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Restoring Erectile Function with L-Citrulline to Improve Nitric Oxide

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

by Lara Pizzorno, MDiv, MA, LMT

 

Managing Erectile Dysfunction

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 Nitric Oxide (NO) precludes the formation of sufficient cGMP to enable benefit from a PDE-5 inhibitor.

Nitric Oxide 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 Nitric Oxide must be increased in their penile tissue.

 

Supplementation with L-citrulline, is Better than L-arginine

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,  ~50-70% of ingested L-arginine is rapidly converted in the body to ornithine, primarily by the enzyme arginase.  Arginine 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. 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 Nitric Oxide 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.

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. 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.

 

L-citrulline Corrects the Cause of Erectile Dysfunction (ED), PDE5-inhibitors like Viagra, Levitra and Cialis do not

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)  and pulmonary hypertension (2006),  confirming that L-citrulline 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.

 

L-citrulline may be great for your female postmenopausal patients

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 Nitric Oxide can prevent it—especially in a diabetic model.

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 Nitric Oxide and/or eNOS activation may have clinical utility in the prevention and treatment of atherosclerosis associated with menopause and diabetes, and with aging.  

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)

    * 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 hypertension

    * 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:L-citrulline has been proven to be safe and effective

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 Nitric Oxide 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.

 

Keywords: restoring erectile function, l-citrulline, improve nitric oxide, nitric oxide, viagra, Erectile Dysfunction, sildenafil, vardenafil, levitra, tadalafil, Cialis, Nitric Oxide (NO), penile erection, l-arginine, ornithine, oxidized LDL, endothelial dysfunction, hypertension, heart failure, atherosclerosis, diabetic vascular disease, cardiovascular disease, vascular disease, NOS, arginase, intestinal or liver metabolism, kidneys, erection hardness score, erection, intercourses, vaginal penetration, penetration, intercourse, erectile function, reverse the endothelial dysfunction, sickle cell disease, pulmonary hypertension, diabetic model, endothelial senescence, high glucose levels, high-cholesterol diet, aging, PDE5 inhibitors, cardiovascular, longevity, arterial stiffness, chronic heart failure, impaired glucose tolerance

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PRIME Nitric Oxide Activator contains L-citrulline, which converts to L-arginine in the body. Researchers have suggested and reported that L-arginine made from L-citrulline is much more effective at raising NO levels than taking L-arginine directly.
 
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