Increased secretion of atrial natriuretic
polypeptide from the left ventricle in patients
with dilated cardiomyopathy.
H Yasue, … , K Nakao, H Imura
J Clin Invest.
1989;
83(1)
:46-51.
https://doi.org/10.1172/JCI113883
.
To examine whether atrial natriuretic polypeptide (ANP) is released from the left ventricle in
patients with dilated cardiomyopathy (DCM) we measured plasma ANP level in the aortic
root (Ao), the anterior interventricular vein (AIV), the great cardiac vein (GCV), and the
coronary sinus (CS) in 11 patients with DCM and 18 control subjects. Plasma ANP levels in
Ao, AIV, GCV, and CS were 454 +/- 360, 915 +/- 584, 1,308 +/- 926, and 1,884 +/- 1,194
pg/ml, respectively, in the patients with DCM and 108 +/- 42, 127 +/- 55, 461 +/- 224, and
682 +/- 341 pg/ml, respectively, in the control subjects. There was no significant difference
in the plasma ANP levels between Ao and AIV in the control subjects. On the contrary, there
was a significant (P less than 0.001) step-up in plasma ANP levels between Ao and AIV in
patients with DCM. Thus, the difference in ANP levels between Ao and AIV was
significantly increased in patients with DCM as compared with the control subjects (461
+/-248 vs. 19 +/- 59 pg/ml, P less than 0.001). The difference in ANP levels between Ao and
CS was also significantly increased in patients with DCM as compared with the control
subjects (1,429 +/- 890 vs. 577 +/- 318 pg/ml, P less than 0.001). We conclude that ANP is
[…]
Research Article
Find the latest version:
http://jci.me/113883/pdf
Increased Secretion of Atrial Natriuretic Polypeptide from the Left Ventricle
in
Patients with Dilated Cardiomyopathy
HirofumiYasue, Kenji Obata, Ken Okumura, Mitsuro Kurose, Hisao Ogawa, Koshi Matsuyama, Michihisa Jougasaki, YoshihikoSaito,* Kazuwa Nakao,* and Hiroo Imura*
Division ofCardiology, Kumamoto UniversityMedicalSchool,Kumamoto860;and *SecondDivision, Department ofMedicine, KyotoUniversity School ofMedicine, Kyoto 606, Japan
Abstract
Toexamine whether
atrial natriuretic polypeptide (ANP)
is releasedfrom theleft ventricle in patients with dilated cardio-myopathy(DCM)
wemeasuredplasma ANP level in theaortic
root
(Ao),
theanteriorinterventricular
vein(AIV),
the greatcardiac vein
(GCV),
and the coronarysinus
(CS)
in 11patients
with DCM and18
control subjects. Plasma ANP levels in Ao, AIV,GCV,
andCS
were454±360, 915±584,
1,308±926,
and1,884±1,194
pg/ml, respectively,
in thepatients
with DCM and108±42,
127±55,
461±224,
and682±341
pg/ml,
respec-tively,
in the controlsubjects.
Therewasnosignificant
differ-ence in the plasma ANP levels between Ao and AIV in the control
subjects. On
the contrary, there was asignificant (P
<
0.001)
step-up inplasma ANP
levels between Ao andAIV inpatients
withDCM. Thus,
thedifference
in ANP levelsbe-tweenAo and AIVwas
significantly
increased inpatients
withDCM as compared
with
the controlsubjects
(461±248
vs.19±59
pg/ml,
P <0.001).
The difference in ANP levelsbe-tween Ao andCSwasalso
significantly
increased inpatients
with DCM as compared
with
the controlsubjects
(1,429±890
vs. 577±318pg/ml,
P <0.001).
We conclude that ANP is released inincreased
amountsinto
thecirculation
from theleft
ventricle as well asfrom
the heart as a whole inpatients
with DCM.Introduction
Atrial
natriuretic
polypeptide
(ANP)'
is
acirculating
hormonewith
awide
rangeof
potentbiological
effects, including
natri-uresis,
diuresis,
vasodilatation,
andinhibition
of renin
and aldosteronesecretion (1-5),
and thereis
nowincreasing
evi-dence thatit plays
animportant
role in theregulation
of fluid
volume and
blood pressure(2-5). Studies
using
RIAhavein-dicated
thatplasma
ANPlevels
areincreased in patients with
congestive
heart failure(6-10)
and that there isalinear
rela-Address correspondence to Dr. HirofumiYasue,Division of Cardiol-ogy, Kumamoto University Medical School, 1-1-1, Honjou,
Kuma-motoCity,Kumamoto 860, Japan.
Receivedfor publication 8 March 1988 and in revisedform 29 June 1988.
1.Abbreviations used in this paper: AIV, anterior interventricular vein; ANP,atrial natriuretic polypeptide; Ao, aortic root; CS, coronary
sinus;DCM, dilatedcardiomyopathy;GCV,greatcardiacvein; hANP, humanANP.
tion between plasma ANP level and atrial pressure (9, 10), implyingthatatrial pressureorstretchplaysanimportantrole inregulatingsecretion of ANP.
Since the pioneering observation of de Bold and his co-workers (11) ANP has been thoughttobepresentintheatria
but not in the ventricles of adultmammals (1-5, 12). How-ever, several recent reports havedemonstrated that the
ventri-cle iscapable ofsynthesizingandstoring substantialamounts
ofANP during cardiac hypertrophy and failure in rats and hamsters (13-17). We have reported a patient with dilated cardiomyopathy(DCM)who died ofcongestive heart failure;
thepatient showed very high levels ofplasma ANP and
in-creased tissue levels of both ANP andANP mRNAinthe left ventricle at autopsy(18). Recently Edwards and his co-workers
demonstrated immunohistochemically the presence ofANP
within human ventricles with congestive heart failure (19). However, it is not known either in animals or in humans whether ANP is actually released from the left ventricle into the circulation. We have shown that ANP is released into the general circulation at least partially by way of the coronary sinus
(CS; 6, 20).
Because the CS receivesblood from both the atria and theventricles,
and becausethe anterior interventric-ular vein(AIV)whichempties into the coronary sinus by way of the great cardiac vein(GCV)
isthought
todrain the leftventricle
and notthe atria (21-23), thedifference of
plasmaANP levels between the AIV and the
aortic
root (Ao) isthought
to reflect theamountof ANP released fromthe
left ventricles and not the atria.The presentstudy wasdesigned to examine whether ANP is
released
inincreased
amountsfrom
theleft
ventricle in
pa-tients with DCM as compared with the control subjects bysampling
bloodfor
ANPfrom
the Ao andvarious sites
in the CS systemincluding
the AIV.Methods
Patients. 11 patients(10menand 1woman, agesranging from 49to 71 yr, with a mean ageof60yr)withDCM in whomdiagnosticcardiac
catheterizations wereperformedandinwhominsertion of catheters intothe AIV waspossiblewerethesubjects ofthis study. The diagnosis of DCMwasbased onhistory,physical examination,chest x-ray,
elec-trocardiogram, echocardiogram, cardiac catheterization, and angio-cardiography, including left ventriculography andcoronary arteriogra-phy.Endomyocardialbiopsywasalso done in sevenofthepatients.In allpatients ischemic heartdisease, hypertension, valvular heart
dis-ease,congenital malformation ofheartand vessels,orintrinsic
pulmo-naryparenchymalorvasculardiseasewereexcluded.Thepatientswere
receiving diuretics and a combination of digitalis (n = 6), calcium
antagonists(n= 3),ornitrates (n=4),althoughtreatment was with-held on theday beforethestudy. We selected as controlsubjects 18
patients withoutheart musclediseasesand heartfailure (12menand 6
women, agesranging from21 to71, witha mean ageof 53) in whom
diagnostic cardiac catheterizationswereperformed and in whom
in-46 Yasueet
J.Clin.Invest.
© TheAmericanSocietyforClinical
Investigation,
Inc.0021-9738/89/0l/0046/06 $2.00
Table I. Catheterization data
HR AOP RAP PCWP CI EF ESVI
beats/min mmHg liters/min/r2 % mi/mr2
Control 72±11 92± 16 4±2 7±2 3.1±0.5 69±8 22±9
DCM 74±14 102±17 6±4 13±10 2.3±0.6 31±9 69±14
P NS NS NS <0.05 <0.001 <0.001 <0.001
AOP, mean aortic pressure;CI, cardiacindex; EF, ejectionfraction;ESVI, end-systolic volume index; HR, heartrate;NS,notsignificant; PCWP, pulmonary capillary wedgepressure;RAP,right atrialpressure.
sertion of catheters intotheAIVwaspossible.They consisted of nine
patientswith chestpainsyndrome with normalcoronaryarteriograms,
fivepatientswith angina pectoris withoutprevious myocardial infarc-tion, and fourpatients withelectrocardiographicabnormalities. None of them hadmyocardial infarction, hypertension,cardiachypertrophy,
orother heart muscle diseases. None of themwasreceivingtherapyat
the time ofthestudyexcepttwopatients withangina pectoriswhowere
onnitrates.
Writteninformedconsent wasobtained from eachpatient.
Cardiac catheterization. Cardiaccatheterization wasperformedin themorninginthefastingstate.Aftertherightheartcatheterization
was doneusingaSwan-Ganz catheter placed inthemain pulmonary
artery, a6-French Goodale-Lubin catheterwasplacedin the CSbyway
ofabrachial vein.Thecatheterwasthen advancedtothe AIVunder fluoroscopy usingaguidewire. Thepositionof the cathetertipin the
AIV wasconfirmed by injection ofcontrastdye. Thiswasthecritical
partof the study and thepatientsin whomatleasttheproximalhalf of theAIV was notvisualized wereexcluded from thestudy. ASones catheterwasplacedattherootoftheaortabywayofabrachialartery.
Sampling of blood forANPwasdonesimultaneouslyattherootofthe
aorta, theAIV, theGCV,and theCS. Carewastakentodraw blood
samples slowly fromthe AIV. Datafromtheinitialpartofthestudy
thatincludedsamplesdrawnforciblywerediscarded becausewefound
thatforcible drawing of blood fromthe AIV resultedinspuriously high levelsofplasmaANP, probably becausebackflow fromthe GCV
oc-curred andcontaminatedthe AIVwithhigher concentrations of ANP.
RIAJorANP.Allbloodsamples werewithdrawn intochilledplastic syringesand transferred to chilled siliconizeddisposable tubes that
containedaprotinin (1,000 kallikrein inactivator units/ml) (Ohkura Pharmaceutical, Kyoto, Japan)and EDTA(Img/ml),then immedi-atelyplacedonice andcentrifugedat4VC.Analiquot of plasmawas
immediately frozenat -20°C andthawed only once atthetime of extraction. PlasmaANPconcentrationwasmeasuredby theRIAfor
ANP aspreviouslyreported(6). Antibodieswereraised in New Zea-land white rabbits immunized with synthetic alpha human ANP (hANP). ThisRIArecognizesacommoncarboxy-terminalsequence
of alphahANPandis equallyspecific for both alpha hANP and alpha
ratANP. Cross-reactivities with beta hANP and gamma hANP in the RIA are 120 and 100% on a molar basis. No cross-reactions were
observedwithrenin, angiotensin II, aldosterone,digoxin,nitrates, cal-ciumantagonists,ordiureticagents.The minimal detectablequantity of alphahANPis1 pg/tube. The intra- and interassay variationswere
7.2 and7.8%, respectively.
Statisticalanalysis. Data were expressedas mean±SD. Data not normallydistributedwerecompared by theWilcoxon's signed rank test ornonpaired ranksum test(24). Normally distributed datawere
compared with thepairedornonpairedt test.P<0.05wasconsidered statisticallysignificant.
Results
Catheterization data. Table I showsthe cardiac catheterization data onthepatients with DCM and control subjects. Cardiac index and ejection fraction were significantly reduced and pul-monarycapillary wedge pressure and left ventricular end-sys-tolic volume index weresignificantly increased in the patients with DCM as compared with the control subjects. Fig. 1 shows arepresentative coronary venogram in the left anterior oblique
projection
and theposition of
the catheter tip for sampling blood from the AIV.Figure1. Arepresentativecoronary venogramintheleftanterioroblique projection(A) and the positionof thecatheter tip (B). The catheter is
Plasma
ANPlevels.Fig.
2 showsplasma ANP levels in the Ao,the
AIV, theGCV, and the CS in the control subjects and inthepatients
with DCM. In the control subjects there was nosignificant difference
intheplasma
ANP levels between the Ao andthe
AIV(108±42
vs. 127±55 pg/ml). On the contrary, there was a markedstep-up
intheplasma
ANPlevels betweenthe AIV and the GCV
(127±55
vs.46i±224 pg/ml,
P<
0.001). There
was also asignificant
step-up in theplasma
ANP
levels between
the GCV and the CS (461±224vs.
682±341 pg/ml,
P <0.001).
Inpatients
with DCM, on theother
hand,
there
wasasignificant
step-up in theplasma
ANPlevels
betweenthe
Aoand the
AIV(454±360
vs.915±584
pg/ml,P
<0.001). There
wasalso
asignificant
step-upin
plasma ANP
levels
betweenthe
AIV andthe GCV
(915±584
vs.
1,308±926 pg/ml,
P<0.001) and between
theGCV and
the
CS
(1,308±926
vs.1,884±1,194 pg/ml,
P<0.001).
Thus,
the difference
inplasma
ANPlevels between the Ao and the AIV wassignificantly increased in
patients
with
DCM ascom-pared
with
thecontrol
subjects (461±248
vs.19±59 pg/ml,
P<
0.001)
asshown
inFig.
3.
The difference inplasma
ANPlevels between the CS and the
Ao wasalso
significantly
in-creased in
patients
with DCM ascompared
with thecontrol
pg/mi 2,
eel
"Is"ip608
"IIIo.
1,411 8 I._ a 0~ 0 4)0 04II-1o
=i1
Y7-v 3J157t,Iw
.1,l1s0
1,166
1,400 C-z F (a 1,2le- 1,110-1I.88 sII. 480-269 I p<,.8I1 r I NS 0 l~~~~~ * 0 * 0. 1 0121!.I*
*$$so
I0:0
.0.Ao AIV GCV
Control * I *0 0*. 0 0 0
I
I. P<ujgl 0 0 *P<LS~lt
P<1.811i~ p<,.I11CS Ao AlV GCV
DCM
Cs
Figure 2. PlasmaANPlevels in the Ao, AIV, GCV, and CS in the
controlsubjectsand thepatients with DCM. Therewas no
signifi-cantdifferenceinthe plasmaANPlevels between theAoand the AIV, but therewerehighlysignificant differencesbetween the AIV
and theGCV and between the
G;CV
and the CS in thecontrolsub-jecis.Ontheotherhand,there was asignificantstep-upinthe
plasmaANPlevels betweenthe Aoand theAIVinthe patients
with DCM.
201-Id
43'
P<Kmill I *0*I.
1:1
Control DCM AIV a 0 @0 0*-* 0*1
0 L1 ip<,.,11
Control DCMCs
Figure 3. ArteriovenousANPdifference in theAIVand the CS in controlsubjectsandpatientswith DCM. Therewasahighly
signifi-cantdifference in the
arteriovenous
ANPdifference between thecon-trolsubjectsand thepatientswith DCM in both theAIVand theCS.
subjects
(1,429±890
vs.577±318
pg/ml,
P <0.001;
Fig. 3).
Plasma ANP levels
weresignificantly
increased in
patients
with DCM
ascompared with
thecontrol
subjects
at each bloodsampling site (in
the
Ao,454±360
vs. 108±42pg/ml,
P<
0.001; in
theAIV,915±584
vs. 127±55 pg/ml, P < 0.001; in theGCV,
1,308±926
vs.461±224
pg/ml,
P<0.001; and in
theCS, 1,884±1,194
vs.682±341
pg/ml,
P<0.001).
The difference in
plasma
ANPlevels
between the AIV andthe Ao had
ahighly
significant positive linear correlation
withend-systolic
volume index (r =0.8334,
P <0.001),
a highlysignificant negative
linear
correlation with ejection fraction
(r=
-0.8262,
P <0.001),
a highly significant negative linearcorrelation with cardiac
index(r
= -0.7210,
P<0.001),
andahighly significant
positive
linearcorrelation with
pulmonary
capillary
wedge
pressure(r
=0.7176,
P<0.001)
asshown inFigs.
4and 5.Discussion
We have shown that ANP
is
released into the generalcircula-tion
at leastpartially by
wayof
the CS (6, 20). The maintributaries of
CS are theGCV, theoblique
vein of Marshall, theposterior vein of
theleft
ventricle, the posteriorinterven-.
Po/ml
2"801
.
r=3.334
P<3.31
o Control
* DCM
0
0 S
o 8 o o
°
il-He
-3 II 23 33 43 53 Is I1 3' 3I
End-Systolic Volume Index (mi/M2)
0 r=-3iJ212
p<3l33 oControl * DCM
0 l0
0 R
to00
0 0
Z 4c
sla
.'
.
I
isis
.
*0
Cardiac Index (liters/min/m2)
C-2
4
.4
er-|
dis
r3.=111
p<Bl31 0 Control * DCM
0 0
00
II 21 33 43 SI Ejection Fraction (%)
Figure 4. The difference in plasma ANP levels between AIV andAo
hadahighly significant positive correlation with the end-systolic vol-umeindex(top) andahighly significant negative correlation with the
ejection fraction (bottom), respectively.
tricularvein,and thesmall cardiac vein(21-23). Althoughthe
exact distribution and location of the venous system that drains the atriaare notknown, theobliquevein ofMarshall
and the small cardiac vein are thoughtto drain the left and
right atrium, respectively (23). The leftposterioratrialveins
also drain the left atrium andempty into the CS. Thus, the
GCV which is upstreamtotheseveinsisthoughtto containa
lowerproportionofblood from the atriathan theCS,and the AIV which is located in the anteriorinterventricular groove
and is upstreamtothe GCVisthoughtto drain the left
ventri-cle butnotthe atria.
Inthepresentstudybloodsamplingfor ANPwasdone in
theAo,theAIV,theGCV,and the CSsimultaneously.Inthe
controlsubjectstherewas no significantdifference inplasma
ANP levelsbetween the Ao and theAIV,buttherewerehighly significant step-ups in plasma ANP levels between the AIV
and the GCV and between theGCV and the CS. This indicates
thatANPisnotreleasedsignificantlyfromthe left ventriclein
the control subjects and isincreasingly released intothe CS
systemasblood flows downstreamfromthe AIV tothe CS.In
contrast, there was ahighly significant step-up in theplasma
ANP levels between theAIV and the Ao in patients with
PCW Pressure (mmHg)
Figure5. The difference in plasma ANP levels between AIV andAo
hadasignificant negative correlation with cardiac index (top) anda
highly positive correlation with pulmonary capillary wedge (PCW)
pressure(bottom), respectively.
DCM. Thus, the present study indicates that increased
amounts of ANPare released from the left ventricle into the
circulation inpatientswithDCM.The fact that the magnitude
of step-up inplasmaANPbetweenthe Aoand theAIV
corre-latedsignificantly with the left ventricular end-systolic volume index, ejection fraction, and cardiac index also supportsthe
above concept.
The presentstudy also shows that the differenceinplasma
ANP levels between the CSand the Aowas significantly in-creased in patients withDCM as comparedwith thecontrol subjects, indicatingthat theamountof ANPreleased from the
heart as a whole was significantly increased in patients with
DCMascomparedwith thecontrol subjects.
Thus, ANPis releasedin increasedamountsfrom the left ventricleaswellasfrom theheartas awhole into the
circula-tion inpatientswith DCMascomparedwith the control
sub-jects.Since thepioneeringwork of de Bold and his co-workers
(11)ANPhasbeenthoughttobe secreted from the atria and
notfrom theventricles in adult mammals(1-5, 12).However, severalrecentreportsindicatethatANP isalsosynthesizedin
smallamountsintheextra-atrialsites, includingtheventricles
(14, 25-28),and in substantialamountsinventricleswith
hy-pg/ml
tooli
333.
Ill
C-z 4
Ia
I-of
a:c;o
c 0Am4.
4"|
213-r=-3.7211
P<lIlI
oCoatr
*DCM
3-pg/Mi
4"11
I-z 4
E'm
aX,
o9I
CLC S.
L.i
Am
233-
211-
pertrophy or heart failure (13-17) in animals. Recently, Ed-wards andhis co-workers demonstrated immunohistochemi-cally thepresenceof immunoreactive ANP in the ventricles of autopsied and biopsied humans with heart failure, butnotin the control autopsied human hearts (19). We also have
re-ported an autopsycaseof DCM in which tissue levels of ANP and ANP mRNAweremarkedlyincreased in theleft ventricle
as compared with those in the control subjects (18). The present study confirms and extends our own previous study and that of Edwards and his co-workers, and demonstrates that an increasedamount of ANP isactually released from the left ventricle into the circulation and contributes significantly totheelevation of
plasma
ANPlevels inpatients
withDCM.The mechanism(s) by which increased secretion of ANP occurs from the left ventricleinpatients with DCMisunclear atthe present time. Increased wall tensionorstretchas a
con-sequenceof volume overload may stimulate the secretion of ANPfrom the left ventricle as from the atria
(29).
The demon-stration in thisstudy
that themagnitude
of step-up in the plasma ANP levels between the Ao and theAIVhad a highlysignificant
positive linear correlation with the left ventricular end-systolic volume index supports this interpretation. We (30) and other workers (8, 31) have shown that infusion of ANPinpatients with
congestive heart failure, including
thosewith DCM, improves left ventricular function by
reducing both the increased preload and afterload. Thus, increasedse-cretion ofANPfrom the leftventricleinpatientswith DCM
may represent an
important
compensatorymechanism
forheartfailure.
Previous
studies
havedemonstrated that
ANPis
synthe-sized in substantial amounts in the ventricles of fetal rats(25-28)
and human fetuses(32);
thus the increased releaseofANP
from the
leftventricle
inpatients
with DCM may indi-catethe presenceofcardiomyocytes
of afetal typeintheven-tricles
ofpatients
with DCM assuggested by
recent studies(33,
34).References
1.deBold, A.J. 1985.Atrial natriuretic factor: ahormone
pro-duced by the heart. Science(Wash. DC).230:767-770.
2.Laragh,J. H. 1985. Atrial natriuretic hormone, the
renin-aldo-steroneaxis,and bloodpressure-electrolyte homeostasis. N.Engl. J.
Med.313:1330-1340.
3. Needleman, P., and J. E. Greenwald. 1986. Atriopeptin:a
car-diac hormone intimately involved influid, electrolyte, and blood-pressurehomeostasis.N.Engl. J.Med. 314:828-834.
4.Ballermann,B.J., and B. M. Brenner. 1986. Role of atrial
pep-tidesinbody fluid homeostasis. Circ. Res. 58:619-630.
5.Genest,J., andM.Cantin. 1987. Atrial natriuretic factor. Circu-lation. 75(Suppl.
I):l
18-124.6. Sugawara,A., K.Nakao,N. Morii, M.Sakamoto,M.Suda, M.
Shimokura,Y.Kiso,M.Kihara,Y.Yamori,K.Nishimura,et al. 1985.
Alpha-human atrialnatriuretic polypeptide is released from the heart and circulates inthe body. Biochem. Biophys. Res. Commun.
129:439-446.
7.Burnett,J.C., Jr., P. C.Kao, D. C. Hu, D. W. Heser, D. Heub-lein, J. P. Granger, T. J.Opgenorth, andG.S. Reeder. 1986. Atrial
natriuretic peptide elevationincongestiveheartfailurein the human.
Science(Wash. DC).231:1145-1147.
8.Cody,R. J., S.A.Atlas, J. H. Laragh, S.H.Kubo,A.B.Covit,
K. S.
Ryman,
A.Shaknovich,
K.Pondolfino,
M.Clark,
M.J. J.Ca-margo, and R. M.Scarborough. 1986. Atrial natriuretic factor in
nor-malsubjects and heart failure patients. J. Clin. Invest. 78:1362-1374. 9.Rodeheffer, R. J.,I.Tanaka, T. Imada,A.S.Hollister, D. Rob-ertson,and T. Inagami. 1986. Atrialpressureand secretion of atrial natriuretic factor into the human central circulation. J. Am. Coll. Cardiol. 8:18-26.
10.Raine,A.E.G.,D.Phil, P. Erne, E.Burgisser,F.B.Muller, P. Bolli, F. Burkart, and F. R. Buhler. 1986. Atrial natriuretic peptide and atrial pressure inpatients with congestive heart failure. N. Engl. J.
Med. 315:533-537.
11. deBold,A.J., H. B.Borenstein, A. T. Veress, and H.
Sonnen-berg. 1981. A rapidand potentnatriuretic response to intravenous injection of atrial myocardialextractinrats.Life Sci. 28:89-94.
12.Kangawa, K., and H. Matsuo. 1984. Purification and complete amino acidsequence ofalpha-human atrial natriuretic polypeptide. Biochem. Biophys. Res. Commun. 118:131-139.
13. Lattion, A. L., J. B. Michel, E. Arnauld, P. Corvol, and F.
Soubrier. 1986. Myocardial recruitment during ANF mRNA increase withvolume overload in therat. Am.J.Physiol. 251 :H890-H896.
14.Day, M. L.,D.Schwartz, R. C. Wiegand,P. T.Stockman,S. R. Brunnert, H.E.Tolunay,M.G.Currie,D.G.Standaert,and P. Nee-dleman. 1987. Ventricularatriopeptin:unmaskingofmessengerRNA andpeptide synthesis by hypertrophyordexamethasone. Hypertension
(Dallas). 9:485-491.
15.Ding,J., G.Thibault,J.Gutkowska,R.Garcia,T.Karabatsos, G.Jasmin,J.Genest,and M.Cantin. 1987. Cardiac andplasmaatrial natriuretic factor inexperimentalcongestiveheartfailure.
Endocrinol-ogy. 121:248-257.
16.Franch,H.A., R.A.Dixon,E.H.Blaine, andP.K.Siegl. 1988. Ventricular atrial natriuretic factor in the cardiomyopathichamster modelofcongestiveheartfailure. Circ. Res. 62:31-36.
17.Arai, H., K. Nakao, Y. Saito, N. Morii,A. Sugawara, T. Ya-mada, H. Itoh, S. Shiono, M.Mukoyama, H. Ohkubo,etal. 1987. Simultaneous measurementof atrial natriureticpolypeptide (ANP)
messengerRNA andANPinratheart.Evidence forapreferentially increasedsynthesisandsecretion ofANPin left atrium of
spontane-ously hypertensive rats(SHR). Biochem. Biophys. Res. Commun. 148:239-244.
18.Saito, Y., K. Nakao, H.Arai,A.Sugawara,N.Morii,T.
Ya-mada,H.Itoh,S.Shiono,M.Mukoyama,K.Obata,etal. 1987. Atrial natriuretic polypeptide (ANP) in human ventricle: increasedgene
ex-pressionof ANP in dilatedcardiomyopathy.Biochem. Biophys.Res. Commun. 148:211-217.
19.Edwards, B. S.,D. M.Ackermann, M. E. Lee, G. S. Reeder, L. E.Wold,and J.C. Burnett, Jr. 1988. Identification of atrial natri-ureticfactor within ventricular tissue in hamsters and humanswith
congestiveheartfailure. J. Clin.Invest.81:82-86.
20.Obata,K., H. Yasue, Y.Horio, S. Naomi,T. Umeda,T. Sato, A.Miyata,and H. Matsuo. 1987. Increase of human atrial natriuretic
polypeptideinresponse tocardiacpacing.Am.HeartJ. 113:845-847. 21.Gensini,G.G.,S. D.Giorgi, 0.Coskun, andA.Palacio.1965.
Anatomy of thecoronarycirculation in livingman: coronary
venogra-phy.Circulation. 31:778-784.
22. Roberts,D.L.,H. K.Nakazawa,and F. J. Klocke. 1976. Origin
ofgreatcardiac vein andcoronarysinus drainage withintheleft
ven-tricle.Am. J.Physiol.230:486-492.
23. Tschabitscher,M. 1984.Anatomyofcoronaryveins.In The
Coronary Sinus. W. Mohl, E. Wolner, and D. Glogar, editors.
Springer-VerlagNew York, Inc.,New York,8-25.
24. Snedecor, G. W., and W. G. Cochran. 1980. Statistical Methods. TheIowaStateUniversityPress,Ames, IA. 135 pp.
25.Bloch,K.D.,J.G. Seidman, J. D. Naftilan,J. T.Fallon, and
C. E.Seidman. 1986. Neonatal atria and ventriclessecreteatrial
natri-uretic factor viatissue-specificsecretory pathways. Cell. 47:695-702. 26.Gardner,D.G.,C. F. Deschepper,W.F.Ganong,S. Hane, J.
Fiddes,J. D.Baxter, andJ.Lewicki. 1986. Extra-atrial expression of
thegene for atrial natriuretic factor. Proc. Natl.Acad. Sci. USA. 83:6697-6701.
27.Nemer,M., J. P.Lavigne, J. Drouin, G. Thibault, M. Gannon, andT. Antakly. 1986.Expression of atrial natriuretic factor gene in heartventricular tissue.Peptides(NY). 7:1147-1152.
28.Wei, Y., C.P.Rodi,M.L. Day, R.C. Wiegand,L.D. Needle-man,B. R.Cole, and P. Needleman. 1987. Developmentalchanges in theratatriopeptin hormonal system. J. Clin. Invest. 79:1325-1329.
29.Edwards,B.S., R. S. Zimmerman,T. R.Schwab,D. M. Heub-lin, and J. C. Burnett, Jr. 1988. Atrial stretch, not pressure, is the principal determinant controlling the acute release of atrial natriuretic factor. Circ. Res. 62:191-195.
30.Saito, Y.,K.Nakao, K.Nishimura,A.Sugawara,K.Okumura,
K.Obata,R.Sonoda, T. Ban,H.Yasue, and H. Imura. 1987. Clinical application of atrial natriureticpolypeptideinpatientswithcongestive
heart failure: beneficial effectsonleft ventricular function. Circulation. 76:115-124.
31.Crozier, I. G., M. G. Nicholls, H. Ikram, E. A. Espiner, H. J. Gomez, and N. J. Warner. 1986. Hemodynamic effects of atrial pep-tide infusion in heart failure. Lancet. ii: 1242-1245.
32.Kikuchi, K., K. Nakao, K. Hayashi, N. Morii, A. Sugawara, M. Sakamoto,H.Imura, and H.Mikawa. 1987. Ontogeny of atrial natri-ureticpolypeptide in human heart. Acta Endocrinol. 115:211-216.
33. Hirzel,H.O., C. R.Tuchschmid, J. Schneider, H. P. Krayen-buehl, andM.C. Schaub. 1985. Relationship between myosin isoen-zymecomposition, hemodynamics, and myocardial structure in var-iousforms of human cardiac hypertrophy. Circ. Res. 57:729-740.