This action might not be possible to undo. Are you sure you want to continue?
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: email@example.com
Word Count: 7578 Key words: impotence, endothelium, cyclic GMP; soluble guanylyl cyclase,
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)
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
The PDE-5 inhibitors prevent the degradation of cGMP. men that are having difficulty with sexual function should seek early medical attention. 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. Nitric oxide and other nitrovasodilators activate soluble guanylate cyclase. which are very effective as oral therapy in the treatment of impotence (1). Pharmacotherapy for erectile dysfunction There are a number of effective drugs to treat impotence. Individuals with low testosterone levels benefit from testosterone replacement therapy. This molecule relaxes vascular smooth muscle. Self-treatment with over-the-counter remedies. Other vasodilators for injection include papaverine and phentolamine. tadalafil (Cialis®). and this symptom may be a harbinger of stroke or heart attack. An alternative approach is the intraurethral application of alprostadil. and vardenafil (Levitra®). However. It does so by activating protein kinases that phosphorylate proteins that reduce cytosolic calcium levels. Other treatments include the self-injection of vasodilators. and be evaluated for serious underlying diseases often associated with this condition. Thus. such as alprostadil. or that dephosphorylate the myosin light chains of vascular smooth muscle(2). because of its implications for the physical and mental well-being of the individual. cGMP is the ‘second messenger’ of nitric oxide. As can be seen from the figure. These drugs include sildenafil. these approaches have been overtaken by the phosphodiesterase-5 inhibitors (PDE-5 inhibitors). which produces cGMP from GTP. Injection of this vasodilator prostanoid into the base or shaft of the penis increases penile blood flow to induce tumescence. without the evaluation of a physician.that an individual is at serious risk of cardiovascular disease. thereby .
which cleaves the high energy phosphate bond of cGMP to produce GMP. . increasing penile blood flow and tumescence. In the penis. The PDE-5 inhibitors were initially developed to treat hypertension. the primary phosphodiesterase is PDE-5. Nitric oxide (NO) is released by nitroglycerin.increasing and prolonging its effect to relax vascular smooth muscle. 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. thus PDE-5 inhibitors such as sildenafil primarily enhance cGMP levels in the penis. Figure 1. Their effect to reduce systemic vascular resistance (and thereby reduce blood pressure) was modest. Endogenous NO is produced by the metabolism of L-arginine to NO (and L-citrulline). by NO synthase. The action of this enzyme is blocked by phosphodiesterase inhibitors. This signaling pathway is inhibited by cGMP phosphodiesterase. The action of this enzyme is inhibited by the endogenous NOS inhibitor. ADMA (asymmetric dimethylarginine). Soluble guanylate cyclase converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) to stimulate other kinases that induce vasodilation and increase blood flow. but a rather positive effect on erectile dysfunction was observed. which cannot induce vasodilation. so as to increase blood flow.
NO released by the endothelium induces vasodilation and In the penile circulation. traumatic or metabolic injury to the cavernous nerve reduces nNOS activation. releasing NO to induce vasodilation. First discovered to be a vasodilator produced by the endothelium lining the blood vessels. and by the neuronal isoform (nNOS) in the nitrergic nerves. Penile tumescence is achieved by a collaboration of these two NOS signaling pathways (8). The NOS enzymes metabolize L-arginine to NO and L-citrulline (Figure). cavernous and dorsal nerves) and eNOS in the endothelium of the cavernosal cisternae and arteries (5-7). In response to sexual stimulation. Both isoforms are present in the penis. secondary to phosphorylation and activation of eNOS (9. NO synthesized by the endothelial isoform of NO synthase (NOS) in the endothelium. In the vasculature. and has diverse functions in the body (3). supplemented by release of NO from nitrergic nerve terminals within the penis(4). the Nobel Prize was awarded to three US pharmacologists (Drs Ferid Murad. Any alteration in either of these NO signaling pathways can attenuate penile blood flow and cause erectile dysfunction. For example. macrophage. Robert Furchgott and Louis Ignarro) for their discovery and characterization of a unique signaling molecule. nNOS in the nerve terminals of penile autonomic nerves (pelvic plexus. this function of the endothelium is increases blood flow. In the case . the gas nitric oxide (NO). and causes erectile dysfunction. Endothelial shear stress is known to induce vasodilation.10).The central role of NO in penile tumescence In 1998. Endothelium-derived NO then amplifies and sustains the increase in penile blood flow (11). Penile blood flow increases. the nitrergic nerves are activated. and other cells. it is now known that NO can be made by neurons. creating a tractive force (shear stress) on the endothelium.
there is strong evidence from pre-clinical studies and clinical investigation. 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). In addition. and those with diabetes. Similarly. Because of these powerful effects of NO on vascular homeostasis. The ability of the endothelium to respond to shear stress or other stimuli. and in the corpora cavernosa from patients with diabetes mellitus. the major cause of NOS impairment in the western world is dysfunction of endothelial NOS. and to induce relaxation of the underlying vascular smooth muscle. This has been attributed to impaired eNOS protein expression and activity and increased oxidative stress (28. 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). hypertension.14). that derangements of the NO synthase pathway can cause erectile dysfunction.16). hypercholesterolemia. sildenafil is capable of enhancing the action of eNOS to preserve erectile function (12). In the penile tissue of animals with experimentally induced hyperglycemia. In addition to relaxing vascular smooth muscle. is impaired in older individuals. 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. .of cavernous nerve injury model. NO suppresses vascular inflammation by reducing the expression of leukocyte adhesion molecules and inflammatory cytokines (17-20). However. but also broadly disrupts vascular homeostasis. there is an impairment in NO synthesis (27). or tobacco exposure (13. and that therapy to augment NO signaling is therapeutic.29).
48. an effect that can be may be reversed by diet and exercise (35). at least in the short-term. the Km of NOS for L-arginine is in the range of 2-3 uM (51). But despite the calculations of enzymologists. In a rather broad range of cardiovascular disorders. 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. Initially our findings faced significant skepticism (50). it appears that the endothelial vasodilator dysfunction observed in these conditions can be reversed. Furthermore. hypertension). diabetes mellitus favors the production of advanced glycosylation endproducts (AGEs) which can also disrupt eNOS activation. 49). 32). and in apparent contradiction of Michaelis-Menton kinetics. Hypercholesterolemia enhances the inhibitory interaction of caveolin-1 with eNOS. the improvements in endothelial vasodilator dysfunction have been associated with . the concentration of L-arginine should not be rate-limiting. alterations in the phosphorylation and activation of eNOS is observed in experimental animals (33). an effect that can be reversed by sildenafil (34).Diabetes mellitus is associated with mitochondrial dysfunction and oxidative stress (30) that can accelerate the degradation of NO (31). The major criticism was that in vitro. diabetes. the ability of the endothelium to induce vasorelaxation is impaired (14). hypercholesterolemia. our observations were confirmed by a number of other groups (52-57). by oral or intravenous administration of L-arginine supplementation. L-arginine: rationale for its use in vascular diseases In a number of cardiovascular disorders associated with erectile dysfunction (eg. and in humans with endothelial vasodilator dysfunction (21. Because L-arginine exists in the plasma at concentrations of about 100uM. With aging. as with formation of N-acetylglucosamine (OGlcNAc) adducts with serine phosphorylation sites on eNOS. Furthermore. (29.
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 . The discrepancy between the in vitro calculations and the in vivo observations has been termed the arginine paradox (63). their antagonism of NOS can be reversed by increasing the concentration of L-arginine (14). This enzyme is exquisitely sensitive to oxidative stress because it expresses a sulfhydryl group in its catalytic site (68). There have been several explanations proffered for the arginine paradox. In humans. congestive heart failure. Both ADMA and MMA are capable of competing with L-arginine for binding to the NOS enzyme. 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 remaining 80% of clearance is largely due the action of the cytoplasmic enzyme dimethylarginine dimethylaminohydrolase (DDAH. These include monomethylarginine (MMA). and hyperhomocysteinemia (69-71). Patrick Vallance and colleagues demonstrated the existence of endogenous antagonists of the NOS pathway (64). whereas SDMA does not. Since ADMA and MMA are competitive inhibitors of NOS. and peripheral artery disease (58-62). Sometime after our observation that arginine restored NO signaling. The plasma concentration of ADMA and MMA are increased in renal failure. asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). About 20% of the clearance of these compounds is due to renal excretion. The arginine paradox and ADMA. and improvements in symptoms in patients with coronary artery disease. The methylarginines are metabolites of the hydrolysis of proteins containing methylated arginine residues (65). The methylarginines are methylated analogues of L-arginine. diabetes mellitus.increased NO synthesis.
Of relevance to this review ADMA is increased in patients with erectile dysfunction.and dose-dependent fashion (81). an increase in NOS activity and a complete reversal of age-related erectile dysfunction (80). in a time. ADMA remains a strong and independent predictor for CAD in patients with ED. which cannot be . oral administration of L-arginine for 8 wk to aged rats resulted in an increase in penile tissue levels of L-arginine. In addition.disease (14). and an impairment in NO synthesis (79). Gur and co-workers found that L-arginine could relax strips of isolated human corpus cavernosum. L-arginine: an herbal Viagra? In a model of atherosclerosis in Sprague-Dawley rats. in humans ADMA is a predictor of the severity and progression of atherosclerosis and myointimal hyperplasia. even after adjusting for the usual CV risk factors (77). than in those without CAD (77). and its utility in promoting sexual function. and is an independent predictor of cardiovascular morbidity and overall mortality (72-75). it is theoretically possible that the efficacy of these agents could be enhanced by the administration of L-arginine. On the strength of the pre-clinical studies and clinical investigations. there is a strong scientific foundation for clinical trials to assess L-arginine supplementation as a method to improve NO signaling in cardiovascular disease. D-arginine. These findings may explain the observations of others. Park and colleagues found that by comparison to control animals. Because the PDE-5 inhibitors do not appear to restore normal plasma levels of ADMA (78). Plasma ADMA levels are higher in ED patients with CAD. cavernosal ADMA was increased in association with a decline in DDAH activity. In one of these. and levels correlate with the severity of erectile dysfunction (76). supporting the use of supplemental L-arginine for erectile function. Cavernosal ADMA was negatively correlated with the intra-cavernosal pressure (79).
In a small randomized clinical trial with cross-over design. as L-NAME (a NOS inhibitor) and ODQ (an antagonist of cGMP synthesis) blocked the effect of L-arginine. 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.8 g/d for 2 wk) subjectively restored erectile function as well as vaginal penetration ability in 6 of 15 patients completing the study.metabolized to NO by NOS. L-arginine 5g/day was administered for 6 weeks (83). The major difference between this trial and the others was the smaller dose of L-arginine in the negative trial. All nine patients treated with L-arginine who improved were noted to have low urinary NOx at the initiation of the study. which may have been ineffective at increasing plasma L-arginine levels (85). whereas sildenafil potentiated the arginine induced relaxation. L-arginine administered orally (2. The effect of L-arginine was due to its conversion to NO. Not all studies have been positive. This beneficial effect was not reported during the placebo phase (82). crossover design. 32 patients with impotence were administered L-arginine (1. Several small clinical trials are supportive of L-arginine supplementation for erectile function. 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. The level of urinary NOx in this subgroup had doubled by the end of the study. suggesting that patients with low levels of NOS activity may be particularly benefited by L-arginine supplementation (83). In a subsequent randomized clinical trial. had no effect. In one small clinical study of 20 impotent men using a placebo controlled. There was no subjective improvement in erectile function (84). .5 g/day) or placebo.
n=10). double-blind. 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). Gentile and colleagues assessed in 40 diabetic patients a dietary supplement product containing a combination of propionyl-L-carnitine. treatment periods of two weeks). and increased frequency of intercourse. The group receiving the dietary supplement product (group A. One month of treatment was associated with subjective improvement. Another recent study assessed a dietary supplement product that contained L-arginine aspartate and pycnogenol (88). n=10) was compared to those receiving vardenafil 20 mg twice weekly (Group B. Patients reported sexual function from diaries. By contrast. crossover design. Pycnogenol is derived from pine bark extract and In a randomly contains oligomeric proanthocyanidins that have anti-oxidant effects. placebo-controlled. At the end of treatment. the group receiving placebo showed no change in the IIEF5.Several studies have examined the use of L-arginine in combination with other nutritional agents. L-arginine and nicotinic acid (87). The group receiving the dietary supplement had 50% of the improvement of the vardenafil group. . allocated. the group receiving vardenafil alone manifested an increment of 4 points on 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. or double placebo (Group D n=10). or the combination of vardenafil with the dietary supplement(group C. 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). There was a tendency of the group receiving both vardenafil and the supplement to have a slightly better outcome. In a randomized placebo controlled study. Erectile function was estimated with the International Index of Erectile Function (IIEF5) questionnaire.
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. reinfarction. with improvements in endothelial vasodilator function. for 30 days) or placebo in addition to standard of care. the clinical evidence is weak for the utility of L-arginine as a therapeutic adjunct in the treatment of erectile dysfunction.02. A number of studies have indicated benefit of L-arginine supplementation in patients with coronary artery disease and congestive heart failure. Thus. and little pharmacokinetic or pharmacodynamic information has been obtained.How hard is the evidence? What is apparent from the discussion above is that though the pre-clinical foundation is strong. resuscitation.i. . there was a strong tendency toward a reduction in cardiovascular morbidity (89).39-1. in the largest study of short-term arginine therapy. shock/pulmonary edema or recurrent myocardial ischemia. little is known regarding the long-term consequences of supplementing dietary arginine. 792 patients with acute myocardial infarction (with ST segment elevation) were randomized to oral Larginine (3.06). The clinical trials have been conducted in small groups of patients. safety concerns have not been addressed.0 t. there was a tendency for a shortterm benefit. Proper dose-ranging studies were not performed. The end point was the composite of 30 day cardiovascular death. improvements in exercise tolerance.o. No serious adverse effects were observed during L-arginine supplementation. in the short-term after a myocardial infarction. Furthermore. p=0. In this randomized clinical trial. penile plethysmography). Furthermore. More importantly. L-arginine was well tolerated. 95% CI 0. and relief of symptoms (58-62). These major adverse cardiovascular events occurred in 24% patients treated with L-arginine and 27% with placebo (OR 0.d p.63. because of the small numbers and short duration of treatment.
for power calculation and for dosing for the subsequent definitive trial. a trend was observed for a greater increase in walking distance in the group treated with 3 g L-arginine daily.However. There was no significant difference observed in absolute claudication distance between the groups. 3. and there was a trend for an improvement in walking speed in patients treated with L-arginine. However. one long-term study suggests that chronic administration of Larginine can induce a form of tolerance (91). Treadmill testing was performed prior to administration of the study drug and again after 12 weeks of treatment. 6 or 9 g of L-arginine daily in three divided doses for 12 weeks (85). in a subsequent study. . The difference between these studies may be related to the duration of therapy. This trial was terminated early by the data and safety monitoring board when 8 deaths occurred in the arginine treated group (90). 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. with no significant adverse effects of Larginine administration. In 220 patients with peripheral arterial disease (PAD) we studied the potential benefit of L-arginine supplementation on endothelial vasodilator function and functional capacity. This pilot study provided data for safety. In a pilot study. Although abundant evidence indicates that short-term administration of L-arginine is beneficial for endothelial vasodilator function and symptoms in patients with cardiovascular disease. patients with PAD and intermittent claudication (n = 80) were randomly assigned to oral doses of 0. The study drug was well tolerated.
Nobel laureate Louis Ignarro has given his imprimatur to a product . 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 supplementation significantly increased plasma L-arginine levels. the improvement in the L-arginine-treated group was significantly less than that in the placebo group (28% versus 12%. long-term administration of L-arginine does not appear to be useful in patients with intermittent claudication and PAD. Thus. It is possible that other methods to enhance plasma L-arginine levels would be more effective.05).In the definitive study. L-arginine undergoes extensive first-pass metabolism by arginase in the small intestine and liver. in patients with PAD. Furthermore. oral L-arginine (3 g/d) versus placebo for 6 months was assessed in subjects (n= 133) with intermittent claudication due to PAD. This latter study raises questions about the long-term efficacy and safety of L-arginine supplementation. Administration of L-citrulline (the precursor of Larginine) escapes this degradation pathway. The primary end point was the change at 6 months in the absolute claudication distance as assessed by the Skinner-Gardner treadmill protocol. However. measures of nitric oxide availability (including flowmediated vasodilation. the expected placebo effect observed in studies of functional capacity was attenuated in the L-arginine-treated group. Although absolute claudication distance improved in both L-arginine. vascular compliance. L-citrulline 3g bid increased urinary nitrate and cGMP by 30% (reflecting increased NO synthesis and bioactivity). p<0. long-term administration of L-arginine does not increase nitric oxide synthesis or improve vascular reactivity. plasma and urinary nitrogen oxides. In this study. Indeed. and increases plasma L-arginine levels to a greater extent than does L-arginine supplementation (92).and placebotreated patients. As opposed to its short-term administration. and plasma citrulline formation) were reduced or not improved compared with placebo.
but the evidence is weak. particularly for the many ED patients that also have known or occult coronary artery disease. Herbal Viagra and NO There are a number of other dietary supplements that purport to improve sexual function. issue a warning or require that the product be removed from the market). . and if necessary can take remedial action (eg. In which case.containing L-citrulline (Niteworks®) that is said to increase NO production and enhance physical and sexual functioning. Some of these may be of modest benefit. There is a known interaction of exogenous nitrates with PDE-5 inhibitors. The Food and Drug Administration has banned several of these products. Some of these agents may be hazardous. Manufacturers are obliged to follow good manufacturing practice (GMP) regulations promulgated by the US Food and Drug Administration (FDA). These regulations require that the product meets purity specifications. However. manufacturers don't need FDA approval before going to market with their product. 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. such that the risk of hypotension is increased. particularly during coadministration of pharmaceutical agents for erectile dysfunction. Whether this adverse interaction might occur with L-arginine has not been definitively studied. Once the product is on the market. the FDA is responsible for monitoring its safety. some of which have contained PDE-5 inhibitors (36). However. there are no long-term randomized clinical trials assessing the safety and efficacy of this dietary supplement for its intended use. studies need to be done to validate this use. It is important to know that the regulation of supplements is not as rigorous as for pharmaceuticals.
yohimbe. and the limitations of the FDA budget. a manufacturer of a calcium supplement can maintain that the product promotes bone health.The claims made by the distributors of the dietary supplement are regulated by the Dietary Supplement Health Education Act (DSHEA) of 1994. these companies can sell their products at a lower cost (which is good for the consumer). a precursor of testosterone). but prohibits claims regarding treatment of a disease. Epimedium is another traditional Chinese medicine for erectile dysfunction that contains an active principle (icariin) with PDE-5 inhibitory activity (38). because of the number of products on the market. Dietary supplements for sexual function include Korean red ginseng (Panax ginseng). frequently scientists at universities not affiliated with or supported by the health food companies. DHEA (dehydroepiandrosterone. anti-oxidants (Vitamin E. which is one of the reasons that the medical community is skeptical of dietary supplements. They must also include a disclaimer that the FDA hasn't evaluated the claim. and has been employed as a traditional Chinese remedy for diverse disorders. but cannot claim that it is useful for the treatment of osteoporosis. it is difficult to provide thorough oversight regarding the safety of these products once on the market. Small studies of ginseng suggest that the herb is safe and has modest benefit for individuals with erectile dysfunction (37). But because they do not support research. Epimedium (horny goat weed). folate and zinc). However. The claims that health food companies make about their products are usually based on research performed by other parties. Ginseng is an herb often brewed as a tea. no randomized clinical trials have assessed safety or efficacy. ginkgo and L-arginine. and they generally do not subject their products to rigorous testing. Finally. For example. Yohimbe is derived from the bark of a West African . they generally do not develop substantially new or more effective therapies (which is not good for the consumer). as one can imagine. Because they don’t perform their own research. which permits the distributor to make structure or function claims.
There is pre-clinical evidence. Conclusion There is compelling evidence that the NOS pathway is critical for erectile function. The nutritional product with . The major active moiety is yohimbine. However. Therefore herbal supplements that enhance NO synthesis or reduce its degradation could be useful for enhancing erectile function. which is of particular concern for individuals with cardiovascular disease (common in men with erectile dysfunction). yohimbine can increase heart rate and blood pressure (42). an alpha 2 adrenergic antagonist. The rationale for the use of DHEA is that this chemical is a precursor to testosterone. providing a rationale for its administration in erectile dysfunction. there is little evidence for the efficacy of DHEA (43). yet questions remain regarding efficacy and safety. However. and thereby preserve NO from oxidative inactivation so as to improve endothelium dependent vasodilation (44). gingko may preserve NO from oxidative degradation (45) to improve vascular reactivity.evergreen containing a variety of pharmacologically active chemicals. L-arginine is the precursor for NO. good sources of information include the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements (46. For that matter. Similarly. For more information regarding the other dietary supplements. and some clinical experience indicating that yohimbine can enhance sexual function (3941). The level of evidence that a dietary supplement can enhance NO production is arguably the strongest for L-arginine. The antioxidant vitamins may reduce oxidative stress. the literature supporting the use of pharmaceutical testosterone for erectile dysfunction is mixed (1).47). and that a derangement of neuronal and endothelial NO signaling is a major contributor to erectile dysfunction in a majority of patients. Furthermore. bolstering the NOS pathway with PDE-5 inhibitors has been a very effective pharmacological approach to treating impotence.
is risky. because erectile dysfunction is often associated with cardiovascular disease. RC2HL103400. Acknowledgements and disclosures This work was supported by grants from the National Institutes of Health (RO1 HL75774. there is no evidence of long-term efficacy and safety. Furthermore. However. References: 1. Dr. Sampson M. Finally. Garritty C. However. and offered effective pharmacotherapy for sexual function. 1U01HL100397). as definitive trials of chronic L-arginine administration have not been done in patients with erectile dysfunction. MacDonald R. self-treatment with herbal remedies. which in pre-clinical studies and in small clinical studies of short duration. Ansari MT. . P50HL083800.the strongest rationale for this use is L-arginine. Individuals with erectile dysfunction should be evaluated by their physician for cardiovascular disease. A few randomized clinical trials of short duration in small groups of patients suggest modest benefit. Cooke is the inventor of patents owned by Stanford University for diagnostic and therapeutic applications of the NOS pathway from which he receives royalties. Fox S. Coulter Translational Research Grant Program. and The Wallace H. Daniel R. Dr. Cooke is a consultant for NiCox. Bella AJ. with respect to the notion that L-arginine or other dietary supplements may safely and effectively improve erectile function. Wilt TJ. Oral Soares-Weiser K. Yazdi F. Tsertsvadze A. Fink HA. R21 HL085743. has been shown to enhance NO synthesis. the California Tobacco Related Disease Research Program of the University of California (18XT-0098). the evidence is soft. K12 HL087746. there is scant information regarding potential interactions with other medications. Moher D. in the absence of physician supervision.
Cyclic GMP-dependent protein kinases and the cardiovascular system: insights from genetically modified mice. J Androl.166:746–255. McVary KT. Bush PA. Andon N.99:4061–4066. Musicki B. 2. Stief CG. Characterization and localization of nitric oxide synthase isoforms in the BB/WOR diabetic rat. de Jonge H. Tran KB. Urol Res. Paduch DA. 2009 Nov 3. Ross AE. Mulhall JP. Bian K. 2003 Nov 14. 11. 2003 Jan 1. 2006. regulation. Nitric oxide (NO)--biogeneration.93(10):907-16. Champion HC. and relevance to human diseases. Loscalzo J. Ignarro LJ. noncholinergic neurotransmission. Chitaley K.97:1047–1052. J Clin Invest 1991 Nov. 8.88(5):1663-71 10. N Engl J Med. Bervig TR. Siroky MB. Front Biosci. Dorey FJ. 4. 3. 12. 9. Scardino PT. Burnett AL. Mullerad M. Murad F. J Urol. Tal R. Machtens SA. Epub 2009 Apr 2. Rossitch E. Jonas U. Master TA. Lohmann SM. Azadzoi KM. Immunocytochemical distribution of nitric oxide synthase in the human corpus cavernosum: an electron microscopical study using the tyramide signal amplification technique. Uckert S. 2009 Jul- modification of constitutive nitric oxide synthase in the penis. Becker RE.phosphodiesterase-5 inhibitors and hormonal treatments for erectile dysfunction: a systematic review and meta-analysis. Circ Res. Gonzalez CM. Kobylarz K. Dzau VJ: Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. Gallis B.29: 168–172. Fluid shear stress-induced nitric oxide production in human cavernosal endothelial cells: inhibition by hyperglycaemia. Posttranslational J Androl. Musicki B. Zelner DJ. 2001. Cooke JP. 2004. Stanarius A. Podlasek CA. Aronson WJ.326(2):90-4. Hofmann F. 1992 Jan 9. Mu¨ ller A. Ann Intern Med. 6. 5. Donohue JF. Teal TH. 2001. Burnett AL. Effect of chronic ischemia on constitutive and inducible nitric oxide synthase expression in erectile tissue. Bivalacqua TJ. Snyder SH. Proc Natl Acad Sci U S A. Li PS. Moriaruty JL. 7. The functional and structural consequences of . Sullivan CJ.25:382– 388. Palese MA. Aug. BJU Int. Hurt KJ. Engel K. 2002. Wessells H. Walter U. Cohen-Gould L.8:d264-78. Wolf G. McKenna KE. Akt-dependent phosphorylation of endothelial nitric oxide synthase mediated penile erection. Crone JC. Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic. Rajfer J.151(9):650-61 Feil R.30(4):352-62.
Loscalzo J. Cooke JP. Mendelsohn ME. Cooke JP: Nitric oxide regulates monocyte chemotactic protein-1. Singer AH. Tsao PS. Smick D.244-253. Cooke JP. Zera P. Circulation 1995 Dec 15. Wang B. Zhang L. Butcher EC. Cooke JP. Buitrago R. Davies PF. Shyy JY. In: Rubanyi G. Lewis NP.cavernous nerve injury are ameliorated by sildenafil citrate. Circ Res 1989 Sep. Loscalzo J: N-acetylcysteine potentates platelet inhibition by endothelium-derived relaxing factor. 13. 1990 17. vol I. Circulation 1996 Oct 1. Cooke JP. Buitrago R. Tsao P. Endothelium-Derived Relaxing Factors. Drexler H. McEvoy LM. Chan JR. Kaneda Y. J Clin Invest 1992 Sep. Cooke JP: Fluid flow inhibits endothelial adhesiveness: Nitric oxide and transcriptional regulation of VCAM-1. Lewis NP. Billingham ME: Anti- atherogenic effects of L-arginine in the hypercholesterolemic rabbit. Dzau VJ: Gene therapy inhibiting neointimal vascular lesion: In vivo transfer of endothelial cell nitric oxide synthase gene.109(15):1813-8.92(4):1137-41 23.5:1126– 1136.89(5):2176-82 18. Coleman SM. Alpert S. 86(1):228-34 14.16(1):44-50 . Tsao P. Andon NA. Amarante P. Dzau VJ: Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest 1990 Jul. Arterioscler Thromb Vasc Biol 1996 Jan. Rowan RA. Loscalzo J: Flow- mediated endothelium-dependent effects on platelet and vascular reactivity. J Sex Med.65(3):789-95 16. Cooke JP. Cooke JP: Exposure to shear stress alters endothelial adhesiveness: Role of nitric oxide. Circulation 1997 Aug 5. Switzerland: Karger Press. Tsao PS. Gibbons GH. 2004 Apr 20. Candipan RC. 2008. Gallagher SJ. Buitrago R.pp. Morishita R. Stamler J. Wang B. Tsao PS. 15. Creager MA. Vanhoutte PM (eds). Cooke JP: Regression or progression: Dependency upon vascular nitric oxide. Nakajima M. Mendelsohn ME. Circulation 1994 May. Andon N. von der Leyen HE.94(7):1682-9 20.92(12):3513-9 19.96(3):934-40 21. Stamler JS. Mendelsohn ME. Basel.90(3):1168-72 22. Tsao PS. Cooke JP: Asymmetrical dimethylarginine: the Uber marker? Circulation. Proc Natl Acad Sci USA 1995 Feb 14. Davies PF. Cooke JP: Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine.
Circulation. Bivalacqua TJ.102:11870–11875 30. Hartmann M. Skatchkov M. Keaney JF Jr. Griendling K. J Sex Med. Circulation.2:347–357. Meinertz T. Science.The pathobiology of diabetic complications: a unifying mechanism. 25.101:9121–9126. Glycosylation of nucleocytoplasmic proteins: signal transduction and O-GlcNAc. J Sex Med. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. 2001. Suwaidi JA. Hink U. 29. Lewis RL. Britten MB. Mollnau H. Predictive value of noninvasively determined endothelial dysfunction for longterm cardiovascular events in patients with peripheral vascular disease. Alvarez X. Kramer MF. Inactivation of phosphorylated endothelial nitric oxide synthase (Ser-1177) by OGlcNAc in diabetes-associated erectile dysfunction. Lerman A. Usta MF.2:187–197. Menzoian JO. 2005. Diabetes. Brownlee M. Gokce N. 31. Webb RC. 2005c. Schachinger V. Kendirci M. Musicki B.41(10):1769-75 27. Munzel T. Champion HC. 2001 Feb 2. Kramer MF. Higano ST.101(9):948-54. Warnholtz A. 2000 Apr 25. Burnett AL. Nishimura RA. Wells L. Forstermann U. Pradhan L. . Musicki B.291:2376–2378. RhoA/ Rho-kinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction.Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Zeiher AM. Harrison DG. Superoxide anion production in the rat penis impairs erectile function in diabetes: influence of in vivo extracellular superoxide dismutase gene therapy. Usta MF. Circ Res. 33. Champion HC. J Am Coll Cardiol. Li H. 32. Burnett AL. Matheis E.24. 2003 May 21. Vita JA.54(6):1615-25. Becker RE. Hellstrom WJ. Hellstrom WJ. Holmes DR Jr. Chitaley K. Stahl RA. Age-related changes in phosphorylation of endothelial nitric oxide synthase in the rat penis. Proc Natl Acad Sci U S A. 26. Cellek S. 2005. Kadowitz PF. Hunter LM. Hart GW. Vosseller K. 2004.101(16):1899-906. 2000 Mar 7. Watkins MT. Becker RE. Kadowitz PJ. Nedeljkovic ZS. 2005 Jun. Thaiss F. 28. Bivalacqua TJ.88(2):E14-22. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Hamasaki S. Mills TM. Oelze M. Proc Natl Acad Sci U S A.
Champion HC. 41. . Dal Cero E. 2008 Sep.71(9):1513-7.gov/Safety/Recalls/EnforcementReports/2008/ucm120534. Black A.fda. Laughlin MH. Jang DJ. Shin BC. 35. 2008. Frei B. Lee MS. Becker RE.12(4):104-12. Emerson L. Kuzmarov I. Red ginseng for treating erectile dysfunction: a systematic review.5:552–561. Guidance for Industry: Botanical drug products. Food and Drug Administration website. Yoshizumii M. Burnett AL. Barkin J. "Long-lasting effects of yohimbine on the ejaculatory function in male dogs". Gerhard MD. Keaney JF Jr. Zironi E. 39. 1996 Mar 15. Vita JA.201. Pharmacological and physiological aspects of sexual exhaustion in male rats. Rodríguez-Manzo G. Ernst E. 44.2220/biomedres. 38. Epub 2008 Sep 9. p45. 2009 Dec.66(4):444-50. Dec 3. 2005. Center for Drug Evaluation and Research (CDER). Dell'Agli M. Yonezawa A. Low-fat diet and exercise preserve eNOS regulation and endothelial function in the penis of early atherosclerotic pigs: a molecular analysis.44(3):257-63. Aging Male. Androgens and sexual function: a placebo-controlled. June 2004 43. Circulation. dehydroepiandrosterone in men with sexual dysfunction and androgen deficiency.S. http://www. Day A. 2003 Jul. Matera R. doi:10. 2008 Oct. Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Biomed Res 26 (5): 201–6.34. Belluti F. 36. J Sex Med. Scand J Psychol. Koulouris SN. Department of Health and Human Services Food and Drug Administration. J Nat Prod. Turk JR. (2005). Sakurada S. Kramer MF. Burnett AL. Epub 2008 Jun 9. U. Potent inhibition of human phosphodiesterase-5 by icariin derivatives.S. Musicki B. Amano T. PMID 16295696.68:226–232. Liu T. Mol Pharmacol. 2008.93(6):1107-13. Enforcement report.htm 37. PMID 12914589 40. Galli GV. Bosisio E. Erection capability is potentiated by chronic sildenafil treatment: role of blood flow-induced endothelial nitric oxide synthase phosphoryrylation. double-blind study of testosterone vs. Lee YC. Ebiko M. Musicki B.26. see National Center for Complementary and Alternative Medicine 42. Jin L. Strong T. randomized. Kimura Y. Fernández-Guasti A. Levine GN. Liu T. Pagliuca G. Morales A. U. Br J Clin Pharmacol.
nih. Meinzer K.gov/ http://dietary-supplements. Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Svendsen E. Hirsch AT.59:35–42. Mügge A. 48. 55.90(4):1248-53 50. Epub 2009 Mar 7. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. Just H. Forstermann U. Randall MD. Pathophysiological consequences of atherosclerosis extend into the coronary microcirculation.15(1):26-9. Andon NA. Circulation 1991 Mar. Chilian WM. Kim JH. Creager MA: Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta. Dzau VJ. L-arginine does not restore endothelial dysfunction in atherosclerotic rabbit aorta in vitro. Restoration of endotheliumdependent responses by L-arginine. Harrison DG.338:1546–1550. Lu XW.info. Barber L. Clarkson P.nih. Correction of endothelial dysfunction in coronary micro-circulation of hypercholesterolaemic patients by L-arginine. Davis MJ. Mitchell JA. Girerd XJ. 51. L-arginine reverses the impairment of nitric oxide-dependent collateral perfusion in dietary-induced hypercholesterolaemia in the rabbit. Donald AE. Cannon MS. Li XS. et al. Chin J Integr Med.70:465–476. Proc NatlAcadSciUSA. 46. J Clin Invest 1992 Oct.97: 1989–1994.45. Zheng WY. Lancet 1991. McCredie R. Ye SH. Drexler H. Davies MG. Powe AJ. Cooke JP: L- arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. 53. Coleman S. Gallagher SJ. Griffith TM. http://nccam. J Clin Invest 1996. 1991 . Schmidt HHHW. Robinson J. 56. Effect of Ginkgo leaf extract on vascular endothelial function in patients with early stage diabetic nephropathy. 47. Blood Vessels. Circ Res 1992. 1991. Control of accelerated vein graft atheroma with the nitric oxide precursor: L-arginine. 52. Pollock JS. Zeiher AM. 87:53–59. Clini Sci (Colch) 1994. Kuo L.28(5):354-7. Creager MA. Ujiie H. Lou SX. Hagen PO. 2009 Feb.83(3):1057-62 49. J Surg Res 1995. Murad F. Adams MR. 54.gov/ Cooke JP. Girerd XJ. Dalen H. Warner TD. Nakane M.88:10480-10484. .
Nat Struct Biol. et al. L-arginine improves exercise capacity in patients with stable angina. Lancet.N’G- dimethylarginine and NG. Holmes DR Jr. Circulation 1996. Kuga T. Frolich JC. 59. Scalera F.57. Sih R. Ignarro LJ. Circulation 1998. Pillai K.8(8):679-83. Identification of two human dimethylaminohydrolases with distinct tissue distributions and dimethylarginine homology with microbial arginine deiminases. McAlister M. Herbaczynska-Cedro K. Phelan J.114(3):295-306. Calver A. 343: 209-214. Effects of L-arginine supplementation on endothelium-dependent coronary vasodilation in patients with angina pectoris and normal coronary arteriograms. Böger R. 154: 179-184. 66.95:2068–2074. Mullen KA. Eickelberg O. 62. Leone A. Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase. 2007 Jun. Hirooka Y. Circulation 1996. Epub 2007 Apr 1 64. 339: 572-575. Chamiec T. Randomized. Santa Maria J. double-blind. 1999.29:157A. Bank AJ. the Bode-Böger SM. Circulation 1998. Long-term L- arginine supplementa-tion improves small-vessel coronary endothelial function in humans. 58. Egashira K. Zakrzewicz D. Chubb A et al. 65. McDermott JR.97:2123–2128. placebo-controlled study of supplemental oral L-arginine in patients with heart failure. Herbaczynska-Cedro K. Pharmacol Ther. Rector TS. 1992. NG. Vallance P.94:130–134. 63. Biochem J. BMC Pulm Med. 2009 Jan 29.9:5. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. J Am Coll Cardiol 1997.93:2135–2141. Leiper J. Alexander K.80:331–333. Tschmumperlin LK. Tilley S. Burnett JC Jr. 61. Am J Cardiol 1997. McKinley LJ. Biochem J. Vallance P. Lerman A. Thiele W. 1976. Higano ST. From arginine methylation to ADMA: a novel mechanism with therapeutic potential in chronic lung diseases. 60. et al. Ceremuzynski L. Tomasz C. The L-arginine paradox: Importance of L-arginine/asymmetrical dimethylarginine ratio. Bode-Böger SM. 2001 Aug. Murray-Rust J. Takeshita A. Santa Maria J. Leiper JM. . 67. McDonald N. Ceremuzynski L. Effect of supplemental oral L-arginine on exercise capacity in patients with stable angina pectoris. 68.NG-dimethylarginine. Mohri M. Studies on the catabolism of NG-methylarginine.
74. Tsuji H.48(6):1004-11 78. Lambert-Hammill M. Int Urol Nephrol. Steenpass A. Tsao PS. Wenske S. Zoccali C. Aktoz M. Krzyzanowska K. Nair N. et al. Shin DS. 75. Solomon H. Tsao PS. Kimoto M. Role of Cooke JP: Impaired nitric oxide synthase pathway in diabetes mellitus: asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Stuhlinger MC. Ng MK. Dec. 1999. Asymmetric dimethyl arginine levels correlate with cardiovascular risk factors in patients with erectile dysfunction. Lin KY.99(24): 3092-5). Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Tsao PS. Mallamaci F et al. Atherosclerosis. Asymmetric dimethylarginine predicts major adverse cardiovascular events in patients with advanced peripheral artery disease. Ito A. Kimoto M. 99:1141-1146 73. 2001.69. coronary artery disease in men with erectile dysfunction. Miyazaki H. Wierzbicki AS. Lyttle K. in press. Circulation 1999 Jun 22. 2005 H. 71. Arteriosclerosis. Böger RH. Turan FN. 104:2569-2575. Her JH. Weatherby C.185(2):421-5. Mittermayer F. 2006 Apr. Cooke JP. Wolzt M. Ventura R. Kaplan M. 2001. Circulation.26(11):2536-2540. Ito A. Barutcu A. Bode-Boger S. Klemm Elevation of asymmetrical dimethylarginine (ADMA) and Eur Urol. Minar E. thrombosis. Amighi J. Lumb PJ. Balint RF. Schillinger M. Tatlı E. Assessment of the relationship between asymmetric dimethylarginine and severity of erectile dysfunction and coronary artery disease. and vascular biology. Noldus J. Exner M. Mlekusch W. Lancet. Cooke for Endothelial Dysfunction : Dysregulation of JP. Adimoolam S. Harada RK. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Muller M. 1-28-10) 76. Novel Mechanism Dimethylarginine Dimethylaminohydrolase 70. Reaven G. Sabeti S. Demir M. 358:2113-2117. Asagami T. Circulation 2002 Aug 20. Matsuoka H. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Aktoz T. Maas R. Kimoto M. Wilson AM. Circulation. Kielstein J and Cooke JP: Asymmetric dimethylarginine predicts adverse cardiovascular events and mortality in peripheral arterial disease (Vascular Medicine.106(8):987-92 72. Adimoolam S. 2010 Jan 21 77. Jackson G. 2006. Zabel M. Atakan IH. Cooke JP. Ogawa T. . Schwedhelm E. Altun A.
86.21(4):228-34 80. placebo-controlled. BJU Int. 88.158:942– 947. double-blind. Szuba A. Dinelli N. Paick JS. Effectiveness of oral L- arginine in first-line treatment of erectile dysfunction in a controlled crossover study. Epub 2007 Aug 16. Chen J. Gonzalez-Cadavid NF. Laidlaw S. Janik K. Improvement of erectile function with Prelox: a randomized. Lizza EF. J Urol 1997. Effect of propionyl-L-carnitine.10(4):265-274. Hervé JM. Lebret T. 2005.25(9):2223-8. 2009 Sep. Gniot J. Trost L. Engelmann U. Int J Impot Res 1994. Mathers MJ. Gorny P.6:33–35. Laskowski H. 81. Matzkin H. 2009 Jul-Aug. Moody JA. Szpajer M. 2008 Mar-Apr. Kim SW. Int J Impot Res. Vernet D. Maciejewski P. 2002 Jun. Antonella Bertozzi M. Cooke JP. Dimethylarginine dimethylaminohydrolase in rat penile tissue: reduced enzyme activity is responsible for erectile dysfunction in a rat model of atherosclerosis. Gentile V. placebo-controlled study. 2007 Oct. Ashraf Virmani M. Park K. Rohdewald P. on erectile dysfunction.83(3):269-73. Effects of long- term oral adminis-tration of L-arginine on the rat erectile response. Rajfer J. Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind. Drozdowska D. crossover trial. Rizzo C. 1999 Feb. Optimizing nitric oxide production by time dependent L-arginine administration in isolated human corpus cavernosum. Iaina A. Worcel M. KawkaEfficacy and safety of oral l- Urbanek T. Eur Urol. Efficacy and safety of a novel combination of L-arginine glutamate and yohimbine hydrochloride: a new oral therapy for erectile dysfunction. Effect of large doses of the nitric oxide precursor. randomized. Curr Med Res Opin. Chernichovsky T.79. Stanislavov R.63(4):220-3 85.41(6):608-13 87. Antonini G. 83. Lee DG. 84. Botto H. Zorgniotti AW. Bednarz B. Koverech A. Gessek J.178(4 Pt 1):1543-8. Oka RK. Nikolova V. Hellstrom WJ. . 82. J Urol. Kadowitz PJ. Braun M. Klotz T. Gur S. Urol Int. Wollman Y. L- arginine. 1999. Int J Impot Res. Sofer M. Giacomini JC. Vascular medicine. L-arginine and nicotinic acid on the efficacy of vardenafil in the treatment of erectile dysfunction in diabetes. Jaxa-Chamiec T. A pilot study of L-arginine supplementation on functional capacity in peripheral arterial disease.20(2):173-80. Bloch W. 89.
. 92. Schulze F.62(5):421-7. Hare JM. 91. Spickler W. L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. Gerstenblith G. Kass DA. Results of the multicenter. Jung D. 2007. Jambrecina A. 2008 Jan.arginine in acute myocardial infarction. Kardiol Pol. Pharmacokinetic and pharmacodynamic properties of oral Lcitrulline and L-arginine: impact on nitric oxide metabolism. Nair N. randomized. Cooke JP. Epub 2007 Jul 27. Kelemen MD. Townsend SN. placebo-controlled ARAMI pilot trial. Schwedhelm E. Jama. doubleblind. Circulation. Becker LC. Wilson AM. Champion HC. 90. Capriotti A.116(2):188-195. Balasubramanian N. Lukacs Z. Schulman SP. Freese R.295(1):58-64. Br J Clin Pharmacol. 2006. Böger RH. Ernst KV. Forman S. Harada R. L-arginine supplementation in peripheral arterial disease: no benefit and possible harm. Maas R.65(1):51-9. 2005 May. Terrin ML.
This action might not be possible to undo. Are you sure you want to continue?