Factors Controlling Plasma Renin and Aldosterone During Pregnancy WILLIAM H. BAY, M.D., AND THOMAS F. FERRIS, M.D.






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Factors Controlling Plasma Renin and Aldosterone

During Pregnancy


SUMMARY The response of plasma renin activity (PR A) and plasma aldosterone (PA) to change in sodium intake was evaluated in pregnant women during the third trimester. After 7 days on a 10 mEq sodium diet, PRA rose from 20.6 ± 6.2 to 59.6 ± 11.6 ng/ml/hr and PA from 47 ± 11 to 127 ± 27 ng% in pregnant women compared to PRA from S ± 1.2 to 18.9 ± 5.2 ng/ml/hr and PA from 7.7 ± 1 to 42 ± 3 ng% in nonpregnant controls. Pregnant women conserved sodium normally with urinary sodium excretion and weight loss similar to nonpregnant women. After 6 days on a 300 mEq sodium intake, PRA and PA in pregnant women were significantly higher, 10.2 ± 1.4 ng/ml/hr and 22 ± 3 ng%, respectively, compared to 1.5 ± 0 J ng/ml/hr and 7.3 ± 1 ng% in controls. On both low- and high sodium intake there was a positive correlation between PRA and PA in pregnant women. Plasma prostaglandin E (PGE) was 0.45 ± 0.06 ng/ml in pregnant women com-pared to 0.1 ± 0.01 ng/ml in control women (p < 0.01) and urinary PGE excretion was 2780 ± 357 ng/24 hr in 28 pregnant women compared to 1191 ± 142 ng/24 hrs (p < 0.01) in 14 nonpregnant controls. These find-ings indicate that although renin and aldosterone secretion respond to change in sodium intake in pregnancy, the cause of the increased renin secretion of pregnancy may be secondary to the increase that occurs in prostaglandin synthesis. (Hypertension 1: 410-415, 1979)

KEY WORDS • sodium balance

renin • aldosterone • pregnancy • toxemia * prostaglandin E


REGNANCY is associated with a striking

in-crease in renin and aldosterone secretion. This has been attributed to either a salt-los-ing tendency induced by the increase in glomerular

filtration rate (GFR) and progesterone secretion,1-2

orthostatic pooling in the extremities, or increased shunting of blood in the uterine circulation. However, blood volume, cardiac output, renal blood flow, and GFR all increase in pregnancy, which argues against functional volume depletion. In addition, the rise in renin secretion occurs in the first trimester before a great increase in uterine size or blood flow. Some

studies1' '• * have suggested no correlation between

plasma renin activity (PRA) and plasma aldosterone From the Department of Medicine, Ohio State University College of Medicine, Columbus, Ohio.

This study was supported by a research grant from the National Institute of Health HL 13653, RF 314701 to the Clinical Research Center, and grants from the Central Ohio Heart Chapter of the American Heart Association.

Present address for Dr. Ferris: Department of Medicine, Medical School, University of Minnesota, 420 Delaware Street S.E., Minneapolis, Minnesota 55455.

Address for reprints: William H. Bay, M.D., Department of Medicine, Ohio State University College of Medicine, 410 West 10th Avenue, Columbus, Ohio 43210.


(PA) in pregnancy, which suggests that factors other than sodium balance control renin secretion in preg-nancy. To evaluate these questions, studies of PRA and PA were carried out in pregnant women in their third trimester on a low- and high-sodium intake. Since decreased sensitivity to angiotensin occurs dur-ing human pregnancy and renal prostaglandin syn-thesis may affect renin secretion, plasma and urinary PGE were also measured.


Normotensive women in their third trimester with no past history of renal or cardiovascular disease were admitted to the Clinical Research Center and placed on either a 10 or 300 mEq sodium, 100 mEq potassium diet. Plasma renin and aldosterone were obtained before arising and at noon. Daily plasma electrolytes and 24-hour urine samples were obtained for creatinine clearance, urinary sodium and potas-sium determination. Nonpregnant hospital employees served as controls and were placed on the same diets, but were allowed to leave the metabolic unit during working hours. Plasma renin activity was measured by

radioimmunoassay according to the method of Haber5

after incubation of plasma for 3 hours at pH 5.5.








Pregnant n • NoPrtgnant n-I 2 3 4 5 6 7 DAYS

FIGURE 1. Weight change and urinary sodium excretion in

pregnant and nonpregnant women on a 10 mEq sodium diet for 7 days. ng/ml/hr. 128-1 64 32- 16-g. 4- 2I -ng/% 165 150 135 120 105 90-75 60 45 30-15


PLASMA ALDOSTERONE n»6 Non Pregnant n - 6 3 4 DAYS

FIGURE 2. Plasma renin activity and aldosterone of

preg-nant and nonpregpreg-nant women on a 10 mEq sodium diet for 7 days.

Plasma and urinary aldosterone and prostaglandin E (PGE) were measured by radioimmunoassay methods

previously reported from this laboratory."17 Recovery

of tritiated PGE, added to all urine and plasma samples reported in this paper was 73 ± 0.53% SEM. The values for plasma renin and aldosterone are those obtained at noon unless otherwise stated. Student's t tests were used for statistical evaluation of the results and all data are presented as the mean ± 1 SEM. Correlation coefficients were determined by a Hewlett-Packard Model 9830 Computer (Hewlett-Packard Co., Palo Alto, CA).

The protocol of this study was approved by the Human Experimentation Committee of the Ohio State University School of Medicine and informed and written consent was obtained from each patient.


On the first day of the study, pregnant women had higher supine PRA, 12 ± 3 ng/ml/hr, than nonpreg-nant women, 2.4 ± 0.9 ng/ml/hr (p < 0.01). After be-ing upright for 4 hours, PRA increased in pregnant women to 18 ± 3 compared to 4 ± 0.8 ng/ml/hr in control women. Plasma aldosterone increased with standing from 20 ± 3 to 36 ± 7 ng% in the pregnant women compared to from 6.3 ± 1 to 7.7 ± 0.8 ng% in controls.

On a daily 10 mEq sodium intake, pregnant and nonpregnant women came into sodium balance as shown in figure 1. By Day 4 pregnant and nonpreg-nant women had similar sodium excretion but over the next 7 days nonpregnant women had greater mean

sodium loss (280 mEq) than pregnant women (215 mEq), although the difference was not statistically significant. Weight loss (1.5 kg) was similar over the 7-day period in both groups. Creatinine clearance was higher in pregnant women, 133 ± 4 , compared to 117 ± 4 ml/min in nonpregnant women (p < 0.05) and no change occurred in either group during sodium restric-tion. On the low sodium diet pregnant and nonpreg-nant women had increased PRA and aldosterone levels (fig. 2); PRA rose in nonpregnant women from 5 ± 1.2 on Day 1 to 18.9 ± 5.2 ng/ml/hr (p < 0.01) on Day 7 and PA increased from 7.7 ± 1 to 42 ± 3 ng% (p < 0.01). In pregnant women, PRA rose from 20.6 ± 5 to 59.6 ± 11 ng/ml/hr (p < 0.01) and plasma aldosterone from 47 ± 11 to 127 ± 27 ng% (p < 0.01) on Day 7. Urinary aldosterone excretion in pregnant women rose from 66 ± 10 on Day 1 to 225 ± 37 Mg/24 hrs (p < 0.01) on Day 7.

On the 300 mEq sodium intake, both groups were in sodium balance by Day 5. Pregnant women retained 170 mEq of sodium with a 1.2 kg weight gain. No weight gain occurred in controls as they came into sodium balance on the first day of the 300 mEq sodium intake. After 7 days of a 300 mEq sodium in-take, serum potassium was unchanged in both groups. However, by Day 6, urinary sodium excretion was similar in both groups but PRA was 10.2 ± 1.4 ng/ml/hr and aldosterone 22 ± 3 ng% in pregnant women compared to 1.5 ± 0.3 ng/ml/hr and 7.3 ± 1 ng% in nonpregnant women. Figure 3 plots the supine PRA and PA in pregnant and nonpregnant women on the 300 mEq sodium intake.




ng/ml/hr. 16 8 4 2 I -n»6 —— Non Prtgnont n*6 p<OI


-£-*—I— PLASMA ALDOSTERONE n g / % 4 0 30 2O-10 (XOOS 2 3 4 5 6 DAYS

FIGURE 3. Supine plasma renin activity and aldosterone in

pregnant and nonpregnant women on a 300 mEq sodium diet for 6 days.

Figure 4 demonstrates the correlation in pregnant women of mean PRA and PA over the 6 days of high sodium and 7 days of low sodium intake. The correla-tion coefficient was r = 0.95 on the low and r = 0.78 on the high sodium diet. The slope of the regression was similar in the pregnant and nonpregnant women on a low sodium intake. On the high sodium intake in the nonpregnant women, no significant change in PRA or PA occurred due to the initial high urinary sodium and low PRA and PA in these women on the first day of the study.

After 6 days of a 300 mEq sodium diet, two women from each group were given 2 liters of normal saline intravenously for 2 consecutive days during which time they remained recumbent. Despite bedrest and 4 liters of saline, the pregnant women had PRA of 3.5 compared to 0.3 ± 0.1 ng/ml/hr in nonpregnant women and their PA level was 12 ± 1 compared to 6 ± 2 ng%. Thus, upright posture is not necessary for persistence of renin secretion in pregnancy. The GFR was significantly higher in the pregnant women, 154 ± 12, compared to 115 ± 5 ml/min in nonpregnant women before the start of the high salt intake and in neither group did the GFR increase during sodium loading.

Figure 5 shows plasma prostaglandin E in 23 preg-nant women in their third trimester and 19

nonpreg-150 100 PLASMA ALD08TCR0NE 5 0 LOW No DIET \ a/r-20 6 0 80



FIGURE 4. Correlation between plasma renin activity and plasma aldosterone in pregnant women on a low

and high sodium intake.


nant women. Prostaglandin E was 0.45 ± 0.06 com-pared to 0.1 ± 0.01 ng/ml in control women (p < 0.01). Twenty-four-hour urine for PGE, obtained from 28 pregnant women on unrestricted sodium in-take, was 2780 ± 357 compared to 1191 ± 142 ng/24 hrs in 14 nonpregnant women [p < 0.025) (fig. 6).


Previous studies of pregnant women have con-sistently demonstrated an increase in renin and aldosterone secretion. However, there have been dis-crepant findings regarding their responsiveness to

changes in sodium intake. Some8'10 but not all1- '• *

studies have demonstrated a variation with changes in sodium intake. We found a significant correlation between PRA and PA on both a high and low sodium intake. Although on both high and low sodium intake PRA and PA were higher in pregnant women, the slope of the regression lines was similar for both preg-nant and nonpregpreg-nant women on the low sodium diet (fig- 4).

The cause of the elevated PRA in pregnancy has been attributed to increased progesterone secretion, a known aldosterone antagonist. Progesterone secre-tion increases in the first trimester and parallels

aldosterone secretion.11 When given to normal

sub-jects or to patients with adrenal insufficiency on

mineralocorticoid replacement, progesterone

in-creases sodium excretion,12'1S and when applied to the

isolated toad bladder it reduces sodium transport by

displacing aldosterone from its binding site.14 In not

all studies of pregnancy, however, has a correlation between plasma progesterone and plasma aldosterone

been found.15 It is also difficult to explain the sodium

retention, expansion of maternal extracellular volume, on the basis of antagonism to aldosterone and a tendency to natriuresis during pregnancy. Landau,

and Lugibihl,12 failed to observe a natriuresis in

preg-nant women given progesterone, and women with Ad-dison's disease do not require added mineralo-corticoid replacement during pregnancy. Thus, mineralocorticoid antagonism does not appear to be a prominent feature of pregnancy, although the failure to develop hypokalemia with increased aldosterone secretion and normal sodium intake might be ex-plained by the increased progesterone secretion. Hypokalemia associated with primary aldosteronism

has been ameliorated during pregnancy.18

The elevation of PRA, in spite of a high sodium in-take, points to factors other than sodium that control renin secretion in pregnancy. Although compression of the inferior vena cava by the gravid uterus in late pregnancy might increase renin secretion, the elevated PRA prior to arising and after intravenous saline and



.8 •

. 6 -.4 •




• • •








FIGURE 5. Plasma prostaglandin E (PGE) in pregnant women in their third trimester and nonpregnant




FIGURE 6. Urinary prostaglandin E (PGE) excretion in

pregnant (third trimester) and nonpregnant women.

recumbency for 2 days argues against posture being a major component in the increased renin secretion. The finding that pregnant women retain more sodium and take longer to come into balance on a high sodium

in-take has been noted by others.2 It may be caused by an

increased venous capacity in pregnancy requiring greater extracellular expansion to achieve balance. However, by Day 4, urinary sodium was similar in both groups but PRA and PA remained higher in the pregnant women.

Increased estrogen secretion during pregnancy in-creases renin substrate concentration but this is not an adequate explanation for the elevated PRA. No significant increase in PRA usually occurs in women

taking oral contraceptives containing estrogen,1' 17

probably due to feedback suppression of renin secre-tion. However, in pregnancy there is an increase in plasma renin, renin substrate, and angiotensin


The uterus and amniotic fluid are potential sources

of renin in pregnancy. Day et al.18 found that human

amniotic fluid contained mainly "big renin" since dialysis at pH 3.3 greatly increased renin activity. Ex-perimental evidence in animals suggests that uterine renin concentration does not respond to change in sodium intake and does not normally enter the

mater-nal circulation.19 The fact that PRA responded

ap-propriately to change in sodium intake in our studies makes it unlikely that uterine renin is a major source of PRA in third-trimester-pregnant women or that "big renin" activated by incubation at pH 5.5 con-tributes significantly to the hyper-reninemia of pregnancy.

The sources of the increased plasma and urinary PGE in pregnant women is unclear. Urinary PGE ex-cretion is thought to represent renal synthesis since the

high prostaglandin dehydrogenase activity of renal cortex should oxidize circulating plasma PGE. In-fusions of PGE, into the renal artery do not increase

urinary PGE excretion.20 However, extraordinary

concentration of PGE have been found in the uterine

vein of pregnant rabbits.8 Whether uterine PGE

secre-tion would increase plasma PGE concentrasecre-tion depends upon the extent to which PGE escapes metab-olism during transit through the pulmonary

circu-lation. Studies in the cat and dog21 indicate that

90-95% of PGEj is metabolized in one passage through the pulmonary capillary bed but in humans only 65% of PGE? injected into the right ventricle is

metabolized in the pulmonary circulation.22 Thus, an

increase in uterine PGE synthesis could possibly elevate plasma PGE concentration.

The role of increased PGE synthesis in pregnancy is unknown. The utems can synthesize prostaglandins of the E and F series and both may have a role in

con-trolling uterine motility.23 Prostaglandin-inhibiting

drugs reduce uteroplacental blood flow in the pregnant rabbit* although autoregulation of uterine blood flow is independent of prostaglandin synthesis. Uterine synthesis of PGE might be necessary for new blood vessel growth and development in the uterus and placenta during pregnancy. The vasodilation and in-crease in blood volume induced by vasodilation would be a teleological advantage in pregnancy; protecting against hypotension and volume depletion if hemorrhage should accompany delivery.

Increase PGE synthesis may also be a factor in the increase in renin secretion of pregnancy. Stimulation of renal prostaglandin synthesis by administration of arachidonic acid to rabbits and dogs increases renin secretion" and indomethacin reduces renin

se-cretion.26 This effect appears to be independent of

change in renal blood flow since prostaglandin syn-thesis appears necessary for renin secretion during in

vitro studies of renal cortical cells.28

Synthesis of PGE may cause the insensitivity to angiotensin that occurs with pregnancy. Prostaglandin antagonizes and inhibition of PGE synthesis enhances the pressor effect of angiotensin and norepinephrine. Angiotensin antagonism has been demonstrated in human pregnancy as early as 10-12 weeks of

gestation.27 Everett et al.28 have reported that

in-domethacin and aspirin reverse this insensitivity. Pregnancy could be similar to Bartter's syndrome

where insensitivity to angiotensin, induced by PGE2, is

thought to cause compensatory increase in renin secre-tion. Like pregnant women, patients with Bartter's syndrome have elevated PRA levels which vary with change in sodium intake and are not suppressed in response to volume expansion. Urinary PGE excre-tion in Bartter's syndrome has been reported elevated to values similar to the results we found in pregnant


One might speculate on the potential role of PGE synthesis in the development of hypertension with tox-emia. Although PRA is variable in toxemia, angioten-sin sensitivity increases and precedes the development


of hypertension." Conceivably, increased sensitivity to ahgiotensin with development of toxemia represents a decrease in PGE synthesis with resultant imbalance of the renin-angiotensin-PGE axis. Serial measure-ments of urinary PGE throughout pregnancy are needed to determine if changes in angiotensin sen-sitivity with toxemia can be correlated with urinary PGE excretion.


The authors acknowledge the expert technical assistance of Ms. Gail Johannes, Elena Popescu, and Linda Howe in these studies.


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