L-Citrulline: Restoring Erectile Function (Viagra Doesn’t)

As we reported more than a year ago in our February 2010 LMR review -- Managing Erectile Dysfunction -- When Viagra Doesn’t  -- phosphodiasterase-5 (PDE-5) inhibitors, e.g., sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis), are ineffective in 30-40% of men diagnosed with erectile dysfunction (ED).  Why? Because the PDE-5 inhibitors help restore erectile function by selectively blocking normal hydrolysis of cGMP, thus promoting cGMP accumulation and partially reversing deficiencies in the NO/cGMP pathway. The key word here is “partially” since insufficient production of NO precludes the formation of sufficient cGMP to enable benefit from a PDE-5 inhibitor.

NO is the physiologic signal essential to penile erection because NO is required for the activation of soluble guanylate cyclase to convert guanosine triphosphate to cyclic guanosine monophosphate (cGMP). cGMP, in turn, triggers penile smooth muscle relaxation.  Thus, if PDE-5 inhibitors are to be of any help to men unresponsive to these drugs, the amount of available NO must be increased in their penile tissue. 1

Recent studies show that natural agents, specifically, the NO-producing substrates, L-arginine and L-citrulline, can do so. L-arginine is produced in the body from L-citrulline, and the most recently published research (discussed below) suggests supplementation with L-citrulline, rather than L-arginine, is the better option.

Although supplemental L-arginine is readily absorbed and well tolerated in single doses of 3-6 grams,2  ~50-70% of ingested L-arginine is rapidly converted in the body to ornithine, primarily by the enzyme arginase.3  Arginase expression and activity is upregulated in the presence of oxidized LDL and conditions associated with endothelial dysfunction, including -- in addition to ED -- hypertension, heart failure, atherosclerosis, and diabetic vascular disease – co-morbidities  so frequently seen in men with ED that a growing number of studies recognize ED as a reliable marker of not only overt cardiovascular disease, but also of subclinical systemic vascular disease.4,5  Thus, in the man with ED, arginase is highly likely to be upregulated, which translates to a greater than “normal” conversion of supplemental L-arginine to ornithine and urea.

Furthermore, L-arginine, in addition to its roles as substrate for NOS and arginase, is also a precursor for the synthesis of proteins, urea, creatine, vasopressin, and agmatine. In addition to NOS, L-arginine that escapes metabolism by arginase is targeted by three other enzymes: arginine:glycine amidinotransferase (to become creatine); arginine decarboxylase (to become agmatine); and arginyl-tRNA synthetase (to become arginyl-tRNA, a precursor to protein synthesis).

Sustained-release preparations of L-arginine have been suggested as a means of helping to maintain blood levels over time, yet arginase’s substantial intestinal and hepatic metabolism of L-arginine to ornithine and urea, combined with L-arginine’s use for other functions in the body, significantly lessens the likelihood of optimal improvement in NO production from oral supplements of L-arginine alone.

In contrast, L-citrulline escapes intestinal or liver metabolism, and enters the kidneys where it is rapidly converted into L-arginine. Oral L-citrulline supplementation (3 grams b.i.d.) was recently shown in a double-blind, randomized, placebo-controlled cross-over study to increase the plasma L-arginine concentration and cGMP, and to augment NO-dependent signaling much more effectively than L-arginine.6

Encouraged by this research, which confirmed the rationale for oral L-citrulline supplementation as a donor for the L-arginine/NO pathway in patients with ED,  researchers in the Department of Urology at the University of Foggia, Foggia, Italy, conducted a single-blind trial, in which 24 men with mild ED (erection hardness score of 3), mean age 56.5 years, received a placebo for 1 month and L-citrulline, 1.5 g/d in 2 doses, for another month.7 The erection hardness score, number of intercourses per month, treatment satisfaction, and adverse events were recorded. All patients completed the study with no adverse events.

Improvement in the erection hardness score from 3 (mild ED--penile rigidity that still allowed some kind of vaginal penetration, but not satisfactory penetration or completion of successful intercourse) to 4 (normal erectile function) occurred in 12 (50%) of the men when taking L-citrulline, and in 2 of the 24 men when taking placebo. All patients reporting an erection hardness score improvement from 3 to 4 were highly satisfied. At the month 2-visit, the men were informed they had received a commercially available nutrient and given the option to continue it or to receive a prescription for a PDE-5 inhibitor. All 12 men who had benefitted chose L-citrulline.

L-citrulline corrects the cause of ED, PDE5-inhibitors do not

Evidence has shown that oral L-citrulline supplementation can reverse the endothelial dysfunction associated with sickle cell disease (2001)8  and pulmonary hypertension (2006)9,  confirming that L-citrullline effectively activates the L-arginine/NO/cGMP/VEGF pathway.

In 2008, it was shown that increased NO production induces corpus cavernosum smooth muscle cell synthesis and the secretion of vascular endothelial growth factor (VEGF), which can restore impaired endothelial function. This provides a rationale for L-citrulline supplementation to not only manage, but reverse penile endothelial dysfunction by correcting the proximate cause of ED. 10

Clinical Pearl: L-citrulline may be of great benefit for your female postmenopausal patients as well. One reason estrogen is cardioprotective is that it inhibits arginase. Researchers have recently shown a close relationship between atherosclerosis and endothelial senescence--and that NO can prevent it—especially in a diabetic model. 16 

Supplementation with the NO-boosting substances, L-citrulline and L-arginine, along with antioxidants, has been demonstrated to delay endothelial senescence despite high glucose levels or a high-cholesterol diet. This delay in endothelial senescence through NO and/or eNOS activation may have clinical utility in the prevention and treatment of atherosclerosis associated with menopause and diabetes, and with aging. 17,18 

PDE5 inhibitors are not innocuous:

  • PDE5 inhibitors cause cardiovascular side effects even in healthy males (i.e., headache, flushing, dyspepsia, visual problems including sudden loss of vision,  and < 10% decreases in systolic and diastolic blood pressures)11
  • are “absolutely contraindicated” in men taking nitrate medications (co-administration of a nitrate is likely to produce a severe, potentially life-threatening hypotensive response), and in patients with severe aortic stenosis, hypertrophic obstructive cardiomyopathy, and pulmonary arterial hypertension13,14,15  
  • should only be used with caution in patients with cardiovascular diseases (and the incidence of “occult” cardiovascular disease in men with ED is quite high),4,5 and in men taking an alpha-blocker or mixed alpha/beta blocker (coadministration may lead to symptomatic hypotension)13
  • are predominantly metabolized by CYP450 2C9 and 3A4, thus inhibitors of this pathway (e.g., cimetidine, erythromycin, digitoxin) and drugs metabolized by these enzymes (CYP3A4 metabolizes simvastatin, atorvastatin, etc.) may increase PDE5-inhibitor plasma concentrations, increasing risk of adverse events11

Conclusion

Given PDE5-inhibitors’ potential for adverse side-effects, a trial of supplementation with L-citrulline, which has been proven to be safe, effective, and psychologically well accepted by patients, and is significantly less expensive than the PDE5-inhibitor drugs, certainly deserves consideration.

Even more importantly for your patient’s long term health and longevity, PDE5-inhibitors do nothing to improve NO production, while using L-citrulline to increase L-arginine availability does.

Increasing systemic levels of L-arginine has been demonstrated to significantly improve endothelial function in individuals with essential hypertension, compromised flow-mediated dilation, arterial stiffness, chronic heart failure, impaired glucose tolerance (MetS) and type 2 diabetes – all  of which are common concomitant medical conditions associated with ED.3, 7 (Current research on this is discussed in Longevity Medicine Strategies for Cardiovascular Disease: Closing the Statin Gap in Endothelial Dysfunction and Insulin Resistance Naturally, with L-Arginine and Citrulline Part I and Part II). Supplementing your ED patients with L-citrulline can provide systemic as well as sexual performance benefits.

Supplementation with L-citrulline may increase the body’s production of nitric oxide (NO) more effectively than L-arginine.

Graphic Created by John Morgenthaler

The NO donor L-arginine is a semi-essential amino acid present in dietary proteins and produced in the body from L-citrulline, another semi-essential amino acid present in watermelon and synthesized in the intestinal tract from glutamine. Ingested L-arginine is first delivered to the intestines and liver where arginase, which converts L-arginine to ornithine and urea, is concentrated. In contrast, L-citrulline avoids intestinal or liver metabolism and enters the kidneys, where it is rapidly converted into L-arginine. Since arginase is much less active in the kidneys, the majority of the L-arginine produced there from L-citrulline is not siphoned off, but goes back into the circulation and is thus made available to the vascular and penile endothelium.

ReferencesClick to Show/Hide References

  1. de Tejada IS.. Therapeutic strategies for optimizing PDE-5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to treat.. Int J Impot Res.. 2004 Jun;16 Suppl 1:S40.
    Abstract

  2. Evans RW, Fernstrom JD, et al.. Biochemical responses of healthy subjects during dietary supplementation with L-arginine.. J Nutr Biochem.. 2004 Sep;15(9):534-9..
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  3. Ochiai M, Hayashi T, Morita M, et al. . Short-term effects of l-citrulline supplementation on arterial stiffness in middle-aged men.. Int J Cardiol.. 2010 Nov 8. [Epub ahead of print] .
    Abstract

  4. [No authors listed] . L-arginine. Monograph.. Altern Med Rev.. 2005 Jun;10(2):139-48. .
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  5. Chang ST, Chu CM, Hsu JT, et al.. Independent Determinants of Coronary Artery Disease in Erectile Dysfunction Patients.. J Sex Med.. 2009 Oct 29. [Epub ahead of print] .
    Abstract

  6. Schwedhelm E, Maas R, Freese R, et al.. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism.. Br J Clin Pharmacol.. 2008;65: 51-59. .
    Abstract

  7. Cormio L, De Siati M, Lorusso F, et al., . Oral L-citrulline supplementation improves erection hardness in men with mild erectile dysfunction. . Urology. . 2011 Jan;77(1):119-22. .
    Abstract

  8. Waugh WH, Daeschner CW, Files BA, et al. . Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results.. J Natl Med Assoc. . 2001;93:363-371. .
    Abstract

  9. Smith HA, Canter JA, Christian KG, et al. . Nitric oxide precursors and congenital heart surgery: a randomized controlled trial of oral citrulline.. . J Thorac Cardiovasc Surg. . 2006;132:58-65. .
    Abstract

  10. Komori K, Tsujimura A, Takao T, et al. . Nitric oxide synthesis leads to vascular endothelial growth factor synthesis via the NO/cyclic guanosine 3=,5=-monophosphate cGMP) pathway in human corpus cavernosal smooth muscle cells.. J Sex Med.. 2008;5:1623-1635..
    Abstract

  11. Görge G, Flüchter S, Kirstein M, Kunz T. . [Sex, erectile dysfunction, and the heart: a growing problem]. . Herz. 2003 Jun;28(4):284-90. .
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  12. Archer SL, Michelakis ED. . Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. . N Engl J Med. . 2009 Nov 5;361(19):1864-71..
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  13. Jackson G, Montorsi P, Cheitlin MD. . Cardiovascular safety of sildenafil citrate (Viagra): an updated perspective. . Urology.. 2006 Sep;68(3 Suppl):47-60..
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  14. [No authors listed] . Sildenafil and mild pulmonary arterial hypertension: unjustified risks, with no tangible benefit. . Prescrire Int. . 2010 Oct;19(109):206..
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  15. Bergot E, Magnier R, Zalcman G. . Phosphodiesterase inhibitors for pulmonary hypertension. . N Engl J Med. . 2010 Feb 11;362(6):559; author reply 560. .
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  16. Hayashi T, Iguchi A. . Possibility of the regression of atherosclerosis through the prevention of endothelial senescence by the regulation of nitric oxide and free radical scavengers.. Geriatr Gerontol Int.. 2010 Apr;10(2):115-30. Epub 2010 Jan 19. .
    Abstract

  17. Hayashi T, Matsui-Hirai H, Miyazaki-Akita A, et al.. Endothelial cellular senescence is inhibited by nitric oxide: implications in atherosclerosis associated with menopause and diabetes.. Proc Natl Acad Sci U S A.. 2006 Nov 7;103(45):17018-23..
    Abstract

  18. T, Juliet PA, Matsui-Hirai H, et al. . l-Citrulline and l-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits.. Proc Natl Acad Sci U S A. . 2005 Sep 20;102(38):13681-6. .
    Abstract

  19. Collins JK, Wu G, Perkins-Veazie P, et al. . Watermelon consumption increases plasma arginine concentrations in adults. Nutrition. . Nutrition. . 2007 Mar;23(3):261-6. .
    Abstract

  20. Ligthart-Melis GC, van de Poll MC, Boelens PG, et al. . Glutamine is an important precursor for de novo synthesis of arginine in humans.. Am J Clin Nutr.. 2008 May;87(5):1282-9. .
    Abstract

 

4 Comments

1. June 10, 2011
3:58am

By Erectile Dysfunction Supplements

this is very interesting thanks. im going to use this information on my blog soon

2. June 13, 2011
1:01am

By Carlos Baca

Great Article
Thank You

3. July 2, 2011
8:32am

By Peter D'Adamo

It has long been known that ASS1 argininosuccinate synthetase, involved in the synthesis of arginine and catalyzing that condensation of citrulline and aspartate to argininosuccinate using ATP, is co-adjacent to the ABO locus. This may explain why ABO seems to be a major distinguishing factor in the response by newborns to inhaled NO therapy.

4. August 2, 2011
6:44pm

By AlekWok

IMPORTANT QUESTION: Can one take Cialis or Viagra WITH Arginine and or Citruline as a way of potentiating the effects of the ED Medication.

Is it safe or should we consider this to be using ED Drugs with a prohibited nitrate?

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Lara Pizzorno is a member of the American Medical Writers Association with 25+ years of experience writing for physicians and the public, Lara is Editor for Longevity Medicine Review as well as Senior Medical Editor for SaluGenecists, Inc. Read more...

Lara Pizzorno, MDiv, MA, LMT

Lara Pizzorno, MDiv, MA, LMT

John Morgenthaler has been active in the field of nutritional medicine since 1986. Today, John travels the world looking for breakthrough nutraceuticals and anti-aging therapies.  He also continues to publish cutting-edge nutrition and medical science books and periodicals. Read more...

John Morgenthaler, Publisher

John Morgenthaler, Publisher