyclin synthesis by COX-2. J Immunol 2001; 167: 283138. Khan MA, Thompson CS, Sullivan ME, Jeremy JY, Mikhailidis DP, Morgan RJ. The role of prostaglandins in the aetiology and treatment of erectile dysfunction. Prostaglandins Leukot Essent Fatty Acids 1999; 60: 16974. Jeremy JY, Morgan RJ, Mikhailidis DP, Dandona P. Prostacyclin synthesis by the corpora cavernosa of the human penis: evidence for muscarinic control and pathological implications. Prostaglandins Leukot Med 1986; 23: 21116. Hedlund H, Andersson KE. Contraction and relaxation induced by some prostanoids in isolated human penile erectile tissue and cavernous artery. J Urol 1985; 134: 124550. Moncada S. Prostacyclin and artery wall biology. Atherosclerosis 1982; 2: 193207. Bosch RJ, Benard F, Aboseif SR. Changes in penile hemodynamics after intra cavernous injection of PGE1 and prostacyclin I2 in pigtailed monkeys. Int J Impotence Res 1989; 1: 21121. Traish AM, Moreland RB, Gallant C, Huang YH, Goldstein I. Gprotein-coupled receptor agonists augment adenylyl cyclase activity induced by forskolin in human corpus cavernosum smooth muscle cells. Recept Signal Transduct 1997; 7: 12132. Aboseif S, Riemer RK, Stackl W, Lue T, Tanagho E. Quanti cation of prostaglandin E1 receptors in cavernous tissue of men, monkeys and dogs. Urol Int 1993; 50: 14852. Jeremy JY, Mikhailidis DP, Thompson CS, Dandona P. Experimental diabetes mellitus inhibits prostacyclin synthesis by the rat penis: pathological implications. Diabetologica 1985; 28: 36568. Sullivan ME, Mikhailidis DP, Thompson CS, Morgan RJ, Angelini GD, Jeremy JY. Differential alterations of prostacyclin, cyclic AMP and cyclic GMP formation in the corpus cavernosum of the diabetic rabbit. Br J Urol 1998; 82: 57884. Minhas S, Cartledge JJ, Eardley I, Joyce AD, Morrison JF. The interaction of nitric oxide and prostaglandins in the control of corporal smooth muscle tone: evidence for production of a cylooxygenasederived endothelium-contracting factor. BJU Int 2001; 87: 88288. Teixeira CE, Moreno RA, Ferreira U et al. Pharmacological characterization of kinin-induced relaxation of human corpus cavernosum. Br J Urol 1998; 81: 43236. Kifor I, Williams GH, Vickers MA, Sullivan MP, Jodbert P, Dluhy RG. Tissue angiotensin II as a modulator of erectile function. I. Angiotensin peptide content, secretion and effects in the corpus cavernosum. J Urol 1997; 157: 192025. Park JK, Kim SZ, Kim SH, Park YK, Cho KW. Renin angiotensin system in rabbit corpus cavernosum: functional characterization of angiotensin II receptors. J Urol 1997; 158: 65358. Drexler H, Hornig B. Endothelial dysfunction in human disease. J Mol Cell Cardiol 1999; 31: 5160. Timmermans PB, Smith RD. Angiotensin II receptor subtypes: selective antagonists and functional correlates. Eur Heart J 1994; 15: 7987. ckert S, Stief CG et al. Plasma levels of angiotensin II Becker AJ, U during different penile conditions in the cavernous and systemic blood of healthy men and patients with erectile dysfunction. Urology 2001; 58: 80510. Davenport AP. International union of pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacol Rev 2002; 54: 21926. Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged
220
221
222
223
224
225
sword in health and disease. Annu Rev Pharmacol Toxicol 2001; 41: 85176. Fahimi-Vahid M, Gosau N, Michalek C et al. Distinct signaling pathways mediated cardiomyocyte phospholipase D stimulation by endothelin-1 and thrombin. J Mol Cell Cardiol 2002; 34: 44153. Sirous ZN, Fleming JB, Khalil RA. Endothelin-1 enhances eicosanoids-induced coronary smooth muscle contraction by activating speci c protein kinase C isoforms. Hypertension 2001; 37: 497504. Nakayama K, Ishigai Y, Uchida H, Tanaka Y. Potentiation by endothelin-1 of 5-hydroxytryptamine-induced contraction in coronary artery of the pig. Br J Pharmacol 1991; 104: 97886. Okatani Y, Taniguchi K, Sagara Y. Amplifying effect of endothelin1 on serotonin-induced vasoconstriction of human umbilical artery. Am J Obstet Gynecol 1995; 172: 124045. Cain AE, Tanner DM, Khalil RA. Endothelin-1-inducedenhancement of coronary smooth muscle contraction via MAPK-dependent and MAPK-independent[Ca2+ ]i sensitization pathways. Hypertension 2002; 39: 54349. Ari G, Vardi Y, Hoffman A, Finberg JP. Possible role for endothelins in penile erection. Eur J Pharmacol 1996; 307: 6974.
226 Kim NN, Dhir V, Azadzoi KM, Traish AM, Flaherty E, Goldstein I. Pilot study of the endothelin-A receptor selective antagonist BMS193884 for the treatment of erectile dysfunction. J Androl 2002; 23: 7683. ckert S, Stief CG et al. Systemic and cavernous plasma 227 Becker AJ, U levels of endothelin in healthy males during different functional conditions of the penis. World J Urol 2000; 19: 5766. ckert S, Stief CG, Truss MC, Hartmann U, Jonas U. 228 Becker AJ, U Systemic and cavernous plasma levels of endothelin (1-21) during different penile conditions in healthy males and patients with erectile dysfunction. World J Urol 2001; 19: 26771. 229 Chilian WM, Koshida R. EDHF and NO: different pathways for production-similar actions. Circ Res 2001; 89: 64849. 230 Brandes RP, Schmitz-Winnenthal FH, Feletou M et al. An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice. Proc Natl Acad Sci U S A 2000; 97: 974752.

Patofisiologi Erectile Disfunc

Uploaded by

Copyright:

Available Formats

You might also like

Patofisiologi Erectile Disfunc

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Patofisiologi Erectile Disfunc

Uploaded by

Copyright:

Available Formats

Vascular Medicine

Society for Vascular Medicine

>> Version of Record - Aug 1, 2002 What is This?

Downloaded from vmj.sagepub.com by guest on March 8, 2012

Vascular Medicine 2002; 7: 213225

NO-mediated pathways and mechanisms of impaired NO synthesis

Downloaded from vmj.sagepub.com by guest on March 8, 2012

Vascular Medicine 2002; 7: 213225

Downloaded from vmj.sagepub.com by guest on March 8, 2012

Erectile dysfunction in relation to endothelial dysfunction and vascular function 215

Availability of the substrate l-arginine

NOS expression and a link to the eicosanoid pathway

Downloaded from vmj.sagepub.com by guest on March 8, 2012

Table 1 Factors regulating expression of endothelial nitric oxide synthase (eNOS).

Oxidative stress and impaired NO availability

Downloaded from vmj.sagepub.com by guest on March 8, 2012

Erectile dysfunction in relation to endothelial dysfunction and vascular function 217

Downloaded from vmj.sagepub.com by guest on March 8, 2012

Condition associated with endothelial dysfunction

Plasma ADMA concentration " 5 elevation versus control

Incidence of erectile dysfunction " 5 elevated risk versus control

NO-independent mechanisms involved in endothelial and erectile dysfunction

Downloaded from vmj.sagepub.com by guest on March 8, 2012

Erectile dysfunction in relation to endothelial dysfunction and vascular function 219

Downloaded from vmj.sagepub.com by guest on March 8, 2012

Vascular Medicine 2002; 7: 213225

Downloaded from vmj.sagepub.com by guest on March 8, 2012

Erectile dysfunction in relation to endothelial dysfunction and vascular function 221

Vascular Medicine 2002; 7: 213225

Downloaded from vmj.sagepub.com by guest on March 8, 2012

119 120 121 122 123 124

Vascular Medicine 2002; 7: 213225

Downloaded from vmj.sagepub.com by guest on March 8, 2012

Erectile dysfunction in relation to endothelial dysfunction and vascular function 223

141 142 143

Vascular Medicine 2002; 7: 213225

Downloaded from vmj.sagepub.com by guest on March 8, 2012

191 192 193 194

Vascular Medicine 2002; 7: 213225

Downloaded from vmj.sagepub.com by guest on March 8, 2012

Erectile dysfunction in relation to endothelial dysfunction and vascular function 225

Vascular Medicine 2002; 7: 213225

Downloaded from vmj.sagepub.com by guest on March 8, 2012

You might also like