Linking erectile dysfunction and coronary artery disease


Coronary artery disease (CAD) and erectile dysfunction (ED) are both highly prevalent conditions that frequently coexist. Additionally, they share mutual vascular risk factors, suggesting that they are both manifestations of systemic vascular disease. The role of endothelial dysfunction in CAD is well established. Normal erectile function is primarily a vascular event that relies heavily on endothelially derived, nitric oxide-induced vasodilation. Accordingly, endothelial dysfunction appears to be a common pathological etiology and mechanism of disease progression between CAD and ED. The risk factors of diabetes mellitus, hypertension, hyperlipidemia, obesity and tobacco abuse contribute to endothelial dysfunction. This article reviews the role of vascular endothelium in health, the abnormalities resulting from vascular risk factors, and clinical trials evaluating the role of endothelial dysfunction in ED.


Coronary artery disease (CAD) and erectile dysfunction (ED) are both highly prevalent conditions that frequently occur concomitantly.1, 2, 3, 4, 5, 6 They share mutual risk factors, including diabetes mellitus (DM), hypertension, hyperlipidemia, obesity and tobacco abuse.1, 2, 3, 4 As the number of cardiovascular risk factors increase, so does the incidence of both CAD and ED.3, 4 These similarities have led to a renewed interest in further defining the similarities between these diseases.

Atherosclerosis is a systemic disease, and it is reasonable to expect penile atherosclerosis and resultant ED to occur in patients with CAD. In a review of seven major studies including 700 cardiac patients, Montorsi et al1 found the rate of ED in patients with CAD to be as high as 42–57%. Likewise, Gazzaruso et al2 found the incidence of ED in diabetic patients with silent ischemia to be 33.8%, compared to 4.7% in those without silent ischemia. Other studies have correlated erectile function score with coronary plaque burden and number of diseased coronary arteries.7, 8

Conversely, ED may also be a harbinger of other vascular disease. Montorsi et al's1 review reported that in patients with ED, the incidence of positive exercise stress testing ranged from 5 to 56%. Another study reported that in patients found to have CAD at angiography and clinical ED, 67% reported experiencing symptoms of ED prior to coronary symptoms. Impressively, 100% of type I diabetic patients experienced sexual dysfunction prior to the onset of CAD. In all patients, sexual symptoms occurred a mean of 38.8 months prior to their cardiac symptoms.9 In a study of patients with vasculogenic ED, Shamloul et al10 found that a penile peak systolic velocity <35 cm/s had a specificity of 100% for predicting ischemic heart disease. Men with ED have also been found to be at higher risk of myocardial infarction and peripheral vascular disease.11, 12 These discoveries have created advocates for considering ED as a penile angina.

As CAD and ED overlap in prevalence and risk factors, they are also thought to share pathological basis of etiology and progression.13 The role of endothelial dysfunction is well established in coronary artery disease and its risk factors.14, 15 Normal erectile function is primarily a vascular event that relies heavily on vasodilation, which occurs largely due to endothelially derived nitric oxide (NO).16, 17, 18 Systemic endothelial-dependent vasodilation is decreased in men with ED.19, 20 Accordingly, endothelial dysfunction has been implicated as a common mechanism between CAD and ED. This review will highlight the mechanisms and consequences of endothelial impairment seen in the disease processes associated with CAD and ED.

Normal endothelial function

The luminal surface of blood vessels is lined with a single layer of cells known as the endothelium. It is a semipermeable membrane that interacts with the circulating blood components. The endothelium has a variety of synthetic and metabolic capabilities that enable it to regulate the coagulation cascade, the functions of circulating cells, as well as local vasodilatory and constrictive responses. Through these multiple functions, the endothelium (in its healthy state) is primarily responsible for enabling the arterial system to deliver sufficient tissue perfusion.21 Endothelial disease impairs the regulation of these important events, and thereby jeopardizes the adequacy of tissue oxygen delivery.

Regulation of the coagulation cascade

Endothelial cells have dichotomous functions in regulating the coagulation cascade. In a normal physiologic state, healthy endothelium serves as an anticoagulant membrane, exerting predominantly fibrinolytic, anticoagulant and antiaggragatory effects. These effects occur with the expression of anti-thrombin III (inhibiting fibrinogen to fibrin conversion), heparin-like molecules (which enhance anti-thrombin III activity), and tissue factor pathway inhibitor (which inactivates the extrinsic pathway). They also secrete tissue-type plasminogen activator (tPA). Additionally, endothelial cells bind thrombin, leading to protein C activation and eventually inactivation of plasminogen activator inhibitor 1.21 In a hemostatic response, they produce key components of platelet activation and aggregation, including von Willebrand factor (vWf), fibronectin and thrombospondin, ultimately leading to the initiation of the coagulation cascade.22 These dynamic thrombotic functions are important, as thrombus formation is a key element in atherosclerosis progression.

Regulation of inflammatory cells

The endothelium regulates transmigration of circulating cells through a complex interplay of trans-signaling molecules. Endothelial cells recruit inflammatory cells via expression of cell adhesion molecules such as selectin and immunoglobulin superfamily adhesion molecules, and by responding to proadhesion signals from circulating cytokines.23 Platelets also have a range of endothelial signaling abilities, including the release of vasodilating agents (such as ADP and serotonin), as well as vasoconstricting and procoagulant factors (such as endothelin-1 and vWf). The effects of these circulating cell signals can further be attenuated by some endothelially derived substances such as NO and prostacyclin.21

Regulation of vasodilation/vasoconstriction

The endothelium produces and reacts to several vasodilator and vasoconstrictor mediators. Vascular flow regulation results from local coordination of these influences to maintain steady and adequate tissue perfusion.24 One of the key contributors to vascular tone is NO, which is produced by endothelial nitric oxide synthase (eNOS).25 As a freely diffusible gas, NO acts not only within the lumen but also on the surrounding smooth muscle cells where it increases cyclic guanosine monophosphate (cGMP)-mediated vasodilation.21 Endothelial cells also produce a number of prostaglandins, most notably prostacyclin (PGI2) and thromboxane A2 (TXA2). PGI2 initiates cyclic adenosine monophosphate (cAMP)-mediated smooth muscle relaxation, while TXA2 causes vasoconstriction. In normal physiologic conditions, PGI2 exerts the predominate vascular effects.26 Another endothelially released factor with variable vascular influences is angiotensin II. This peptide has vasoconstricting, prothrombotic, oxidant and atherogenic effects, as well as the ability to counteract these effects depending on the receptor (subtype AT1 or AT2) activated. The endothelium also stimulates the production of bradykinin, which further results in the release of the vasodilating agents NO and endothelium-derived hyperpolarizing factor (EDHF). In contrast, the endothelium also produces the vasoconstricting hormones known as the endothelins.21

As the exact roles of each of these agents in health and disease are delineated, it is clear that the endothelium has a diverse role in maintaining vascular tone as well as arterial flow through a variety of mechanisms. Furthermore, a disruption in these regulatory functions at any level could lead to impaired and insufficient tissue perfusion.

Endothelial dysfunction

Endothelial dysfunction has gained increasing notoriety as a key player in the pathogenesis of atherosclerosis.27 As atherosclerosis is the commonest cause of vasculogenic erectile dysfunction in older men, it is frequently considered another manifestation of vascular disease.1, 28 The mutual risk factors shared by ED and CAD each contribute to endothelial dysfunction. Just as the presence of these risk factors overlaps within patient populations, so do their effects on the endothelium. The mechanisms and manifestations of endothelial dysfunction are outlined here.

Diabetes mellitus

Diabetic men with impotence have dysfunctional neurogenic and endothelium-dependent penile smooth muscle relaxation.29 On a cellular level, there may be impairment of the L-arginine NO pathway at a number of sites. While the precise mechanisms have not been clearly defined, endothelial damage may either decrease basal release of NO, or may lead to increased breakdown. Furthermore, eNOS activity may be attenuated by accumulation of NOS inhibitors.15 Proposed mechanisms of altered NO bioactivity include lack of cofactors essential for NOS activity,30, 31 overproduction of NOS inhibitors such as asymmetric and symmetric dimethylarginine (ADMA and SDMA),32 and altered NO formation due to adverse effects of advanced end-product glycosylation.33, 34 In addition to endothelial alterations, vascular smooth muscle cells appear to have a blunted response to NO.15, 35 Additionally, increased plasma and corporal body endothelin levels have been seen in diabetic men with ED.36, 37 This appears to be important in the pathogenesis of ED, as ET-1 is a key factor in maintaining corpus cavernosal smooth muscle tone.38, 39

While not completely defined, manifestations of endothelial dysfunction may differ between type I and II DM.15

Type I

Studies on endothelial dysfunction in type I DM have been conflicting, and may be related to degree of glycemic control and disease duration. Several (but not all) studies have demonstrated forearm endothelial dysfunction, as well as impaired endothelial-dependent microvascular responses. Most studies reveal preserved responses to endothelium-independent agonists, suggesting decreased NO bioactivity.15 Endothelial function may also be related to microalbuminuria, which appears to influence endothelium-dependent and -independent vasodilation.40, 41

Type II

Patients with type II DM have impaired vasodilation in response to both endothelium-dependent and -independent agonists.20 These patients also have increased generation of reactive oxygen species (ROS),42 which damage endothelial cells either directly, or indirectly via effects on lipid peroxidation and by scavenging NO to produce peroxynitrite, a potent oxidant.15 Patients with type II DM also tend to have smaller LDL particles that are more susceptible to oxidation; oxidized LDL, in turn, damages the endothelium, and has been shown in animals to inhibit endothelium-dependent vasodilation to a greater degree than native LDL.43

It should be noted that DM can adversely affect erectile function through a number of other mechanisms. Significant neurologic alterations also appear to play an important role. Peripheral and autonomic neuropathy decreased release of acetylchoine by cholinergic nerves, and sparse penile noradrenergic nervous innervation are a few of the proposed neurologic derangements contributing to ED.44, 45, 46, 47


The hallmarks of primary hypertension are increased peripheral sympathetic activity, increased vasoconstrictor tone and decreased endothelium-dependent vasodilation.48, 49, 50 Some cases of hypertension-associated endothelial dysfunction may be related to eNOS gene variations.51, 52 Changes in the cyclooxygenase pathway also appear to play a major role, as increased COX activity can lead to increased ROS, with further disruption of ‘normal’ endothelial activity.50, 53, 54 Decreased NOS levels in essential hypertension have been reported, as well as muted vasoconstrictor response to L-NMMA, although this is not a universal finding.55 It should be emphasized that dysfunctional endothelium-dependent vasodilation is not merely a cause of hypertension; it exists in several disease states (as outlined here), and degree of endothelial dysfunction does not correlate with blood pressure values.15

Hypertension plays an etiologic role in ED beyond its correlation with endothelial dysfunction. Structural alterations with vascular and corporal remodeling occur that reduce vasodilatory capacity.56 Animal studies have also revealed vascular smooth muscle proliferation and fibrosis.57 Clearly, endothelial dysfunction is one of many vascular disturbances that occur in hypertension and appears to contribute to ED.


Hypercholesterolemia has a well-established link to endothelial dysfunction, with oxidized low-density lipoprotein being a key mediator. In familial hypercholesterolemia, endothelial dysfunction is seen prior to clinical arterial disease.15 Even in the setting of angiographically normal coronary arteries, reduced endothelium-derived NO bioavailability has been seen in the setting of hypercholesterolemia.58 Endothelial dysfunction is not only related to LDL concentration but also to LDL size, with smaller particles being associated with such dysfunction. In general, however, there does not appear to be an alteration in endothelial NO, tPA or ET-1 levels.15 There are emerging data suggesting that high-density lipoprotein may independently and favorably effect endothelial function.59, 60, 61 The effects of hypertriglyceridemia, however, are less clear.


Disturbed endothelial function has been seen in both resistance and conductance arteries of the obese patient, independent of other vascular comorbidities.15 One mechanism may be the apparent relationship between obesity and a chronic inflammatory state. Elevated levels of the circulating intercellular adhesion molecules-1 (ICAM-1), vascular adhesion molecule (VCAM-1), E and P selectins, tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6) have been reported in obese men and women.62, 63 These cytokines have been demonstrated to influence endothelial function,64 and are key contributors in the early atherogenic process.65 Additionally, this inflammatory process can be a source of oxidative stress, leading to free radical formation and thereby secondarily decreasing NO bioavailability. It has been suggested that COX and ROS may be contributors to endothelial dysfunction in obesity.66 Finally, obese patients appear to have greater basal ET-1 vascular tone that contributes to impaired endothelium-dependent vasodilation.67


Tobacco smoke has direct toxicities to endothelial cells, causing architectural and functional changes. These include decreased eNOS activity, increased adhesion expression and impaired regulation of important thrombotic factors. These adverse effects are related in part to ROS endothelial damage, and seem to be dose-related.15

Implications of endothelial dysfunction in CAD

Endothelial dysfunction plays a key role in the progression of atherosclerosis, contributing to exaggerated intimal proliferation and malregulation of the inflammatory processes that can lead to arterial plaque destabilization. When coupled with paradoxical vasoconstriction and improper ‘policing’ of vascular thrombosis, this can lead to catastrophic events such as seen with acute coronary syndromes and myocardial infarctions.14 Impaired endothelium-dependent vasomotion has been correlated with increased myocardial ischemia and events,68, 69 independent of traditional associated cardiac risk factors.70

Impaired endothelium-independent vasodilation in ED

Men with ED also appear to have impaired endothelial-dependent and -independent vasodilation beyond that accounted for by vascular risk factors. Yavuzgil et al compared brachial artery flow-mediated dilation (FMD) and nitroglycerine-mediated dilation (NMD) in three sets of patients: those with presumed vasculogenic ED and cardiac risk factors, those with similar risk factors but no ED, and a control population without cardiac risk factors or ED. They found that brachial artery FMD and NMD were significantly reduced in patients with ED compared to healthy controls. Patients without ED but who had similar risk factors had decreased FMD, but not NMD compared with healthy controls. This suggests impairment in endothelial-independent vasodilation.19 This study confirmed earlier findings by Kaiser et al, who also compared patients with ED and no known CAD to a healthy control group. They too discovered patients with ED to have impaired FMD and NMD compared with controls.20 It remains to be seen whether this discrepancy in endothelial-independent vasodilation may confer additional cardiovascular risk beyond that of the traditional cardiac risk factors.

Hormone therapy

Little is known about the effects of hormone therapy in patients with CAD and ED. The beneficial effects of the hormone replacement therapy in non-elderly hormone-deficient individuals raised the hope that hormone substitutes might reverse symptoms of ED as well.

The three male endocrine axes are characterized by age-related changes in the concentrations of circulatory hormones:71

  1. 1)

    Hypothalamic–pituitary–testicular axis with lower serum level of testosterone.

  2. 2)

    Hypothalamic–adrenal axis with gradual decline in dehydroepiandrosterone (DHEA).

  3. 3)

    The growth hormone (GH) insulin-like growth factor (IGF).

The debate on the role of testosterone is still ongoing. Testosterone replacement definitely should be used in men who have deficiency in their male hormone levels, occasionally in men with borderline low levels of testosterone and never used in men who have normal or elevated levels of androgens.72

Human GH has become an important topic in the field of anti-aging medicine.

GH may play an important role in maintenance of penile erection function perhaps by promotion of the NO-cGMP pathway, stimulating the regeneration of the NO containing nerve fibers and the augmentation of the androgenic action.73

Lis et al74 found in an animal study that GH can improve erectile function of internal iliac ligation rats, which can be explained by the increase in the number of neuronal NOS-containing nerve fibers in corpus carvosum of rats.

However, due to the insulin antagonistic effect of GH as well as its IGF-I-mediated mitogenic effect, there is a question about its safety.75

Gene therapy

Gene and growth factor and stem cell therapy might provide future options in the management of patients with CAD and ED.

Nitric oxide (NOS) is synthesized by eNOS and neuronal NOS (nNOS) in the penis. Recently, the role of gene therapy has been studied in different animal models.76 In a study by Bivalacques et al, the effects of combination eNOS synthase gene therapy and sildenafil on erectile function in diabetic rats were studied. The study showed that the cavernosal cGMP levels were significantly decreased in diabetic rats but increased after transfection with AD CMV eNOS compared with controls. Overexpression of eNOS and cGMP in combination with sildenafil significantly increased both peak intracavernosal pressure (ICP) and total ICP to CNS of diabetic rats, similar to controls. The overall erectile response was greater in diabetic rats receiving eNOS gene therapy and sildenafil than rats receiving sildenafil or eNOS gene alone.77, 78, 79

Another in vivo study used adenovirally mediated transfer of eNOS gene with or without cGMP PDE, showing promising results as a future treatment for ED.80

Myoblast-mediated gene therapy was tested in vivo and was more superior in delivering inducible NOS into the corpus cavernosum than direct adenovirus or a plasmid transfection method.81 Future therapy may also involve augmentation of K+ channel expression by gene transfer or increasing channel function by using PDE-5.82 Currently, however, direct vaso-active therapy by use of PDE-5 inhibition seems to be the most realistic option for the treatment of ED, in particular also in patients with endothelial dysfunction and stable CAD.


CAD and ED are common diseases that frequently coexist. In addition to sharing common risk factors, they appear to share a common pathological basis: endothelial dysfunction. Altered inflammatory and vasodilator endothelial regulation appears to carry clinical implications independent of the associated vascular risk factors. Symptoms of ED may precede clinical cardiac manifestations, and should prompt a cardiac risk assessment. Understanding the etiology and role of endothelial dysfunction at a cellular level may provide insight into common screening and treatment modalities.


  1. 1

    Montorsi P et al. Common grounds for erectile dysfunction and coronary artery disease. Curr Opinion Urol 2004; 14: 361–365.

    Google Scholar 

  2. 2

    Gazzaruso C et al. Relationship between erectile dysfunction and silent myocardial ischemia in apparently uncomplicated type 2 diabetic patients. Circulation 2004; 110: 22–26.

    PubMed  PubMed Central  Google Scholar 

  3. 3

    Virag R, Bouilly P, Frydman D . Is impotence an arterial disorder? A study of arterial risk factors in 440 impotent men. Lancet 1985; 1: 181–184.

    CAS  Google Scholar 

  4. 4

    Fung MM, Bettencourt R, Barrett-Connor E . Heart disease risk factors predict erectile dysfunction 25 years later: The Rancho Bernardo Study. J Am Coll Cardiol 2004; 43: 1405–1411.

    Article  PubMed Central  Google Scholar 

  5. 5

    Roose SP . Depression: links with ischemic heart disease and erectile dysfunction. J Clin Psychiatry. 2003; 64: 26–30.

    PubMed  Google Scholar 

  6. 6

    Tan RS, Pu SJ . The interlinked depression, erectile dysfunction and coronary heart disease syndrome in older men: a triad often underdiagnosed. J Gend Specif Med 2003; 6: 31–36.

    PubMed  Google Scholar 

  7. 7

    Solomon H, Man JW, Wierzbicki AS, Jackson G . Relation of erectile dysfunction to angiographic artery disease. Am J Cardiol 2003; 91: 230–231.

    PubMed  PubMed Central  Google Scholar 

  8. 8

    Greenstein A et al. Does severity of ischemic coronary disease correlate with erectile function? Int J Impot Res 1997; 9: 123–126.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Montorsi F et al. Erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. Eur Urol 2003; 44: 360–364.

    PubMed  PubMed Central  Google Scholar 

  10. 10

    Shamloul R et al. Correlation between penile duplex findings and stress electrocardiography in men with erectile dysfunction. Int J Impot Res 2004; 16: 235–237.

    CAS  PubMed  Google Scholar 

  11. 11

    Blumentals WA, Gomez-Caminero A, Joo S, Vannappagari V . Is erectile dysfunction predictive of peripheral vascular disease? Aging Male 2003; 6: 217–221.

    CAS  PubMed  Google Scholar 

  12. 12

    Blumentals WA, Gomez-Caminero A, Joo S, Vannappagari V . Should erectile dysfunction be considered as a marker for acute myocardial infarction? Results of a retrospective cohort study. Int J Impot Res 2004; 16: 350–353.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Kirby M, Jackson G, Simonsen U . Endothelial dysfunction links erectile dysfunction to heart disease. Int J Clin Pract 2005; 59: 225–229.

    CAS  PubMed  Google Scholar 

  14. 14

    Schachinger V, Zeiher AM . Prognostic implications of endothelial dysfunction: does it mean anything? Coronary Artery Dis 2001; 12: 435–443.

    CAS  Google Scholar 

  15. 15

    Brunner H et al. Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. J Hypertens 2005; 23: 233–246.

    CAS  PubMed  Google Scholar 

  16. 16

    Andersson K, Stief C . Penile erection and cardiac risk: pathophysiologic and pharmacologic mechanisms. Am J Caridol 2000; 86: 23f–26f.

    CAS  Google Scholar 

  17. 17

    Kloner RA, Zusman RM . Cardiovascular effects of sildenafil citrate and recommendations for its use. Am J Cardiol 1999; 84: 11n–17n.

    CAS  PubMed  Google Scholar 

  18. 18

    Jeremy JY et al. Effects of sildenafil, a type-5 cGMP phosphodiesterase inhibitor, and papaverine on cGMP and cAMP levels in the rabbit corpus cavernosum in vitro. Br J Urol 1997; 79: 958–963.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Yavuzgil O et al. Endothelial function in patients with vasculogenic erectile dysfunction. Int J Cardiol 2005; 103: 19–26.

    PubMed  Google Scholar 

  20. 20

    Kaiser DR et al. Impaired brachial artery endothelium-dependent and -independent vasodilation in men with erectile dysfunction and no other clinical cardiovascular disease. J Am Coll Cardiol 2004; 43: 179–184.

    PubMed  PubMed Central  Google Scholar 

  21. 21

    Kharbanda RK, Deanfield JE . Functions of the healthy endothelium. Coron Artery Dis 2001; 12: 485–491.

    CAS  PubMed  Google Scholar 

  22. 22

    Sagripanti A, Carpi A . Antithrombotic and prothrombotic activities of the vascular endothelium. Biomed Pharmacother 2000; 54: 107–111.

    CAS  PubMed  Google Scholar 

  23. 23

    Panes J, Perry M, Granger DN . Leukocyte-endothelial cell adhesion: avenues for therapeutic intervention. Br J Pharmacol 1999; 126: 537–550.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Mombouli J, Vanhoutte PM . Endothelial dysfunction: from physiology to therapy. J Mol Cell Cardiol 1999; 31: 61–74.

    CAS  PubMed  Google Scholar 

  25. 25

    Fleming I, Busse R . Control and consequences of endothelial nitric oxide formation. Adv Pharmacol 1995; 34: 187–206.

    CAS  PubMed  Google Scholar 

  26. 26

    Duffy SJ et al. Continuous release of vasodilator prostanoids contributes to regulation of resting forearm blood flow in humans. Am J Physiol 1998; 274: H1174–H1183.

    CAS  PubMed  Google Scholar 

  27. 27

    Ross R . The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801–809.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Russell S, Nehra A . The physiology of erectile dysfunction. Herz 2003; 28: 277–283.

    PubMed  Google Scholar 

  29. 29

    Saenz de Tejada I et al. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989; 320: 1025–1030.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Escrig A et al. Changes in mating behavior, erectile function, and nitric oxide levels in penile corpora cavernosa in streptozotocin-diabetic rats. Biol Reprod 2002; 66: 185–189.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Vallance P, Chan N . Endothelial function and nitric oxide: clinical relevance. Heart 2001; 85: 342–350.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Leiper JM et al. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deaminases. Biochem J 1999; 343: 209–214.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Seftel AD et al. Advanced glycation end products in human penis: elevation in diabetic tissue, site of deposition and possible effect through iNOS or eNOS. Urology 1997; 50: 1016–1026.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Cartledge JJ, Eardley I, Morrison JF . Advanced glycation end-products are responsible for the impairment of corpus cavernosal smooth muscle relaxation seen in diabetes. BJU Int 2001; 87: 402–407.

    CAS  PubMed  Google Scholar 

  35. 35

    Jevtich MJ, Edson M, Jarman WD, Herrera HH . Vascular factor in erectile failure among diabetics. Urology 1982; 19: 163–168.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Francavilla S et al. Endothelin-1 in diabetic and non-diabetic men with erectile dysfunction. J Urol 1997; 158: 1770–1774.

    CAS  PubMed  Google Scholar 

  37. 37

    Bell CR et al. The density and distribution of endothelin 1 and endothelin receptor subtypes in normal and diabetic rat corpus cavernosum. Br J Urol 1995; 76: 203–207.

    CAS  PubMed  Google Scholar 

  38. 38

    Becker AJ et al. Systemic and cavernosal plasma levels of endothelin (1–21) during different penile conditions in healthy males and patients with erectile dysfunction. World J Urol 2001; 19: 371–376.

    CAS  PubMed  Google Scholar 

  39. 39

    Takahashi K et al. Elevated plasma endothelin in patients with diabetes mellitus. Diabetalogia 1990; 33: 306–310.

    CAS  Google Scholar 

  40. 40

    Dogra G, Rich L, Stanton K, Watts GF . Endothelium-dependent and -independent vasodilation studies at normoglycaemia in type 1 diabetes mellitus with and without microalbuminuria. Diabetologia 2001; 44: 593–601.

    CAS  PubMed  Google Scholar 

  41. 41

    Elliott TG et al. Inhibition of nitric oxide synthesis in forearm vasculature of insulin-dependent diabetic patients: blunted vasoconstriction in patients with microalbuminuria. Clin Sci 1993; 85: 687–693.

    CAS  PubMed  Google Scholar 

  42. 42

    Chowienczyk PJ et al. Oral treatment with an antioxidant (raxofelast) reduces oxidative stress and improves endothelial function in men with type 2 diabetes. Diabetologia 2000; 43: 974–977.

    CAS  PubMed  Google Scholar 

  43. 43

    Jacobs M, Plane F, Bruckdorfer KR . Native and oxidized low-density-lipoproteins have different inhibitory effects on endothelium-derived relaxing factor in the rabbit aorta. Br J Pharmacol 1990; 100: 21–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Head RJ . Hypernoradrenergic innervation: its relationship to functional and hyperplastic changes in the vasculature of spontaneously hypertensive rat. Blood Vessels 1989; 26: 1–20.

    CAS  PubMed  Google Scholar 

  45. 45

    Bemelmans BL et al. Erectile dysfunction in diabetic men: the neurological factor revisited. J Urol 1994; 151: 884–889.

    CAS  PubMed  Google Scholar 

  46. 46

    Blanco R et al. Dysfunctional penile cholinergic nerves in diabetic impotent men. J Urol 1999; 144: 278–280.

    Google Scholar 

  47. 47

    Melman A, Bressler RS, Henry DP, Macadoo VK . Ultrastructure of human penile erectile tissues in patients with abnormal norepinephrine content. Invest Urol 1981; 19: 46–48.

    CAS  PubMed  Google Scholar 

  48. 48

    Panza JA, Quyyumi AA, Brush Jr JE, Epstein SE . Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990; 323: 22–27.

    CAS  PubMed  Google Scholar 

  49. 49

    Koga T et al. Age and hypertension promote endothelium-dependent contractions to acetylcholine in the aorta of the rat. Hypertension 1989; 14: 542–548.

    CAS  PubMed  Google Scholar 

  50. 50

    Kung CF, Luscher TF . Different mechanisms of endothelial dysfunction with aging and hypertension in the rabbit aorta. Hypertension 1995; 25: 194–200.

    CAS  PubMed  Google Scholar 

  51. 51

    Nakayama M et al. T-786-C mutation in the 5′flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 1999; 99: 2864–2870.

    CAS  PubMed  Google Scholar 

  52. 52

    Rossi GP et al. The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients. J Am Coll Cardiol 2003; 41: 938–945.

    CAS  PubMed  Google Scholar 

  53. 53

    Taddei S et al. Cyclooxygenase inhibition restores nitric oxide activity in essential hypertension. Hypertension 1997; 29: 274–279.

    CAS  PubMed  Google Scholar 

  54. 54

    Behr-Roussel D et al. Erectile dysfunction in spontaneously hypertensive rats: pathophysiological mechanisms. Am J Physiol Regul Integr Comp Physiol 2003; 284: R682–R688.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Calver A, Collier J, Moncada S, Vallance P . Effect of local intra-arterial NG-monomethyl-L-arginine in patients with hypertension: nitric oxide dilator mechanism appears abnormal. J Hypertens 1992; 10: 1025–1031.

    CAS  PubMed  Google Scholar 

  56. 56

    Folkow B . Structural factor' in primary and secondary hypertension. Hypertension 1990; 16: 89–101.

    CAS  PubMed  Google Scholar 

  57. 57

    Toblli JE et al. Morphological changes in cavernous tissue in spontaneously hypertensive rats. Am J Hypertens 2000; 13: 686–692.

    CAS  Google Scholar 

  58. 58

    Quyyumi AA et al. Coronary vascular nitric oxide activity in hypertension and hypercholesterolemia. Comparison of acetylcholine and substance P. Circulation 1997; 95: 104–110.

    CAS  PubMed  Google Scholar 

  59. 59

    Kuvin JT et al. A novel mechanism for the beneficial vascular effects of high-density lipoprotein cholesterol: enhanced vasorelaxation and increased endothelial nitric oxide synthase expression. Am Heart J 2002; 144: 165–172.

    CAS  PubMed  Google Scholar 

  60. 60

    Lupattelli G et al. Direct association between high-density lipoprotein cholesterol and endothelial function in hyperlipemia. Am J Cardiol 2002; 90: 648–650.

    CAS  PubMed  Google Scholar 

  61. 61

    Spieker LE et al. High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation 2002; 105: 1399–1402.

    CAS  Google Scholar 

  62. 62

    Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW . C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction. A potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vas Biol 1999; 19: 972–978.

    CAS  Google Scholar 

  63. 63

    Ziccardi P et al. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002; 105: 804–809.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Bhagat K, Vallance P . Inflammatory cytokines impair endothelium-dependent dilatation in human veins in vivo. Circulation 1997; 96: 3042–3047.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Giugliano D et al. L-arginine for testing endothelium-dependent vascular functions in health and disease. Am J Physiol 1997; 273: E606–E612.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Perticone F et al. Obesity and body fat distribution induce endothelial dysfunction by oxidative stress: protective effect of vitamin C. Diabetes 2001; 50: 159–165.

    CAS  PubMed  Google Scholar 

  67. 67

    Mather KJ et al. Endothelin contributes to basal vascular tone and endothelial dysfunction in human obesity and type 2 diabetes. Diabetes 2002; 51: 3517–3523.

    CAS  PubMed  Google Scholar 

  68. 68

    Suwaidi JA et al. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000; 101: 948–954.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Schachinger V, Zeiher AM . Quantitative assessment of coronary vasoreactivity in humans in vivo: importance of baseline vasomotor tone in atherosclerosis. Circulation 1995; 92: 2087–2094.

    CAS  PubMed  Google Scholar 

  70. 70

    Schachinger V, Britten MB, Zeiher AM . Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000; 101: 1899–1906.

    CAS  Google Scholar 

  71. 71

    Hermann M, Berger P . Hormonal changes in aging men: a therapeutic indication? Exp Gerontol 2001; 36: 1075–1082.

    CAS  PubMed  Google Scholar 

  72. 72

    Aversa A et al. Hormonal supplementation and erectile dysfunction. Euro Urol 2005; 47: 564.

    Google Scholar 

  73. 73

    Huang X, Li S, Hu L . Growth hormone deficiency and age-related erectile dysfunction. Zhonghus Nan Ke Xue 2004; 10: 867–869.

    CAS  Google Scholar 

  74. 74

    Li S, Hu L, Zhao J . Effect of growth hormone on erectile function and number of nNOS-containing verve fibers in internal iliac arterial ligation rats. Zhonghua Nan Ke Xue 2004; 10: 103–106.

    CAS  PubMed  Google Scholar 

  75. 75

    Becker AJ et al. Growth hormone, somatomedins and men's health. Aging Male 2002; 5: 258–262.

    CAS  PubMed  Google Scholar 

  76. 76

    Bivalacqua TJ et al. Gene therapy techniques for the delivery of endothelial nitric oxide synthase to the corpa cavernosa for erectile dysfunction. Methods Mol Biol 2004; 279: 173–185.

    CAS  PubMed  Google Scholar 

  77. 77

    Bivalacqua TJ et al. Effect of combination endothelial nitric oxide synthase gene therapy and sildenafil on erectile function in diabetic rats. Int J Impot Res 2004; 16: 21–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Bivalacqua TJ et al. Gene transfer of endothelial nitric oxide synthase partially restores nitric oxide synthesis and erectile function in streptozotocin diabetic rats. J Urol 2003; 169: 1911–1917.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Akinba AG, Burnett AL . Endothelial nitric oxide synthase protein expression, localization, and activity in the penis of the alloxan-induced diabetic rat. Mol Urol 2001; 5: 189–197.

    Google Scholar 

  80. 80

    Champion HC et al. Gene transfer of endothelial nitric oxide synthase to the penis augments erectile responses in the aged rat. Pharmacology 1999; 96: 11648–11652.

    CAS  Google Scholar 

  81. 81

    Tirney S et al. Nitric oxide synthase gene therapy for erectile dysfunction: comparison of plasmid, adenovirus, and adeno virus-transduced myoblast vectors. Mol Urol 2001; 5: 37–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Archer SL . Potassium channels and erectile dysfunction. Vascul Pharmacol 2002; 38: 61–71.

    CAS  PubMed  Google Scholar 

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Correspondence to E R Schwarz.

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Rodriguez, J., Al Dashti, R. & Schwarz, E. Linking erectile dysfunction and coronary artery disease. Int J Impot Res 17, S12–S18 (2005).

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  • endothelial dysfunction
  • coronary artery disease
  • erectile dysfunction
  • atherosclerosis
  • vascular disease
  • sexual function

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