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(Hypertension. 1995;25:631-636.)
© 1995 American Heart Association, Inc.
Articles |
Atrial Natriuretic Peptide and Hemodynamic Changes During Normal Human Pregnancy
From the Istituto di Clinica Medica and Centro Fisiologia Clinica e Ipertensione (C.S., A.Z., A.M.), Divisione Nefrologia Ospedale Maggiore Milano (M.C., G.A.), and Cattedra Ostetricia e Ginecologia (T.M.), Università di Milano (Italy).
Correspondence to Dr Carla Sala, Centro Fisiologia Clinica e Ipertensione, Via F. Sforza 35, 20122 Milano, Italy.
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Abstract |
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Abstract We compared plasma atrial natriuretic peptide (ANP) and cGMP levels during normal pregnancy—a condition characterized by hypervolemia, high cardiac output, and decreased vascular resistance—with postpartum levels and assessed their relation to pregnancy-induced hemodynamic changes. Humoral and hemodynamic variables were measured in healthy women subjects in the supine and upright postures at each trimester of pregnancy and postpartum. Supine plasma ANP was increased throughout pregnancy (32±5, 21±3, and 19±2 versus 15±1 pmol · L-1, respectively, at each trimester versus postpartum), as was cGMP (8.6±1, 7.1±1, and 6.6±1 versus 5.6±1 nmol · L-1), and their increments were directly related (r=.68, P<.01). Both ANP and cGMP levels did not differ from postpartum levels after subjects stood. Supine stroke volume was initially increased but declined below postpartum levels in late pregnancy (69±4, 60±3, and 44±3 versus 58±4 mL · m-2), whereas after subjects stood it was always higher (56±3, 58±3, and 49±2 versus 44±2 mL · m-2); thus, stroke volume tended to increase in response to standing in late pregnancy. Supine cardiac index had a similar trend, which was opposite to that of total peripheral resistance (1213±62, 1265±79, and 1729±89 versus 1654±92 dyne · s-1 · cm-5 · m-2). The increments of supine ANP throughout pregnancy were directly related to the changes of stroke volume (r=.40, P<.01), and those of cGMP were inversely related to the changes of total peripheral resistance (r=-.46, P<.01). We conclude that in early pregnancy ANP secretion is stimulated by hypervolemia, which also increases stroke volume. In late pregnancy, these changes in the supine position wear off because of the impairment of venous return by the pregnant uterus, which is relieved after standing. The increased plasma ANP may contribute to the systemic vasodilation during pregnancy, and this effect is mediated by its second messenger cGMP.
Key Words: atrial natriuretic peptide • cyclic guanosine 3'-5' monophosphate • pregnancy • hemodynamics • blood volume
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Introduction |
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Pregnancy is a condition of chronic volume overload in which hypervolemia is the result of an active sodium and water retention primarily induced by the activation of the renin-angiotensin system.1 Plasma volume increases from the early weeks of gestation up to a plateau in midpregnancy, when it is almost doubled compared with before pregnancy.2 The rise in blood volume is essential for the development of the fetoplacental unit, as an adequate uteroplacental flow is provided by the increased cardiac output as a consequence of the enhanced cardiac filling.3 These hemodynamic adaptations are associated with a systemic vasodilation that is already present before the development of the placental bed.4 The mechanism of the decrease in vascular resistance is poorly defined and has been attributed either to an increase of vasodilating agents such as prostaglandins5 and nitric oxide6 or to a decreased sensitivity to vasoconstrictive substances such as angiotensin II.7
Atrial natriuretic peptide (ANP) is secreted by the heart in response to atrial distension; it is diuretic, natriuretic, and vasorelaxant and antagonizes the renin-angiotensin system at multiple levels.8 Most of the biological effects of ANP are mediated by the second messenger cGMP.9 Elevated circulating levels of ANP have been described in physiological and pathological conditions of volume overload.10 Whether ANP secretion is enhanced during pregnancy is still controversial, as increased plasma ANP levels have been reported by some authors, at least at some stages of pregnancy,11 12 13 14 but not by others.15 16 17 Although in a few studies ANP has been prospectively assessed throughout pregnancy,14 16 18 only rarely have its levels been compared with postpartum levels. Moreover, body posture, which can markedly affect circulating levels of ANP,17 19 has not always been taken into account, as in most of the studies ANP was measured only with subjects in the supine12 13 or sitting position.15 16 Finally, to our knowledge only one attempt has been made to correlate the changes in ANP20 with pregnancy-induced hemodynamic changes, which are known to be markedly and differently influenced by body posture at the different stages of gestation.21 Unfortunately, in the study of Milsom et al,20 ANP was measured in unextracted plasma, a method that has a high degree of nonspecific interference that does not allow one to draw any firm conclusions on this issue. The aim of the present study was (1) to prospectively measure the circulating levels of ANP and its second messenger cGMP as well as the activity of the renin-angiotensin-aldosterone system throughout pregnancy in a group of healthy women and to compare these values with those observed after delivery, (2) to evaluate the influence of changes in body posture on these humoral factors by measuring them with subjects in both the supine and upright positions, and (3) to correlate the circulating levels of ANP and cGMP with pregnancy-induced hemodynamic changes.
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Methods |
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Twenty-two normotensive pregnant women without a previous history of cardiovascular or renal disease were enrolled in the study. Only 15 of these women (age, 29.7±1.4 years; range, 19 to 37) were included in the final analysis because 1 woman had a voluntary abortion at week 18 for fetus malformation, 1 became HIV positive, and 5 did not have available postpartum data. Eight women were primiparous and 7 multiparous; no medication was administered during pregnancy (13 singleton and 2 twin) except for iron supplements starting from the 24th week. At each visit, a routine clinical examination was performed, and blood for routine chemistry and 12-hour overnight urine were collected. The protocol was approved by the Ethics Committee of our institution; all subjects gave informed consent.
Protocol
Each woman was studied four times: once at each trimester of
gestation (that is, between weeks 11 and 16 [median, 13], 21 and 28
[24], 31 and 39 [37]) and after delivery (between weeks 6 and 13
[6]).
The subjects were placed in the supine position for 60 minutes, after which time the following hemodynamic parameters were measured: systolic and diastolic arterial pressures, heart rate, and stroke volume (SV). Blood samples for plasma ANP, cGMP, renin activity (PRA), and aldosterone were also collected from an antecubital vein. The same hemodynamic and humoral variables were measured again after subjects had stood for 60 minutes.
Hemodynamic Variables
Arterial pressure was measured with a mercury sphygmomanometer.
The fourth Korotkoff sound was used for diastolic pressure when
muffling was present; otherwise, the fifth phase was considered.
Mean arterial pressure was calculated as diastolic pressure plus one
third pulse pressure. Heart rate was calculated from the RR intervals
of an electrocardiographic tracing.
SV was measured by impedance cardiography.22 23 Two pairs of electrodes were placed on the neck at least 5 cm apart, a third pair on the lateral thorax at the xiphisternal level, and a fourth one 5 cm below. The upper and lower electrodes were excited by a 70-kHz sinusoidal current, and the resulting voltage was monitored from the two inner electrodes with an impedance cardiograph (BOMED NCCOM3, Medical Manufacturing). SV was derived from the following formula:
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where 
(ohms x centimeter) is the resistivity of blood, L
(centimeters) is the distance between the two inner recording
electrodes, Zo (ohms) is the average base impedance between
these two electrodes, T (seconds) is the ventricular ejection time, and
dZ/dtmax (ohms per second) is the magnitude of the
peak value of the impedance derivative. The validity of this method for
the longitudinal assessment of SV throughout pregnancy has been
recently confirmed.24 25 Cardiac index was calculated as
SV index (SVI=SV/Body Surface Area) times heart rate. Total peripheral
resistance index (TPRI) was calculated with the usual formula:
TPRI=(Mean Arterial Pressure/Cardiac Index)x80.
Blood Assays
Blood was collected in tubes containing 7
mmol · L-1 Na2EDTA that were placed on
ice (for ANP and cGMP) or kept at room temperature (for PRA and
aldosterone), centrifuged at 4°C, and stored at -40°C until
assay.
ANP was measured by radioimmunoassay after extraction of plasma on C18
Sep-Pak cartridges (Waters Chromatography) (mean recovery of labeled
ANP, 85%). The assay used a commercial antiserum for 
-h-ANP
(Peninsula Laboratories Europe Ltd) and tracer (IM 185, Amersham
International PLC). The sensitivity of the assay is 0.5 fmol per tube.
The normal range of supine ANP in our laboratory is 6.37 to 29.4
pmol · L-1 (14.77±1.96, mean±SEM). Plasma cGMP was
measured by radioimmunoassay with a commercial kit (RPA 525, Amersham)
after the extraction of plasma on C18 Sep-Pak cartridges (mean recovery
of labeled and unlabeled cGMP >90%). The sensitivity of the assay is
50 fmol per tube. PRA and aldosterone were measured by radioimmunoassay
with a commercial kit (Technogenetics-Recordati). The sensitivities of
the assays are 0.25 ng · mL-1 · h-1
and 10 pg · mL-1, respectively. The intra-assay
and interassay variabilities for all the assays were less than
10%.
Hematocrit was determined by an automated Coulter counter and plasma proteins by an autoanalyzer (Monarch 2000, Instrumentation Laboratory). Urinary sodium was measured by a direct potentiometric method (Nova1, Nova Biomedical).
Statistical Analysis
Results are reported as mean±SEM. ANOVA for repeated measures
was applied to compare the variables studied. If the difference was
statistically significant (P<.05), Dunnett's procedure was
used for the single comparisons between the values during pregnancy and
those after delivery, which were considered as control values.
Relationships between variables were calculated by linear regression
analysis and Pearson's correlation coefficient.
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Results |
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All pregnancies ended on average at week 40.3±1. Delivery occurred by vaginal route (n=11) or by elective cesarean section (n=4, 2 for twin pregnancies, 1 for acute fetal distress, 1 for a sudden increase of maternal transaminases at week 36). Birth weight of infants (10 male, 7 female) was 3344±143 g.
Body weight (Table 1) increased progressively throughout pregnancy and was still higher after delivery than in the first trimester. Hematocrit was slightly decreased in early pregnancy compared with postpartum values, and the reduction reached statistical significance in the following months. In contrast, plasma proteins concentration was already significantly decreased at the first trimester.
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Hemodynamic Parameters
Both supine and upright systolic pressure values (Table 2) during pregnancy were not different from postpartum
values, whereas diastolic pressure in the second trimester was
significantly lower with subjects in both positions. The increase of
diastolic pressure in response to active standing was statistically
significant only postpartum. Supine heart rate increased progressively,
with a peak at the third trimester, whereas upright heart rate was
increased only in late pregnancy, at which time the increment of heart
rate in response to standing was markedly depressed.
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Supine SVI was highest in the first trimester but declined subsequently and tended to be lower in late pregnancy than postpartum values; in contrast, the upright values were always higher than postpartum values. The physiological decrease of SV in response to standing was still present in early pregnancy but was abolished later and tended to increase in late pregnancy. These changes were similar to changes in cardiac index. TPRI followed an opposite trend, as supine values were decreased in the first and second trimesters but in the third trimester increased to postpartum values. The upright values of TPRI in pregnancy were always lower than postpartum values; thus, the physiological increase of TPRI in response to standing that was present postpartum was abolished in early and midpregnancy, and in late pregnancy TPRI even decreased.
Humoral Parameters
Supine plasma ANP values in early pregnancy were twice those
postpartum (31.9±4.9 versus 14.6±1.3
pmol · L-1, respectively; P<.05)
(Fig 1). It is of interest that two of the highest
values were observed in the twin pregnancies (75 and 36
pmol · L-1, respectively). In the second and
third trimesters, ANP tended to decrease (20.8±3.1 and 19.1±1.8
pmol · L-1, respectively) and was not different
from postpartum values. In contrast, with subjects in the upright
posture, ANP in pregnancy was always similar to postpartum values
(13.8±1.4, 12.2±1.0, and 14.5±0.9 versus 12.2±1.3
pmol · L-1, respectively, at each trimester
versus postpartum). A significant decrease of ANP after subjects stood
was present at all times of pregnancy, although the postural
decrements of ANP were progressively smaller with advancing pregnancy.
The trend of cGMP with subjects in the supine position (8.6±0.6
[P<.05 versus postpartum], 7.1±1.0, and 6.6±0.7 versus
5.6±0.4 nmol · L-1) and upright (5.3±0.3, 5.4±0.4,
and 5.7±0.4 versus 5.5±0.4 nmol · L-1) was similar
to that of ANP (Fig 1); the increments of supine cGMP throughout
pregnancy compared with postpartum were directly related to those of
ANP (r=.68, P<.01) (Fig 2). The
increments of supine ANP in turn were directly related to the changes
of SVI in the same position (r=.40, P<.01) (Fig 3); moreover, the percent decrements of ANP after
subjects had stood at each trimester of pregnancy were directly related
to the postural changes of SVI (r=.40,
P<.01).
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The increments of supine cGMP and those of ANP were inversely related to the changes of supine TPRI throughout pregnancy (r=-.46, P<.01, Fig 4; and r=-.31, P<.05, respectively).
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With respect to postpartum values, PRA was higher at the first trimester with subjects in both the supine and upright positions and reached a plateau at the second trimester. The physiological increase of PRA in response to standing was reduced after the second trimester. Plasma aldosterone steadily increased throughout pregnancy with subjects in both the supine and upright positions. The increments of supine PRA and aldosterone throughout pregnancy were inversely related to those of ANP (r=-.39, P<.01; r=-.31, P<.05, respectively).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study shows that supine plasma ANP in the first trimester of pregnancy was twice as high compared with postpartum values in a group of healthy normotensive women. With the progression of pregnancy, however, ANP tended to decrease toward postpartum values, which were within the normal range observed in our laboratory in nonpregnant control subjects. Thus, it seems reasonable to consider the postpartum values as representative of those before gestation. In contrast to the supine position, after active standing ANP values throughout pregnancy were similar to postpartum values. The high plasma ANP levels observed in early pregnancy are more likely caused by an enhanced secretion by atrial myocytes than by a reduced clearance of this peptide. Indeed, both renal function and the endothelial surface, where the clearance receptors and the neutral endopeptidase are mostly located,10 are increased during pregnancy because of the development of the fetoplacental unit.26
The most likely stimulus for ANP secretion in pregnant women is the increased cardiac preload due to the hypervolemia. An increase in the afterload can be excluded because blood pressure was, if anything, decreased and total peripheral resistance was lower. Although we did not measure plasma volume in the present study, several pieces of evidence may indirectly show that an expansion of the circulating volume was already present at the first trimester. First, hematocrit and plasma proteins concentration decreased as a consequence of the expansion of intravascular fluids.1 Second, two of the highest ANP values were observed in the twin pregnancies, which are known to be associated with a greater expansion of blood volume.1 Finally, the hemodynamic evidence is provided by the increase in SV, which is related to enhanced cardiac filling.27 Indeed, an enlargement of both right and left cardiac chambers has been documented from early pregnancy by several echocardiographic studies28 29 30 with the exception of one.31 It is worth noting that the increments of SV that we observed in early pregnancy were similar to those reported by an echo Doppler study at the same time of gestation compared with preconception values.30
The ANP increments were observed only with subjects in the supine position and tended to wear off with the progression of gestation. One possible explanation is that the stimulus of hypervolemia on atrial wall tension is more pronounced in the supine position, when venous return to the heart is enhanced, whereas after active standing the stimulus is offset by the pooling of blood in the lower body. With the progression of pregnancy, however, venous return is impaired in the supine position because of the compression of the vena cava by the pregnant uterus. This mechanism may be responsible for the decrease of SV with subjects in the supine position that has been reported also by others27 30 and for the tendency of SV to increase in response to standing as a consequence of the relief of caval compression. The progressive decrease of supine ANP, the changes of which were directly related to those of SV, can also be attributed to the same mechanism. This mechanism has not been confirmed by Lowe et al,17 who were unable to observe a consistent decrease of ANP in pregnant women moving from the left lateral to the supine position. However, a closer analysis of the results shows that ANP actually decreased in most of the women, and an impressive decrement occurred in one woman who experienced a dramatic fall in blood pressure. It is possible that in the remaining subjects the decrements of ANP were not fully apparent in the 20 minutes of the study because of the interindividual differences in the time course of the responses.
Our observation that the circulating levels of ANP are markedly affected by body posture may explain some of the discrepancies reported in the literature. Indeed, no increments of ANP during gestation were generally observed with subjects in the sitting position15 16 ; in contrast, ANP was found to be elevated during pregnancy when measured with subjects in the supine position12 13 or in left lateral recumbency,18 a position in which the stimulus of hypervolemia is not counterbalanced by the caval compression even in late pregnancy. Actually, in this last study18 the authors concluded that ANP is not increased during gestation, although the values were in the same order of magnitude as those we observed in early pregnancy. This most likely occurred because ANP was extremely high in their nonpregnant control subjects, probably as a result of a previous maneuver of water loading.
Plasma cGMP rose in parallel to the increments of ANP, as has been observed in physiological and pathological conditions in response to either endogenous or exogenous ANP.32 This suggests that the ANP activity at the target cells was increased through the activation of the particulate guanylate cyclase. Indeed, plasma cGMP does not appear to be affected by the activity of the nitric oxide–dependent soluble enzyme.33 Although the circulating levels of cGMP are probably derived from the endothelial cells, the experimental evidence shows that they are closely related to the cGMP concentration within the vascular wall33 and to the vasorelaxant effect of ANP.34 Moreover, in healthy subjects, the vasodilation induced by ANP was found to be related to the increments of plasma cGMP,35 which in turn were similar to those observed here. Thus, the inverse relation between the changes of cGMP and vascular resistance in our pregnant women suggests that the stimulated production of this nucleotide induced by ANP may contribute to the systemic vasodilation during pregnancy. This is also in accordance with the observation that in healthy pregnant women the increments of ANP in response to an acute volume loading were inversely related to the peripheral vasodilation.36
A marked activation of the renin system occurs during pregnancy,37 38 the mechanism of which is still incompletely defined. It is possible that in late pregnancy the activation of the cardiopulmonary receptors by the decreased venous return due to the caval compression may stimulate the renin system with subjects in the supine position.39 On the other hand, our observation that the changes of supine ANP throughout pregnancy were inversely related to those of PRA and plasma aldosterone may suggest that ANP modulates this system during normal pregnancy, as has already been suggested to occur in preeclampsia.36
In conclusion, our data show that ANP secretion in the supine position is enhanced in early pregnancy probably as a consequence of the hypervolemia, which also causes an increase of SV. In late pregnancy, supine ANP tends to decrease as the stimulus of hypervolemia is counterbalanced by the impairment of cardiac filling due to the compression of the vena cava by the pregnant uterus, as shown by the progressive decrease of supine SV and by its tendency to increase in response to standing. The high circulating levels of ANP may contribute to the systemic vasodilation of pregnancy either by a cGMP-mediated vasorelaxant effect or indirectly by antagonizing the activity of the renin-angiotensin system.
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Acknowledgments |
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We dedicate this article to the memory of our friend and colleague Stefano Casati, MD, whose invaluable collaboration made this work possible. The authors are grateful to Dr Esmeralda Pulazzini and Elide Oggiano for technical assistance.
Received May 23, 1994; first decision July 14, 1994; accepted November 21, 1994.
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