Atrial natriuretic polypeptide is removed by the lungs and released into the left atrium as well as the right atrium in humans

Atrial natriuretic polypeptide is removed by the lungs and released into the left atrium as well as the right atrium in humans

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 natriur...

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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

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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

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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
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)

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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.

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