EUROP. J. OBSTET. GYNEC. REPROD. BIOL., 1975, 5/l-2, 75-85.

EXCERPTA MEDICA

Va9opressor substances in normal and abnormal cww3nancv R. J. Weir

Many theories have been advanced to account for the rise in blood pressure and frequently associated proteinuria which occurs in some women in late pregnancy. To date, however, the etiology of this condition remains unknown. In view of the association between raised blood pressure and increased circulating levels of vasopressor substances in a number of other conditions (Brown, Fraser, Lever and Robertson, 1971), it is attractive to postulate a similar association in hypertensive disease of pregnancy. The purpose of this paper is to evaluate current thoughts about the role of these circulating vasopressor substances in the development of pregnancy hypertension.

Catecholamines

Increased production of catecholamines by the chromaffin cells of the adrenal medulla or extraadrenal sites is an uncommon cause of hypertension in nonpregnant subjects (Brown et al., 1971). In late normal pregnancy, the urinary excretion of adrenaline, noradrenaline and their metabolites appears to be within the normal nonpregnant range (Pekkarinen and Castren, 1968; Zuspan, 1970). Blood levels in late normal pregnancy have also been reported to be similar to those found in normal nonpregnant women (Israel, Stroup, Seligson and Seligson, 1959) although another study found increased plasma adrenaline and decreased noradrenaline in the second trimester (Stone, Piliero, Hammer and

Portnoy, 1960). Women with preeclampsia have similar urinary values as normal pregnant women (Pekkarinen and Castren, 1968) but to date no satisfactory comparison of plasma levels in normotensive and hypertensive pregnancies has been reported. Based on present evidence, therefore, hypertensive disease of pregnancy does not appear to be associated with an increased production of catecholamines, although this remains to be confirmed by satisfactory controlled studies of plasma levels using the more sensitive methods of measurement which have been recently developed.

Renin and angiotensin

Renin is formed in the juxtaglomerular cells of the kidney and released into the blood where it reacts with a substrate in the alpha-Zglobulin fraction to form a decapeptide, angiotensin I; this is then converted to an active octapeptide, angiotensin II. A renin-like substance has also been demonstrated in other tissues, including the uterus, placenta and amniotic fluid (see Robertson, Weir, Dlisterdieck, Fraser and Tree, 1971). In addition to its potent vasopressor effect, angiotensin II stimulates aldosterone secretion and alters the excretion of sodium and water by the kidney; it may also stimulate the release of antidiuretic hormone and provoke thirst (Brown, Fraser, Lever and Robertson, 1968). Raised plasma concentrations of renin and angio-

76

tensin II may be found in cases of renal hypertension, malignant-phase hypertension and hypertension associated with rare renin-secreting tumors of the kidney (Brown et al, 1971); also in normotensive subjects during sodium deprivation and diuretic administration (Brown, Fraser, Lever, Love, Morton and Robertson, 1972a). Normal pregnancy is usually associated with increased plasma concentrations of renin (Weir, Paintin, Brown, Fraser, Lever, Robertson and Young, 1971; Weir, Brown, Fraser, Lever, Logan, MC Ilwaine, Morton, Robertson and Tree, 1975a; Skinner, Lumbers and Symonds, 1972; Symonds, Anderson and Pickles, 1974), renin substrate (Skinner et al., 1972; Weir et al., 1975a) and angiotensin II (Robertson et al., 1971; Weir, Brown, Fraser, Kraszewski, Lever, McIlwaine, Morton, Robertson and Tree, 1973; Weir et al., 1975a; Gordon, Symonds, Wilmshurst and Pawsey, 1973). Plasma renin activity, a less quantitative measurement which may be influenced by the concentration of renin substrate as well as renin, has also been reported to be generally increased during normal gestation (Skinner et al., 1972; Gordon et al., 1973; Symonds et al., 1974; Katz, Beck and Makowski, 1974). The reason for the raised circulating levels of these substances in normal pregnant women is not known. It is possible that part of the renin measured may be an inactive isoenzyme derived from maternal chorion rather than maternal kidney (Skinner et al., 1972). In this context it is noteworthy that the positive relationship which exists between concurrent renin and angiotensin II concentrations in other situations (Brown et al., 1971) does not exist in pregnancy (Weir et al., 1975a). In 1973 a study was reported from Glasgow which described the plasma concentrations of renin, renin substrate and angiotensin II in a group of pregnant women with hypertension and proteinuria, compared with a group of normal pregnant women matched for age, parity, time of gestation and posture (Weir et al., 1973). Hypertensive disease of pregnancy was arbitrarily defined as a rise of blood pressure to 140190 mm Hg or over on at least two separate occasions after the 24th week of gestation. Proteinuria was defined as the presence of at least 0.3 G protein per liter when measured by a turbidometric method, in the absence of urinary tract

B. J. Weir, Vasopressor substances

disease. All the women in both groups were taking an unrestricted diet and none was receiving hypotensive drugs or diuretics. Venous blood samples were taken in the supine position after at least 30 minutes’ recumbency. Plasma renin concentration was measured by the method of Brown, Davies, Lever, Robertson and Tree (1964), plasma renin substrate by the technique of Tree (1973) and plasma angiotensin II by radioimmunoassay (Diisterdieck and McElwee, 1971). The group with hypertension and proteinuria had significantly lower mean plasma levels of renin, renin substrate and angiotensin II than the normal group, the plasma angiotensin II concentration in particular being within the normal nonpregnant range in every case (Table I, Fig. 1). On the basis of this study, therefore, elevation of circulating renin and angiotensin II cannot be invoked in the pathogenesis of pregnancy hypertension. This is in accord with the results of other less well controlled studies which have shown, compared with the results in normal pregnancy, reduced plasma concentrations of renin (Brown, Davies, Doak, Lever, Robertson and Trust, 1966), reduced or normal plasma renin activity (Tapia, Johnson and Strong, 1972; Gordon et al., 1973), normal plasma renin substrate (Tapia et al., 1972), and normal circulating angiotensin (Gordon et al., 1973). In states of sodium excess the pressor effect of infused angiotensin II is enhanced (Brown et al., 1971). An increased pressor response to infused angiotensin II has also been found in preeclampsia as compared with normal pregnancy (Gant, Daley, Chand, Whalley and MacDonald, 1973). The lower plasma angiotensin II concentrations in pregnancy hypertension may therefore have a greater effect on blood pressure than the higher concentrations found in normal pregnant women. Even so, on present evidence it seems unlikely that angiotensin has a major causative role in the development of preeclampsia. A possible explanation for the lower plasma concentrations of renin and angiotensin in hypertensive disease of pregnancy is that the renin-angiotensin system is suppressed relative to normal pregnancy by retention of sodium induced by an excess of circulating mineralocorticoid.

R. J. Weir,

TABLE I

Vosopressor

77

substances

Comparison

between normal and hypertensive

_. ~~ ~.____~

Normal non-pregnant range

___

____~.

_-._____-.

Renin (units/l) Renin substrate (PM) Angiotensin II (pg/ml) Aldosterone (ng/lOO ml)

__-__

pregnant women

-_ Normal pregnancy (mean i I SD)

.~

_~...-4-20 0.45- I .28 5-3s 18.0

Hypertension and proteinuria (mean &l SD)

43.8* 17.3 3.73hl.52 78.2h67.4 50.9154.7

Wilcoxon test for pair differences No. of P pairs

_

_ 30.6114.8 2.76hO.93 14.9k6.0 23.0* 13.3

< 0.01 “ 0.01

12

0.05

Student’s Nr.

DOC (ng/lOO ml) Cortisol bg/lOO ml) Corticosterone (pg/lOO ml) ADH (pglml) ~. -___-

4.1-13.5 6.0-20.0 0.13-2.30 4.0-8 .O

Aldosterone and other corticosteroids

Aldosterone is a mineralocorticoid secreted by the adrenal cortex. Its principal site of action is the renal tubule where it promotes sodium reabsorption and causes increased potassium excretion. Hypertension associated with elevated plasma concentrations of aldosterone may be found in primary hyperaldosteronism due to an adenoma or hyperplasia of the adrenal glands, or in secondary hyperaldosteronism which may complicate renal hypertension, malignant-phase hypertension and renin-secreting renal tumors (Brown et al., 1971; Brown, Fraser, Lever and Robertson, 1972b). Raised circulating levels of aldosterone may also be found in normotensive subjects during diuretic therapy and sodium deprivation (Brown et al., 1972a). In normal pregnant women, increased plasma concentrations of aldosterone have been observed (Weir et al., 1971, 1974a; Beitins, Bayard, Levitsky, Antes, Kowarski and Migeon, 1972; Katz et al., 1974). Unlike most other situations, in pregnancy renin and angiotensin do not appear to play a major role in the control of aldosterone secretion (Weir et al., 1971, 1974a; Katz et al., 1974). The elevated circulating aldosterone may be associated with alterations in maternal sodium and potassium balance, increased glomerular filtration rate, raised secretion of progesterone and estrogens or production of human placental lactogen or chorionic

20.4110.1 18.7*5.7 0.91&0.52 9.7&4.1

10.212.7 23.6h9.4 0.81 kO.33 11.5h4.5

16 17 16

-_-

__....

20 18 8

23 .-.. -_-

: 0.01

t-test P i 0.05 > 0.1 > 0.1

> 0.1 .---~--

gonadotropin (see Robertson et al., 1971; Weir et al., 1971; Weir et al., unpublished data). In the Glasgow comparison of normotensive and hypertensive pregnant women described earlier in this paper, plasma aldosterone concentration was also measured, using a modification of the double isotope derivative technique of Fraser and James (1968). As shown in Table I and Figure 2, the mean level in the hypertensive group was significantly lower than that found in the matched normotensive controls. It seems unlikely, therefore, that aldosterone plays a significant role in the development of hypertensive disease of pregnancy. Of the other known corticosteroids, hypertension is a well-recognized feature of excess cortisol production as found in Cushing’s Syndrome and may rarely occur in association with increased circulating levels of corticosterone, 1 1-deoxycorticosterone (DOC) or I8-OH-DOC (Brown et al., 1972b). During normal gestation, a gradual rise occurs in plasma cortisol concentration, mainly due to increased protein binding, although a small rise in the unbound fraction also takes place (see Hytten and Leitch, 1971). Plasma corticosterone concentration is unchanged (Weir et al., 1971) or slightly increased (Martin and Martin, 1968). Plasma DOC is usually raised in late pregnancy (Wilson and Fraser, 1971; Brown, Strott and Liddle, 1972; Weir et al., 1973). To my knowledge no measurement of plasma 18-OH-DOC has been described in pregnant women.

78

R. J. Weir, Vasopressor substunces

PLASMA ANGIOTENSIN CONCENTRATION

creased levels compared with normal pregnancy (Brown et al., 1972), the results in that study showing no difference between normotensive and hypertensive pregnant women. Our results for plasma cortisol are in accord with other reports (Kopelman and [email protected] 1970; Galvao-Teles and Burke, 1973). There is, therefore, no evidence to incriminate raised circulating levels of any of the known adrenal corticosteroids in the pathogenesis of hypertensive disease of pregnancy. However, the steroid binding capacity of plasma is altered in pregnancy (Hytten and Leitch, 1971) and there is to date no adequate information about the plasma concentration of unbound DOC in hypertensive pregnant women. Also,

II

PQhl

PLASMA ALDOSTERONE

0’

NORMAL

CONCENTRATION mug /lOOml

HYPERTENSION ALB”M+IN”RIA

Plasma angiotensin II concentration in normal Fig. 1 and hypertensive pregnant women. Normal nonpregnant range shown by hatched area (Weir et al., 1973). l

In our group of women with hypertension and proteinuria in late pregnancy, the mean plasma concentration of DOC, estimated by the method of Wilson and Fraser (1971), was reduced relative to normal pregnancy (Table 1, Fig. 3), all the measurements in the hypertensive women being within the normal nonpregnant range. Plasma cortisol and corticosterone measured by the method of Fraser and James (1968) showed no significant difference between the two groups (Table 1, Fig. 4). The only other report of plasma DOC in pregnancy hypertension to date has also failed to demonstrate in-

0’

NORMAL

HYPERTENSION ALEi”;IN”RIA

Plasma aldosterone concentration in normal and Fig. 2 hypertensive pregnant women. Normal nonpregnant range shown by hatched area (Weir et al., 1973).

79

R. J. Weir, Vasopressor substances

PLASMA DOC CONCENTRATION ng/lOOml 40

1

Y

0

20-

v

I

0

t;:

...::

0 l

lower than those found in normal gestation (Kreikenbaum, Elsaesser and Hahn, 1974). Prolactin may affect fluid and electrolyte balance (Horrobin, Burstyn, et al., 1971) and it is possible, therefore, that it may play a role in the development of pregnancy hypertension. Prolactin secretion is increased in pregnancy (Tyson, Hwang, Guy& and Friesen, 1972; Fournier, Desjardins and Friesen, 1974) but, to date, there is no data regarding plasma prolactin concentration in hypertensive pregnant women. Human placental lactogen (HPL; human chorionic somatomammotropin, HCS) shows a gradual increase in plasma throughout normal pregnancy, with reduced plasma levels in hypertensive pregnancies (Lindberg and Nilsson, 1973; Kreikenbaum et al., 1974).

t PLASMA

oJ

NORMAL

HYPERTENSION ALB”MtN”RlA

Fig. 3 Plasma DOC concentration in normal and hypertensive pregnant women. Normal nonpregnant range shown by hatched area.

CORTICOSTERONE CONCENTRATION (lJg/100ml)

2.3

1

..

I

-i_

-i-

more has to be learned about the lesser-known corticosteroids and their metabolites, using the more sensitive assays which are gradually being introduced.

::

8

0-I PLASMA

CORTISOL

CONCENTRATION (rg/100mI)

Progesterone, prolactin and placental lactogen .

Based on rabbit studies, Horrobin and Lloyd (1970) suggested that the rise of blood pressure in preeclampsia could be due to the effect of progesterone, although their work was not confirmed by Winter, Veldhuyzen and Dorhout Mees (1972). No case has yet been reported of hypertension associated with excessive circulating levels of progesterone and women given synthetic progestogens do not develop significantly increased blood pressure (Spellacy and Birk, 1972). Plasma progesterone concentration rises steadily throughout normal pregnancy (see Hytten and Leitch, 1971) and, in general, women with hypertensive disease of pregnancy show circulating levels of progesterone similar to or

NORMAL

HYPERTENSION + ALBUMINURIA

Fig. 4 Plasma cortisol and corticosterone concentrations in normal and hypertensive pregnant women. Normal nonpregnant range shown by hatched area.

80

R. J. Weir, Vasopressor substances

Vasopressin

(ADHI

Arginine vasopressin (antidiuretic hormone, ADH) is known to have vasopressor effects but no case has yet been reported where hypertension has been associated with raised circulating levels of this hormone. Antidiuretic activity in blood from normal pregnant women was demonstrated by Paterson (1960) although other studies failed to show this (Hughes, Lloyd, Jones, Lobotsky, Rienzo and Avery, 1954; Gupta, Chaudhury and Chhuttani, 1967). Paterson (1960) also found greater ADH activity in preeclamptic women, unlike Hughes et al. (1954) who showed levels similar to those in normal pregnancy.

These reports were based on bioassay methods of measurement. Using the more sensitive technique of radioimmunoassay developed by Morton (1973), plasma arginine vasopressin (ADH) concentration was measured in the Glasgow study of normotensive and hypertensive pregnancy. A preliminary description of these results has been reported (Weir, Fraser, McIlwaine, Kraszewski, Morton, Tree, Wilson and Young, 1975b). As shown in Table I and Figure 5, mean plasma ADH concentration was increased, in both normal and hypertensive women in the last trimester, with no significant difference between the two groups.

Conclusions PLASMA A.D. H. CONCENTRATION (w/ml) 26

. 0 .

0 0

0

. 10

0 NORMAL

HYPERTENSION + ALBUMINURIA

Fig. 5 Plasma ADH concentration in normal and hypertensive pregnant women. Normal nonpregnant range shown by hatched area.

In view of the abrupt onset of marked hypertension in some women in late pregnancy and the dramatic fall to normal levels after delivery of the placenta, the possible secretion of a potent circulating pressor agent has been postulated on many occasions. Perhaps the commonest and most longstanding theory to explain the release of such a substance has been that of uterine and placental ischemia. When compared with normal pregnant women, women with hypertension in pregnancy show a reduction in both choriodecidual and myometrial blood flow (Dixon, Brown and Davey, 1963) and proliferative endarteritis and degeneration of the uteroplacental arteries are also found more frequently (Brosens, 1964; Robertson, Brosens and Dixon, 1967). Interference with the placental circulation in animals can result in an elevation of blood pressure (Hodari, 1969), and the apparent release of a circulating pressor substance (Berger and Boucek, 1964). In women, a recent controlled study has demonstrated a slight rise in blood pressure on reinfusing after delivery blood drawn from subjects with hypertension in late pregnancy (Pirani, 1975). Although it seems likely that the uterine and placental vascular lesions are the result rather than the cause of the raised blood pressure, the possibility remains that the reduction in blood flow may stimulate the secretion of a vasopressor agent into the maternal circulation. However, it has now been shown conclusively that, in hypertensive disease of

R. J. Weir,

Vasopressor

81

substances

pregnancy, plasma angiotensin I I concentrations are not increased and that the plasma concentrations of renin, aldosterone, cortisol, corticosterone, DOC and ADH are similar to or lower than those found in normal pregnant women. Also, there is no evidence to suggest that raised circulating levels of catecholamines, progesterone, prolactin or placental lactogen are implicated in this disease. It is possible that women with pregnancy hypertension may have an increased sensitivity to vasopressor substances present in normal or reduced amounts, but this remains to be further elucidated. The fact that the plasma levels of many of these hormones are depressed in relation to normal pregnancy suggests that a circulating vasopressor agent or mineralocorticoid remains to be discovered.

Acknowledgements

Brown, J. J., Fraser, R., Lever, A. F. and Robertson, J. 1. S. (1971): Hypertension: a review of selected topics. Abstr. World Med.,

45, 549.

Brown, J. J., Fraser, R., Lever, A. F., Love, D. R., Morton, J. J. and Robertson, J. I. S. (1972a): Raised plasma angiotensin- and aldosterone during dietary sodium restriction. in man. Lancet, 2, 1106. Brown, 3. J., Fraser, R., Lever, A. F. and Robertson, J. I. S. (1972b): Hypertension with aldosterone excess. Brit. med. J., 2, 391.

Brown, R. D., Strott, C. A. and Liddle, G. W. (1972): Plasma deoxycorticosterone in normal and abnormal human pregnancy. J. clin. Endocr., 35, 736. Dixon, H. G., Browne, J. C. McC. and Davey, D. A. (1963): Choriodecidual and myometrial blood-flow. Lancer, 2, 369. Diisterdieck, G. and McElwec, G. (1971): Estimation of angiotensin-II concentration in human plasma by radioimmunoassay. Some applications to physiological and clinical states. Europ. J. clin. Invest., 2, 32. Fournier, P. J. R., Desjardins, P. D. and Priesen, H. G. (1974): Current understanding of human prolactin physiology and diagnostic and therapeutic applications: A review. Amer. J. Obstet.

I am grateful to Dr. R. Fraser, Dr. J. J. Morton, Dr. M. Tree and Dr. A. Wilson for the measurements carried out in the laboratories of the M. R.C. Blood Pressure Unit, Western Infirmary, Glasgow; also to the obstetricians at the Queen Mother’s Hospital, Royal Maternity Hospital, and Stobhill General Hospital, Glasgow. References

Beitins,I. Z., Bayard, F., Levttsky, L., Antes, I. C., Kowarski, A. and M&on, C. J. (1972): Plasma aldosterone concentration at delivery and during the newborn period. J. clin. Invest., 51, 386. Berger, M. and Boucek, R. J. (1964): Irreversible uterine and renal changes induced by placental ischaemia (rabbit). Amer. J. Obstet.

Gynec., 89, 230.

Brosens, I. (1964): A study of the spiral arteries of the decidua basalis in normotensive and hypertensive pregnancies. J. Obstet.

Gynaec. Brit. Cwlth. 71. 222.

Brown, J. J., Davies, D. L., L&;,ATF., Robertson, J. I. S. and Tree, M. (1964): The estimation of renin in human plasma. Biochem. J., 93, 594. Brown, J. J., Davies, D. L., Doak, P. B., Lever, A. F., Robertson, J. I. S. and Trust, P. (1966): Plasma renin concentratration in the hypertensive diseases of pregnancy. J. Obstet. Gynaec.

Brit. Cwlth,

73, 410.

Brown, J. J., Fraser, R., Lever, A. F.. and Robertson, J. I. S. (1968): Renin and angiotensin in the control of water and electrolyte balance; relation to aldosterone. RecentAdvances in Endocrinology, 8th ed., p. 271. Editor: V. H. T. James. J. & A. Churchill Ltd., London.

Gym-c., 118, 337.

Fraser, R. and James, V. H. T. (1968): Double isotope assay of aldosterone, corticosterone and cortisol in human peripheral plasma. J. Endocr., 40, 59. Galvao-Teles, A. and Burke, C. W. (1973): Cortisoi levels in toxaemic and normal pregnancy. Lancet, I, 737. Gant, N. F., Daley, G. L., Chand, S., Whalley, P. J. and MacDonald, P. C. (1973): A study of angiotensin-II pressot response throughout primigravid pregnancy. J. clin. Invest., 52, 2682. Gordon, R. D., Symonds, E. M., Wilmshurst, E. G. and Pawsey, C. G. K. (1973): Plasma renin activity, plasma angiotensin and plasma and urinary electrolytes in normal and toxaemic pregnancy, Clin. Sci. mol. Med., 45, 115. Gupta, K. K., Chaudhury, R. R. and Chhuttani, P. M. (1967): Plasma antidiuretic hormone concentrations in normal subjects and in persons with oedema of cardiac and renal origin, and in normal pregnancy. Indian 1. med. Res., 55, 643.

Hodari, A. A. (1969): Chronic uterine ischaemia and reversible experimental “toxemia of pregnancy".Amer. J. Obstet. Gynec., 97, 597.

Horrobin, D. F. and Lloyd, 1. J. (1970): Pre-eclamptic toxaemia: possible relevance of progesterone, salt and frusemide. J. Obstet. Gynaec. Brit. Cwlth, 77, 253. Horrobin, D. F., Burstyn, P. G., Lloyd, I. J., Durkin, N., Lipton, A. and Muiruri, K. L. (1971): Actions of prolactin on human renal function. Lancet, 2, 352. Hughes, E. C., Lloyd, C. W., Jones, D., Lobotsky, J., Rienzo, J. S. and Avery, G. M. (1954): Some recent observations concerning the toxemias of pregnancy. Amer. J. Obstet. Gynec., 67, 782.

Hytten, F. E. and Leitch, 1. (1971): The Physiology ofHuman Pregnancy, 2nd ed. Blackwell Scientific Publications, Gxford.

82 Israel, S. L., Stroup, P. E., Seligson, H. T. and Seligson, D. (1959): Epinephtrine and norepinephrine in pregnancy and labour. Obstet. and Gynec., 14, 68. Katz, F. H., Beck, P. and Makowski, E. 0. (1974): The reninaldosterone system in mother and foetus at term. Amer. J. Obstet. Gynec., 118, 51. Kopelman, J. J. and Levitz, M. (1970): Plasma cortisol levels and cortisol binding in normal and pre-eclamptic pregnancies. Amer. J. Obstet. Gynec., 108, 925. Kreikenbaum, K., Elsaesser, F. and Hahn, N. (1974): Serum levels of HCS and progesterone during normal and pathologic pregnancies. Acta endocr. (Rbh.), Suppl. 184, 116. Lindberg, B. S. and Nilsson, B. A. (1973): Human placental lactogen (HPL) levels in abnormal pregnancies. J. Obstet. Gynaec. Brit. Cwlth, 80, 1046. Martin, M. M. and Martin, A. L. A. (1968): Simultaneous fluorimetric determination of cortisol and corticosterone in human plasma. J. clin. Endocr., 28, 137. Morton, J. J. (1973): The measurement of arginine vasopressin in human plasma by radio-immunoassay. Clin. Ski. mol. Med., 45, 5p. Paterson, M. L. (1960): The role of the posterior pituitary antidiuretic hormone in toxaemia of pregnancy. J. Obstet. Gynaec. Brit. Cwlth, 67, 883. Pekkarinen, A. and Castren, 0. (1968): Excretionof vanilmandelic acid (VMA) in the third trimester of normal and toxaemic pregnancy and other clinical conditions. Ann. Chir. Gynaec. Fenn. 57, 373. Pirani, B. B. K. (1975): The effect of plasma retransfusion on the blood pressure in the puerperium. In: Proc., 6th Meeting of Organisation Gestosis, Glasgow, 1973. In press. Robertson, J. I. S., Weir, R. J., Diisterdieck, G. O., Fraser, R. and Tree, M. (1971): Renin, angiotensin and aldosterone in human pregnancy and the menstrual cycle. Scot. med. J. 16, 183. Robertson, W. B., Brosens, I. and Dixon, H. G. (1967): The pathological response of the vessels of the placental bed to hypertensive pregnancy. J. Path. Bact., 93, 581. Skinner, S. L., Lumbers, E. R. and Symonds, E. M. (1972): Analysis of changes in the renin-angiotensin system during pregnancy. Chn. Sci., 42, 479. Spellacy, W. N. and Birk, S. A. (1972): The effect of intrauterine devices, oral contraceptives, estrogens and progestogens on blood pressure. Amer. J. Obstet. Gynec., 112, 912. Stone, M. L., Piliero, S. J., Hammer, H. and Portnoy, A. (1960): Epinephrine and norepinephrine in pregnancy. Obstet. and Gynec., 16, 674. Symonds, E. M., Anderson, G. J. and Pickles, B. (1974): Inappropriate renin secretion in pregnancy. Amer. J. Obstet. Gynec., 118, 6. Tapia, H. R., Johnson, C. E. and Strong, C. G. (1972): Renin-angiotensin system in normal and in hypertensive disease of pregnancy. Lancer, 2, 847. Tree, M. (1973): Measurement of plasma renin-substrate in man. J. Endocr., 56, 159A. Tyson, J. E., Hwang, P., Guyda, H. and Friesen, H. G. (1972): Studies of prolactin secretion in human pregnancy. Amer. J. Obstet. Gynec., 113, 14.

R. J. Weir, Vasopressor substances Weir, R. J., Paintin, D. B., Brown, J. J., Fraser, R., Lever, A. F., Robertson, J. I. S. and Young, J. (1971): A serial study in pregnancy of the plasma concentrations of renin, corticosteroids, electrolytes and proteins: and of haematocrit and plasma volume. J. Obstet. Gynaec. Brit. Cwlth, 78, 590. Weir, R. J., Brown, J. J., Fraser, R., Kraszewski, A., Lever, A. F., McIlwaine, G. M., Morton, 5. J., Robertson, I. I. S. and Tree, M. (1973): Plasma renin, renin-substrate, angiotensin-II and aldosterone in hypertensive disease of pregnancy. Lancet, 1, 291. Weir, R. J., Brown, J. J., Fraser, R., Lever, A. F., Logan, R. W., McIlwaine, G. M., Morton, J. J., Robertson, J. I. S. and Tree, M. (1975a): Relationship between plasma renin, renin-substrate, angiotensin-II, aldosterone and electrolytes in normal pregnancy. J. clin. Endocr., 40, 108. Weir, R. J., Fraser, R., McIlwaine, G. M., Kraszewski, A., Morton, J. J., Tree, M., Wilson, A. and Young, J. (1975b): Plasma angiotensin, aldosterone, DOC and ADH in normal and hypertensive pregnancy. In: Proc., 6th Meeting of Organisation Gestosis, Glasgow, 1973. In press. Wilson, A. and Fraser, R. (1971): The estimation of plasma 11-deoxycorticosterone in man using gas-liquid chromatography with electron capture detection. J. Endocr., 51, 557. Winter, M., Veldhuyzen, B. and Dorhout Mees, E. J. (1972): Failure of progesterone to produce high blood pressure in rabbits and rats. Lancet, I, 1263. Zuspan, F. P. (1970): Urinary excretion of epinephrine and norepinephrine during pregnancy. J. clin. Endocr., 30, 357.

Discussion ASSALI: I

am wondering, and I have always asked this same question of those working in the field of preeclampsia, what are really the meanings of measurements of concentrations such as so many microgrammes per 100 millilitres of blood. These measurements do not give the whole picture about the output by the adrenal or whatever system is involved in the renin-angiotensin-aldosterone story. I am wondering whether the preeclamptic or the clamptic patient may have this apparently low contentration level because they might be metabolizing these substances so rapidly, as in thyrotoxicosis for instance. The most severe cases of thyrotoxicosis have very low blood levels of thyroxine because they metabolise it so rapidly. Thus the measure of a concentration in a given sample of blood, taken at a given moment, may give you neither the output by the kidney nor by the adrenal, nor the reactivity of the blood vessels to a given blood level, So there are two factors here; it could be that these low levels merely represent, active metabolism by an inherently predisposed patient who as a result of preeclampsia, is metabolizing these substance very rapidly. Or, as you suggest, and this definitely has been proved by Chesley and his co-workers and by us before them, that the vascular bed of these patients is very much more sensitive than normally to small quantities of angiotensin. Here

83

R. J. Weir, Vasopressor substances

again it may be a question of metabolism by a target organ some such mechanism.

or

Yes, I think this is a very fair question. I would make the point that, generally speaking, in the practical situation it is usually easier to take a blood sample than to arrange a 24hour urine collection. Also, it is possible to correlate changes is a number of circulating hormones when plasma samples are taken concurrently. As far as methodology is concerned, with immunoasay methods it is easier now to measure these hormones in blood than it is in urine. WEIR:

I didn’t say that; I’m not all in favor of urine assays because they give most unsatisfactory results.

ASSALI:

As far as aldosterone is concerned there is very good evidence that the secretion rate is also reduced in the hypertensive pregnant woman. Tair, Little, Tait and Flood (1962) have shown that there is no evidence of increased metabolism of aldosterone in hypertensive pregnancy compared to normotensive pregnancy. As far as the vascular sensitivity is concerned the higher the levels of circulating angiotensin II then the lower the sensitivity of the vessels will be when you infuse angiotensin. Therefore one would expect that cases of normal pregnancy with high circulating levels of angiotensin or renin will be less reactive to infused angiotensin whereas the opposite occurs with a reduced level of angiotensin when one would expect a greater reactivity. It is interesting that in hypertensive pregnant women the vascular reactivity to angiotensin infusion is not any greater than in normotensive, nonpregnant women; vascular reactivity is similar. Now, having said that, Gant has given evidence that women who go on to develop hypertension later in pregnancy, when compared with women whose blood pressure remains normal, have a greater reactivity to angiotensin infusion before the hypertension develops. I think this possibly answers the question which was asked earlier on in connection with the uterine arteries, in that Gant has shown that this increased sensitivity occurs at about 18 to 20 weeks gestation and becomes signiticantly different from the normotensive group by about 24 weeks, that is before the hypertension had developed. I would criticize his findings on one score in that he does not give concurrent measurements of the circulating plasma angiotensin in the two groups. It may well be that circulating angiotensin is lower in the more reactive group. But I think it is a very interesting observation and I believe that possibly this is the answer, or one of the answers, namely that the vessels are primed in some way in the hypertension of pregnancy to react more than they do in normal pregnancy.

hypertension later in pregnancy. This is a deficiency which we are trying to remedy. This would be very interesting and might answer your question as to whether, when a woman develops hypertension, she shows a low level of angiotensin or whether she, in fact, shows an increased level. The reason I asked is because in a small pilot study designed to administer immunotherapy to women with angiotensin sensitivity, we found three young patients who, following treatment with hyperimmune multiparous plasma, became angiotensin resistant when they had been previously highly sensitive. Could this occur normally? BEER:

WEIR: 1 think

there is no answer to that at this stage.

WEIR:

BEER: Have you ever experienced a situation where you documented depressed levels in a hypertensive pregnancy which corrected themselves as the pregnancy progressed?

We ourselves have not serially measured plasma angiotensin during pregnancy when the woman has developed WEIR:

KLOPPER: Could I take up and expand Assali’s point about the meaning of a plasma concentration figure? I think that we should have somewhat different attitudes to plasma concentration and amniotic fluid concentration. I am very unhappy about attributing any physiological significance to an amniotic fluid concentration figure. Part of the reason is that, after all, the concentration figure is as much an expression of the ebb and flow of fluid inside that compartment as it is of changes in production of the substance you are measuring. When you have the fluid volume controlled by such aberrant nonphysiological factors as fetal urination, you begin to get kind of crazy figures which don’t relate to the physiological parameter that you are trying to study. I really think that your figures for the amniotic fluid concentration of angiotensin for instance would have rather more physiological impact if one knew how the angiotensin got there in the first place. In the case of angiotensin it was simply passing through the umbilical cord and if the amniotic fluid concentration has some sort of relevance to the concentration inside the fetal circulation, all right, then it may mean that the fetus is using angiotensin in some way; but if it is getting there because the fetus is urinating it, as it does with estriol, then the amount in that fluid is going to just depend on when the fetus last passed urine.

Yes, I think this a very valid point and I would emphasize that we are not drawing any definite conclusions. The fact is that these are concentrations of renin, not angiotensin. The fact that the renin levels we measured in amniotic fluid are so high makes us wonder about the possibility that the chorion does secrete renin as has been shown by others. This raises the question; why does it secrete renin? Could the renin secreted by the chorion be having the same effect in its local situation in the placenta as renin secreted by the kidney which seems to affect the countercurrent mechanism in the kidney in fluid and electrolyte exchange? It is purely speculative. WEIR:

ASSALI: Could I just add a little information to Klopper’s question? Some of my colleagues have recently produced data from experiments in sheep in which they measured angio-

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R. J. Weir, Vasopressor substances

tensin levels in fetal blood, taken from both the umbilical artery and vein. The fetal values were significantly higher than the maternal concentration of the same animal, taking samples simultaneously. Since the amniotic fluid is a product of recirculation of tracheal fluid from the fetus, plus urine, plus a variety of things, 1 do not believe -and I am surprised to see that the amniotic fluid concentration could be higher -but, for the first time in my life I agree with Klopper, that, unless you know at a given time the movement of water, the concentration of these substances in the amniotic fluid could be completely misleading. That goes for creatinine and anything else that is measured in the amniotic fluid. WEIR:

Yes, I would accept that.

GRUENWALD: I have two brief questions. We are trying, of course, to measure all kinds of things in the amniotic fluid to prognosticate what is going to happen to an infant. Has this been used in this respect, or might it be useful?

I don’t really think so for the reasons which have been stated. I should say that the data regarding renin in amniotic fluid is probably now about 8 years old; these measurements were made in 1966, I think. We haven’t really seen fit to repeat these measurements again for the very reasons which have been discussed. As for predicting the possible outcome of pregnancy, Gant has suggested that, from his work, if a woman at about 20,24 or 30 weeks of pregnancy has a greater than average pressor response to angiotensin infusion then she is a candidate for preeclampsia. I wouldn’t be too happy however, about infusing angiotensin routinely into pregnant women. WEIR:

have a very general second question from a point that was made in passing today and I wondered whether it might be discussed further. We all realise that in many pregnancies in which the woman eventually gets clinical preeclampsia, she must have had the disease long before, otherwise her fetus couldn’t be as small as it is for its gestational age. Preeclampsia, it seems, is not a disease that begins only when the woman gets a blood pressure of 140 over 90. GRUENWALD:

I

WEIR: Yes, I think this is important, as Robertson has mentioned earlier in his discussion of the spiral arteries. At the moment we are conducting a study where we are measuring angiotensin concentrations in plasma from early in pregnancy in a large group of women expecting that some of these women will develop preeclampsia. We hope to see whether, in fact, there is any change very early on to suggest a difference between the two groups.

There was a paper in the American Journal of PhysiolI think, reporting that angiotensin will increase placental blood flow by dilating the uteroplacental arteries. Could you comment on this?

MOLL:

ogy,

WEIR: It would be contrary to what happens to vessels elsewhere in the body but again, as we discussed earlier, the vessels in the placenta and the uterus in pregnancy seem to be considerably different from those inother situations. I would find it rather hard to believe and I would like to see very good confirmatory evidence on that. ASSALI: Could

I add this too? If you give pentobarbitol to the pregnant sheep or dog and then you give angiotensin, the response of the uterine vesselsis completely reversed from what it is in the unanesthetized pregnant animal. If you give a completely unanesthetized animal angiotensin there is a marked increase in uteroplacental vascular resistance and a rise in blood pressure. So it depends on the status of the animal and we have shown that pentobarbitol alters the reactivity of the blood vessels to a variety of drugs other than angiotensin. In fact the article you are referring to is mine and I am confessing now that it was in error due to the effect of anesthesia. KLOPPER: May I take Weir up on a part of what he said which nobody has explored yet? I am rather hoping I can tempt Assali into this. It was your observation about ADH which seems to me to be rather thrown out as a fishing line as much as anything else. The difficulty which people working on posterior pituitary hormones have experienced, certainly as far as oxytocin is concerned, has been the problem that in pregnancy this hormone is released in spurts and therefore any plasma concentration figures that you can come up with for oxytocin have very little meaning and are almost impossible to relate to a set of physiological phenomena. How far does this apply to the ADH situation?

I would take this as quite possible, which brings us back to the point of just single, isolated readings of plasma concentration. We know, for instance, that aldosterone has a possible diurnal variation. There is no doubt that if you could measure secretion rates of these hormones this may make interpretation a lot easier in this kind of situation, but that is much more difficult to do technically. Another thing which we are thinking of and planning at the moment, in relation to what you are saying, is measuring antidiuretic hormone at various times throughout the day in a small group of women in pregnancy, both normotensive and hypertensive, say for a week or two weeks and comparing the two groups and by that hoping to overcome any possible variation in secretion. But it is interesting all the same that we have this consistent pattern all the way through, whether it’s aldosterone secretion rate, excretion rate or plasma concentration, that this pressor and mineralocorticoid system is apparently suppressed in preeclampsia. This is shown not only by our work but also by others and this is what gives rise to the fascinating problem as to why.

WEIR:

MACGILLIVRAY:

The reason for my question will become ap-

R. J. Weir, Vasopressor

substances

parent after 1 have given my paper but I would like to ask and I have asked before but you hadn’t looked for the answer then - if ther is any difference between the plasma levels in primigravida and parous women. WEIR: We looked at our data again, in fact, after you had mentioned it. When we divided the data into two groups we found no significant differences between them.

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REFERENCE Tait, J. F., Little, B., Tait, S. A. S. and Flood, C. (1962): The metabolic clearance rate of aldosterone in pregnant and non-pregnant subjects estimated by both single injected and constant infusion methods. J. din. Invest., 41, 2093,

Vasopressor substances in normal and abnormal pregnancy.

EUROP. J. OBSTET. GYNEC. REPROD. BIOL., 1975, 5/l-2, 75-85. EXCERPTA MEDICA Va9opressor substances in normal and abnormal cww3nancv R. J. Weir Many...
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