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source:

L-Citrulline: Restoring Erectile Function (Viagra oesn!t"

#$ Lara %i&&orno' iv' )' L*

)s we reporte+ more than a $ear ago in our Fe#ruar$ , LR review -- anaging

Erectile $sunction -- 0hen Viagra oesn!t -- phospho+iasterase-1 (%E-1" inhi#itors'

e.g.' sil+enail (Viagra"' var+enail (Levitra"' an+ ta+alail (Cialis"' are ineective in 2-

34 o men +iagnose+ with erectile +$sunction (E". 0h$5 6ecause the %E-1

inhi#itors help restore erectile unction #$ selectivel$ #loc7ing normal h$+rol$sis o

c8%' thus promoting c8% accumulation an+ partiall$ reversing +eiciencies in the9/c8% pathwa$. *he 7e$ wor+ here is ;partiall$ since insuicient pro+uction o 9

preclu+es the ormation o suicient c8% to ena#le #eneit rom a %E-1 inhi#itor.

9 is the ph$siologic signal essential to penile erection #ecause 9 is re=uire+ or the

activation o solu#le guan$late c$clase to convert guanosine triphosphate to c$clic

guanosine monophosphate (c8%". c8%' in turn' triggers penile smooth muscle

relaation. *hus' i %E-1 inhi#itors are to #e o an$ help to men unresponsive to these

+rugs' the amount o availa#le 9 must #e increase+ in their penile tissue.

Recent stu+ies show that natural agents' speciicall$' the 9-pro+ucing su#strates' L-

arginine an+ L-citrulline' can +o so. L-arginine is pro+uce+ in the #o+$ rom L-citrulline'

an+ the most recentl$ pu#lishe+ research (+iscusse+ #elow" suggests supplementation

with L-citrulline' rather than L-arginine' is the #etter option.

)lthough supplemental L-arginine is rea+il$ a#sor#e+ an+ well tolerate+ in single +oses

o 2-? grams' @1-A4 o ingeste+ L-arginine is rapi+l$ converte+ in the #o+$ to

ornithine' primaril$ #$ the en&$me arginase. )rginine epression an+ activit$ isupregulate+ in the presence o oi+i&e+ LL an+ con+itions associate+ with en+othelial

+$sunction' inclu+ing -- in a++ition to E -- h$pertension' heart ailure' atherosclerosis'

an+ +ia#etic vascular +isease B co-mor#i+ities so re=uentl$ seen in men with E that a

growing num#er o stu+ies recogni&e E as a relia#le mar7er o not onl$ overt

car+iovascular +isease' #ut also o su#clinical s$stemic vascular +isease. *hus' in the

man with E' arginase is highl$ li7el$ to #e upregulate+' which translates to a greater

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than ;normal conversion o supplemental L-arginine to ornithine an+ urea.

Furthermore' L-arginine' in a++ition to its roles as su#strate or 9 an+ arginase' is

also a precursor or the s$nthesis o proteins' urea' creatine' vasopressin' an+ agmatine.

Dn a++ition to 9' L-arginine that escapes meta#olism #$ arginase is targete+ #$ three

other en&$mes: arginine:gl$cine ami+inotranserase (to #ecome creatine" arginine

+ecar#o$lase (to #ecome agmatine" an+ argin$l-tR9) s$nthetase (to #ecome argin$l-

tR9)' a precursor to protein s$nthesis".

ustaine+-release preparations o L-arginine have #een suggeste+ as a means o

helping to maintain #loo+ levels over time' $et arginase!s su#stantial intestinal an+

hepatic meta#olism o L-arginine to ornithine an+ urea' com#ine+ with L-arginine!s use

or other unctions in the #o+$' signiicantl$ lessens the li7elihoo+ o optimal

improvement in 9 pro+uction rom oral supplements o L-arginine alone.

Dn contrast' L-citrulline escapes intestinal or liver meta#olism' an+ enters the 7i+ne$s

where it is rapi+l$ converte+ into L-arginine. ral L-citrulline supplementation (2 grams

#.i.+." was recentl$ shown in a +ou#le-#lin+' ran+omi&e+' place#o-controlle+ cross-over

stu+$ to increase the plasma L-arginine concentration an+ c8%' an+ to augment 9-

+epen+ent signaling much more eectivel$ than L-arginine.

Encourage+ #$ this research' which conirme+ the rationale or oral L-citrulline

supplementation as a +onor or the L-arginine/9 pathwa$ in patients with E'

researchers in the epartment o rolog$ at the niversit$ o Foggia' Foggia' Dtal$'

con+ucte+ a single-#lin+ trial' in which ,3 men with mil+ E (erection har+ness score o

2"' mean age 1?.1 $ears' receive+ a place#o or month an+ L-citrulline' .1 g/+ in ,

+oses' or another month. *he erection har+ness score' num#er o intercourses per

month' treatment satisaction' an+ a+verse events were recor+e+. )ll patients complete+

the stu+$ with no a+verse events.

Dmprovement in the erection har+ness score rom 2 (mil+ E--penile rigi+it$ that still

allowe+ some 7in+ o vaginal penetration' #ut not satisactor$ penetration or completion

o successul intercourse" to 3 (normal erectile unction" occurre+ in , (14" o the men

when ta7ing L-citrulline' an+ in , o the ,3 men when ta7ing place#o. )ll patients

reporting an erection har+ness score improvement rom 2 to 3 were highl$ satisie+. )t

the month ,-visit' the men were inorme+ the$ ha+ receive+ a commerciall$ availa#le

nutrient an+ given the option to continue it or to receive a prescription or a %E-1

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inhi#itor. )ll , men who ha+ #eneitte+ chose L-citrulline.

L-citrulline corrects the cause o E' %E1-inhi#itors +o not

Evi+ence has shown that oral L-citrulline supplementation can reverse the en+othelial

+$sunction associate+ with sic7le cell +isease (," an+ pulmonar$ h$pertension

(,?"' conirming that L-citrullline eectivel$ activates the L-arginine/9/c8%/VE8F

pathwa$.

Dn ,G' it was shown that increase+ 9 pro+uction in+uces corpus cavernosum smooth

muscle cell s$nthesis an+ the secretion o vascular en+othelial growth actor (VE8F"'

which can restore impaire+ en+othelial unction. *his provi+es a rationale or L-citrullinesupplementation to not onl$ manage' #ut reverse penile en+othelial +$sunction #$

correcting the proimate cause o E.

Clinical %earl: L-citrulline ma$ #e o great #eneit or $our emale postmenopausal

patients as well. ne reason estrogen is car+ioprotective is that it inhi#its arginase.

Researchers have recentl$ shown a close relationship #etween atherosclerosis an+

en+othelial senescence--an+ that 9 can prevent itHespeciall$ in a +ia#etic mo+el.

upplementation with the 9-#oosting su#stances' L-citrulline an+ L-arginine' along

with antioi+ants' has #een +emonstrate+ to +ela$ en+othelial senescence +espite high

glucose levels or a high-cholesterol +iet. *his +ela$ in en+othelial senescence through

9 an+/or e9 activation ma$ have clinical utilit$ in the prevention an+ treatment o

atherosclerosis associate+ with menopause an+ +ia#etes' an+ with aging.

%E1 inhi#itors are not innocuous:

I %E1 inhi#itors cause car+iovascular si+e eects even in health$ males (i.e.'

hea+ache' lushing' +$spepsia' visual pro#lems inclu+ing su++en loss o vision' an+