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

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

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

the Nobel Prize was awarded to three US pharmacologists (Drs Ferid Murad.The central role of NO in penile tumescence In 1998. In response to sexual stimulation. Robert Furchgott and Louis Ignarro) for their discovery and characterization of a unique signaling molecule. it is now known that NO can be made by neurons. cavernous and dorsal nerves) and eNOS in the endothelium of the cavernosal cisternae and arteries (5-7). NO released by the endothelium induces vasodilation and In the penile circulation. secondary to phosphorylation and activation of eNOS (9. In the vasculature. and has diverse functions in the body (3). Both isoforms are present in the penis. The NOS enzymes metabolize L-arginine to NO and L-citrulline (Figure). traumatic or metabolic injury to the cavernous nerve reduces nNOS activation. In the case . First discovered to be a vasodilator produced by the endothelium lining the blood vessels. and by the neuronal isoform (nNOS) in the nitrergic nerves. macrophage. the gas nitric oxide (NO). this function of the endothelium is increases blood flow. and causes erectile dysfunction. For example. Endothelial shear stress is known to induce vasodilation. Penile blood flow increases. NO synthesized by the endothelial isoform of NO synthase (NOS) in the endothelium. supplemented by release of NO from nitrergic nerve terminals within the penis(4). releasing NO to induce vasodilation. nNOS in the nerve terminals of penile autonomic nerves (pelvic plexus. and other cells.10). the nitrergic nerves are activated. creating a tractive force (shear stress) on the endothelium. Penile tumescence is achieved by a collaboration of these two NOS signaling pathways (8). Endothelium-derived NO then amplifies and sustains the increase in penile blood flow (11). Any alteration in either of these NO signaling pathways can attenuate penile blood flow and cause erectile dysfunction.

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

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

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

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

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

In a randomized placebo controlled study. n=10). n=10). treatment periods of two weeks). The group receiving the dietary supplement had 50% of the improvement of the vardenafil group. By contrast. allocated. or double placebo (Group D n=10). . 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. the group receiving placebo showed no change in the IIEF5. or the combination of vardenafil with the dietary supplement(group C. At the end of treatment. The group receiving the dietary supplement product (group A. the group receiving vardenafil alone manifested an increment of 4 points on the IIEF5. There was a tendency of the group receiving both vardenafil and the supplement to have a slightly better outcome. 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. and increased frequency of intercourse. Gentile and colleagues assessed in 40 diabetic patients a dietary supplement product containing a combination of propionyl-L-carnitine. placebo-controlled. 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). 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. Another recent study assessed a dietary supplement product that contained L-arginine aspartate and pycnogenol (88). crossover design. Erectile function was estimated with the International Index of Erectile Function (IIEF5) questionnaire.Several studies have examined the use of L-arginine in combination with other nutritional agents. One month of treatment was associated with subjective improvement. L-arginine and nicotinic acid (87). double-blind. Patients reported sexual function from diaries.

L-arginine was well tolerated. in the short-term after a myocardial infarction. improvements in exercise tolerance.d p. Furthermore. Furthermore. penile plethysmography). resuscitation. and little pharmacokinetic or pharmacodynamic information has been obtained. 792 patients with acute myocardial infarction (with ST segment elevation) were randomized to oral Larginine (3. reinfarction. little is known regarding the long-term consequences of supplementing dietary arginine. A number of studies have indicated benefit of L-arginine supplementation in patients with coronary artery disease and congestive heart failure. there was a tendency for a shortterm benefit. No serious adverse effects were observed during L-arginine supplementation.0 t. Proper dose-ranging studies were not performed. shock/pulmonary edema or recurrent myocardial ischemia. p=0. Thus. because of the small numbers and short duration of treatment.How hard is the evidence? What is apparent from the discussion above is that though the pre-clinical foundation is strong. More importantly. for 30 days) or placebo in addition to standard of care. The clinical trials have been conducted in small groups of patients. safety concerns have not been addressed. 95% CI 0. .i. there was a strong tendency toward a reduction in cardiovascular morbidity (89).02.06). the clinical evidence is weak for the utility of L-arginine as a therapeutic adjunct in the treatment of erectile dysfunction. in the largest study of short-term arginine therapy. Although L-arginine is a component of the diet (about 3-5 g/day in the western diet). and for the most part have used subjective indices of erectile function without objective assessments (eg. In this randomized clinical trial. The end point was the composite of 30 day cardiovascular death.39-1.63. These major adverse cardiovascular events occurred in 24% patients treated with L-arginine and 27% with placebo (OR 0.o. and relief of symptoms (58-62). with improvements in endothelial vasodilator function.

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

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

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

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

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

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

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