Herbal Viagra and nitric oxide: how hard is the evidence?

John P. Cooke

*Address Correspondence to: John P. Cooke, MD, PhD Professor and Associate Director, Stanford Cardiovascular Institute Stanford University, Stanford, CA; 300 Pasteur Drive, Stanford, CA 94305-5406 Email: john.cooke@stanford.edu

Word Count: 7578 Key words: impotence, endothelium, cyclic GMP; soluble guanylyl cyclase,
vasodilation

Abbreviations:

asymmetric

dimethylarginine

(ADMA);

cyclic

guanosine

monophosphate (cGMP); dimethylarginine dimethylaminohydrolase (DDAH); endothelial nitric oxide synthase (eNOS); nitric oxide (NO); nitric oxide synthase (NOS); soluble guanylyl cyclase (sGC); coronary artery disease (CAD); peripheral arterial disease (PAD); phosphodiesterase (PDE)

Abstract
A central role of endothelium- and neuronal-derived NO in erectile function is strongly supported by pre-clinical studies and human data. This endogenous vasodilator

increases penile blood flow and tumescence. An impairment of NO synthesis and/or bioactivity plays a major role in erectile dysfunction in many patients. Indeed, effective pharmacotherapy for impotence augments the action of endogenous NO; sildenafil (Viagra®) was the first of these drugs to market. By increasing the stability of cyclic

GMP (the ‘second messenger’ of NO) phosphodiesterase-5 inhibitors such as sildenafil enhance NO-induced penile blood flow. A number of dietary supplements are purported to be herbal equivalents of sildenafil, by enhancing NO synthesis and/or bioavailability. This review examines the evidence for these claims.

Etiology of erectile dysfunction
Erectile dysfunction is the inability to maintain a penile erection that is sufficient for sexual intercourse. There are multiple etiologies, both psychological and physical. With respect to the latter, erectile dysfunction may be the manifestation of neuropathy (such as that associated with the autonomic neuropathy of diabetes mellitus, or with surgical or radiological treatments of pelvic pathology); with structural alterations in the penis (as with Peyronie’s disease); hormonal disturbances (as with low testosterone levels);

adverse effects of certain medications (such as hormonal therapy for prostate cancer) or vascular disease (as with atherosclerotic obstruction of the internal iliac arteries, or with vascular dysfunction). Of these, vascular dysfunction may be the most common cause of erectile dysfunction. Vascular dysfunction is commonly observed in individuals with hypertension, diabetes mellitus, insulin resistance, hypercholesterolemia, aging or tobacco use, and with atherosclerosis. Notably, impotence may be the first indication

Nitric oxide and other nitrovasodilators activate soluble guanylate cyclase. Pharmacotherapy for erectile dysfunction There are a number of effective drugs to treat impotence. It does so by activating protein kinases that phosphorylate proteins that reduce cytosolic calcium levels. and vardenafil (Levitra®). thereby .that an individual is at serious risk of cardiovascular disease. Thus. these approaches have been overtaken by the phosphodiesterase-5 inhibitors (PDE-5 inhibitors). cGMP is the ‘second messenger’ of nitric oxide. such as alprostadil. This molecule relaxes vascular smooth muscle. tadalafil (Cialis®). which are very effective as oral therapy in the treatment of impotence (1). An alternative approach is the intraurethral application of alprostadil. Self-treatment with over-the-counter remedies. These drugs include sildenafil. Individuals with low testosterone levels benefit from testosterone replacement therapy. The PDE-5 inhibitors prevent the degradation of cGMP. and be evaluated for serious underlying diseases often associated with this condition. and this symptom may be a harbinger of stroke or heart attack. or that dephosphorylate the myosin light chains of vascular smooth muscle(2). The PDE-5 inhibitors increase penile blood flow by inhibiting the degradation of cyclic guanosine monophosphate (cGMP) by its phosphodiesterase (Figure). places the individual at serious risk. because of its implications for the physical and mental well-being of the individual. Injection of this vasodilator prostanoid into the base or shaft of the penis increases penile blood flow to induce tumescence. which produces cGMP from GTP. men that are having difficulty with sexual function should seek early medical attention. As can be seen from the figure. without the evaluation of a physician. However. Other vasodilators for injection include papaverine and phentolamine. Other treatments include the self-injection of vasodilators.

The action of this enzyme is inhibited by the endogenous NOS inhibitor. the primary phosphodiesterase is PDE-5.increasing and prolonging its effect to relax vascular smooth muscle. Endogenous NO is produced by the metabolism of L-arginine to NO (and L-citrulline). ADMA (asymmetric dimethylarginine). but a rather positive effect on erectile dysfunction was observed. The PDE-5 inhibitors were initially developed to treat hypertension. by NO synthase. Figure 1. which cleaves the high energy phosphate bond of cGMP to produce GMP. which cannot induce vasodilation. Nitric oxide (NO) is released by nitroglycerin. Their effect to reduce systemic vascular resistance (and thereby reduce blood pressure) was modest. . This signaling pathway is inhibited by cGMP phosphodiesterase. Soluble guanylate cyclase converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) to stimulate other kinases that induce vasodilation and increase blood flow. increasing penile blood flow and tumescence. so as to increase blood flow. thus PDE-5 inhibitors such as sildenafil primarily enhance cGMP levels in the penis. The action of this enzyme is blocked by phosphodiesterase inhibitors. This serendipitous observation was made possible by the fact that NO is a major mediator of penile blood flow. or provided by other nitrovasodilators to stimulate soluble guanylate cyclase. In the penis.

the gas nitric oxide (NO). releasing NO to induce vasodilation. and has diverse functions in the body (3). Endothelial shear stress is known to induce vasodilation. Penile blood flow increases. NO released by the endothelium induces vasodilation and In the penile circulation. creating a tractive force (shear stress) on the endothelium. The NOS enzymes metabolize L-arginine to NO and L-citrulline (Figure). For example. this function of the endothelium is increases blood flow. and by the neuronal isoform (nNOS) in the nitrergic nerves.The central role of NO in penile tumescence In 1998.10). traumatic or metabolic injury to the cavernous nerve reduces nNOS activation. supplemented by release of NO from nitrergic nerve terminals within the penis(4). Robert Furchgott and Louis Ignarro) for their discovery and characterization of a unique signaling molecule. secondary to phosphorylation and activation of eNOS (9. Any alteration in either of these NO signaling pathways can attenuate penile blood flow and cause erectile dysfunction. In response to sexual stimulation. First discovered to be a vasodilator produced by the endothelium lining the blood vessels. and other cells. the Nobel Prize was awarded to three US pharmacologists (Drs Ferid Murad. nNOS in the nerve terminals of penile autonomic nerves (pelvic plexus. In the case . macrophage. it is now known that NO can be made by neurons. the nitrergic nerves are activated. NO synthesized by the endothelial isoform of NO synthase (NOS) in the endothelium. cavernous and dorsal nerves) and eNOS in the endothelium of the cavernosal cisternae and arteries (5-7). Penile tumescence is achieved by a collaboration of these two NOS signaling pathways (8). Both isoforms are present in the penis. Endothelium-derived NO then amplifies and sustains the increase in penile blood flow (11). In the vasculature. and causes erectile dysfunction.

that derangements of the NO synthase pathway can cause erectile dysfunction. sildenafil is capable of enhancing the action of eNOS to preserve erectile function (12). hypercholesterolemia. An impairment of endothelial NOS not only reduces the ability of a blood vessel to relax. NO is a potent inhibitor of platelet adhesion and aggregation (15. and those with diabetes. In addition.29). This has been attributed to impaired eNOS protein expression and activity and increased oxidative stress (28. or tobacco exposure (13. hypertension. enhancement of NO synthesis (as with L-arginine administration or overexpression of eNOS protein) has been shown in animal models to reduce the progression of atherosclerosis and myointimal hyperplasia (21-23). .16). the major cause of NOS impairment in the western world is dysfunction of endothelial NOS. Similarly. In the penile tissue of animals with experimentally induced hyperglycemia. and in the corpora cavernosa from patients with diabetes mellitus. In addition to relaxing vascular smooth muscle. The importance of NO in vascular homeostasis is supported by a large number of studies revealing that an impairment of endothelial vasodilator function is an independent risk factor for cardiovascular morbidity and mortality (24-26). and to induce relaxation of the underlying vascular smooth muscle.14). NO suppresses vascular inflammation by reducing the expression of leukocyte adhesion molecules and inflammatory cytokines (17-20). However. there is strong evidence from pre-clinical studies and clinical investigation. but also broadly disrupts vascular homeostasis. Because of these powerful effects of NO on vascular homeostasis. there is an impairment in NO synthesis (27).of cavernous nerve injury model. and that therapy to augment NO signaling is therapeutic. is impaired in older individuals. The ability of the endothelium to respond to shear stress or other stimuli.

alterations in the phosphorylation and activation of eNOS is observed in experimental animals (33). the concentration of L-arginine should not be rate-limiting. Our group was the first to provide evidence that administration of L-arginine could restore endothelial vasodilator function and enhance NO synthesis in animal models of disease. hypercholesterolemia. by oral or intravenous administration of L-arginine supplementation. an effect that can be may be reversed by diet and exercise (35). (29. With aging. the Km of NOS for L-arginine is in the range of 2-3 uM (51). and in apparent contradiction of Michaelis-Menton kinetics. In a rather broad range of cardiovascular disorders. The major criticism was that in vitro. an effect that can be reversed by sildenafil (34). Hypercholesterolemia enhances the inhibitory interaction of caveolin-1 with eNOS. it appears that the endothelial vasodilator dysfunction observed in these conditions can be reversed. our observations were confirmed by a number of other groups (52-57).Diabetes mellitus is associated with mitochondrial dysfunction and oxidative stress (30) that can accelerate the degradation of NO (31). Furthermore. hypertension). Furthermore. as with formation of N-acetylglucosamine (OGlcNAc) adducts with serine phosphorylation sites on eNOS. 32). Because L-arginine exists in the plasma at concentrations of about 100uM. at least in the short-term. and in humans with endothelial vasodilator dysfunction (21. diabetes. 48. L-arginine: rationale for its use in vascular diseases In a number of cardiovascular disorders associated with erectile dysfunction (eg. But despite the calculations of enzymologists. the ability of the endothelium to induce vasorelaxation is impaired (14). the improvements in endothelial vasodilator dysfunction have been associated with . Initially our findings faced significant skepticism (50). diabetes mellitus favors the production of advanced glycosylation endproducts (AGEs) which can also disrupt eNOS activation. 49).

The remaining 80% of clearance is largely due the action of the cytoplasmic enzyme dimethylarginine dimethylaminohydrolase (DDAH. Both ADMA and MMA are capable of competing with L-arginine for binding to the NOS enzyme. The methylarginines are methylated analogues of L-arginine. their antagonism of NOS can be reversed by increasing the concentration of L-arginine (14). asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). but one of the most compelling is the existence of an endogenous NOS inhibitor. ADMA is elevated in all of the conditions associated with cardiovascular . Since ADMA and MMA are competitive inhibitors of NOS. The methylarginines are metabolites of the hydrolysis of proteins containing methylated arginine residues (65). These include monomethylarginine (MMA). and hyperhomocysteinemia (69-71). whereas SDMA does not. In humans. This enzyme is exquisitely sensitive to oxidative stress because it expresses a sulfhydryl group in its catalytic site (68). Patrick Vallance and colleagues demonstrated the existence of endogenous antagonists of the NOS pathway (64). We have shown that the enzyme activity is impaired with a number of disorders associated with cardiovascular disease including hypercholesterolemia. 66) which is expressed ubiquitously as two isoforms (67). The discrepancy between the in vitro calculations and the in vivo observations has been termed the arginine paradox (63). About 20% of the clearance of these compounds is due to renal excretion. The arginine paradox and ADMA. and peripheral artery disease (58-62).increased NO synthesis. There have been several explanations proffered for the arginine paradox. Sometime after our observation that arginine restored NO signaling. diabetes mellitus. The plasma concentration of ADMA and MMA are increased in renal failure. and improvements in symptoms in patients with coronary artery disease. congestive heart failure.

disease (14). than in those without CAD (77). These findings may explain the observations of others. Gur and co-workers found that L-arginine could relax strips of isolated human corpus cavernosum. Cavernosal ADMA was negatively correlated with the intra-cavernosal pressure (79).and dose-dependent fashion (81). even after adjusting for the usual CV risk factors (77). Of relevance to this review ADMA is increased in patients with erectile dysfunction. On the strength of the pre-clinical studies and clinical investigations. Park and colleagues found that by comparison to control animals. and its utility in promoting sexual function. in humans ADMA is a predictor of the severity and progression of atherosclerosis and myointimal hyperplasia. D-arginine. ADMA remains a strong and independent predictor for CAD in patients with ED. there is a strong scientific foundation for clinical trials to assess L-arginine supplementation as a method to improve NO signaling in cardiovascular disease. and levels correlate with the severity of erectile dysfunction (76). it is theoretically possible that the efficacy of these agents could be enhanced by the administration of L-arginine. supporting the use of supplemental L-arginine for erectile function. in a time. and an impairment in NO synthesis (79). cavernosal ADMA was increased in association with a decline in DDAH activity. which cannot be . Plasma ADMA levels are higher in ED patients with CAD. oral administration of L-arginine for 8 wk to aged rats resulted in an increase in penile tissue levels of L-arginine. In one of these. an increase in NOS activity and a complete reversal of age-related erectile dysfunction (80). L-arginine: an herbal Viagra? In a model of atherosclerosis in Sprague-Dawley rats. Because the PDE-5 inhibitors do not appear to restore normal plasma levels of ADMA (78). In addition. and is an independent predictor of cardiovascular morbidity and overall mortality (72-75).

crossover design. . In a subsequent randomized clinical trial.5 g/day) or placebo. The effect of L-arginine was due to its conversion to NO. suggesting that patients with low levels of NOS activity may be particularly benefited by L-arginine supplementation (83).8 g/d for 2 wk) subjectively restored erectile function as well as vaginal penetration ability in 6 of 15 patients completing the study. as L-NAME (a NOS inhibitor) and ODQ (an antagonist of cGMP synthesis) blocked the effect of L-arginine. 32 patients with impotence were administered L-arginine (1. Nine of 29 (31%) patients taking L-arginine and two of 17 controls reported a significant subjective improvement in sexual function using a validated questionnaire. The level of urinary NOx in this subgroup had doubled by the end of the study. In one small clinical study of 20 impotent men using a placebo controlled. Several small clinical trials are supportive of L-arginine supplementation for erectile function. whereas sildenafil potentiated the arginine induced relaxation. which may have been ineffective at increasing plasma L-arginine levels (85). The major difference between this trial and the others was the smaller dose of L-arginine in the negative trial. L-arginine 5g/day was administered for 6 weeks (83). All nine patients treated with L-arginine who improved were noted to have low urinary NOx at the initiation of the study. L-arginine administered orally (2. These observations demonstrated that supplemental L-arginine (in addition to the endogenous levels of L-arginine in the tissue) could induce relaxation by increasing NO synthesis. Not all studies have been positive. In a small randomized clinical trial with cross-over design. There was no subjective improvement in erectile function (84). This beneficial effect was not reported during the placebo phase (82). had no effect.metabolized to NO by NOS.

or the combination of vardenafil with the dietary supplement(group C. At the end of treatment. Gentile and colleagues assessed in 40 diabetic patients a dietary supplement product containing a combination of propionyl-L-carnitine. 50 patients with mild to moderate erectile dysfunction (ED) were administered for 1 month a placebo or the combination of L-arginine aspartate and pycnogenol. n=10). Another recent study assessed a dietary supplement product that contained L-arginine aspartate and pycnogenol (88). L-arginine and nicotinic acid (87).Several studies have examined the use of L-arginine in combination with other nutritional agents. Erectile function was estimated with the International Index of Erectile Function (IIEF5) questionnaire. In a randomized placebo controlled study. n=10). One month of treatment was associated with subjective improvement. treatment periods of two weeks). and increased frequency of intercourse. Erectile function was modestly but significantly improved by comparison to placebo for the primary endpoint of change in the Erectile Function Domain of the International Index of Erectile Function (IIEF). the group receiving vardenafil alone manifested an increment of 4 points on the IIEF5. double-blind. allocated. placebo-controlled. . The group receiving the dietary supplement had 50% of the improvement of the vardenafil group. There was a tendency of the group receiving both vardenafil and the supplement to have a slightly better outcome. the group receiving placebo showed no change in the IIEF5. Lebret and co-workers (86) studied the combination of yohimbine (6mg) and Larginine (6g) daily in a randomized clinical trial with cross-over design (n=45. By contrast. or double placebo (Group D n=10). crossover design. Patients reported sexual function from diaries. The group receiving the dietary supplement product (group A. n=10) was compared to those receiving vardenafil 20 mg twice weekly (Group B. Pycnogenol is derived from pine bark extract and In a randomly contains oligomeric proanthocyanidins that have anti-oxidant effects.

Proper dose-ranging studies were not performed. for 30 days) or placebo in addition to standard of care. there was a strong tendency toward a reduction in cardiovascular morbidity (89). with improvements in endothelial vasodilator function. and little pharmacokinetic or pharmacodynamic information has been obtained. in the largest study of short-term arginine therapy.39-1. shock/pulmonary edema or recurrent myocardial ischemia.63. improvements in exercise tolerance. because of the small numbers and short duration of treatment. Thus.0 t. p=0. The end point was the composite of 30 day cardiovascular death.i. In this randomized clinical trial. there was a tendency for a shortterm benefit. A number of studies have indicated benefit of L-arginine supplementation in patients with coronary artery disease and congestive heart failure. No serious adverse effects were observed during L-arginine supplementation. the clinical evidence is weak for the utility of L-arginine as a therapeutic adjunct in the treatment of erectile dysfunction. in the short-term after a myocardial infarction. Although L-arginine is a component of the diet (about 3-5 g/day in the western diet).How hard is the evidence? What is apparent from the discussion above is that though the pre-clinical foundation is strong. More importantly. and relief of symptoms (58-62). Furthermore. penile plethysmography). reinfarction. The clinical trials have been conducted in small groups of patients. These major adverse cardiovascular events occurred in 24% patients treated with L-arginine and 27% with placebo (OR 0. 792 patients with acute myocardial infarction (with ST segment elevation) were randomized to oral Larginine (3. L-arginine was well tolerated.o. .02. safety concerns have not been addressed. little is known regarding the long-term consequences of supplementing dietary arginine. and for the most part have used subjective indices of erectile function without objective assessments (eg.06).d p. resuscitation. 95% CI 0. Furthermore.

The study drug was well tolerated. Treadmill testing was performed prior to administration of the study drug and again after 12 weeks of treatment. However. and there was a trend for an improvement in walking speed in patients treated with L-arginine. This trial was terminated early by the data and safety monitoring board when 8 deaths occurred in the arginine treated group (90). for power calculation and for dosing for the subsequent definitive trial. This pilot study provided data for safety. Although abundant evidence indicates that short-term administration of L-arginine is beneficial for endothelial vasodilator function and symptoms in patients with cardiovascular disease. In 220 patients with peripheral arterial disease (PAD) we studied the potential benefit of L-arginine supplementation on endothelial vasodilator function and functional capacity. one long-term study suggests that chronic administration of Larginine can induce a form of tolerance (91).However. 6 or 9 g of L-arginine daily in three divided doses for 12 weeks (85). There was no significant difference observed in absolute claudication distance between the groups. a trend was observed for a greater increase in walking distance in the group treated with 3 g L-arginine daily. . patients with PAD and intermittent claudication (n = 80) were randomly assigned to oral doses of 0. In a pilot study. with no significant adverse effects of Larginine administration. 3. in a subsequent study. patients (n=150) patients with acute myocardial infarction were randomized to placebo or L-arginine supplementation for a longer term of therapy (6 months) following acute myocardial infarction. The difference between these studies may be related to the duration of therapy.

in patients with PAD. long-term administration of L-arginine does not increase nitric oxide synthesis or improve vascular reactivity. L-arginine supplementation significantly increased plasma L-arginine levels. Nobel laureate Louis Ignarro has given his imprimatur to a product . and plasma citrulline formation) were reduced or not improved compared with placebo.05). the improvement in the L-arginine-treated group was significantly less than that in the placebo group (28% versus 12%. Although absolute claudication distance improved in both L-arginine. plasma and urinary nitrogen oxides. Thus. This latter study raises questions about the long-term efficacy and safety of L-arginine supplementation.In the definitive study. and increases plasma L-arginine levels to a greater extent than does L-arginine supplementation (92). Administration of L-citrulline (the precursor of Larginine) escapes this degradation pathway. measures of nitric oxide availability (including flowmediated vasodilation. Furthermore. The primary end point was the change at 6 months in the absolute claudication distance as assessed by the Skinner-Gardner treadmill protocol. L-citrulline 3g bid increased urinary nitrate and cGMP by 30% (reflecting increased NO synthesis and bioactivity). The study suggests that an ‘arginine tolerance’ or tachyphylaxis to the effects of chronic administration of L-arginine could even induce dysfunction of the NO synthase pathway. L-arginine undergoes extensive first-pass metabolism by arginase in the small intestine and liver. In this study. Indeed. long-term administration of L-arginine does not appear to be useful in patients with intermittent claudication and PAD. It is possible that other methods to enhance plasma L-arginine levels would be more effective. As opposed to its short-term administration. the expected placebo effect observed in studies of functional capacity was attenuated in the L-arginine-treated group. However. vascular compliance. p<0.and placebotreated patients. oral L-arginine (3 g/d) versus placebo for 6 months was assessed in subjects (n= 133) with intermittent claudication due to PAD.

manufacturers don't need FDA approval before going to market with their product. Some of these may be of modest benefit. There is a known interaction of exogenous nitrates with PDE-5 inhibitors. and if necessary can take remedial action (eg. However. However. It is important to know that the regulation of supplements is not as rigorous as for pharmaceuticals. . issue a warning or require that the product be removed from the market). studies need to be done to validate this use. particularly for the many ED patients that also have known or occult coronary artery disease. These regulations require that the product meets purity specifications. In which case. Manufacturers are obliged to follow good manufacturing practice (GMP) regulations promulgated by the US Food and Drug Administration (FDA). It is possible that intermittent administration of L-arginine may avoid the problem of ‘arginine tolerance’ and maintain efficacy as an enhancer of penile NO synthesis. The Food and Drug Administration has banned several of these products. some of which have contained PDE-5 inhibitors (36). there are no long-term randomized clinical trials assessing the safety and efficacy of this dietary supplement for its intended use. Once the product is on the market. Herbal Viagra and NO There are a number of other dietary supplements that purport to improve sexual function. particularly during coadministration of pharmaceutical agents for erectile dysfunction. Whether this adverse interaction might occur with L-arginine has not been definitively studied. the FDA is responsible for monitoring its safety.containing L-citrulline (Niteworks®) that is said to increase NO production and enhance physical and sexual functioning. Some of these agents may be hazardous. but the evidence is weak. such that the risk of hypotension is increased.

these companies can sell their products at a lower cost (which is good for the consumer). However. a precursor of testosterone). as one can imagine. but cannot claim that it is useful for the treatment of osteoporosis. For example. and they generally do not subject their products to rigorous testing. they generally do not develop substantially new or more effective therapies (which is not good for the consumer). because of the number of products on the market. ginkgo and L-arginine. The claims that health food companies make about their products are usually based on research performed by other parties. a manufacturer of a calcium supplement can maintain that the product promotes bone health. it is difficult to provide thorough oversight regarding the safety of these products once on the market. But because they do not support research. and has been employed as a traditional Chinese remedy for diverse disorders. yohimbe. Epimedium is another traditional Chinese medicine for erectile dysfunction that contains an active principle (icariin) with PDE-5 inhibitory activity (38). frequently scientists at universities not affiliated with or supported by the health food companies. DHEA (dehydroepiandrosterone. anti-oxidants (Vitamin E. and the limitations of the FDA budget. Dietary supplements for sexual function include Korean red ginseng (Panax ginseng). Finally. which is one of the reasons that the medical community is skeptical of dietary supplements. which permits the distributor to make structure or function claims. Epimedium (horny goat weed). but prohibits claims regarding treatment of a disease.The claims made by the distributors of the dietary supplement are regulated by the Dietary Supplement Health Education Act (DSHEA) of 1994. Ginseng is an herb often brewed as a tea. no randomized clinical trials have assessed safety or efficacy. Yohimbe is derived from the bark of a West African . folate and zinc). They must also include a disclaimer that the FDA hasn't evaluated the claim. Small studies of ginseng suggest that the herb is safe and has modest benefit for individuals with erectile dysfunction (37). Because they don’t perform their own research.

47). Furthermore. However. and some clinical experience indicating that yohimbine can enhance sexual function (3941). The major active moiety is yohimbine. which is of particular concern for individuals with cardiovascular disease (common in men with erectile dysfunction). bolstering the NOS pathway with PDE-5 inhibitors has been a very effective pharmacological approach to treating impotence. Similarly. There is pre-clinical evidence. providing a rationale for its administration in erectile dysfunction. For that matter. The antioxidant vitamins may reduce oxidative stress. yet questions remain regarding efficacy and safety. Conclusion There is compelling evidence that the NOS pathway is critical for erectile function. an alpha 2 adrenergic antagonist. The rationale for the use of DHEA is that this chemical is a precursor to testosterone. and thereby preserve NO from oxidative inactivation so as to improve endothelium dependent vasodilation (44). yohimbine can increase heart rate and blood pressure (42). Therefore herbal supplements that enhance NO synthesis or reduce its degradation could be useful for enhancing erectile function. and that a derangement of neuronal and endothelial NO signaling is a major contributor to erectile dysfunction in a majority of patients. L-arginine is the precursor for NO. The level of evidence that a dietary supplement can enhance NO production is arguably the strongest for L-arginine. the literature supporting the use of pharmaceutical testosterone for erectile dysfunction is mixed (1). there is little evidence for the efficacy of DHEA (43). gingko may preserve NO from oxidative degradation (45) to improve vascular reactivity. For more information regarding the other dietary supplements.evergreen containing a variety of pharmacologically active chemicals. The nutritional product with . good sources of information include the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements (46. However.

because erectile dysfunction is often associated with cardiovascular disease. Tsertsvadze A. Dr. Ansari MT. A few randomized clinical trials of short duration in small groups of patients suggest modest benefit. with respect to the notion that L-arginine or other dietary supplements may safely and effectively improve erectile function. 1U01HL100397). there is scant information regarding potential interactions with other medications. Finally. and offered effective pharmacotherapy for sexual function. Individuals with erectile dysfunction should be evaluated by their physician for cardiovascular disease. is risky. Furthermore. Garritty C. Bella AJ. Dr. References: 1. Acknowledgements and disclosures This work was supported by grants from the National Institutes of Health (RO1 HL75774. Oral Soares-Weiser K. Cooke is the inventor of patents owned by Stanford University for diagnostic and therapeutic applications of the NOS pathway from which he receives royalties. the California Tobacco Related Disease Research Program of the University of California (18XT-0098). Fink HA. Sampson M. self-treatment with herbal remedies. Moher D. and The Wallace H. P50HL083800.the strongest rationale for this use is L-arginine. However. MacDonald R. R21 HL085743. has been shown to enhance NO synthesis. which in pre-clinical studies and in small clinical studies of short duration. in the absence of physician supervision. Yazdi F. RC2HL103400. Wilt TJ. as definitive trials of chronic L-arginine administration have not been done in patients with erectile dysfunction. the evidence is soft. K12 HL087746. Daniel R. Fox S. Coulter Translational Research Grant Program. there is no evidence of long-term efficacy and safety. Cooke is a consultant for NiCox. However. .

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