Relationship Between Plasma Renin, Renin-Substrate, Angiotensin II, Aldosterone and Electrolytes in Normal Pregnancy RONALD J. WEIR*, JEHOIADA, J. BROWN, ROBERT FRASER, ANTHONY F. LEVER, ROBERT W. LOGAN, GILLIAN M. McILWAINE, JAMES J. MORTON, J. IAN S. ROBERTSON, AND MALCOLM TREE M.R.C. Blood Pressure Unit, Western Infirmary: Department of Obstetrics, Royal Maternity Hospital: Department of Biochemistry, The Queen Mother s Hospital, Glasgow, Scotland ABSTRACT. Plasma concentrations of renin, reninsubstrate, angiotensin II and aldosterone were measured in normal pregnant women at various stages of gestation and postpartum. The mean circulating levels of renin-substrate, angiotensin II and aldosterone increased significantly from the first to the third trimester. Mean plasma renin concentration was highest in the first trimester and fell significantly to the third trimester, although it remained above the normal nonpregnant range throughout pregnancy. Unlike many other physiological and pathological situations in man, no significant relationship was found between concurrent plasma concentrations of renin and angiotensin II, renin and aldosterone or angiotensin II and aldosterone. Plasma renin-sub-
T
HE concept that one of the principal functions of the renin-angiotensin system is the regulation of aldosterone secretion (1,2,3) has stimulated considerable interest in recent years. The importance of this role in man, however, remains controversial (4,5,6,7). Nevertheless, in many physiological and pathological situations in man, plasma concentrations of the enzyme renin, its principal active product angiotensin II and aldosterone are closely correlated, in a manner which suggests an important connection between them. Normal human pregnancy presents, however, an exception to this general rule. Although in this situation some of the greatest increases in circulating levels of renin, renin-substrate and aldosterone are found of any physiological circumstance (8,9,10,11,12,13), the concentrations of these components are not closely correlated (9,10).
Received April 15, 1974. * Present address: Gartnavel General Hospital, Glasgow, Scotland.
strate concentration did not correlate with plasma angiotensin II concentration, but it did have a positive correlation with plasma aldosterone concentration. The plasma concentration of aldosterone was positively related to plasma sodium concentration, which was below the normal nonpregnant range in
most women throughout gestation. The reason for this dissociation between the major components of the renin-angiotensin-aldosterone system in normal pregnancy remains unclear. In pregnant women it appears that, although angiotensin II may be one of the factors affecting aldosterone secretion, it is a relatively minor one and other influences are of greater importance. (/ Clin Endocrin'ol Metab 40: 108, 1975)
The present study was designed to confirm and extend our earlier observations. In particular, the inclusion of concurrent estimations of renin-substrate and angiotensin II, not studied together previously in pregnancy as far as we are aware, might possibly illuminate the reasons for the dissociation between plasma renin and aldosterone concentrations. Materials and Methods One hundred and twelve women were studied at least once during pregnancy. Fifty-five of these were primigravid, while 30 had had one and 27 had had more than one previous pregnancy. Ages ranged from 17 to 41 yr (mean 26.0 yr). All had normal full-term pregnancies apart from 7 healthy women who had been admitted for termination of apparently normal early pregnancy. No case was included where a blood pressure of 140/90 mmHg. or over was recorded at any stage of gestation. All were taking an unrestricted diet and none was receiving diuretics. .. Venous blood samples were taken with the women in the supine position (i.e., lying on
108
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RENIN, ANGIOTENSIN AND ALDOSTERONE IN NORMAL PREGNANCY
109
their backs). Fifty-nine were inpatients and were sampled about 9:00 AM after 10 hr recumbency. The remainder (53) were seen as out-patients when samples were taken after they had rested supine for 30 min. Plasma renin concentration was measured by the method of Brown et al. (14), (normal nonpregnant range 4 to 20 U/l); plasma renin substrate concentration by the technique of Tree (15) (normal nonpregnant range 0.45 to 1.28 /AM); and plasma aldosterone concentration by a modification (16) of the double isotope derivative technique of Fraser and James (17) (normal nonpregnant range 0.1), renin-substrate of renin and angiotensin II (r = 0.07), renin(t = 1.90, 0.1 > p > 0.05) or aldosterone substrate and angiotensin II (r = 0.03), renin (t = 1.08, p > 0.1), but mean plasma angio- and aldosterone (r = 0.06) or angiotensin II tensin II concentration was higher in multi- and aldosterone (r = 0.01). These correla-
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110
WEIR ET AL.
JCE & M • 1975 Vol 40 • No 1
PLASMA RENIN SUBSTRATE CONCENTRATION uM 70-, RENIN
PLASMA CONCENTRATION units/ I 120-1
• •
t A
•• 80-
3-5-
• 9 •
40-
T* ••
I
A
X
A
1
1
X
•!
•• • •
t V
t•• t
t • •
• • •
• ••• t
t•
Y
•
0 - 1 2
13-26
T*
0-1 0 - 1 2
13-26
27-Term
G E S T A T I O N (weeks)
0 - 2
6 - 1 2
POST-PARTUM(weeks)
27-Term
G E S T A T I O N (weeks)
0 - 2
6 - 1 2
P O S T - PARTUM(weeks)
FIG. 1 (left). Plasma renin concentration in normal pregnancy and postpartum. Stippled area indicates normal non-pregnant range. Comparison: 0-12 weeks 13-26 weeks: t = 1.60 p>0.1 13-26 weeks 27 weeks-term: t = 0.87 p>0.1 0-12 weeks 27 weeks-term: t = 3.37 p < 0.01 27 weeks-term t = 6.40 0- 2 weeks p.p. p < 0.001 t = 3.33 p < 0.01 0- 2 weeks p.p. 6-12 weeks p.p. FIG. 2 (right). Plasma renin substrate concentration in normal pregnancy and postpartum. Stippled area indicates normal non-pregnant range. 0-12 weeks Comparison: 13-26 weeks: t = 6.76 p < 0.001 27 weeks-term: 13-26 weeks t = 4.68 p < 0.001 27 weeks-term: 0-12 weeks t = 10.84 p < 0.001 0- 2 weeks p.p.: 27 weeks-term t = 2.10 p < 0.05 6-12 weeks p.p.: 0- 2 weeks p.p. t = 4.08 p < 0.001
tions remained insignificant when the in- renin-substrate and aldosterone concenpatients and outpatients were considered trations during pregnancy (r = 0.25, 0.01 separately, and the dissociations seem there- < p < 0.05). In the puerperium, a positive fore not to be due to the different times of relationship was demonstrated between the recumbency before sampling. plasma concentrations of renin and angioA loose but statistically significant posi- tensin II (r = 0.55, 0.01 < p < 0.05). In contrast to an earlier study (21) we tive correlation was found between plasma The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 11:07 For personal use only. No other uses without permission. . All rights reserved.
RENIN, ANGIOTENSIN AND ALDOSTERONE IN NORMAL PREGNANCY
111
PLASMA ANGIOTENSIN IJ CONCENTRATION pg/ml 500-i
PLASMA ALDOSTERONE CONCENTRATION mug/lOOml
375-
180-i
250-
120-
-
125-
: 60-
! 1
± 0 - 1 2
13-26
27-TERM
G E S T A T I O N (weeksi | week si
0 - 2
0
T
J
6 - 1 2
0 - 1 2
P O S T - P A R T U M (weeks) (weeks)
13-26
27-TERM 0
G E S T A T I O N (weeks)
-
2
6 - 1 2
PPOST-PARTUM(weeks) O S T - P A R T U M (weeks)
FIG. 3 (left). Plasma angiotensin II concentration in normal pregnancy normal non-pregnant range. Comparison: 0-12 weeks 13-26 weeks: 13-26 weeks 27 weeks-term: 0-12 weeks 27 weks-term: 0- 2 weeks p.p.: 27 weeks-term 0- 2weeksp.p. 6-12 weeks p.p.:
and postpartum. Stippled area indicates
FIG. 4 (right). Plasma aldosterone concentration in normal pregnancy normal non-pregnant range. Comparison: 0-12 weeks 13-26 weeks: 13-26 weeks 27 weeks-term 0-12 weeks 27 weeks-term: 27 weeks-term 0- 2 weeks p.p.
and postpartum. Stippled area indicates
found no significant relationship between plasma aldosterone concentration and the product of plasma renin and renin-substrate concentrations (r = 0.14); nor was there a correlation between plasma angiotensin II concentration and the product of plasma renin and renin-substrate concentrations (r = 0.12). The plasma concentration of aldosterone was positively related to plasma sodium concentration (r = 0.26, 0.01 < p < 0.05), and a
t = 2.98 t = 2.18 t = 3.60 t = 3.31 t = 1.19
t = 1.21 t = 0.91 t = 2.05 t = 1.82
p < 0.01 p < 0.05 p < 0.001 p < 0.01 p>0.1
p > 0.1 p > 0.1 p < 0.05 0.05 < p < 0.1
significantly positive correlation was present between plasma angiotensin II concentration and plasma osmolality (r = 0.58, 0.001 < p < 0.01). Discussion Lack of relationship between renin, angiotensin and aldosterone. The present study has confirmed the dissociation, in normal pregnancy, between the circulating periph-
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112
JCE & M • 1975 Vol 40 • No 1
WEIR ETAL.
TABLE 1. Comparison of plasma concentrations of renin, renin-substrate, angiotensin II and aldosterone between in-patients and out-patients in early and late gestation Renin substrate
Angiotensin II pg/ml
Aldosterone ng/100 ml
40.6± 14.0 46.8± 19.2 0.84 38 >0.1
1.96± 0.41 1.68± 0.72 1.04 37 >0.1
32.4± 16.6 32.0± 25.9 0.04 35 >0.1
28.4± 27.4 34.7± 19.0 0.63 22 >0.1
35.0± 15.0 41.3± 15.9 1.26
3.78± 1.03 3.94± 1.17 0.44
Renin U/l Gestation 8th-12th week In-patient (M ± SD) Out-patient (M ± SD) t-statistic Degrees of freedom Significance, p Gestation 36th -40th week In-patient (M ± SD) Out-patient (M ± SD) t-statistic Degrees of freedom Significance, p
38
35
>0.1
>0.1
*
41.9± 32.2 44.5± 27.0 0.18
—
17
— —
>0.1
* Insufficient numbers for statistical comparison.
eral plasma concentrations of renin and aldosterone (9,13). Dissociations between concurrent plasma concentrations of renin and angiotensin II and also between angiotensin II and aldosterone have also been demonstrated. This lack of correlation between concurrent estimations of renin and angiotensin II in pregnancy contrasts markedly with the close relationship established using the same techniques, in a wide variety of other circumstances (22,23,24,25, 26,27). There are several possible explanations for this. One is that in pregnancy part of the renin circulating in plasma is in an inactive form, becoming activated in the process of extraction (28,29,30). If this were
the only explanation, renin should on average be high in relation to angiotensin II at all stages of pregnancy, but this is not the case (Figs. 1, 3, 5). Another possibility is that high circulating levels of renin-substrate contribute to the dissociation. There is now good evidence that substrate concentration is normally within a range capable of influencing angiotensin formation (31,32). A third possibility is that immunoreactive fragments of angiotensin are present in greater or more variable amovunts in the venous plasma of pregnant women (19,20). The other main dissociation demonstrated in pregnancy is between angiotensin II and aldosterone. Again, utilizing the same
TABLE 2. Correlations (r) between the components of the renin-angiotensin-aldosterone system and plasma electrolytes during pregnancy
Renin Renin Renin-substrate Angiotensin II Aldosterone
Renin x substrate
Plasma Na
Plasma K
Plasma OSM
0.03 0.04
0.08 0.14
0.02
— 0.12
0.01
0.14
+0.58** (n = 16)
0.14
+0.26* (n = 65)
0.14
0.26
Substrate
Angio II
Aldo
0.12
0.07 0.03
0.06
—
+0.25* 0.01
0.10
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113
CONCENTRATION
PLASMA SODIUM mEq/l 142-,
132PLASMA POTASSIUM mEq/l 47-,
PIASMA ANQOTtNSIN D CONCENTIATION
31J PLASMA OSMOLALITY mosm/kg 288-1
PIASMA AIDO3TMONC CONCtNTtATlON •uig/HMml JJO-i
276-
POS1-PA«TUM
NORMAL NON-PREGNANT RANGE
0-12
13-26
27-Ter
GESTATION (weeks)
0 - 2
6 - 1 2
POST-PARTUM (weeks)
FIG. 5 (left). Serial changes in plasma concentrations of renin, reninsubstrate, angiotensin II and aldosterone in 6 pregnant women. Stippled area indicates normal non-pregnant range. FIG. 6 (right). Plasma sodium partum (mean ± 1 SD). Sodium: 0-12 weeks 13-26 weeks 0-12 weeks 27 weeks-term 0 - 2 weeks p.p. Potassium: 0-12 weeks 13-26 weeks 0-12 weeks 27 weeks-term 0 - 2 weeks p.p. Osmolality: 0-12 weeks 13-26 weeks 0-12 weeks 27 weeks-term 0 - 2 weeks p.p.
and potassium concentrations and osmolality in normal pregnancy and 13-26 weeks 27 weeks-term 27 weeks-term 0 - 2 weeks p.p. 6-12 weeks p.p.;
n n n n n
= = = = =
59 69 76 69 40
t t t t t
= = = = =
0.59 2.09 1.67 2.34 0.46
p>0.1 p < 0.05 p>0.1 p < 0.05 p>0.1
13-26 weeks 27 weeks-term 27 weeks-term 0 - 2 weeks p.p. 6-12 weeks p.p.
n n n n n
= = = = =
61 70 77 71 41
t t t t t
= = = = =
0.56 0.30 0.35 4.95 2.85
p>0.1 p>0.1 p>0.1 p < 0.001 p < 0.01
13-26 weeks 27 weeks-term 27 weeks-term 0 - 2 weeks p.p. 6-12 weeks p.p.
n n n n n
= = = = =
27 46 47 56 35
t t t t t
= = = = =
1.68 0.52 2.33 3.96 1.07
p>0.1 p>0.1 p < 0.05 p < 0.001 p>0.1
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114
JCE & M • 1975 Vol 40 • No 1
WEIR ETAL.
methods as employed here, a close correlation has been shown between concurrent measurements of these substances in a number of physiological and pathological situations in man (6,7,22,25,33,34,35). In pregnancy it appears that, although angiotensin II may be one of the factors affecting aldosterone secretion, it is a relatively minor one and other influences (perhaps electrolytes, ACTH and human placental lactogen) are of greater importance.
the major stimulants to aldosterone production in pregnancy, other factors must be involved. The role of ACTH, human placental lactogen and human chorionic gonadotropin in fluid and electrolyte balance in pregnancy remains unclear (9,10), but it is possible that one or more of these substances, or a substance not yet identified, may be governing aldosterone secretion in pregnant women. Acknowledgment
Aldosterone and electrolytes in pregnancy. In nonpregnant subjects, aldosterone secretion is increased by sodium depletion and also by potassium loading; this may be brought about in part by a direct effect of changes in plasma electrolyte concentration on the adrenal cortex (36,37). Alterations in electrolyte balance may also modify the response of aldosterone to other trophic factors (7,38). The present study is in accord with our previous report (9) that there is no close correlation between circulating plasma levels of potassium and aldosterone (Table 2) in normal pregnant women. During gestation a number of potential sources of relative maternal sodium depletion have been identified. These include increased glomerular filtration rate, raised plasma progesterone and estrogens, and diversion of sodium to the feto-placental unit (9,10). It might be expected, therefore, that the increase in plasma aldosterone concentration in pregnancy would be a normal response to maternal sodium depletion. However, although plasma sodium concentration has been shown to be low throughout pregnancy (Fig. 6) and a significant correlation with plasma aldosterone has also been demonstrated (Table 2), this correlation was positive rather than negative as found in other hyponatraemic states. Plasma sodium concentration is therefore unlikely to be of major importance in the control of aldosterone secretion in pregnancy. As changes in circulating angiotensin II, potassium and sodium do not appear to be
The authors would like to thank the clinical staff of the Queen Mother's Hospital and Royal Maternity Hospital, Glasgow for their cooperation in this study.
References 1. Gross, F., Klin WochenSchr 36: 693, 1968. 2. , In Bock, K. D., and P. T. Cottier (eds.), Essential Hypertension, Springer-Verlag, Berlin, 1960, p. 92. 3. Davis, J. O., Recent Progr Horm Res 17: 293,1961. 4. Best, J. B., J. H. N. Bett, J. P. Coghlan, E. J. Cran, and B. A. Scoggins, Lancet 2: 1353, 1971. 5. Boyd, C. W., A. R. Adamson, M. Arnold, V. H. T. James, and W. S. Peart, Clin Sci 42: 91, 1972. 6. Brown, J. J., R. Fraser, A. F. Lever, J. J. Morton, W. Oelkers, J. I. S. Robertson, and J. Young, In Sanibhi, M.P. (ed.), Mechanisms of Hypertension, Excerpta Medica American Elsevier, New York, 1973, p. 148. 7. Oelkers, W., J. J. Brown, R. Fraser, A. F. Lever, J. J. Morton, and J. I. S. Robertson, Circ Res 34: 69, 1974. 8. Helmer, O. M., and W. E. Judson, Am J Obstet Gynecol 99: 9, 1967. 9. Weir, R. J., D. B. Paintin, J. J. Brown, R. Fraser, A. F. Lever, J. I. S. Robertson, and J. Young, J Obstet Gynaecol Br Commonw 78: 580, 1971. 10. Robertson, J. I. S., R. J. Weir, G. O. Diisterdieck, R. Fraser, and M. Tree, Scot MedJ 16: 183, 1971. 11. Beitins, I. Z., F. Bayard, L. Levitsky, I. G. Ances, A. Kowarski, and C. J. Migeon, / Clin Invest 51: 386, 1972. 12. Gordon, R. D., E. M. Symonds, E. G. Wilmshurst, and C. G. K. Pawsey, Clin Sci Mol Med 45: 115, 1973. 13. Katz, F. H., P. Beck, and E. L. Makowski, Am J Obstet Gynecol 118: 51, 1974. 14. Brown, J. J., D. L, Davies, A. F. Lever, J. I. S. Robertson, and M. Tree, BiochemJ 93: 594, 1964. 15. Tree, M . J Endocrinol 56: 159, 1973. 16. Fraser, R., S. Guest, and J. Young, Clin Sci Mol Med 45: 411, 1973. 17. , and V. H. T. James, J Endocrinol 40: 59, 1968.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 11:07 For personal use only. No other uses without permission. . All rights reserved.
RENIN, ANGIOTENSIN AND ALDOSTERONE IN NORMAL PREGNANCY 18. Dusterdieck, G., and G. McElwee, Eur J Clin Invest 2: 32, 1971. 19. Cain, M. D., K. J. Cart, and J. P. CoghlanJ Clin Endocrinol Metab 29: 1639, 1969. 20. Oelkers, W., G. Dusterdieck, and J. J. Morton, Clin Sci 43: 209, 1972. 21. Weir, R. J., D. B. Paintin, J. I. S. Robertson, M. Tree, R. Fraser, and J. Young, Proc R Soc Med 63: 1101, 1970. 22. Brown, J. J., G. Dusterdieck, R. Fraser, A. F. Lever, J. I. S. Robertson, M. Tree, and R. J. Weir, Br Med Bull 27: 128, 1971. 23. , R. Fraser, A. F. Lever, and J. I. S. Robertson, BrMedj2: 391, 1972. 24. Medina, A., P. R. F. Bell, J. D. Briggs, J. J. Brown, A. Fine, A. F. Lever, J. J. Morton, A. M. Paton, J. I. S. Robertson, M. Tree, M. A. Waite, R. Weir, and J. Winchester, Br Med] 4: 694, 1972. 25. , D. L. Davies, J. J. Brown, R. Fraser, A. F. Lever, N. P. Mallick, J. J. Morton, J. I. S. Robertson, and M. Tree, Nephron 12: 233, 1974. 26. Davies, D. L., D. G. Beevers, J. J. Brown, R. Fraser, J. B. Ferriss, A. F. Lever, A. Medina, J. J. Morton, and J. I. S. Robertson, Excerpta Medica Int Congr Ser No. 273: 693, 1974. 27. Beevers, D. G., J. J. Brown, D. L. Davies, R. Fraser, M. Lebel, A. F. Lever, A. Medina, J. J. Morton, J. I. S. Robertson, M. A. D. H. Schalekamp,
28. 29. 30. 31. 32. 33. 34.
35. 36. 37.
38.
115
M. Tree, and M. A. Waite, Excerpta Medica Int Congr Ser No. 302: 133, 1974. Lumbers, E. R., Enzymologia 40: 329, 1971. Skinner, S. L., E. R. Lumbers, and E. M. Symonds, Clin Sci 42: 479, 1972. Leckie, B., Clin Sci 44: 301, 1973. Gould, A. B., and G. Green, Cardiovasc Res 5: 86, 1971. Bangham, D. R., J. I. S. Robertson, I. Robertson, C. J. Robinson, and M. Tree. Clin Sci Mol Med (In press). Brown, J. J., R. Fraser, A. F. Lever, D. R. Love, J. J. Morton, and J. I. S. Robertson, Lancet 2: 1106, 1972. , R. H. Chinn, R. Fraser, A. F. Lever, J. J. Morton, J. I. S. Robertson, M. Tree, M. A. Waite, and D. M. Park, Br Med] 1: 650, 1973. , R. Fraser, A. F. Lever, J. J. Morton, J. I. S. Robertson, M. Tree, P. R. F. Bell, J. K. Davidson, and I. S. Ruthven, Lancet 2: 1228, 1973. Fraser, R., J. J. Brown, R. Chinn, A. F. Lever, and J. I. S. Robertson, Scot Med] 14: 420, 1969. Brown, J. J., R. Fraser, A. F. Lever, and J. I. S. Robertson, In Stuart:Mason, A. (ed.), Clinics in Endocrinology and Metabolism, vol. 1, 1972, p. 397, W. B. Saunders, London. James, V. H. T., J. Landon, and R. Fraser, Mem Soc Endocrinol 17: 141, 1967.
Proceedings of the Fifth Asia and Oceania Congress of Endocrinology Proceedings of this Congress held in January 1974, comprising 16 invited symposia and 22 sessions of free communications convering different fields in endocrinology, are now available: Proceedings of the Fifth Asia and Oceania Congress of Endocrinology, G. K. Rastogi, editor, published by the Endocrine Society of India, two volumes, 1000 pages, price Indian Rs. 100.00. Orders may be placed with the Secretary, Endocrine Society of India, Department of Endocrinology, Postgraduate Medical Institute, Chandigarh 160011, India. Due to the limited number of copies printed, preference will be given to orders from libraries and departments of endocrinology.
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T
HE concept that one of the principal functions of the renin-angiotensin system is the regulation of aldosterone secretion (1,2,3) has stimulated considerable interest in recent years. The importance of this role in man, however, remains controversial (4,5,6,7). Nevertheless, in many physiological and pathological situations in man, plasma concentrations of the enzyme renin, its principal active product angiotensin II and aldosterone are closely correlated, in a manner which suggests an important connection between them. Normal human pregnancy presents, however, an exception to this general rule. Although in this situation some of the greatest increases in circulating levels of renin, renin-substrate and aldosterone are found of any physiological circumstance (8,9,10,11,12,13), the concentrations of these components are not closely correlated (9,10).
Received April 15, 1974. * Present address: Gartnavel General Hospital, Glasgow, Scotland.
strate concentration did not correlate with plasma angiotensin II concentration, but it did have a positive correlation with plasma aldosterone concentration. The plasma concentration of aldosterone was positively related to plasma sodium concentration, which was below the normal nonpregnant range in
most women throughout gestation. The reason for this dissociation between the major components of the renin-angiotensin-aldosterone system in normal pregnancy remains unclear. In pregnant women it appears that, although angiotensin II may be one of the factors affecting aldosterone secretion, it is a relatively minor one and other influences are of greater importance. (/ Clin Endocrin'ol Metab 40: 108, 1975)
The present study was designed to confirm and extend our earlier observations. In particular, the inclusion of concurrent estimations of renin-substrate and angiotensin II, not studied together previously in pregnancy as far as we are aware, might possibly illuminate the reasons for the dissociation between plasma renin and aldosterone concentrations. Materials and Methods One hundred and twelve women were studied at least once during pregnancy. Fifty-five of these were primigravid, while 30 had had one and 27 had had more than one previous pregnancy. Ages ranged from 17 to 41 yr (mean 26.0 yr). All had normal full-term pregnancies apart from 7 healthy women who had been admitted for termination of apparently normal early pregnancy. No case was included where a blood pressure of 140/90 mmHg. or over was recorded at any stage of gestation. All were taking an unrestricted diet and none was receiving diuretics. .. Venous blood samples were taken with the women in the supine position (i.e., lying on
108
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RENIN, ANGIOTENSIN AND ALDOSTERONE IN NORMAL PREGNANCY
109
their backs). Fifty-nine were inpatients and were sampled about 9:00 AM after 10 hr recumbency. The remainder (53) were seen as out-patients when samples were taken after they had rested supine for 30 min. Plasma renin concentration was measured by the method of Brown et al. (14), (normal nonpregnant range 4 to 20 U/l); plasma renin substrate concentration by the technique of Tree (15) (normal nonpregnant range 0.45 to 1.28 /AM); and plasma aldosterone concentration by a modification (16) of the double isotope derivative technique of Fraser and James (17) (normal nonpregnant range 0.1), renin-substrate of renin and angiotensin II (r = 0.07), renin(t = 1.90, 0.1 > p > 0.05) or aldosterone substrate and angiotensin II (r = 0.03), renin (t = 1.08, p > 0.1), but mean plasma angio- and aldosterone (r = 0.06) or angiotensin II tensin II concentration was higher in multi- and aldosterone (r = 0.01). These correla-
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110
WEIR ET AL.
JCE & M • 1975 Vol 40 • No 1
PLASMA RENIN SUBSTRATE CONCENTRATION uM 70-, RENIN
PLASMA CONCENTRATION units/ I 120-1
• •
t A
•• 80-
3-5-
• 9 •
40-
T* ••
I
A
X
A
1
1
X
•!
•• • •
t V
t•• t
t • •
• • •
• ••• t
t•
Y
•
0 - 1 2
13-26
T*
0-1 0 - 1 2
13-26
27-Term
G E S T A T I O N (weeks)
0 - 2
6 - 1 2
POST-PARTUM(weeks)
27-Term
G E S T A T I O N (weeks)
0 - 2
6 - 1 2
P O S T - PARTUM(weeks)
FIG. 1 (left). Plasma renin concentration in normal pregnancy and postpartum. Stippled area indicates normal non-pregnant range. Comparison: 0-12 weeks 13-26 weeks: t = 1.60 p>0.1 13-26 weeks 27 weeks-term: t = 0.87 p>0.1 0-12 weeks 27 weeks-term: t = 3.37 p < 0.01 27 weeks-term t = 6.40 0- 2 weeks p.p. p < 0.001 t = 3.33 p < 0.01 0- 2 weeks p.p. 6-12 weeks p.p. FIG. 2 (right). Plasma renin substrate concentration in normal pregnancy and postpartum. Stippled area indicates normal non-pregnant range. 0-12 weeks Comparison: 13-26 weeks: t = 6.76 p < 0.001 27 weeks-term: 13-26 weeks t = 4.68 p < 0.001 27 weeks-term: 0-12 weeks t = 10.84 p < 0.001 0- 2 weeks p.p.: 27 weeks-term t = 2.10 p < 0.05 6-12 weeks p.p.: 0- 2 weeks p.p. t = 4.08 p < 0.001
tions remained insignificant when the in- renin-substrate and aldosterone concenpatients and outpatients were considered trations during pregnancy (r = 0.25, 0.01 separately, and the dissociations seem there- < p < 0.05). In the puerperium, a positive fore not to be due to the different times of relationship was demonstrated between the recumbency before sampling. plasma concentrations of renin and angioA loose but statistically significant posi- tensin II (r = 0.55, 0.01 < p < 0.05). In contrast to an earlier study (21) we tive correlation was found between plasma The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 11:07 For personal use only. No other uses without permission. . All rights reserved.
RENIN, ANGIOTENSIN AND ALDOSTERONE IN NORMAL PREGNANCY
111
PLASMA ANGIOTENSIN IJ CONCENTRATION pg/ml 500-i
PLASMA ALDOSTERONE CONCENTRATION mug/lOOml
375-
180-i
250-
120-
-
125-
: 60-
! 1
± 0 - 1 2
13-26
27-TERM
G E S T A T I O N (weeksi | week si
0 - 2
0
T
J
6 - 1 2
0 - 1 2
P O S T - P A R T U M (weeks) (weeks)
13-26
27-TERM 0
G E S T A T I O N (weeks)
-
2
6 - 1 2
PPOST-PARTUM(weeks) O S T - P A R T U M (weeks)
FIG. 3 (left). Plasma angiotensin II concentration in normal pregnancy normal non-pregnant range. Comparison: 0-12 weeks 13-26 weeks: 13-26 weeks 27 weeks-term: 0-12 weeks 27 weks-term: 0- 2 weeks p.p.: 27 weeks-term 0- 2weeksp.p. 6-12 weeks p.p.:
and postpartum. Stippled area indicates
FIG. 4 (right). Plasma aldosterone concentration in normal pregnancy normal non-pregnant range. Comparison: 0-12 weeks 13-26 weeks: 13-26 weeks 27 weeks-term 0-12 weeks 27 weeks-term: 27 weeks-term 0- 2 weeks p.p.
and postpartum. Stippled area indicates
found no significant relationship between plasma aldosterone concentration and the product of plasma renin and renin-substrate concentrations (r = 0.14); nor was there a correlation between plasma angiotensin II concentration and the product of plasma renin and renin-substrate concentrations (r = 0.12). The plasma concentration of aldosterone was positively related to plasma sodium concentration (r = 0.26, 0.01 < p < 0.05), and a
t = 2.98 t = 2.18 t = 3.60 t = 3.31 t = 1.19
t = 1.21 t = 0.91 t = 2.05 t = 1.82
p < 0.01 p < 0.05 p < 0.001 p < 0.01 p>0.1
p > 0.1 p > 0.1 p < 0.05 0.05 < p < 0.1
significantly positive correlation was present between plasma angiotensin II concentration and plasma osmolality (r = 0.58, 0.001 < p < 0.01). Discussion Lack of relationship between renin, angiotensin and aldosterone. The present study has confirmed the dissociation, in normal pregnancy, between the circulating periph-
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112
JCE & M • 1975 Vol 40 • No 1
WEIR ETAL.
TABLE 1. Comparison of plasma concentrations of renin, renin-substrate, angiotensin II and aldosterone between in-patients and out-patients in early and late gestation Renin substrate
Angiotensin II pg/ml
Aldosterone ng/100 ml
40.6± 14.0 46.8± 19.2 0.84 38 >0.1
1.96± 0.41 1.68± 0.72 1.04 37 >0.1
32.4± 16.6 32.0± 25.9 0.04 35 >0.1
28.4± 27.4 34.7± 19.0 0.63 22 >0.1
35.0± 15.0 41.3± 15.9 1.26
3.78± 1.03 3.94± 1.17 0.44
Renin U/l Gestation 8th-12th week In-patient (M ± SD) Out-patient (M ± SD) t-statistic Degrees of freedom Significance, p Gestation 36th -40th week In-patient (M ± SD) Out-patient (M ± SD) t-statistic Degrees of freedom Significance, p
38
35
>0.1
>0.1
*
41.9± 32.2 44.5± 27.0 0.18
—
17
— —
>0.1
* Insufficient numbers for statistical comparison.
eral plasma concentrations of renin and aldosterone (9,13). Dissociations between concurrent plasma concentrations of renin and angiotensin II and also between angiotensin II and aldosterone have also been demonstrated. This lack of correlation between concurrent estimations of renin and angiotensin II in pregnancy contrasts markedly with the close relationship established using the same techniques, in a wide variety of other circumstances (22,23,24,25, 26,27). There are several possible explanations for this. One is that in pregnancy part of the renin circulating in plasma is in an inactive form, becoming activated in the process of extraction (28,29,30). If this were
the only explanation, renin should on average be high in relation to angiotensin II at all stages of pregnancy, but this is not the case (Figs. 1, 3, 5). Another possibility is that high circulating levels of renin-substrate contribute to the dissociation. There is now good evidence that substrate concentration is normally within a range capable of influencing angiotensin formation (31,32). A third possibility is that immunoreactive fragments of angiotensin are present in greater or more variable amovunts in the venous plasma of pregnant women (19,20). The other main dissociation demonstrated in pregnancy is between angiotensin II and aldosterone. Again, utilizing the same
TABLE 2. Correlations (r) between the components of the renin-angiotensin-aldosterone system and plasma electrolytes during pregnancy
Renin Renin Renin-substrate Angiotensin II Aldosterone
Renin x substrate
Plasma Na
Plasma K
Plasma OSM
0.03 0.04
0.08 0.14
0.02
— 0.12
0.01
0.14
+0.58** (n = 16)
0.14
+0.26* (n = 65)
0.14
0.26
Substrate
Angio II
Aldo
0.12
0.07 0.03
0.06
—
+0.25* 0.01
0.10
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113
CONCENTRATION
PLASMA SODIUM mEq/l 142-,
132PLASMA POTASSIUM mEq/l 47-,
PIASMA ANQOTtNSIN D CONCENTIATION
31J PLASMA OSMOLALITY mosm/kg 288-1
PIASMA AIDO3TMONC CONCtNTtATlON •uig/HMml JJO-i
276-
POS1-PA«TUM
NORMAL NON-PREGNANT RANGE
0-12
13-26
27-Ter
GESTATION (weeks)
0 - 2
6 - 1 2
POST-PARTUM (weeks)
FIG. 5 (left). Serial changes in plasma concentrations of renin, reninsubstrate, angiotensin II and aldosterone in 6 pregnant women. Stippled area indicates normal non-pregnant range. FIG. 6 (right). Plasma sodium partum (mean ± 1 SD). Sodium: 0-12 weeks 13-26 weeks 0-12 weeks 27 weeks-term 0 - 2 weeks p.p. Potassium: 0-12 weeks 13-26 weeks 0-12 weeks 27 weeks-term 0 - 2 weeks p.p. Osmolality: 0-12 weeks 13-26 weeks 0-12 weeks 27 weeks-term 0 - 2 weeks p.p.
and potassium concentrations and osmolality in normal pregnancy and 13-26 weeks 27 weeks-term 27 weeks-term 0 - 2 weeks p.p. 6-12 weeks p.p.;
n n n n n
= = = = =
59 69 76 69 40
t t t t t
= = = = =
0.59 2.09 1.67 2.34 0.46
p>0.1 p < 0.05 p>0.1 p < 0.05 p>0.1
13-26 weeks 27 weeks-term 27 weeks-term 0 - 2 weeks p.p. 6-12 weeks p.p.
n n n n n
= = = = =
61 70 77 71 41
t t t t t
= = = = =
0.56 0.30 0.35 4.95 2.85
p>0.1 p>0.1 p>0.1 p < 0.001 p < 0.01
13-26 weeks 27 weeks-term 27 weeks-term 0 - 2 weeks p.p. 6-12 weeks p.p.
n n n n n
= = = = =
27 46 47 56 35
t t t t t
= = = = =
1.68 0.52 2.33 3.96 1.07
p>0.1 p>0.1 p < 0.05 p < 0.001 p>0.1
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114
JCE & M • 1975 Vol 40 • No 1
WEIR ETAL.
methods as employed here, a close correlation has been shown between concurrent measurements of these substances in a number of physiological and pathological situations in man (6,7,22,25,33,34,35). In pregnancy it appears that, although angiotensin II may be one of the factors affecting aldosterone secretion, it is a relatively minor one and other influences (perhaps electrolytes, ACTH and human placental lactogen) are of greater importance.
the major stimulants to aldosterone production in pregnancy, other factors must be involved. The role of ACTH, human placental lactogen and human chorionic gonadotropin in fluid and electrolyte balance in pregnancy remains unclear (9,10), but it is possible that one or more of these substances, or a substance not yet identified, may be governing aldosterone secretion in pregnant women. Acknowledgment
Aldosterone and electrolytes in pregnancy. In nonpregnant subjects, aldosterone secretion is increased by sodium depletion and also by potassium loading; this may be brought about in part by a direct effect of changes in plasma electrolyte concentration on the adrenal cortex (36,37). Alterations in electrolyte balance may also modify the response of aldosterone to other trophic factors (7,38). The present study is in accord with our previous report (9) that there is no close correlation between circulating plasma levels of potassium and aldosterone (Table 2) in normal pregnant women. During gestation a number of potential sources of relative maternal sodium depletion have been identified. These include increased glomerular filtration rate, raised plasma progesterone and estrogens, and diversion of sodium to the feto-placental unit (9,10). It might be expected, therefore, that the increase in plasma aldosterone concentration in pregnancy would be a normal response to maternal sodium depletion. However, although plasma sodium concentration has been shown to be low throughout pregnancy (Fig. 6) and a significant correlation with plasma aldosterone has also been demonstrated (Table 2), this correlation was positive rather than negative as found in other hyponatraemic states. Plasma sodium concentration is therefore unlikely to be of major importance in the control of aldosterone secretion in pregnancy. As changes in circulating angiotensin II, potassium and sodium do not appear to be
The authors would like to thank the clinical staff of the Queen Mother's Hospital and Royal Maternity Hospital, Glasgow for their cooperation in this study.
References 1. Gross, F., Klin WochenSchr 36: 693, 1968. 2. , In Bock, K. D., and P. T. Cottier (eds.), Essential Hypertension, Springer-Verlag, Berlin, 1960, p. 92. 3. Davis, J. O., Recent Progr Horm Res 17: 293,1961. 4. Best, J. B., J. H. N. Bett, J. P. Coghlan, E. J. Cran, and B. A. Scoggins, Lancet 2: 1353, 1971. 5. Boyd, C. W., A. R. Adamson, M. Arnold, V. H. T. James, and W. S. Peart, Clin Sci 42: 91, 1972. 6. Brown, J. J., R. Fraser, A. F. Lever, J. J. Morton, W. Oelkers, J. I. S. Robertson, and J. Young, In Sanibhi, M.P. (ed.), Mechanisms of Hypertension, Excerpta Medica American Elsevier, New York, 1973, p. 148. 7. Oelkers, W., J. J. Brown, R. Fraser, A. F. Lever, J. J. Morton, and J. I. S. Robertson, Circ Res 34: 69, 1974. 8. Helmer, O. M., and W. E. Judson, Am J Obstet Gynecol 99: 9, 1967. 9. Weir, R. J., D. B. Paintin, J. J. Brown, R. Fraser, A. F. Lever, J. I. S. Robertson, and J. Young, J Obstet Gynaecol Br Commonw 78: 580, 1971. 10. Robertson, J. I. S., R. J. Weir, G. O. Diisterdieck, R. Fraser, and M. Tree, Scot MedJ 16: 183, 1971. 11. Beitins, I. Z., F. Bayard, L. Levitsky, I. G. Ances, A. Kowarski, and C. J. Migeon, / Clin Invest 51: 386, 1972. 12. Gordon, R. D., E. M. Symonds, E. G. Wilmshurst, and C. G. K. Pawsey, Clin Sci Mol Med 45: 115, 1973. 13. Katz, F. H., P. Beck, and E. L. Makowski, Am J Obstet Gynecol 118: 51, 1974. 14. Brown, J. J., D. L, Davies, A. F. Lever, J. I. S. Robertson, and M. Tree, BiochemJ 93: 594, 1964. 15. Tree, M . J Endocrinol 56: 159, 1973. 16. Fraser, R., S. Guest, and J. Young, Clin Sci Mol Med 45: 411, 1973. 17. , and V. H. T. James, J Endocrinol 40: 59, 1968.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 11:07 For personal use only. No other uses without permission. . All rights reserved.
RENIN, ANGIOTENSIN AND ALDOSTERONE IN NORMAL PREGNANCY 18. Dusterdieck, G., and G. McElwee, Eur J Clin Invest 2: 32, 1971. 19. Cain, M. D., K. J. Cart, and J. P. CoghlanJ Clin Endocrinol Metab 29: 1639, 1969. 20. Oelkers, W., G. Dusterdieck, and J. J. Morton, Clin Sci 43: 209, 1972. 21. Weir, R. J., D. B. Paintin, J. I. S. Robertson, M. Tree, R. Fraser, and J. Young, Proc R Soc Med 63: 1101, 1970. 22. Brown, J. J., G. Dusterdieck, R. Fraser, A. F. Lever, J. I. S. Robertson, M. Tree, and R. J. Weir, Br Med Bull 27: 128, 1971. 23. , R. Fraser, A. F. Lever, and J. I. S. Robertson, BrMedj2: 391, 1972. 24. Medina, A., P. R. F. Bell, J. D. Briggs, J. J. Brown, A. Fine, A. F. Lever, J. J. Morton, A. M. Paton, J. I. S. Robertson, M. Tree, M. A. Waite, R. Weir, and J. Winchester, Br Med] 4: 694, 1972. 25. , D. L. Davies, J. J. Brown, R. Fraser, A. F. Lever, N. P. Mallick, J. J. Morton, J. I. S. Robertson, and M. Tree, Nephron 12: 233, 1974. 26. Davies, D. L., D. G. Beevers, J. J. Brown, R. Fraser, J. B. Ferriss, A. F. Lever, A. Medina, J. J. Morton, and J. I. S. Robertson, Excerpta Medica Int Congr Ser No. 273: 693, 1974. 27. Beevers, D. G., J. J. Brown, D. L. Davies, R. Fraser, M. Lebel, A. F. Lever, A. Medina, J. J. Morton, J. I. S. Robertson, M. A. D. H. Schalekamp,
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M. Tree, and M. A. Waite, Excerpta Medica Int Congr Ser No. 302: 133, 1974. Lumbers, E. R., Enzymologia 40: 329, 1971. Skinner, S. L., E. R. Lumbers, and E. M. Symonds, Clin Sci 42: 479, 1972. Leckie, B., Clin Sci 44: 301, 1973. Gould, A. B., and G. Green, Cardiovasc Res 5: 86, 1971. Bangham, D. R., J. I. S. Robertson, I. Robertson, C. J. Robinson, and M. Tree. Clin Sci Mol Med (In press). Brown, J. J., R. Fraser, A. F. Lever, D. R. Love, J. J. Morton, and J. I. S. Robertson, Lancet 2: 1106, 1972. , R. H. Chinn, R. Fraser, A. F. Lever, J. J. Morton, J. I. S. Robertson, M. Tree, M. A. Waite, and D. M. Park, Br Med] 1: 650, 1973. , R. Fraser, A. F. Lever, J. J. Morton, J. I. S. Robertson, M. Tree, P. R. F. Bell, J. K. Davidson, and I. S. Ruthven, Lancet 2: 1228, 1973. Fraser, R., J. J. Brown, R. Chinn, A. F. Lever, and J. I. S. Robertson, Scot Med] 14: 420, 1969. Brown, J. J., R. Fraser, A. F. Lever, and J. I. S. Robertson, In Stuart:Mason, A. (ed.), Clinics in Endocrinology and Metabolism, vol. 1, 1972, p. 397, W. B. Saunders, London. James, V. H. T., J. Landon, and R. Fraser, Mem Soc Endocrinol 17: 141, 1967.
Proceedings of the Fifth Asia and Oceania Congress of Endocrinology Proceedings of this Congress held in January 1974, comprising 16 invited symposia and 22 sessions of free communications convering different fields in endocrinology, are now available: Proceedings of the Fifth Asia and Oceania Congress of Endocrinology, G. K. Rastogi, editor, published by the Endocrine Society of India, two volumes, 1000 pages, price Indian Rs. 100.00. Orders may be placed with the Secretary, Endocrine Society of India, Department of Endocrinology, Postgraduate Medical Institute, Chandigarh 160011, India. Due to the limited number of copies printed, preference will be given to orders from libraries and departments of endocrinology.
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