Re iew
Acu e neu ohumo al modula ion o dias olic unc ion
Rica do Ladei as-Lopes, Joa
˜o Fe ei a-Ma ins, Adelino F. Lei e-Mo ei a *
Depa men o Physiology, Facul y o Medicine, Uni e si y o Po o, Po ugal
Con en s
1. In oduc ion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
2. In acellula mechanisms modula ing dias olic unc ion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
2.1. Dias olic calcium homeos asis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
2.2. Sa come ic p o eins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
3. Acu e neu ohumo al media o s o dias olic unc ion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
3.1. Endo helin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
3.1.1. The e ec s o ET-1 on myoca dial elaxa ion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
3.1.2. The e ec s o ET-1 on passi e myoca dial p ope ies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
3.2. Angio ensin-II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
3.2.1. The e ec s o AngII on myoca dial elaxa ion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
3.2.2. The e ec s o AngII on passi e myoca dial p ope ies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
3.3. Ni ic oxide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
3.4. U o ensin-II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
3.5. Gh elin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
Re e ences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
1. In oduc ion
Dias olic unc ion has a cen al ole in ca dio ascula home-
os asis. I s impo ance is ob ious no only as a physiological
unc ion o he no mal ca diac cycle (allowing he en icle o elax
and fill wi h blood) bu also as a dys unc ional componen on
Pep ides 30 (2009) 419–425
ARTICLE INFO
A icle his o y:
Recei ed 9 Sep embe 2008
Recei ed in e ised o m 26 Oc obe 2008
Accep ed 27 Oc obe 2008
A ailable online 5 No embe 2008
Keywo ds:
Dias ole
Ca dio ascula physiology
Hea ailu e
Angio ensin-II
Endo helin-1
ABSTRACT
Dias ole plays a cen al ole in ca dio ascula homeos asis. I s wo main de e minan s, myoca dial
elaxa ion and passi e p ope ies o he en icula wall, a e nowadays ega ded as physiological
mechanisms suscep ible o ac i e modula ion. Fu he mo e, dias olic dys unc ion and hea ailu e wi h
no mal ejec ion ac ion (p e iously called dias olic hea ailu e) a e wo subjec s o majo clinical
ele ance and an in ense a ea o esea ch. The ole o se e al neu ohumo al media o s like angio ensin-II
and endo helin-1 on he modula ion o dias olic unc ion was sys ema ically desc ibed as ha ing only
ch onic dele e ious e ec s such as ca diac hype ophy and fib osis. Howe e , o e he las yea s a
g owing body o e idence desc ibed a new ole o se e al pep ides on he acu e modula ion o dias olic
unc ion. In he acu e se ing, some o hese media o s may ha e he po en ial o induce an adap i e
ca diac esponse. In his e iew, we desc ibe he ole o angio ensin-II, endo helin-1, ni ic oxide,
u o ensin-II and gh elin on he acu e modula ion o dias olic unc ion, emphasizing i s pa hophysio-
logical ele ance. Only a ho ough unde s anding o dias olic physiology as well as i s ac i e modula ion,
bo h in he acu e and ch onic se ings, will imp o e ou knowledge on dias olic dys unc ion and allow us
o sol e he enigmas o hea ailu e wi h no mal ejec ion ac ion.
ß2008 Else ie Inc. All igh s ese ed.
*Co esponding au ho a : Depa men o Physiology, Facul y o Medicine,
Alameda P o esso He na
ˆni Mon ei o, 4200-319 Po o, Po ugal.
Tel.: +351 22 5513644; ax: +351 22 5513646.
E-mail add ess: [email p o ec ed] (A.F. Lei e-Mo ei a).
Con en s lis s a ailable a ScienceDi ec
Pep ides
jou nal homepage: www.else ie .com/loca e/pep ides
0196-9781/$ – see on ma e ß2008 Else ie Inc. All igh s ese ed.
doi:10.1016/j.pep ides.2008.10.018
impo an ca dio ascula diseases such as hea ailu e wi h
no mal ejec ion ac ion (HFNEF) [31].
The wo main de e minan s o dias olic unc ion a e myoca dial
elaxa ion and passi e p ope ies o he en icula wall (see
[16,24,31] o comp ehensi e e iews on dias ole and dias olic
dys unc ion). The o me is modula ed by load, inac i a ion
(including mechanisms ela ed o calcium homeos asis and
myofilamen s p ope ies) and non-uni o mi y whe eas he la e
depends on ca diomyocy es hemsel es (mainly he cy oskele on)
and ca diac ex acellula ma ix.
The modula ion o dias olic unc ion by neu ohumo al agen s
has been an a ea o in ense in es iga ion o e he las decade. The
ad ene gic sys em is he bes desc ibed neu ohumo al mechanism
capable o acu ely modula e bo h sys olic and dias olic unc ions.
Fu he mo e, pep ides such as endo helin (ET) and angio ensin-II
(AngII) we e sys ema ically ega ded as ha ing only ch onic
dele e ious e ec s on sys olic and dias olic unc ion, con ibu ing
o en icula emodeling wi h myoca dial hype ophy and
fib osis. No wi hs anding hese ominous e ec s, o e he ecen
yea s he e was an inc easing body o e idence linking se e al
neu ohumo al media o s o he acu e modula ion o dias ole, wi h
special emphasis on he ac i e myoca dial elaxa ion and passi e
p ope ies o he ca diac muscle [33,34,50].
In his way, his wo k aims o p o ide an up- o-da e desc ip ion
on he la es neu ohumo al mechanisms ound o acu ely
modula e dias olic unc ion. Fi s , he mos impo an in acellula
mechanisms playing a ole on dias ole will be b iefly desc ibed.
The ea e , he acu e e ec s o some neu ohumo al media o s on
dias olic unc ion will be e iewed. A be e unde s anding o
dias olic physiology and i s modula ion will p obably con ibu e o
unmask some o he cu en enigmas o HFNEF and o o e a
b oade pe spec i e on po en ial and clinically ele an
app oaches o he ea men o dias olic dys unc ion and HFNEF.
2. In acellula mechanisms modula ing dias olic unc ion
2.1. Dias olic calcium homeos asis
Calcium homeos asis plays a de e minan ole in myoca dial
elaxa ion [31]. Indeed, calcium ex usion om he cy osol is
c ucial o a no mal dias ole and he mechanisms con ibu ing o
educe in acellula calcium le els a e al e ed in dias olic
dys unc ion. In he human hea , he main p ocesses esponsible
o calcium ex usion a e i s up ake by he sa coplasmic e iculum
calcium-ATPase (SERCA) pump and he ac i i y o he sa colemmal
sodium–calcium exchange (NCX). SERCA pump ac i i y is
inhibi ed by phospholamban (PLB) in i s dephospho yla ed o m.
Howe e , PLB phospho yla ion emo es i s inhibi o y e ec on
SERCA and p omo es a as e a e o elaxa ion due o inc eased
SERCA ac i i y. In his way, inc eased ac i i y o SERCA by di ec
ac i a ion o phospho yla ion o PLB by p o ein kinases allows he
en icle o accele a e myoca dial elaxa ion. Howe e , dec eased
SERCA ac i i y o hypophospho yla ed PLB con ibu e o a slow
a e o ension decline.
2.2. Sa come ic p o eins
Key egula o y myofilamen p o eins such as oponins and
myosin binding p o ein C (MyBP-C) also play a ole modula ing
ca diac dias olic p ope ies. Phospho yla ion o oponin (Tn)-I by
PKA [26], PKC [45] and PKG [30] is esponsible o enhanced
elaxa ion esul ing om he dec eased myofilamen calcium-
sensi i i y. In e es ingly, a ecen wo k [10] demons a ed ha
myofilamen desensi iza ion induced by PKA equi es he p esence
o ano he sa come ic p o ein, MyBP-C. The la e seems o be an
impo an media o o dias ole [51] bu u he esea ch is needed
o allow a be e unde s anding o a dynamic in e ac ion be ween
hese myofilamen p o eins on he modula ion o dias olic
unc ion.
Ti in is a gian sa come ic p o ein inc easingly ecognized as an
impo an de e minan o myoca dial s i ness and con ibu o o
he pa hophysiology o hea ailu e [18]. Indeed, passi e s i ness
can be adjus ed by modula ing he mechanical p ope ies o i in’s
ex ensible egion mainly by phospho yla ion and changes in
in acellula calcium le els.
PKA-dependen phospho yla ion o i in’s N2B unique sequence
educes passi e ension o bo h animal [64] and human [28]
ca diomyocy es. This ep esen s one o he mechanisms con-
ibu ing o he imp o emen o ca diac dias olic p ope ies upon
b
ad ene gic s imula ion. A ecen wo k [60] sugges s ha PKC
may also phospho yla e i in bu a p esen is unclea whe he only
PKA can phospho yla e i in o whe he PKC is also e ec i e.
Calcium and he p o ein S100A1, a calcium-binding p o ein,
also con ibu e o he modula ion o myoca dial passi e s i ness.
Toge he , hey inhibi i in–ac in in e ac ion, one o he de e mi-
nan s o passi e myocy e s i ness, in a calcium-dependen manne
[63]. Howe e , u u e wo k is equi ed o cla i y he a ay o apid
adjus men mechanisms in ol ing i in as well as o unde s and
hei physiological ole in he modula ion o dias olic unc ion.
3. Acu e neu ohumo al media o s o dias olic unc ion
3.1. Endo helin
Endo helin-1 was isola ed in 1988 and was cha ac e ized as he
mos po en endogenous asocons ic o e e iden ified [65].A
fi s ega ded as ‘‘ he bad guy o ci cula o y con ol’’ [61], ET-1 is
nowadays conside ed an impo an egula o o ca dio ascula
homeos asis (see [6] o a comp ehensi e e iew on his opic).
ET-1 has p edominan ly au oc ine and pa ac ine ac ions by
binding o wo main sub ypes o G-p o ein coupled ecep o s, ET
A
and ET
B
.ET
A
ecep o ac i a ion e okes asocons ic ion [41],
mi ogenesis [46] and inc eased ino opism [22,25] whe eas ET
B
ecep o s imula ion is associa ed wi h asodila a ion and g ow h
inhibi o y e ec s [40] associa ed wi h apop osis [47]. The la e
was u he subdi ided in ET
B1
and ET
B2
ecep o sub ypes: he
ET
B1
ecep o is p edominan ly exp essed in he ascula and
endoca dial endo helium and i s s imula ion elici s asodila a ion
[12] and a nega i e ino opic e ec [32] and he ET
B2
ecep o is
loca ed on ascula smoo h muscle and myoca dial cells, media -
ing asocons ic ion [59] and posi i e ino opism [32]. The ET
B
ecep o is also esponsible o he pulmona y clea ance [15] and
endo helial eup ake [48] o ci cula ing ET-1. I is impo an o
emembe ha ET-1 plasma le els in heal hy subjec s a e e y low,
in he en omola ange, being unlikely ha his pep ide ac s as a
ci cula ing ho mone. Howe e , he e is a onic pa ac ine elease o
ET-1 om endoca dial endo helial cells inasmuch as ET ecep o
blockade elici ed a dec ease in sys olic con ac ili y demons a ed
by a educ ion in he a e o le en icula p essu e de elopmen
[39,55]. Despi e he as knowledge abou he ole o ET-1 on
ca dio ascula physiology, i s dias olic e ec s ha e only ecen ly
s a ed o be unco e ed. Accu a e e idence was ga he ed in he
se ing o isola ed muscle p epa a ions and hemodynamic s udies,
inasmuch as in he in ac hea i is di ficul o di e en ia e
be ween e ec s o ET-1 on in insic myoca dial dias olic p ope ies
om hose ela ed o load changes [16,35] and co ona y
asocons ic ion [13,23]. Indeed, in he in ac hea , e ec s o
ET-1 on dias olic unc ion migh esul om di ec ac ions o he
pep ide and om indi ec e ec s ha a e mainly he consequence
o co ona y and/o sys emic asocons ic ion. Such a complex
R. Ladei as-Lopes e al. / Pep ides 30 (2009) 419–425
420
egula ion o myoca dial dias ole wi h po en ially simul aneous
opposing e ec s o ET-1 migh explain why no conclusi e e ec s
on he modula ion o dias olic unc ion by ET-1 in he in ac hea
ha e been epo ed.
3.1.1. The e ec s o ET-1 on myoca dial elaxa ion
In isola ed muscle p epa a ions, ET-1 elici s a dose-dependen
(0.1, 1 and 10 nM) accele a ion o he a e o ension decline
(inc eased dT/d
min
)[33,38]. To unde s and he physiologic
mechanisms o his posi i e lusi opic e ec , s udies we e
pe o med in isola ed abbi papilla y muscles. We could obse e
ha he inc eased lusi opism in he p esence o ET-1 (1 nM) was
inhibi ed a e nonselec i e ET
A
/ET
B
ecep o blockade wi h PD-
145065 and e en e e sed when a selec i e ET
A
ecep o
an agonis (BQ-123) was used. Fu he mo e, selec i e ET
B
ecep o
inhibi ion wi h BQ-788 in he p esence o ET-1 showed a endency
o enhance he posi i e lusi opic esponse [33]. In e es ingly, he
accele a ion o he a e o ension decline elici ed by ET-1 does no
depend on he in eg i y o he endoca dial endo helium [3,4] no
on he p esence o NO o p os aglandins [4].
To u he cla i y he ole o ET
B
ecep o on he ET-1-induced
posi i e lusi opism, ano he expe imen al p o ocol was con-
duc ed. We demons a ed ha selec i e ET
B1
ecep o s imula ion
slowed myoca dial elaxa ion (dec eased dT/d
min
) h ough he
elease o NO and p os aglandins, whe eas he e was a as e
elaxa ion upon p e e en ial ET
B2
ecep o s imula ion [32]. Mo e
ecen ly, we demons a ed ha he lusi opic e ec o selec i e ET
B
ecep o s imula ion is dependen in he in eg i y o he
endoca dial endo helium, being nega i e when i is in ac and
posi i e when i is damaged [32].
O e all, hese esul s sugges ha he ET-1-induced posi i e
lusi opic esponse is p edominan ly media ed by ET
A
ecep o s
and ha he in e ac ion wi h ET
B1
and ET
B2
s imula ion and he
endo helium may also con ibu e o he modula ion o his
esponse.
3.1.2. The e ec s o ET-1 on passi e myoca dial p ope ies
I is well es ablished ha ch onically ele a ed le els o ET-1 a e
associa ed wi h myoca dial hype ophy and fib osis, leading o an
inc ease in myoca dial s i ness and hus comp omising he
dias olic unc ion o he hea [5,11]. Howe e , he acu e dias olic
e ec s o ET-1 a e being p og essi ely un a eled wi h ob ious
implica ions o he unde s anding o dias olic physiology.
Expe imen s pe o med by ou g oup in isola ed abbi
papilla y muscles and human au icula s ips e ealed ha ET-1
dose dependen ly (using he concen a ions 0.1, 1 and 10 nM)
inc eases myoca dial dis ensibili y (dec eases myoca dial s i -
ness) in acu ely loaded ca diac muscles by binding o ET
A
ecep o s
and ac i a ing he Na+/H+ exchange (NHE). This e ec was no
inhibi ed by selec i e ET
B
ecep o inhibi ion wi h BQ-788, which
is conside ed o p edominan ly block he ET
B2
ecep o sub ype
[33]. In he clinical se ing, upon ET
A
ecep o s imula ion and in
he p esence o ca diac o e load, he en icle can each highe
filling olumes a lowe filling p essu es, wi h a mo e e ficien
ec ui men o he p eload ese e. This may ep esen a qui e
powe ul adap a ion mechanism o ca diac dias olic unc ion in
si ua ions o acu e ca diac o e load, dec easing he odds o
backwa ds conges ion.
Subsequen s udies demons a ed ha he ET-1-induced
dec ease in myoca dial s i ness also equi es an in ac endoca dial
endo helium [3,4] and ac i e endo helial ET
B1
ecep o s (al hough
selec i e ET
B1
o ET
B2
di ec s imula ion did no elici any e ec on
his pa ame e ) [3]. This sugges s ha acu e modula ion o passi e
dias olic p ope ies o he myoca dium by ET-1 is p obably
dependen on a complex balance and in e ac ion be ween ET
A
and ET
B1
ecep o s s imula ion and equi es a unc ional endo-
ca dial endo helium o de e mine he o e all physiologic esponse.
In a ecen wo k, we demons a ed ha a e blocking NO and
p os aglandins syn hesis wi h N
G
-ni o-
L
-a ginine (L-NNA) and
indome hacin, espec i ely, he ET-1-induced dec ease in es ing
ension (inc ease in myoca dial dis ensibili y) was no longe
obse ed [4]. Since NO and p os aglandins a e impo an
endo helial media o s and a e known o be eleased by he
endo helium upon selec i e ET
B1
ecep o s imula ion [6], hese
esul s sugges ha hese subs ances p obably play an impo an
ole modula ing he acu e dias olic e ec s o ET-1 in a complex
c oss- alk be ween he endo helium and ca diac muscle.
3.2. Angio ensin-II
The oc apep ide AngII plays a de e minan ole in he
main enance o ca dio ascula homeos asis, as well as in di e en
ca dio ascula diseases such as hype ension and hea ailu e (see
[43] o a ho ough e iew o AngII physiological and pa hological
e ec s in he ca dio ascula sys em).
The exis ence and unc ion o a local enin–angio ensin sys em
(RAS) in he hea i is now well es ablished [49]. Fu he mo e, he
p edominan physiological ole o he ca diac RAS is p obably he
in eg a ion o se e al s imuli media ing adap i e esponses o
myoca dial s ess (such as he esponse o myocy e s e ch) as well
as o modula e he local e ec s o g ow h and p oli e a i e s imuli.
The e o e, he local RAS migh as well con ibu e o he modula ion
o myoca dial dias olic unc ion in he acu e se ing.
AngII s imula es wo ypes o G p o ein-coupled ecep o s: AT
1
ecep o , associa ed no only wi h acu e asocons ic ion and
posi i e ino opism bu also wi h ch onic en icula emodeling,
by means o myoca dial hype ophy and fib osis; and he AT
2
ecep o , commonly associa ed wi h an i-p oli e a i e and p o-
apop o ic e ec s and asodila a ion [1].
No wi hs anding he dele e ious e ec s o ch onically ele a ed
le els o AngII o e bo h sys olic and dias olic unc ions, he acu e
dias olic esponse o AngII was sys ema ically o e looked.
3.2.1. The e ec s o AngII on myoca dial elaxa ion
The ea ly findings on AngII-dependen modula ion o myoca -
dial elaxa ion e idenced a p olonged elaxa ion ime in he ca
en icle as well as in o he species [21,42,44,54]. Howe e , ou
ecen esul s in isola ed abbi papilla y muscles and in si u abbi
hea s sugges ha AngII (using inc easing concen a ions om
10
7
o 10
5
M) exe s a posi i e lusi opic e ec cha ac e ized by
an inc ease in he peak a e o ension decline (dT/d
min
)[8,34].We
also demons a ed ha he AngII-induced accele a ion o myo-
ca dial elaxa ion was comple ely abolished wi h losa an
(selec i e compe i i e AT
1
ecep o an agonis ) and significan ly
a enua ed a e nonselec i e endo helin ET
A
/ET
B
ecep o and
selec i e ET
A
ecep o blockade as well as a e selec i e emo al o
he endoca dial endo helium. These esul s sugges ha he
accele a ion o he a e o ension decline induced by AngII is
indeed dependen on AT
1
ecep o ac i a ion and p obably esul s
om an acu e in e ac ion be ween he local enin–angio ensin
sys em and he endo helin sys em wi h he endo helium playing
an impo an ole in i s modula ion.
In a subsequen s udy [9], ou g oup demons a ed ha he
selec i e s imula ion o abbi myoca dial AT
2
ecep o s was
associa ed wi h a slowing o myoca dial elaxa ion and hus a
nega i e lusi opic e ec ha was comple ely abolished a e
emo al o he endoca dial endo helium and significan ly a e-
nua ed wi h hyd oxocobalamin (a NO sca enge ) and Hoe-140 (an
an agonis o b adykinin B
2
ecep o s). A link be ween AT
2
ecep o
signaling pa hway and s imula ion o endo helial b adykinin B
2
R. Ladei as-Lopes e al. / Pep ides 30 (2009) 419–425
421
ecep o s (wi h ac i a ion o cons i u i e ni ic oxide syn hase)
was al eady desc ibed in he hea [29]. O e all, hese findings
demons a ed ha selec i e AT
2
ecep o -s imula ion is associa ed
wi h a nega i e lusi opic e ec modula ed by he endoca dial
endo helium and media ed by b adykinin B
2
ecep o s h ough NO
elease.
3.2.2. The e ec s o AngII on passi e myoca dial p ope ies
In a ecen wo k, ou g oup desc ibed o he fi s ime a
significan AngII concen a ion dependen (10
7
–10
5
M) dec ease
o myoca dial s i ness [34]. Indeed, AngII acu ely dec eased
passi e ension by 46% in he isola ed muscle and LV dias olic
p essu es by 40–44% in he in ac hea . To u he cla i y his
finding, selec i e AT
1
(losa an and ZD-7155) and AT
2
(PD-
123,319) ecep o s an agonis s we e used. In e es ingly, only
AT
1
ecep o blockade inhibi ed he inc ease in myoca dial
dis ensibili y. We also demons a ed ha his e ec was com-
ple ely blun ed upon PKC inhibi ion and significan ly a enua ed
a e NHE inhibi ion. These esul s sugges ha he p e iously
desc ibed acu e dec ease o myoca dial s i ness by AngII equi es
AT1 ecep o ac i a ion and is media ed by PKC and NHE. I is
emp ing o hypo hesize ha a possible mechanism accoun ing o
his e ec may be a PKC-dependen phospho yla ion o i in
p omo ing a dec ease in myoca dial s i ness in a way simila o
i in’s phospho yla ion by PKA. Howe e , u u e esea ch is
equi ed o u he cla i y his issue.
3.3. Ni ic oxide
Resea ch wo k pe o med o e he las decade e idenced ha
NO plays an impo an ole in ca dio ascula homeos asis, as well
as in he pa hophysiology o hea diseases such as hea ailu e
(see [53] o a comp ehensi e e iew). Howe e , NO-induced
dias olic e ec s we e only ecen ly unmasked and emain a
p esen an in e es ing ma e o in es iga ion.
The o iginal obse a ions on he e ec s o NO in he se ing o
isola ed papilla y muscles we e desc ibed as a elaxa ion-
has ening e ec , cha ac e ized by educed peak isome ic ension
because o ea lie onse o elaxa ion. These esul s we e also
e iden in expe imen al p epa a ions using a whole animal hea
model, whe e bo h exogenous and endogenous NO we e ound o
induce a as e a e o myoca dial elaxa ion [19,20]. Likewise, he
same e ec s we e obse ed in he no mal human hea upon
in aco ona y injec ion o sodium ni op usside du ing ca diac
ca he e iza ion [50].
A no el and in e es ing dias olic e ec o NO was demons a ed
in 1994 in isola ed ca diomyocy es [57] and in he in ac human
le en icle, in which [50] NO was shown o p omo e a shi ing o
he leng h- ension and LV dias olic p essu e– olume ela ions o
he igh , espec i ely. Physiologically, hese esul s clea ly
indica e ha NO signaling a o s a mo e dis ensible ca diomyocy e
and a mo e complian le en icula chambe . On he o he hand,
in he se ing o isola ed animal hea he p esence o N
G
-
monome hyl-
L
-a ginine (a specific inhibi o o ni ic oxide
syn hase) esul s in ele a ion o LV end-dias olic p essu e
sugges ing a s i e en icle [52]. Due o he aised myoca dial
concen a ion o cGMP elici ed by NO, one o he mechanisms
sugges ed o media e he NO-dependen inc ease in dias olic
dis ensibili y is he phospho yla ion o Tn-I by PKG elici ing a
educ ion o myofilamen a y calcium sensi i i y [56]. As ecen ly
desc ibed, a PKG-media ed phospho yla ion o i in is also likely o
accoun o he obse ed e ec [27].
Taken oge he , hese esul s sugges ha NO is p obably an
impo an egula o o dias olic unc ion in a complex acu e
in e play among co ona y pe usion, co ona y endo helium and
dias olic LV pe o mance h ough elaxa ion-has ening and dis-
ensibili y-inc easing e ec s. Acu ely, ele a ion o ca diac wo k-
load and shea s ess p omo es endo helial NO elease which
op imizes LV dias olic unc ion by p olonging he dias olic ime
in e al and allowing he en icle o accommoda e highe
olumes a lowe filling p essu es.
3.4. U o ensin-II
U o ensin-II is a cyclic pep ide isola ed in 1985 which was
ecen ly in oduced as a media o in ca dio ascula homoeos asis
and disease (see [66] o a comp ehensi e e iew on he ole o U-II
on ca dio ascula and enal physiology). Howe e , a e mo e han
20 yea s o esea ch, he p ecise ole o U-II on dias olic unc ion
s ill dese es u u e in es iga ion.
To u he cla i y he dias olic e ec s o U-II and some o hei
unde lying mechanisms, he s udy model o isola ed abbi
papilla y muscles was employed [14]. Rega ding myoca dial
elaxa ion, we ound a concen a ion-dependen (10
8
–10
6
M)
nega i e lusi opic e ec ha was no a ec ed by damaging he
endoca dial endo helium no blocking NO and p os aglandins
syn hesis. Howe e , he mos in e es ing finding o his s udy was
he e idence o a dose-dependen acu e inc ease in myoca dial
dis ensibili y upon U-II addi ion. Blocking U-II ecep o s wi h
u an ide and NO syn hesis wi h L-NNA o ally inhibi ed his e ec
whe eas cyclooxygenase inhibi ion wi h indome hacin signifi-
can ly a enua ed i . In e es ingly, endoca dial endo helium
emo al did no al e he dis ensibili y-inc easing e ec o U-II.
Taken oge he , hese esul s sugges ha he U-II-induced
inc ease in myoca dial dis ensibili y depends on U-II ecep o
s imula ion and NO and p os aglandins elease p obably om he
mic o ascula co ona y endo helium, which is a ecognized
al e na i e sou ce o hese media o s [7]. These findings demon-
s a ed he likelihood o U-II as a media o o an acu e adap a ion
mechanism ha allows he en icle o each highe dias olic
olumes a lowe filling p essu es. Ne e heless, one should no
neglec ha ch onically ele a ed le els o U-II con ibu e o
ca diac fib osis and hype ophy [2,66] and accele a e he
a he oscle o ic p ocess [62] leading o ca dio ascula unc ion
impai men .
3.5. Gh elin
Gh elin is a 28-amino acid pep ide mos ly syn hesized in he
s omach wi h impo an me abolic and homeos a ic oles by
p o iding an endoc ine link be ween s omach, hypo halamus
and pi ui a y (see [37] o a ho ough e iew on he
physiological, pa hological and he apeu ic oles o gh elin).
Gh elin also pa icipa es in se e al aspec s o physiologic and
pa hologic s a es o he ca dio ascula sys em [36]. Howe e , i s
ole in dias ole s ill emains poo ly unde s ood. In a ecen wo k
[58], ou g oup desc ibed he nega i e lusi opic e ec o gh elin
(using concen a ions o 10
9
–10
6
M) in isola ed a papilla y
muscles, consis ing on a slowe a e o ension decline and an
ea lie onse o myoca dial elaxa ion. The dec eased lusi op-
ism was no a ec ed by endoca dial endo helium damage o
blocking NO and p os aglandins syn hesis. Ne e heless, he
p ema u e onse o elaxa ion induced by gh elin was blun ed
by inhibi ion o p os aglandins elease and exace ba ed by NO
syn hase inhibi ion, bu no a ec ed by a dys unc ional
endoca dial endo helium. These esul s sugges ha he acu e
modula ion o he onse o myoca dial elaxa ion by gh elin may
depend on a complex in e ac ion be ween NO, p os aglandins
and he endo helium ha should be add essed in u u e esea ch
wo k. In e es ingly, an agonizing he g ow h ho mone sec e a-
R. Ladei as-Lopes e al. / Pep ides 30 (2009) 419–425
422
gogue- ecep o (GHS-R1a), one o he mos impo an media o s
o gh elin ac ion, did no modi y he nega i e lusi opic and
elaxa ion-has ening e ec o gh elin, implying ha some o i s
ac ions a e media ed by o he ecep o s dis inc om he GHS-
R1a. The GHS-R1b is also exp essed in he myoca dium [17] and
hus is a pu a i e candida e o media ing some o he ca diac
ac ions o gh elin.
4. Conclusion
The concep ha dias ole is no a me ely passi e phenomenon
bu is ins ead unde ac i e con ol is now a common g ound in
bo h clinical and basic esea ch se ings. Indeed, he ecogni ion
ha dias ole i sel can be ac i ely modula ed has been s ee ing
cu en esea ch so ha i s pa hophysiological media o s a e
Fig. 1. Majo signaling pa hways desc ibed o con ibu e o he acu e modula ion o dias olic unc ion. Dashed a ows ep esen phospho yla ions. AC, adenylyl cyclase; AR,
ad ene gic ecep o ; AT
1
R, AT
1
ecep o ; AT
2
R, AT
2
ecep o ; B
2
R, b adykinin B2 ecep o ; cAMP, cyclic AMP; cGMP, cyclic GMP; COX, cyclooxygenase; DAG, diacylglyce ol;
ET
A
R, ET
A
ecep o ; ET
B1
R, ET
B1
ecep o ; ET
B2
R, ET
B2
ecep o ; GC, guanylyl cyclase; Gq, Gs, G-p o ein subuni s; IP3, inosi ol 1,4,5- iphospha e; MyBPC, myosin binding
p o ein C; NHE, Na+/H+ exchange ; NO, ni ic oxide; NOS, NO syn hase; PG’s, p os aglandins; PKA, PKC, PKG, p o ein kinases A, C and G, espec i ely; PLB, phospholamban;
PLC, phospholipase-C; SERCA, SR Ca
2+
pump; SR, sa coplasmic e iculum; TnI, oponin I.
Table 1
O e iew o he acu e e ec s o se e al neu ohumo al media o s on dias olic unc ion.
Media o E ec Re e ence(s)
Endo helin-1 ET
A
ecep o s imula ion
Posi i e lusi opism independen o endoca dial endo helium, NO and p os aglandins [3,4]
Dec ease in myoca dial s i ness dependen on ac i e ETB1 ecep o s, in ac endoca dial endo helium,
NO and p os aglandins and Na+/H+ exchange ac i a ion
[3,4,33]
ET
B1
ecep o s imula ion
Nega i e lusi opism dependen on NO and p os aglandins elease and in ac endoca dial endo helium [32]
ET
B2
ecep o s imula ion
Posi i e lusi opism (unknown mechanism) [32]
Angio ensin-II AT
1
ecep o s imula ion
Posi i e lusi opism dependen on ET
A
and ET
B
ecep o in eg i y and in ac endoca dial endo helium [8,34]
Dec ease in myoca dial s i ness dependen on Na+/H+ exchange and p o ein kinase C [34]
AT
2
ecep o s imula ion
Nega i e lusi opism dependen on in ac endoca dial endo helium, NO and b adykinin B2 ecep o [9]
Ni ic oxide Ea lie onse o elaxa ion (‘‘ elaxa ion-has ening e ec ’’) [19,20]
Posi i e lusi opism [19,20]
Dec ease in myoca dial s i ness [50,57]
U o ensin-II Nega i e lusi opism independen o in ac endoca dial endo helium, NO and p os aglandins [14]
Dec ease in myoca dial s i ness dependen on u o ensin-II ecep o s imula ion, NO and p os aglandins [14]
Gh elin Ea lie onse o elaxa ion blun ed by inhibi ion o p os aglandins elease and exace ba ed by NO syn hase inhibi ion [58]
Nega i e lusi opism independen o in ac endoca dial endo helium, NO and p os aglandins [58]
R. Ladei as-Lopes e al. / Pep ides 30 (2009) 419–425
423

un eiled and new pha macological app oaches a e designed and
implemen ed in he se ing o dias olic dys unc ion and HFNEF.
As o he ad ene gic sys em, many o he neu ohumo al
mechanisms commonly associa ed wi h he p og ession o hea
ailu e synd ome ha e been desc ibed o acu ely and posi i ely
modi y ca diac unc ion. In ega d o myoca dial dias olic
p ope ies, AngII and ET-1 figu e as wo unques ionable new
pa adigms o such modula ion (schema ically depic ed in Fig. 1).
Being mos ly ega ded as posi i e ino opic and asocons ic o
mechanisms in acu e hea ailu e bu decompensa o y ones in
he ch onic hea ailu e se ing, hei abili y o acu ely modi y
dias olic unc ion has been widely dismissed. This gap has been
filled by ou ecen obse a ions ha AngII and ET-1 can
significan ly imp o e dias olic unc ion by means o inc easing
elaxa ion eloci y and dec easing myoca dial s i ness in a ime-
ame ha is oo sho o al e he ECM. In he clinical g ound,
hese e ec s may ansla e in o an enhanced capaci y o he
en icle o inc ease i s end-dias olic olume a concu en ly
lowe filling p essu es. In he acu e hea ailu e se ing and upon
neu ohumo al ac i a ion, en icula wall s ess dec eases and
he odds o conges ion a e significan ly a enua ed. The same
e ec s a e asc ibed o NO and, mo e ecen ly, o U-II (see Table 1
o an o e iew). Though, he ne e ec in he human
myoca dium in eg a ing he ac ions o all hese pep ides should
always be ega ded as a complex and s ill incomple ely unde -
s ood issue ha also depends on he in eg i y o he endo he-
lium, p obably leading o di e en dias olic ca diac beha io s in
he heal hy s a e and in he diseased hea . An obse a ion ha
u he unde sco es he impo ance o dias olic unc ion
modula ion in ca dio ascula homeos asis is he edundancy
o e ec s among neu ohumo al media o s ha ac i a e di e en
in acellula signaling pa hways. Mul iple signaling media o s
seem o con e ge on a simila e ec in he egula ion o
myofilamen a y calcium sensi i i y and myoca dial dis ensibil-
i y. Ei he h ough di ec o indi ec s imula ion o PKA
(ad enalin), PKC (AngII and ET-1) and/o PKG (NO and U-II),
hese media o s sha e he acu ely-dec easing e ec o myoca -
dial s i ness, highligh ing he exis ence o se e al ways o
achie e a common end: an enhanced dias olic unc ion.
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