Download Atrial natriuretic polypeptide is removed by the lungs and released

JACC Vol. 15, No. 7
June 1!39O:t.537-43
537
Atrial natriuretic polypeptide is a c~rc~~ati~g
wide range of potent biologic effects, including natriuresis,
diuresis, vasodilation and inhibitionof renin and aldosterone
secretion, and is implicated in the homeostasis of body fluid
volume and blood pressure (l-4). It has been shown that
plasma levels of atria1natriuretic polypeptide are increased
in various disease states, including congestive heart failure
(5-S), renal failure (3,9), hypertensive (4.10)and supraventricular tachycardias (11) and that there is a positive correlation between plasma atria] natriuretic polypeptide levels
and right atrial or pulmonary capillary wedge pressure,
From the Division of Cardiology, Kumamoto University Medical School.
Kumamoto, Japan; *the Second Division. Department of Medicine, Kyoto
University School of Medicine, Kyoto, Japan and the iDivision of Cardiology, Kokura Memorial Hospital, Kokura. Japan. This study was supported in
part by ., grant from the Smoking Research Foundation, Japan.
Manuscript received August 7.1989; revised manuscript received January
17, 1990, accepted February 13, 1!290.
-for
Hirofumi Yasue, MD, Division of Cardiology,
Kumamoto University Medical School, l-I-1 Honjo, Kumamotn 860, Japan.
Q 19!M by the American
College of Cardiology
indicating that atria] pressure, or stretch, is involved in the
regulationof secretion of atria1natriureticpolypeptide (8,1214). Although atrial natriuretic polypeptide was initially
thought to be synthesized and stored in the atria but not in
the ventricles in adult mammals, more recent studies (IS-lg)
show that it is also present in tiny amounts in extra-atria]
sites, including the ventricles.
Three distinct molecular forms of human atrial natriuretic
polypeptide, (Y,/3and y, have been isolatedfrom human atria
(19-21). a-human atria1natriuretic polypeptide (human atria]
natriuretic factor-[99-1261)
is a biologicallyactive form consisting of 28 amino acids with an intramolecular disulfide
link; rhuman atria1 natriuretic polypeptide (human atrial
natriuretic factor-[l-126])is a prohormone with 126 amino
acids, carrying the sequence of 28 amino acids of a-human
atrial natriuretic polypeptide at its carboxy-terminus; and
@human atrial natriuretic polypeptide is an antiparallel
dimer of a-human atria1 natriuretic polygeptide with intermoleculardisuhide bridges. We demonstrated that the major
0735 m97/90/$3.50
1538
OBATA ET AL.
ATRJAL NATRIURETIC
POLYPEPTIDE
IN THE LUNGS
circulating form of atrial natriuretic polypeptide is the (rhuman form (22,23).
However, sites of release and removal of atrial nattiuretic
polypeptide in the circulation have not been rompletely
identified.We (23,24)and other investigators(4)have shown
that atrial natriuretic polypeptide is released into the circulation at least partly by way of the coronary sinus and hence
the right atrium. The venous outflow system from the heart
consists of the anterior cardiac veins and the coronary sinus,
which empty into the right atrium, and the smallest cardiac
veins of Thebesius, which empty into all the chambers of the
heart (25).The smallest cardiac veins are particularly dense
in the right and the left atrium. Thus, it is possible that atrial
natriuretic polypeptide is released into the circulation not
only by way of the right atrium through the coronary sinus,
the anterior cardiac veins and the smallestcardiac veins, but
also by way of the left atrium through the smallest cardiac
veins.
Atrial natriuretic polypeptide released from the right
atrium would hrst pass through the lungs, and it is possible
that it is altered during this passage. Recent animal studies
(26-28) indicate that there are specific receptors for atrial
natriuretic polypeptide in the lungs and that the lungs could
be a target organ for this hormone. Previous studies (29,30)
in humans, however, reported that atrial natriuretic polypep
tide was not removed by the lungs, although it was extracted
by the kidney, liver and lower limbs.
The present study was designed to examine in humans
whether atrial natriuretic polypeptide is released directly
into the left atrium and whether it is removed by the lungs,
by measuring plasma atrial natriuretic polypeptide levels at
various sites in the pulmonary as well as in the systemic
circulation.
Study patients. The study group comprised 33 patients,
12 men and 21 women aged 29 to 75 years (mean 53.9) who
underwent diagnostic cardiac catheterization and in whom
transseptal catheterization was successfully performed.
Twenty-two patients had mitral stenosis (the mitral stenosis
group) and 11 patients had atypical chest pain with normal
coronary arteriograms and no evidence of myocardial ischemia (the control group). Of the 22 patients with mitral
stenosis, 6 had mitral regurgitation, 3 had aortic regurgitation and 2 had tricuspid regurgitation. Sixteen of the 22
patients with mitral stenosis subsequently underwent balloon mitral valvuloplasty using the transseptal technique.
Twenty patients had been taking diuretics, 16digitalis and 5
nitrates.
None of the control group patients had heart failure,
hypertension, ventricular hypertrophy, ischemic heart disease, vah~lar heart disease, congenital heart disease or
arrhythmias. In addition, nine patients, four men and five
JACC Vol. IS, No. 7
June 1990: 1X37-43
women aged 20 to 68 years (mean 50.4) with atrial septal
defect and without a right to left shunt, were also studied by
simultaneous blood sampling from the pulmonary capillary
bed and the pulmonary vein. All medications were withdrawn 72 h before the study in the control group and at least
12 h before the study in the mitral stenosis group.
After the procedure was explained, written informed
consent was obtained from each patient and his or her
family. This procedure and study are in compliance with the
human studies guidelines of our institutioa and have been
approved by the ethical corn ttee at our institution.
Cardiic catbe~r~tio~.
patients underwent diagnostic cardiac catheterization in the fasting state. In addition, to
cross from the right atrium to the left atrium through the
fossa ovalis (31), transseptal catheterization was performed
in all patients except those with atria1septal defect. Successful entry into the left atrium was confirmed by both the
recording of a left atria1pressure waveform and the withdrawal of oxygenated blood, Blood samples were taken to
measure atrial natriuretic polypeptide levels, and left atria!
pressure was recorded. A Swan-Ganzcatheter was inserted
through the internal jugular vein into the pulmonary artery
under ffuoroscopic guidance. Pulmonary artery
pulmonary capillary wedge pressure were then measured
and blood samples were taken at each position. Blood
samplingfor measurement of atria1natriuretic polypeptide in
the pulmonary capillarybed was performed by occludingthe
pulmonary artery with the Swan-Ganz catheter balloon. To
confirm whether the atrial natriuretic polypeptide levels in
the pulmonary capillary blood samples truly reflect those in
the pulmonary veins, samples were also taken from the
pulmonary vein, as well as from the pulmonary artery,
pulmonary capillary bed and left atrium in the II control
subjects, 5 patients with mitral stenosis and 9 patients with
atrial septal defect. One operator took blood samples from
the pulmonary capillary bed by way of the Swan-Ganz
catheter and then from the pulmonary artery, while another
operator simultaneously took samples from the pulmonary
vein and then from the left atrium. Samples for measurement
of atrial natriuretic polypeptide in the aortic root were taken
with a Sones catheter or a pigtail catheter after pressure was
measured. The time disparity between blood samplingsfrom
various sites was 53 min.
Cardiac output or pulmonary blood flow was determined
three times by the thermodilution method immediatelyafter
blood sampling. In the nine patients with atrial septal defect
end the two patients with tricuspid regurgitation, the Fick
method was used to determine cardiac output. To minimize
the fluctuations in cardiac output, care was taken to avoid
respiratory and cardiac cycle fluctuation. The error of the
thermodilution method in the present study was approximately 5%. Heart rate was continuously monitored by the
electrocardiogram. Cardiac index or pulmonary blood flow
JACC Vol. 15, No. 7
June I
:1537-43
stenosis
4TRIAL NATRKJRETK
group (n = 22)
POLYPE
QBATA ET AL.
1539
aa t 22
represented as mean values -+ SD.
was considered
statistically
significant.
noassay are 920% and
No cross-reactions we
aldosterone,
digitalis,
As an index of the amount
of atria9 natri-
bed. As an index of the amount of atria9 natriuretic polypeptide released into the left atrium, we calculated the product
of the pulmonary plasma flow index and the difference in the
2). Plasma atria9 natriuretic polypeptide levels were
cantly increased at each sampling site in patients with
mitral stenosis compared with the control subjects (p <
I at each site, respectively). In both groups there was a
ly significant increase between the femoral vein and the
right atrium, a significant decrease between the pulmonary
artery and the ~~9rno~a~y capillary bed and a significant
bed and the left
increase between the pu9mo~ary capi
de levels, as we99
atrium in plasma atria9 natri
< 0.01) decrease in
e femoral vein. The
PA
ial stenosis group (n = 22)
PC
LA
Ao
1540
OBATA ET AL.
ATRIAL NATBIUBETIC POLYPEPTIDE IN THE LUNGS
poof _
4-
im_
0
w
eyI
RA
LA
PC
A0
Figure 1. Plasma atrial natriuretic polypeptide (ANP) levels at
various sites. In II control subjects and 22 patients with mitral
stenosis(MS),there was a significantincreasein plasmaANP levels
between the femoral vein (FV) and right atrium @A) and between
the pulmonary capillary bed (PC) and left atrium (LA) and a
significantdecrease in plasmalevelsbetweenthe pulmonaryartery
(PA)andpulmonarycapillarybed (PC)andbetweenthe aorticroot
(Ao)and femoral vein (FV). Plasma atria1natriuretic polypeptide
levels were increased significantlyat each sampling site in the
patients with mitralstenosisas comparedwith the control subjects.
increase in plasma atrial natriuretic polypeptide levels was
higher between the femoral vein and the right atrium than
between the pulmonary capillary bed and the left atrium in
both the control subjects and the patients with mitral stenosis (61 * 54 versus 23 2 21 pglml, p < 0.01 and 179 + 166
versus 79 f 51 pglml, p < 0.001, respectively). In both
groups there was no significant difference in plasma levels
between the right atrium and the pulmonary artery or
between the left atrium and the aortic root. The plasma atrial
Figure 2. Simultaneousplasmaatrial natriureticpolypeptide (ANP)
levelsin the pulmonaryartery (PA),pulmonarycapillarybed (PC),
pulmonaryvein (PV)andleftatrium(LA)in 25 patients. There was
a significantdecreasein plasmalevels betweenthe pulmonaryartery
and pulmonarycapillary bed, or pulmonaryvein,and a significant
increasebetweenthe pulmonarycapillarybed,or pulmonaryvein,
and the left atrium. However,there was no differencein plasma
levels between the pulmonarycapillary bed and pulmonaryvein.
,1
n=25
r-==l
P&OOl
1
?zi--z
I-II-
Pa.01
JACC Vol. 15, No. 7
June 1990:1537-43
natriuretic polypeptide levels in the right atrium tended to be
high compared with those in the pulmonary artery, probably
because blood samples were taken in the low right atrium
near the tricuspid valve and thus near the ostium of the
coronary sinus.
Figure 2 shows the plasma atria1natriuretic polypeptide
levels in the pulmonary artery, pulmonary capillary bed,
pulmonary vein and left atrium in 25 patients (11 control
subjects, 5 patients with mitral stenosis and 9 patients with
atria1 septal defect). The plasma levels in the pulmonary
artery, pulmonary capillary bed, pulmonary vein and left
atrium were 277 f 240,222 + 195,232 t 195and 267 -C220
pg/ml, respectively. There was a significantdecrease of the:
plasma atria1natriuretic polypeptide level between the pulmonary artery and the pulmonary capillary bed (p -K0.001)
and the pulmonary artery and pulmonary vein (p C 0.001).
There was a significantincrease of plasma atrial natriuretic
polypeptide level between the pulmonary capillary bed and
the left atrium (p < 0.001)and between the pulmonary vein
and the left atrium (p < 0.01). However, there was no
difference in plasma atria1 natriuretic polypeptide levels
between the pulmonary capillary bed and the pulmonary
vein.
Thus, atria1 natriuretic polypeptide is released into the
right atrium, removed by the lungs and released again into
the left atrium as blood flows from the femoral vein to the
aorta across the lungs and heart. Atrial natriuretic polypeptide is also removed by the lower limbs.
ypeptide levelsand
pressures(Fig. 3 and 4). The amount of atrial natriuretic
polypeptide removed by the lungs correlated significantly
with mean pulmonary capillary wedge pressure (r = 0.587,
p < 0.001)and mean pulmonary artery pressure (r = 0.595,
p < 0.001)(Fig. 3); the amount released into the left atrium
correlated significantly with mean pulmonary capillary
wedge pressure (r = 0.515, p < 0.01) and mean pulmonary
artery pressure (r = 0.571, p < 0.001) (Fig. 4).
Release of atrial natriureticpolypeptidefrom the left
atrium. In both the control subjects and the patients with
mitral stenosis, there was a marked increase of plasma atria1
natriuretic polypeptide level between the femoral vein and
the right atrium. This confirmsprevious reports (8,12,13)and
indicates that atrial natriuretic polypeptide is released into
the circulation primarilyby way of the right atrium, probably
through the coronary sinus (23,24).
The patients with mitral stenosis had markedly higher
levelsof atrial natriuretic polypeptide in the right atrium than
did the control subjects, even though right atrial pressure
was the same in both groups. This difference was probably a
result of three factors in the patients with mitral stenosis: 1)
atrial natriuretic polypeptide levels in blood returning to the
JACC Vat. 15, No. 7
June 1990~1537-43
0
MS
Control
n =33
I- =0.595
P<O.OOl
Mean Dulmonary caoillary wedge rxessure
(mmHo)
right atrium were already
levels in the femoral vei
po~ype~t~dewere released from the coronary
a §~~~ifi~ant
increase in
MS
0 Control
Mean oulmonary arterial Dressure (mrnH@
Figure 3. The amount of atrial natriuretic polypeptide (ANP) removed by the lungs, repre
ed by the product of
plasma flow index and the d
ence in plasma levels b
onary capillary bed (PC), had a
pulmonary artery (PA) and
significant positive correlation with mean p
wedge pressure (A) and mean pulmonary artery
mitral stenosis.
The amount of atrial natriuretic polypeptide (ANP) released into the left atrium, represented by the product of pulmonary
plasma flow index and the difference in plasma levels between the
left atrium (LA) and pulmonary capillary bed (PC), had a significant
positive correlation with mean pulmonary
(A) and mean pulmonary arterial pressure (
IVIS
MS
0 Control
0 Control
a
F
%
0
0
Mean oulmonary caDillary wedge Dressure
(mmHs)
Mean oulmonary arterial Dressure (mmHa)
1542
OBATA ET AL.
ATRIAL NATRIURETIC POLYPEPTIDE IN THE LUNGS
increase was significantly smaller than that between the
femoral vein and the right atrium. These results indicate that
atrial natriuretic polypeptide is released directly into the left
atrium.
The venous outflow from the /Wart consists of the
systems: the coronary sinus, which empties into the right
atrium, the anterior cardiac veins, which also empty into the
right atrium, and the smallest cardiac veins of Thebes&
which empty into all the chambers of the heart (25). The
smallest cardiac veins are most dense in the right and left
atria and are found sporadicallyin the ventricles.Thus, atrial
natriuretic polypeptide is probably released directly into the
cavity of the left atrium by way of the cardiac veins of
Thebesius. It is also possible that atrial natriuretic polypeptide may be released directly through the endocardial lining,
blood vessel walls and endothelium. Therefore, the present
study indicates that atrial natriuretic polypeptide is released
into the circulation by way of not only the right atrium but
also the left atrium, although the contribution of the latter Is
small compared with the former.
The amount of atria1 natriuretic polypeptide released into
the left atrium, as represented by the product of the pulmo-
nary plasma flow index and the difference in plasma atrial
natriuretic polypeptide levels between the left atrium and the
pulmonary capillary bed, correlated significantlywith mean
pulmonary capillary wedge pressure and mean pulmonary
artery pressure and was greater in patients with mitral
stenosis than in control subjects. Although this result suggests that left atrial pressure, or stretch (l4), is a potent
stimulus for atrial natriuretic polypeptide secretion into the
left atrial cavity, the scatter of data points was high and the
cause and effect relation could not be establishedfrom these
data.
Removalof at&l aatriureticpolypeptideby the lungs. In
both the patients and control subjects there was a significant
decrease in plasma atrial natriuretic polypeptide levels between the pulmonaryartery and the pulmonarycapillary bed
and the pulmonary artery and the pulmonary vein. This
finding indicates that atrial natriuretic polypeptide is removed or degraded as it passes through the lungs. The
amount removed by the lungs, as represented by the product
of the pulmonary plasma flow index and the difference in
plasma atrial natriuretic polypeptide levels between the
pulmonary artery and the pulmonary capillary bed, correlated significantly with mean pulmonary capillary wedge
pressure and mean pulmonary artery pressure and was
greater in the patients than in the control subjects. However,
the scatter of data points was high, and the implication of
these results was not clear,
The mechanisms of the removal of atria! natriuretic
poh@de
by the luny
are not known but could include
breakdown of the hormone by specific or nonspecific enzymes, the action of binding receptors, or transfer to extravascular spaces. Indeed, recent studies (26-28) indicate
JACC Vol. 15, No. 7
June 1990:153743
the presence of atria1natriuretic polypeptide and its receptors in the lungs, and Turrin and Gillis (33)report that atrial
natriuretic polypeptide is removed in a single pass through
perfused rabbit lung.
Other investigators (29,30)have reported that levels of
plasma atrial natriuretic polypeptide in humans were altered
little in the pulmonary circulation, although there was extensive clearance of atrial natriuretic polypeptide during the
passage of blood through the ckidney,liver and lower limb.
However, in these studies, blood samples were not obtained
from the pulmonary capillary ed or the pulmonary veins.
Recently, Hollister et al. (34)measured plasma levels at the
pulmonary artery, pulmonary capillary bed and pulmonary
vein in a few patients and several dogs, and demonstrated
that atrial natriuretic polypeptide is removed by the lungs.
They did not measure plasma atrial natriuretic polypeptide
levels at the left atrium and thus could not show the
hormone’s release from the left atrium.
Rodeheffer et al. (12) reported significant decreases in
plasma atrial natriuretic polypeptide levels in the pulmonary
capillary bed compared with the pulmonary artery and the
aorta in humans and suggested the possibility that either the
hormone was secreted from Icft atria1 endocardium or its
plasma concentrations were decreased as a result of the
pulmonary capillary sampling technique. In the present
study the pulmonary capillary site was verifiedby a pressure
waveform, fluoroscopy
a blood sample with more than
95% oxygen saturation. oreover, there was no difference
in plasma atria1natriuretic polypeptide levels between samples simultaneously taken from the pulmonary capillary bed
and the pulmonary vein. Thus, the decrease in plasma levels
in the pulmonary capillary bed compared with the pulmonary artery could not be attributed to the blood sampling
technique.
Removalof atrial n
tide by the lower
limbs. The significant decrease in plasma indicates that
atrial natriuretic polypeptide is removed by the lower limbs;
this finding is in agreement with previous reports (29,30).
Clinical implications.We (7) and other investigators
(6,35)have shown that infusion of atrial natriuretic polypep
tide in patients with congestive heart failure reduces pulmonary capillary wedge pressure and pulmonary vascular resistance, resulting in alleviation of pulmonary congestion
and pulmonary hypertension. Moreover, a recent study
(36) reported that atrial natriuretic polypeptide suppresses
the development of edema in isolated perfused guinea
pig lung. Thus, increased removal of atrial natriuretic
polypeptide by the lungs as well as increased secretion of
atrial natriuretic polypeptide from the right and left atria in
patients with congestive heart failure may constitute an
important compensatory mechanism in congestive heart
failure.
JACC Vol. 15. No. 7
June 1990:1537-43
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