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Prostaglandin E2 attenuates the pressor response to angiotensin II in pregnant subjects but not in nonpregnant subjects
Prostaglandin E2 attenuates the pressor response to angiotensin II in pregnant subjects but not in nonpregnant subjects FIONA BROUGHTON PIPKI"K, M.A., D.PHIL.
J.
C. HUNTER, M.R.C.O.G.
S. R. TURNER, M.R.C.O.G. P. :VI. S. O'BRIEN, M.D., M.R.C.O.G.
Nottingham, England The effect of prostaglandin E2 (PGE2), 5 ,ug/min-', on the pressor response to exogenous angiotensin II (All) has been examined in 22 women in second-trimester pregnancy and in 10 nonpregnant control subjects. PGE 2 diminished the diastolic pressor response in both groups without altering basal blood pressure. This effect was significant in the pregnant group, and not significant in the nonpregnant patients. The effect was achieved by a significant increase in threshold to All, rather than an alteration in the slope of the dose-response curve. Five pregnant patients who were given two identical infusion regimes of All withoUt PGE 2 showed no diminution of response. The effect of PGE 2 was greatest in the pregnant women who showed greatest initial sensitivity to All, perhaps suggesting a relative deficiency ot E series prostaglandins in some women by midtrimester pregnancy. (AM. J. OesTET. GYNECOL. 142:168, 1982.)
IT HAS BEEN CALCULATED 1 that in normotensive adult human beings angiotensin II (All) is usually present in concentrations only just below those capable of affecting arterial blood pressure. The concentration of All is raised in normal pregnancy, but the pregnant woman is usually protected from the potential hypertensive effects of this increased concentration by a diminution in vascular reactivity to AII. 2-• This diminution, which appears to be specific for All, is apparent by 8 weeks' gestation and reaches a maximum at 16 to 18 weeks' gestation .4 The underlying mechanism has not been elucidated, but it is known that in at least one major vascular bed, the kidney, there is a delicate balance between Ail concentrations and the vasodilator prostaglandins, notably those of the E series, which appears to control the distribution of renal blood flow.
From the Department of Obstetrics and Gynaecology, University of Nottingham, City Hospital. Received for publication March 6, 1981. Revised july 20, 1981. ,Jccepted August 26, 1981. Reprint requests: Dr. Fiona Broughton Pipkin, Department of Obstetrics and Gynaecology, University of Nottingham, University Hospital, Nottingham NG7 2UH, England.
168
Patients with pregnancy-induced hypertension (P.l H) exhibit a sensitivity to exogenous All very close to that of the nonpregnant subject, that is, the blunting of response seen in normal pregnancy is lost. 2• 4 • :; Furthermore, depressed placental levels of PGE 26 and prostacyclin7 have been found in patients with Pll-:1. Experiments carried out on anesthetized pregnam rabbits suggested that PGE 2 in concentrations of 100 and 500 ng/kg- 1/min- 1 markedly diminished the pressor response to exogenous All. s It was subsequently shown that pregnant rabbits fed a diet very low in essential fatty acids, which might be supposed to be PG deficient, had significantly greater responses to exogenous All than did control animals. 9 We have therefore examined the effect of infused PGE 2 on the pressor response to exogenous All in the nonpregnant subject and in second-trimester human pregnancy. The results obtained indicate that PG£ 2 , at a dose which does not affect basal blood pressure, significantly attenuates the pressor response to All in pregnant, but not in nonpregnant subjects.
Methods Patient selection. Women between 14 and 17 weeks' gestation age were studied. All had been accepted for therapeutic termination of pregnancy with prosta0002·9378/82/020168+09$00.90/0 © 1982 !he C. V. :O,fo>b) Co
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PGE 2 attenuates pressor response to All
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Table I. Some basal data concerning the subjects in the three study groups Patient A.M.
JR. J. s. s. s.
F.. S.
s.
L. c. D.W.
P. H. K. B.
J. v. C. B. B. P.L. M.G. L. s. M.P. c. L. E. W. C. D. F. M. L. G.
J.
s. c.
Gravida I 1 1 1 I I 1 1 1 1 I
1 5 3
Age (vr)
Weight (kg)
GA (wk)
Basal b.p. (rnm Hg)
23 19 16 22 18 17 18 17 17 22 16 16
60 53 62 46 74 51 57
101157 119170 106/66 126174 114/59* 104/64 110173 93/56 104/68 114174 105/66 113/69
29
59 70 70 54 53 39 47 53
16 16 16 1.5 16 16 15 15 15 17 15 16 16 16 16 15 15 16 16 15 14 15
19 19 18 16 18
52 61 74 45 51
17 15 16 17 16
91/58 104/61 113/69 103/67 112/64
69 50 52
52 53 5.5
27
60
21 23 39 28 21 19 22
4
4 4 2 3 4 4 4
35
M.S.
J.J.
A. T.
.J.G. A. L. B.
Age
Subject
Sex
(yr)
F.B.P.
F F F F F M M M M M
33 23 28 27 20 28 33 32 30 32
.J.D.
E.J.
K. G. L.C.
S.R.T.
P.S.C.
H. .J.
A.D. F. M.S.
99159 96/60 104/51 110171
97159 93/58 114/69 102/60 92/57 100/52
Weight (kg)
Basal b.p. (mrn Hg)
67 65 62 64
121174 114178 114173 105172 11179 107171 125/8.5 106177 110173 121174
!\7 86
85 77 75 81
*Negro. glandin E 2 (PGE 2), following counseling by a consultant gynaecologist unconnected with the project. Fully informed consent was obtained from all patients. The project was formally approved by the Ethical Committee of the City Hospital, Nottingham. Twenty-seven women were studied. Twelve primigravidas and 10 multiparas (Group 1) received infusions of All without and with the simultaneous infusion of PGE 2 (see below); five women, all primigravidas (Group 2) were given two identical infusions of All without any prostaglandin, as controls. Ten nonpregnant volunteers, five male, five female, also received All without and with simultaneous PGE 2 infusion (Group 3). Basic data concerning all 37 subjects are summarized in Table I. No subject had a personal or direct family history of hypertension or of renal or metabolic disease. All were
taking unrestricted diets and were not receiving any medication. Protocol. The subject lay supine throughout. Indwelling cannulas (Argyle Medicut, 16 or 18G; Sherwood Industries) were placed in both antecubital fossae. Normal saline solution was infused continuously at I ml/min- 1 via the right arm with an IV AC drop counter (IVAC Corporation, San Diego, California). The cannula in the left antecubital fossa was used solely for blood sampling for various hormonal and biochemical measurements. These will be reported upon in a subsequent paper and are not further discussed here. Arterial blood pressure was measured at 2 minute intervals from the left arm with an Arteriosonde Doppler automatic blood pressure recorder (Roche Medical Electronics, Cranbury, New Jersey). Heart rate was derived from the electrocardiogram.
170 Broughton Pipkin et al.
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Time (minl Fig. 1. Schematic diagram of the course of an experiment. The basal blood pressure, systolic or diastolic, was calculated as the mean of the stable blood pressures bracketing that infusion, and is shown as broken lines. Absolute increases in blood pressure, shown as double arrows, were then calculated from these baselines.
Fig. 1 is a schematic diagram of the protocol used. Arterial blood pressure was allowed to stabilize for a minimum of 20 minutes after setting up, until random fiuctuations in diastolic blood pressure were within 6 mm Hg. An initial blood sample was taken at this point [see arrows]. After a further l 0 minutes, provided that the blood pressure had restabilized, All (Hypertensin: Ciba-Geigy, Basle) was infused· intravenously via a needle connection into the indwelling cannula of the right arm, so that it was Hushed in by the saline infusion. The Ail was made up freshly each day from lyophylized All in normal saline: the stock solution was then stored on ice. This was infused with a Braun pump (B. Braun, Melsungen) at rates of 0.3, 0.6, and 1.2 mllmin~ 1 in all experiments. Doses of Ail given were 4, 8, and 16 ng/kg~ 1 /min~ 1 to pregnant patients and 0.8, 1.6, and 3.2 ng/kg- 1/ min~ 1 to nonpregnant subjects. Each infusion step lasted 10 minutes. At the end of the third step a second blood sam pie was obtained and the All infusion was discontinued. A minimum of 20 minutes recovery was allowed, until the blood pressure had again stabilized. In the two groups given PGE 2 , the infusion of normal saline was then discontinued, and one of PGE 2 , 5 p.g/ ml~ 1 (Prostin: Upjohn Company, Kalamazoo, Michigan) in normal saline, was substituted, also given at a rate of l ml/min- 1 • A minimum of 20 minutes was allowed to elapse before a third blood sample was obtained. Provided that the blood pressure was again stable, the All infusion was repeated l 0 minutes after this. The All was di-
luted freshly for each infusion. At the end of the third infusion step a final blood sample was obtained, and the infusion was discontinued. The blood pressure was monitored for a further 20 minutes, and when it was again stable the experiment was concluded. Calculations. A basal systolic and diastolic blood pressure was calculated for each experimental period with the use of the stable blood pressures bracketing each infusion (this basal pressure is represented on Fig. I. by the broken lines). The pressor response to Ail was calculated as the mean systolic or diastolic blood pressure over the last 6 minutes of each infusion step. The absolute evoked change was then calculated bv comparison with the baseline (shown as double arrows on Fig. 1). The threshold for response was calculated for each patient as being that dose of All requited to evoke a 5 mm Hg rise in blood pressure. For this purpose the linear relationship between log 10 Ail and evoked rise in diastolic blood pressure, \'""a+ bx was used, where y = evoked response (mm Hg), a = intercept on the y axis, b slope relating dose and response, and x = infused dose of All (log 10). This identity has previously been used by other workers investigating the pressor effect of AII. 1 Mean values are quoted ± l SEM throughout. Student's t test has been used where appropriate to test for significance of differences in paired samples. Student's unpaired r has been used, following an F test to deter-
PGE 2 attenuates pressor response to All
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Table II. Basal blood pressures and heart rates in the three groups studied
Blood pressure (mm Hg): Infusion I*
Infusion II
Heart rate (bpm): Infusion I infusion II
Group 1 (pregnant)
Group 2 (pregnant control)
105.2 ± 1.9 63.2 ± 1.5
104.5 ± 4.0 63.6 ± 1.9
104.8 ± 2.3 63.2 ± 1.4
104.9 ± 3.9 61.2 ± 1.5
115.9 + 1.7 75.1 ± 1.5
74.4 ± 2.3 90.8 ± 2.2
73.5 ± 1.8 75.9 ± 1.2
fi4.8 ± 1.9 76.4 ± 2.5
Group 3 (nonjJregnant)
*"infusion I" refers to the first infusion period in which no PGE, was administered; "Infusion II" relates to the second infusion period during which Groups I and 3 also received PGE, 5 ~Jog/min_,.
mine suitability, for unpaired data. Linear regression analysis has been carried out by the method of least squares.
Results Initial data. Basal blood pressures and heart rates in the three study groups are summarized in Table II. Basal blood pressure was significantly higher in the nonpregnant (Group 3) than the pregnant (Group l) subjects (P < 0.02, P < < 0.001 for systolic and diastolic, respectively). Conversely, basal heart rates were significantly lower in the nonpregnant group (P < 0.005). Basal values in Group 2, the pregnant control group. were effectively identical with those in Group 1.
The infusion of All resulted, as expected, in statistically highly significant increases in both systolic and diastolic blood pressure in pregnant and nonpregnant subjects (P < < 0.001 for both; Fig. 2). As Fig. 2 shows, the absolute rise in diastolic pressure was greater than that for systolic, and this difference was highly significant in the pregnant group (P < < 0.001 at each dose). In the nonpregnant group, however, the difference was much less marked, and achieved significance only at the lowest close of All used [P < 0.005]. In Fig. 2, calculated group means have been connected by lines drawn by eye. When the line of best fit was calculated for all individual data, it was found that the over-all slope of the lines relating dose of AI I to the
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Fig. 3. The initial dose-response curves to All in Groups I and 2 (open symbols) were effect.ivel\ identical. However, when PGE 2 was given simultaneously in Group I (closed circles) the response was significantly depressed; this was not seen in the second curve in Group 2 (closed squares) to whom no PGE 2 was given (mean± SEM).
evoked response in diastolic pressure were very similar in both the pregnant and nonpregnant groups (P > 0.2). Slopes for the systolic dose-response curves were also very similar (P > 0.7). The calculated thresholds for effect (see Methods) were, however, markedly different in the two groups. The mean diastolic threshold dose was 1.94 ± 0.25 ng/kg- 1/min- 1 in the pregnant group and 0.74 ± 0.11 ng/kg- 1/min- 1 in the nonpregnant (P < 0.001) (Table III): systolic thresholds were 5.23 ± 1.15 and 1.05 ± 0.10 ng/kg- 1/min- 1 , respectively (P < 0.005). Thus in pregnancy, rather more than twice as much All was needed to evoke a 5 mm rise in systolic blood pressure as in diastolic (P < 0.02), although the required doses were not significantly different in the nonpregnant subjects. The administration of Ali in pregnant subjects therefore resulted in a highly significant fall in pulse pressure at all doses (P < < 0.001 for all). Smaller falls in pulse pressure were seen in the nonpregnant group, but achieved significance only at the lowest dose (P < 0.002). Mean heart rate fell somewhat in both groups over the period of infusion of AIL This fall was significant in the pregnant group (P < 0.005). As Fig. 3 shows, the initial diastolic pressor response was effectively identical in Groups 1 and 2. The systolic pressure response and evoked bradycardia were also very similar in the two pregnant groups.
The effect of prostaglandin E 2 • The infusion ot PGE 2 , 5 ,ug/min- 1 , had no effect on basal arterial blood pressure in either group (see Table II). Mean resting heart rates, however, increased considerably in both pregnant (Group 1, P < < 0.001) and nonpregnant (Group 3, P < 0.002) patients, the increase being ob· served after as little as 4 to 5 minutes in most patients (Fig. 4). This increase was not seen in the patients of Group 2, who were not given PGE 2 • Facial flushing was noted in seven pregnant and two nonpregnant subjects during the PGE 2 infusion: one patient in each group complained of mild headache, and three pregnant patients experienced a degree of nausea. The infusion of All simultaneouslv with PGF.~ resulted in smaller rises in diastolic blood pressure in both groups than those seen with the initial infusion. As can be seen from Fig. 5, the diminution in response was considerably greater in the pregnant than in the nonpregnant su~jects. and was statistically significant at all doses (P < 0.02, P < 0.005, P < 0.01, respectively); the change was not statistically significant in the nonpregnant group. The blunting of the pressor response to All during PGE 2 infusion was greatest in those patients in whom angiotensin II had evoked the greatest initial response. This effect is illustr<~,ted in Fig. 6. The relationship wall &tatistically highly significant at all three doses of All, whether studied individually (P < 0.001, P < 0.00 l.
PGE 2 attenuates pressor response to All
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Fig. 4. Basal heart rates meaned over 10 minute periods in Group I (closed circles) and Group 3 (open circles) during the first and second experimental periods. The increase in heart rate observed with PGE 2 was highly significant in both groups (P < < 0.001 and P < 0.002, respectively). The open triangles represent mean heart rates during the period of All infusion (mean ::!:: SEM).
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173
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P < 0.005 respectively) or in concert (P < < 0.001). A similar relationship was present, but in a much attenuated form, in the nonpregnant subjects, achieving statistical significance only at the lowest dose (P < 0.05) and, weakly, over all (P < 0.05). The response of systolic pressure was not significantly changed (P > 0.3 at all doses in both groups). The pulse pressure therefore fell less in both the pregnant (P < 0.01, P < 0.01, P < 0.005) and nonpregnant (P < 0.025, ns. ns) groups than during the initial infusiom. The simultaneous administration of PGE 2 did not significantly alter the slope of the dose-response cunes ro Ail (P > 0.8. P > 0.95 for pregnant and nonpregnant groups). However, as can be seen from Table III. the threshold for response to All was significantly increased in the pregnant group. A much smaller, nonsignificant increase was seen in the nonpregnant subjects, so that the difference in threshold between the two groups increased still further. In neither group did systolic threshold alter. The second dose-response curve in Group 2 (control), where normal saline was infused instead of PGE 2 was effectively identical with the first. The only slight alteration seen was a tendency to increased, rather than diminished, response (Fig. 3). Neither systolic nor diastolic threshold changed (Table III).
Bradycardia was again seen during the period of All infusion; this was statistically highlv significant in Group 1 ( P < 0.00 I) but not significant in the ntlnpregnant subjects. PGE 2 did not alter the magnitude of the fall in heart rate in either group. Effect of parity. Mean basal systolic and diastolic blood pressures were somewhat lower in the multiparas than in the primigravidas (P < 0.025 tor both), hut during the infusion of PGE 2 this difference was lost. :\o significant consistent difference was observed in the pressor response to AI I. However, the initial threshold was lm,·er in the primigravidas, and increased more in the presence of PGE~. This alteration in threshold was significant in the primigravidas alone (P < 0.05). :\o other differences were obser\'ed with respect to pari!\.
Comment In normal human pregnancy there 1s an earl~· increase in cardiac output with a simultaneous fall in arterial blood pressure, especially diastolic. It is therefore assumed that total peripheral resistance (TPR) falls, and it can be calculated that this fall in TPR will be maximal at 14 to 24 weeks, the period of this study. Normal pregnancy is also associated with a marked diminution in the pressor response to All, but not to epinephrine. 2 Lumbers3 examined the peripheml vas~ cular reactivity to intra-arterial injections of these two
PGE 2 attenuates pressor response to All
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175
Table III. A comparison of the dose of Ali (ng/kg-'/min-') required to evoke a 5 mm Hg rise in diastolic blood pressure (threshold) in the three groups of patients studied
Threshold 1 (no PGE 2)
Threshold 2 (PGE 2 5 J.L/min- 1 to Groups 1 and 3)
Pregnant control
Pregnant
Nonpregnant
(Group 2)
(Group 1)
(Group 3)
1.61 :!:: 0.38
1.94:!:: 0.25 <- p < 0.001-
<-ns__,.
0.74 :!:: 0.11
i
i
t
n.s.
p < 0.02
n.s.
~ 1.73 ± 0.35
.._ p < 0.05 ___,.
hormones in third-trimester pregnancy. She concluded that the observed reduction in sensitivity to Ali was, at least in part, a reflection of decreased responsiveness of the vessels themselves. Cant and associates 10 found that, following acute volume expansion with normal saline, the dose of Ali required to evoke a 20 mm Hg rise in diastolic blood pressure (pressor dose) was halved in nonpregnant patients but unchanged in pregnant. The final plasma renin activity (PRA) was the same in both groups. The rapid infusion of an equal amount of sodium chloride as 5% saline did, however, result in a diminution in pressor response to All in the pregnant patients, with a similar decrease in PRA. It therefore appears possible that vascular reactivity per se is altered in pregnancy and that the blunted response is not simply a question of prior receptor occupancy. Messina, Weiner, and Kaley 11 reviewed the evidence that the E series prostaglandins could counteract the vasopressor effects of such vasoconstrictors as All and vasopressin. It was suggested that this inhibition was a separate entity from the vasodilatation which can be evoked by these hormones, since reactivity was still affected when the direct vasodilator results had ceased. The E series prostaglandins thus seemed to be reasonable subjects for investigation with regard to their effect on pressor responsiveness to All in normal human pregnancv. Because arterial blood pressure falls in secondtrimester pregnancy, the basal blood pressures in the subjects of this study were somewhat lower than would have been those in the pregnant women studied near term by Chesley .2 However, the relative increase in the amount of All required to evoke a given pressor response in pregnant by comparison with nonpregnant patients is remarkably similar ( x 2.6 in both studiessee Table III). Likewise, a recalculation of the thresholds reported in this paper to assess the dose required to evoke a 20 mm Hg. rather than a 5 mm Hg, rise in
~
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pressure reveals excellent agreement over the comparable period of gestation with the data of Gant and associates, 4 who found a mean value of 13.4 ± 0.8 ng/ kg- 1 /min- 1 , compared with 13.3 ± 1.5 ng/kg- 1/min- 1 in the patients of this study. In neither of the two earlier studies is there comment on the reflex bradycardia usually observed with an angiotensin-induced pressor effectY For a comparable pressor response, the evoked bradycardia was similar in the pregnant and nonpregnant patients of this paper, suggesting that baroreflex sensitivity to All in pregnancy is not grossly altftred. However. a formal investigation of this aspect of the response to All in pregnancy remains to be undertaken. As Fig. 5 shows, the simultaneous administration of PGE~ and All resulted in a diminution in pressor response in both pregnant and nonpregnant subjects, but this was of substantially greater magnitude in the pregnant subjects at equipressor doses. To ensure that this diminution in response was genuine, and not related to the conditions of the experiment, duplicate doseresponse curves were performed in the control patients of Group 2. Fig. 3 confirms that the pressor responses to the second infusion were, if anything. greater than to the first, so that the observed alteration in Group 1 appears to be specifically related to the infusion of PGE2. It appears, from experiments on pregnant animals, that utero placental blood flow may well be governed by interactions between Ali and E series prostaglandins, 13 • 14 such that the administration of Ail results in an increase in uterine blood flow. Blockade of endogenous prostaglandin production with indomethacin blocks this increase. 14 It has been found that the administration of indomethacin to pregnant women markedly increases the vascular sensitivity to exogenous All, presupposing a role for the prostaglandins in regulating vascular reactivity. 1 " We have now demonstrated directly that in the
Januar) 15.
176 Broughton Pipkin et al. ,\111
pregnant human being in the second trimester, PGE~ can markedlv attenuate the pressor response to All. The observation, that the antagonistic effect of PGE 2 is at its greatest in those patients who were initially most sensitive to All (Fig. 6). is of especial interest in this context. If one accepts the hypothesis of a mutually interregulatory role for PGE 2 and AI I, then it might be imagined that those patients showing the greatest diminution in response were relatively prostaglandin deficient. The suggestion that pregnancy-induced hvpertension (PIH) may in part reflect an imbalance in prostaglandin production was made in 197:'1. 11 ; Since then, evidence has built up to support this hypothesis: thus, for example, placental prostaglandin E concentrations haYe been found to be markedly depressed in PIH 6 and. more recently, prostacyclin production has been found to be significantly depressed in both placental and fetal blood vessels from pregnancies complicated bv hypertension by comparison with those from normotensive pregnancies.' Vascular reactivity to AlI, which is blunted in normal pregnancy. increases, sometimes dramatically. in women with PIH. 2 • '1· " One cannot help but wonder whether the primigravidas with thresholds of 0.35 and
0.68 ng/kg-'/min ' initially, increasing to 4.fH and 3.15 ng/kg-· 1/min- 1 in the presence of PGE" would have developed PIH had their pregnancies continued. In conclusion, we have shown that in ~econd .. trimester human pregnancy. the administration ol PGE 2 at a dose which did not alter basal blood pressun: had a pronounced inhibitory effect on the pres~or rc· sponse to exogenous All. This appear~ to give fttrther support to the hypothesis of an interdependence hetween E series prostaglandins. or possibly prostanclin, and All in the normal control of blood pressure in pregnancy. If this interdependence breaks down in PIH, through inadequate production of prostaglandins, then All would be expected to exert an unopposed ,·asoconstrictor effect, potentiallv extremely damaging to mother and fetus. We are grateful to the consultant staff of the Maternity Gnit, City Hospital, ;..Jottingham, tor allowing us access to their patients. We are also most grateful to the patiems and colleagues who took part as subjects. Our especial thanks go to Miss Carol Gledhill for her expert and conscientious technical help. Hypertensin was kindly supplied bv CIBA-Basle Ltd.
REFERENCES 1. Chinn, R. H., and Di.isterdieck. G.: The response of blood pressure to infusion of angiotensin II: Relation to plasma
2.
:'1.
4.
5.
6. 7.
8.
concentrations of renin and angiotensin II, Clin. Sci. 42:489. 1972. Chesley. L. C.: Vascular reactivity in normal and toxemi( pregnancy. Clin. Obstet. Gynecol. 9:871, 1966. Lumbers, E. R.: Peripheral vascular reactivity to angiotensin and noradrenaline in pregnant and nonpregnant women, Aust. J. Exp. Bioi. Med. Sci. 48:493, 1970. Gant, l\. F., Daley. G. L., Chand. S., Whalley. P. J., and MacDonald, P. C.: A study of angiotensin II pressor response throughout primigravid pregnancy, J. Clin. Invest. 52:2682, 1973. Talledo, 0. E., Chesley, L. C., and Zuspan, F. P.: Renin, angiotensin system in normal and toxaemic pregnancies. I I I. Differential sensitivity to angiotensin II and norepinephrine in toxemia of pregnancy. AM. J. OBSTET. GY:-!ECOL. 100:218, 1968. Demers, L. M .. and Gabbe, S. G.: Placental prostaglandin levels in pre-eclampsia, AM. J. 0BSTET. GYNECOL 126: 137, 1976. Remuzzi, G., Marchesi, D., Zoja, C., Muratore, D., Mecca, G., Misiani, R., Rossi, E., Barbato, M., Capetta, P., Donati, M. B., and de Gaetano, G.: Reduced umbilical and placental vascular prostacyclin in severe pre-eclampsia, Prostaglandins 20:105, 1980. O'Brien, P.M. S., Filshie, G. M., and Broughton Pipkin, F.: The effect of prostaglandin E2 on the cardiovascular
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9.
10.
II.
12.
13.
14.
15.
16.
response to angiotensin II in pregnant rabbits. Prostaglandins 13:171, 1977. O'Brien, P.M. S., and Broughton Pipkin, F.: The effects of deprivation of prostaglandin precursors on vascular sensitivity to angiotensin II and on the kidney in the pregnant rabbit, Br. J. Pharmacal. 65:29, 1979. Gant, l\. F.. Chand, S.. Whalley, P.J., and MacDonald, P. C.: The nature of pressor responsiveness to angiotensin li in human pregnancy, Obstet. Gynecol. 43:854, 1974. Messina, E. J., Weiner, R., and Kaley, G.: Prostaglandins and local circulatory control, Fed. Proc. 35:2367, 1976. DeBono, E.. Lee, G. de J., Mottram. F. R., Pickering, G. W., Brown,J.J., Keen, H., Peart, W. S., and Sanderson, P. H.: The action of angiotensin in man, Clin. Sci. 25:123. 1963. Terragno. N. A .. Terragno, D. A., Pacholczyk, D., and McGiff, J. C.: Prostaglandins and the regulation of uterine blood How in pregnancy, Nature (Lond.) 249:57. 1974. Speroff, L., Haning, R. V., and Levin, R. M.: The effect of angiotensin II and indomethacin on uterine artery blood How in pregnant monkeys, Obstet. Gynecol. 50: 611, 1977. Everett, R. B., Worley, R.J., MacDonald, P. C., and Gam, l\. F.: Effect of prostaglandin synthetase inhibitors on pressor response to angiotensin II in human pregnancy . .J. Clin. Endocrinol. Metab. 46:1007, 1978. Speroff, L.: An essay: prostaglandins and toxaemia of pregnancy, Prostaglandins 3:721, 197~.
J.
C. HUNTER, M.R.C.O.G.
S. R. TURNER, M.R.C.O.G. P. :VI. S. O'BRIEN, M.D., M.R.C.O.G.
Nottingham, England The effect of prostaglandin E2 (PGE2), 5 ,ug/min-', on the pressor response to exogenous angiotensin II (All) has been examined in 22 women in second-trimester pregnancy and in 10 nonpregnant control subjects. PGE 2 diminished the diastolic pressor response in both groups without altering basal blood pressure. This effect was significant in the pregnant group, and not significant in the nonpregnant patients. The effect was achieved by a significant increase in threshold to All, rather than an alteration in the slope of the dose-response curve. Five pregnant patients who were given two identical infusion regimes of All withoUt PGE 2 showed no diminution of response. The effect of PGE 2 was greatest in the pregnant women who showed greatest initial sensitivity to All, perhaps suggesting a relative deficiency ot E series prostaglandins in some women by midtrimester pregnancy. (AM. J. OesTET. GYNECOL. 142:168, 1982.)
IT HAS BEEN CALCULATED 1 that in normotensive adult human beings angiotensin II (All) is usually present in concentrations only just below those capable of affecting arterial blood pressure. The concentration of All is raised in normal pregnancy, but the pregnant woman is usually protected from the potential hypertensive effects of this increased concentration by a diminution in vascular reactivity to AII. 2-• This diminution, which appears to be specific for All, is apparent by 8 weeks' gestation and reaches a maximum at 16 to 18 weeks' gestation .4 The underlying mechanism has not been elucidated, but it is known that in at least one major vascular bed, the kidney, there is a delicate balance between Ail concentrations and the vasodilator prostaglandins, notably those of the E series, which appears to control the distribution of renal blood flow.
From the Department of Obstetrics and Gynaecology, University of Nottingham, City Hospital. Received for publication March 6, 1981. Revised july 20, 1981. ,Jccepted August 26, 1981. Reprint requests: Dr. Fiona Broughton Pipkin, Department of Obstetrics and Gynaecology, University of Nottingham, University Hospital, Nottingham NG7 2UH, England.
168
Patients with pregnancy-induced hypertension (P.l H) exhibit a sensitivity to exogenous All very close to that of the nonpregnant subject, that is, the blunting of response seen in normal pregnancy is lost. 2• 4 • :; Furthermore, depressed placental levels of PGE 26 and prostacyclin7 have been found in patients with Pll-:1. Experiments carried out on anesthetized pregnam rabbits suggested that PGE 2 in concentrations of 100 and 500 ng/kg- 1/min- 1 markedly diminished the pressor response to exogenous All. s It was subsequently shown that pregnant rabbits fed a diet very low in essential fatty acids, which might be supposed to be PG deficient, had significantly greater responses to exogenous All than did control animals. 9 We have therefore examined the effect of infused PGE 2 on the pressor response to exogenous All in the nonpregnant subject and in second-trimester human pregnancy. The results obtained indicate that PG£ 2 , at a dose which does not affect basal blood pressure, significantly attenuates the pressor response to All in pregnant, but not in nonpregnant subjects.
Methods Patient selection. Women between 14 and 17 weeks' gestation age were studied. All had been accepted for therapeutic termination of pregnancy with prosta0002·9378/82/020168+09$00.90/0 © 1982 !he C. V. :O,fo>b) Co
Volume 142 Number 2
PGE 2 attenuates pressor response to All
169
Table I. Some basal data concerning the subjects in the three study groups Patient A.M.
JR. J. s. s. s.
F.. S.
s.
L. c. D.W.
P. H. K. B.
J. v. C. B. B. P.L. M.G. L. s. M.P. c. L. E. W. C. D. F. M. L. G.
J.
s. c.
Gravida I 1 1 1 I I 1 1 1 1 I
1 5 3
Age (vr)
Weight (kg)
GA (wk)
Basal b.p. (rnm Hg)
23 19 16 22 18 17 18 17 17 22 16 16
60 53 62 46 74 51 57
101157 119170 106/66 126174 114/59* 104/64 110173 93/56 104/68 114174 105/66 113/69
29
59 70 70 54 53 39 47 53
16 16 16 1.5 16 16 15 15 15 17 15 16 16 16 16 15 15 16 16 15 14 15
19 19 18 16 18
52 61 74 45 51
17 15 16 17 16
91/58 104/61 113/69 103/67 112/64
69 50 52
52 53 5.5
27
60
21 23 39 28 21 19 22
4
4 4 2 3 4 4 4
35
M.S.
J.J.
A. T.
.J.G. A. L. B.
Age
Subject
Sex
(yr)
F.B.P.
F F F F F M M M M M
33 23 28 27 20 28 33 32 30 32
.J.D.
E.J.
K. G. L.C.
S.R.T.
P.S.C.
H. .J.
A.D. F. M.S.
99159 96/60 104/51 110171
97159 93/58 114/69 102/60 92/57 100/52
Weight (kg)
Basal b.p. (mrn Hg)
67 65 62 64
121174 114178 114173 105172 11179 107171 125/8.5 106177 110173 121174
!\7 86
85 77 75 81
*Negro. glandin E 2 (PGE 2), following counseling by a consultant gynaecologist unconnected with the project. Fully informed consent was obtained from all patients. The project was formally approved by the Ethical Committee of the City Hospital, Nottingham. Twenty-seven women were studied. Twelve primigravidas and 10 multiparas (Group 1) received infusions of All without and with the simultaneous infusion of PGE 2 (see below); five women, all primigravidas (Group 2) were given two identical infusions of All without any prostaglandin, as controls. Ten nonpregnant volunteers, five male, five female, also received All without and with simultaneous PGE 2 infusion (Group 3). Basic data concerning all 37 subjects are summarized in Table I. No subject had a personal or direct family history of hypertension or of renal or metabolic disease. All were
taking unrestricted diets and were not receiving any medication. Protocol. The subject lay supine throughout. Indwelling cannulas (Argyle Medicut, 16 or 18G; Sherwood Industries) were placed in both antecubital fossae. Normal saline solution was infused continuously at I ml/min- 1 via the right arm with an IV AC drop counter (IVAC Corporation, San Diego, California). The cannula in the left antecubital fossa was used solely for blood sampling for various hormonal and biochemical measurements. These will be reported upon in a subsequent paper and are not further discussed here. Arterial blood pressure was measured at 2 minute intervals from the left arm with an Arteriosonde Doppler automatic blood pressure recorder (Roche Medical Electronics, Cranbury, New Jersey). Heart rate was derived from the electrocardiogram.
170 Broughton Pipkin et al.
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20
40
60
80
100
120
140
160
180
Time (minl Fig. 1. Schematic diagram of the course of an experiment. The basal blood pressure, systolic or diastolic, was calculated as the mean of the stable blood pressures bracketing that infusion, and is shown as broken lines. Absolute increases in blood pressure, shown as double arrows, were then calculated from these baselines.
Fig. 1 is a schematic diagram of the protocol used. Arterial blood pressure was allowed to stabilize for a minimum of 20 minutes after setting up, until random fiuctuations in diastolic blood pressure were within 6 mm Hg. An initial blood sample was taken at this point [see arrows]. After a further l 0 minutes, provided that the blood pressure had restabilized, All (Hypertensin: Ciba-Geigy, Basle) was infused· intravenously via a needle connection into the indwelling cannula of the right arm, so that it was Hushed in by the saline infusion. The Ail was made up freshly each day from lyophylized All in normal saline: the stock solution was then stored on ice. This was infused with a Braun pump (B. Braun, Melsungen) at rates of 0.3, 0.6, and 1.2 mllmin~ 1 in all experiments. Doses of Ail given were 4, 8, and 16 ng/kg~ 1 /min~ 1 to pregnant patients and 0.8, 1.6, and 3.2 ng/kg- 1/ min~ 1 to nonpregnant subjects. Each infusion step lasted 10 minutes. At the end of the third step a second blood sam pie was obtained and the All infusion was discontinued. A minimum of 20 minutes recovery was allowed, until the blood pressure had again stabilized. In the two groups given PGE 2 , the infusion of normal saline was then discontinued, and one of PGE 2 , 5 p.g/ ml~ 1 (Prostin: Upjohn Company, Kalamazoo, Michigan) in normal saline, was substituted, also given at a rate of l ml/min- 1 • A minimum of 20 minutes was allowed to elapse before a third blood sample was obtained. Provided that the blood pressure was again stable, the All infusion was repeated l 0 minutes after this. The All was di-
luted freshly for each infusion. At the end of the third infusion step a final blood sample was obtained, and the infusion was discontinued. The blood pressure was monitored for a further 20 minutes, and when it was again stable the experiment was concluded. Calculations. A basal systolic and diastolic blood pressure was calculated for each experimental period with the use of the stable blood pressures bracketing each infusion (this basal pressure is represented on Fig. I. by the broken lines). The pressor response to Ail was calculated as the mean systolic or diastolic blood pressure over the last 6 minutes of each infusion step. The absolute evoked change was then calculated bv comparison with the baseline (shown as double arrows on Fig. 1). The threshold for response was calculated for each patient as being that dose of All requited to evoke a 5 mm Hg rise in blood pressure. For this purpose the linear relationship between log 10 Ail and evoked rise in diastolic blood pressure, \'""a+ bx was used, where y = evoked response (mm Hg), a = intercept on the y axis, b slope relating dose and response, and x = infused dose of All (log 10). This identity has previously been used by other workers investigating the pressor effect of AII. 1 Mean values are quoted ± l SEM throughout. Student's t test has been used where appropriate to test for significance of differences in paired samples. Student's unpaired r has been used, following an F test to deter-
PGE 2 attenuates pressor response to All
Volume 142 \lumber 2
171
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Table II. Basal blood pressures and heart rates in the three groups studied
Blood pressure (mm Hg): Infusion I*
Infusion II
Heart rate (bpm): Infusion I infusion II
Group 1 (pregnant)
Group 2 (pregnant control)
105.2 ± 1.9 63.2 ± 1.5
104.5 ± 4.0 63.6 ± 1.9
104.8 ± 2.3 63.2 ± 1.4
104.9 ± 3.9 61.2 ± 1.5
115.9 + 1.7 75.1 ± 1.5
74.4 ± 2.3 90.8 ± 2.2
73.5 ± 1.8 75.9 ± 1.2
fi4.8 ± 1.9 76.4 ± 2.5
Group 3 (nonjJregnant)
*"infusion I" refers to the first infusion period in which no PGE, was administered; "Infusion II" relates to the second infusion period during which Groups I and 3 also received PGE, 5 ~Jog/min_,.
mine suitability, for unpaired data. Linear regression analysis has been carried out by the method of least squares.
Results Initial data. Basal blood pressures and heart rates in the three study groups are summarized in Table II. Basal blood pressure was significantly higher in the nonpregnant (Group 3) than the pregnant (Group l) subjects (P < 0.02, P < < 0.001 for systolic and diastolic, respectively). Conversely, basal heart rates were significantly lower in the nonpregnant group (P < 0.005). Basal values in Group 2, the pregnant control group. were effectively identical with those in Group 1.
The infusion of All resulted, as expected, in statistically highly significant increases in both systolic and diastolic blood pressure in pregnant and nonpregnant subjects (P < < 0.001 for both; Fig. 2). As Fig. 2 shows, the absolute rise in diastolic pressure was greater than that for systolic, and this difference was highly significant in the pregnant group (P < < 0.001 at each dose). In the nonpregnant group, however, the difference was much less marked, and achieved significance only at the lowest close of All used [P < 0.005]. In Fig. 2, calculated group means have been connected by lines drawn by eye. When the line of best fit was calculated for all individual data, it was found that the over-all slope of the lines relating dose of AI I to the
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Fig. 3. The initial dose-response curves to All in Groups I and 2 (open symbols) were effect.ivel\ identical. However, when PGE 2 was given simultaneously in Group I (closed circles) the response was significantly depressed; this was not seen in the second curve in Group 2 (closed squares) to whom no PGE 2 was given (mean± SEM).
evoked response in diastolic pressure were very similar in both the pregnant and nonpregnant groups (P > 0.2). Slopes for the systolic dose-response curves were also very similar (P > 0.7). The calculated thresholds for effect (see Methods) were, however, markedly different in the two groups. The mean diastolic threshold dose was 1.94 ± 0.25 ng/kg- 1/min- 1 in the pregnant group and 0.74 ± 0.11 ng/kg- 1/min- 1 in the nonpregnant (P < 0.001) (Table III): systolic thresholds were 5.23 ± 1.15 and 1.05 ± 0.10 ng/kg- 1/min- 1 , respectively (P < 0.005). Thus in pregnancy, rather more than twice as much All was needed to evoke a 5 mm rise in systolic blood pressure as in diastolic (P < 0.02), although the required doses were not significantly different in the nonpregnant subjects. The administration of Ali in pregnant subjects therefore resulted in a highly significant fall in pulse pressure at all doses (P < < 0.001 for all). Smaller falls in pulse pressure were seen in the nonpregnant group, but achieved significance only at the lowest dose (P < 0.002). Mean heart rate fell somewhat in both groups over the period of infusion of AIL This fall was significant in the pregnant group (P < 0.005). As Fig. 3 shows, the initial diastolic pressor response was effectively identical in Groups 1 and 2. The systolic pressure response and evoked bradycardia were also very similar in the two pregnant groups.
The effect of prostaglandin E 2 • The infusion ot PGE 2 , 5 ,ug/min- 1 , had no effect on basal arterial blood pressure in either group (see Table II). Mean resting heart rates, however, increased considerably in both pregnant (Group 1, P < < 0.001) and nonpregnant (Group 3, P < 0.002) patients, the increase being ob· served after as little as 4 to 5 minutes in most patients (Fig. 4). This increase was not seen in the patients of Group 2, who were not given PGE 2 • Facial flushing was noted in seven pregnant and two nonpregnant subjects during the PGE 2 infusion: one patient in each group complained of mild headache, and three pregnant patients experienced a degree of nausea. The infusion of All simultaneouslv with PGF.~ resulted in smaller rises in diastolic blood pressure in both groups than those seen with the initial infusion. As can be seen from Fig. 5, the diminution in response was considerably greater in the pregnant than in the nonpregnant su~jects. and was statistically significant at all doses (P < 0.02, P < 0.005, P < 0.01, respectively); the change was not statistically significant in the nonpregnant group. The blunting of the pressor response to All during PGE 2 infusion was greatest in those patients in whom angiotensin II had evoked the greatest initial response. This effect is illustr<~,ted in Fig. 6. The relationship wall &tatistically highly significant at all three doses of All, whether studied individually (P < 0.001, P < 0.00 l.
PGE 2 attenuates pressor response to All
Volume 142 !'lumber 2
100
T
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-30 -20 -10 0
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Fig. 4. Basal heart rates meaned over 10 minute periods in Group I (closed circles) and Group 3 (open circles) during the first and second experimental periods. The increase in heart rate observed with PGE 2 was highly significant in both groups (P < < 0.001 and P < 0.002, respectively). The open triangles represent mean heart rates during the period of All infusion (mean ::!:: SEM).
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Fig. 5. The diastolic pressor response to All (closed symbols) was attenuated in both groups in the presence of PGE 2 , 5~J-g min- 1 • This difference was statistically significant in the pregnant patients (see text) (mean ± SEM).
173
januan !'1, I9H:!
174 Broughton Pipkin et al.
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P < 0.005 respectively) or in concert (P < < 0.001). A similar relationship was present, but in a much attenuated form, in the nonpregnant subjects, achieving statistical significance only at the lowest dose (P < 0.05) and, weakly, over all (P < 0.05). The response of systolic pressure was not significantly changed (P > 0.3 at all doses in both groups). The pulse pressure therefore fell less in both the pregnant (P < 0.01, P < 0.01, P < 0.005) and nonpregnant (P < 0.025, ns. ns) groups than during the initial infusiom. The simultaneous administration of PGE 2 did not significantly alter the slope of the dose-response cunes ro Ail (P > 0.8. P > 0.95 for pregnant and nonpregnant groups). However, as can be seen from Table III. the threshold for response to All was significantly increased in the pregnant group. A much smaller, nonsignificant increase was seen in the nonpregnant subjects, so that the difference in threshold between the two groups increased still further. In neither group did systolic threshold alter. The second dose-response curve in Group 2 (control), where normal saline was infused instead of PGE 2 was effectively identical with the first. The only slight alteration seen was a tendency to increased, rather than diminished, response (Fig. 3). Neither systolic nor diastolic threshold changed (Table III).
Bradycardia was again seen during the period of All infusion; this was statistically highlv significant in Group 1 ( P < 0.00 I) but not significant in the ntlnpregnant subjects. PGE 2 did not alter the magnitude of the fall in heart rate in either group. Effect of parity. Mean basal systolic and diastolic blood pressures were somewhat lower in the multiparas than in the primigravidas (P < 0.025 tor both), hut during the infusion of PGE 2 this difference was lost. :\o significant consistent difference was observed in the pressor response to AI I. However, the initial threshold was lm,·er in the primigravidas, and increased more in the presence of PGE~. This alteration in threshold was significant in the primigravidas alone (P < 0.05). :\o other differences were obser\'ed with respect to pari!\.
Comment In normal human pregnancy there 1s an earl~· increase in cardiac output with a simultaneous fall in arterial blood pressure, especially diastolic. It is therefore assumed that total peripheral resistance (TPR) falls, and it can be calculated that this fall in TPR will be maximal at 14 to 24 weeks, the period of this study. Normal pregnancy is also associated with a marked diminution in the pressor response to All, but not to epinephrine. 2 Lumbers3 examined the peripheml vas~ cular reactivity to intra-arterial injections of these two
PGE 2 attenuates pressor response to All
Volume 142 Number 2
175
Table III. A comparison of the dose of Ali (ng/kg-'/min-') required to evoke a 5 mm Hg rise in diastolic blood pressure (threshold) in the three groups of patients studied
Threshold 1 (no PGE 2)
Threshold 2 (PGE 2 5 J.L/min- 1 to Groups 1 and 3)
Pregnant control
Pregnant
Nonpregnant
(Group 2)
(Group 1)
(Group 3)
1.61 :!:: 0.38
1.94:!:: 0.25 <- p < 0.001-
<-ns__,.
0.74 :!:: 0.11
i
i
t
n.s.
p < 0.02
n.s.
~ 1.73 ± 0.35
.._ p < 0.05 ___,.
hormones in third-trimester pregnancy. She concluded that the observed reduction in sensitivity to Ali was, at least in part, a reflection of decreased responsiveness of the vessels themselves. Cant and associates 10 found that, following acute volume expansion with normal saline, the dose of Ali required to evoke a 20 mm Hg rise in diastolic blood pressure (pressor dose) was halved in nonpregnant patients but unchanged in pregnant. The final plasma renin activity (PRA) was the same in both groups. The rapid infusion of an equal amount of sodium chloride as 5% saline did, however, result in a diminution in pressor response to All in the pregnant patients, with a similar decrease in PRA. It therefore appears possible that vascular reactivity per se is altered in pregnancy and that the blunted response is not simply a question of prior receptor occupancy. Messina, Weiner, and Kaley 11 reviewed the evidence that the E series prostaglandins could counteract the vasopressor effects of such vasoconstrictors as All and vasopressin. It was suggested that this inhibition was a separate entity from the vasodilatation which can be evoked by these hormones, since reactivity was still affected when the direct vasodilator results had ceased. The E series prostaglandins thus seemed to be reasonable subjects for investigation with regard to their effect on pressor responsiveness to All in normal human pregnancv. Because arterial blood pressure falls in secondtrimester pregnancy, the basal blood pressures in the subjects of this study were somewhat lower than would have been those in the pregnant women studied near term by Chesley .2 However, the relative increase in the amount of All required to evoke a given pressor response in pregnant by comparison with nonpregnant patients is remarkably similar ( x 2.6 in both studiessee Table III). Likewise, a recalculation of the thresholds reported in this paper to assess the dose required to evoke a 20 mm Hg. rather than a 5 mm Hg, rise in
~
2.92
::!:
0.22 .._ p < < 0.001 ...... 0.95
t ::!:
0.20
pressure reveals excellent agreement over the comparable period of gestation with the data of Gant and associates, 4 who found a mean value of 13.4 ± 0.8 ng/ kg- 1 /min- 1 , compared with 13.3 ± 1.5 ng/kg- 1/min- 1 in the patients of this study. In neither of the two earlier studies is there comment on the reflex bradycardia usually observed with an angiotensin-induced pressor effectY For a comparable pressor response, the evoked bradycardia was similar in the pregnant and nonpregnant patients of this paper, suggesting that baroreflex sensitivity to All in pregnancy is not grossly altftred. However. a formal investigation of this aspect of the response to All in pregnancy remains to be undertaken. As Fig. 5 shows, the simultaneous administration of PGE~ and All resulted in a diminution in pressor response in both pregnant and nonpregnant subjects, but this was of substantially greater magnitude in the pregnant subjects at equipressor doses. To ensure that this diminution in response was genuine, and not related to the conditions of the experiment, duplicate doseresponse curves were performed in the control patients of Group 2. Fig. 3 confirms that the pressor responses to the second infusion were, if anything. greater than to the first, so that the observed alteration in Group 1 appears to be specifically related to the infusion of PGE2. It appears, from experiments on pregnant animals, that utero placental blood flow may well be governed by interactions between Ali and E series prostaglandins, 13 • 14 such that the administration of Ail results in an increase in uterine blood flow. Blockade of endogenous prostaglandin production with indomethacin blocks this increase. 14 It has been found that the administration of indomethacin to pregnant women markedly increases the vascular sensitivity to exogenous All, presupposing a role for the prostaglandins in regulating vascular reactivity. 1 " We have now demonstrated directly that in the
Januar) 15.
176 Broughton Pipkin et al. ,\111
pregnant human being in the second trimester, PGE~ can markedlv attenuate the pressor response to All. The observation, that the antagonistic effect of PGE 2 is at its greatest in those patients who were initially most sensitive to All (Fig. 6). is of especial interest in this context. If one accepts the hypothesis of a mutually interregulatory role for PGE 2 and AI I, then it might be imagined that those patients showing the greatest diminution in response were relatively prostaglandin deficient. The suggestion that pregnancy-induced hvpertension (PIH) may in part reflect an imbalance in prostaglandin production was made in 197:'1. 11 ; Since then, evidence has built up to support this hypothesis: thus, for example, placental prostaglandin E concentrations haYe been found to be markedly depressed in PIH 6 and. more recently, prostacyclin production has been found to be significantly depressed in both placental and fetal blood vessels from pregnancies complicated bv hypertension by comparison with those from normotensive pregnancies.' Vascular reactivity to AlI, which is blunted in normal pregnancy. increases, sometimes dramatically. in women with PIH. 2 • '1· " One cannot help but wonder whether the primigravidas with thresholds of 0.35 and
0.68 ng/kg-'/min ' initially, increasing to 4.fH and 3.15 ng/kg-· 1/min- 1 in the presence of PGE" would have developed PIH had their pregnancies continued. In conclusion, we have shown that in ~econd .. trimester human pregnancy. the administration ol PGE 2 at a dose which did not alter basal blood pressun: had a pronounced inhibitory effect on the pres~or rc· sponse to exogenous All. This appear~ to give fttrther support to the hypothesis of an interdependence hetween E series prostaglandins. or possibly prostanclin, and All in the normal control of blood pressure in pregnancy. If this interdependence breaks down in PIH, through inadequate production of prostaglandins, then All would be expected to exert an unopposed ,·asoconstrictor effect, potentiallv extremely damaging to mother and fetus. We are grateful to the consultant staff of the Maternity Gnit, City Hospital, ;..Jottingham, tor allowing us access to their patients. We are also most grateful to the patiems and colleagues who took part as subjects. Our especial thanks go to Miss Carol Gledhill for her expert and conscientious technical help. Hypertensin was kindly supplied bv CIBA-Basle Ltd.
REFERENCES 1. Chinn, R. H., and Di.isterdieck. G.: The response of blood pressure to infusion of angiotensin II: Relation to plasma
2.
:'1.
4.
5.
6. 7.
8.
concentrations of renin and angiotensin II, Clin. Sci. 42:489. 1972. Chesley. L. C.: Vascular reactivity in normal and toxemi( pregnancy. Clin. Obstet. Gynecol. 9:871, 1966. Lumbers, E. R.: Peripheral vascular reactivity to angiotensin and noradrenaline in pregnant and nonpregnant women, Aust. J. Exp. Bioi. Med. Sci. 48:493, 1970. Gant, l\. F., Daley. G. L., Chand. S., Whalley. P. J., and MacDonald, P. C.: A study of angiotensin II pressor response throughout primigravid pregnancy, J. Clin. Invest. 52:2682, 1973. Talledo, 0. E., Chesley, L. C., and Zuspan, F. P.: Renin, angiotensin system in normal and toxaemic pregnancies. I I I. Differential sensitivity to angiotensin II and norepinephrine in toxemia of pregnancy. AM. J. OBSTET. GY:-!ECOL. 100:218, 1968. Demers, L. M .. and Gabbe, S. G.: Placental prostaglandin levels in pre-eclampsia, AM. J. 0BSTET. GYNECOL 126: 137, 1976. Remuzzi, G., Marchesi, D., Zoja, C., Muratore, D., Mecca, G., Misiani, R., Rossi, E., Barbato, M., Capetta, P., Donati, M. B., and de Gaetano, G.: Reduced umbilical and placental vascular prostacyclin in severe pre-eclampsia, Prostaglandins 20:105, 1980. O'Brien, P.M. S., Filshie, G. M., and Broughton Pipkin, F.: The effect of prostaglandin E2 on the cardiovascular
19K~
J. Obstet. Gvneml
9.
10.
II.
12.
13.
14.
15.
16.
response to angiotensin II in pregnant rabbits. Prostaglandins 13:171, 1977. O'Brien, P.M. S., and Broughton Pipkin, F.: The effects of deprivation of prostaglandin precursors on vascular sensitivity to angiotensin II and on the kidney in the pregnant rabbit, Br. J. Pharmacal. 65:29, 1979. Gant, l\. F.. Chand, S.. Whalley, P.J., and MacDonald, P. C.: The nature of pressor responsiveness to angiotensin li in human pregnancy, Obstet. Gynecol. 43:854, 1974. Messina, E. J., Weiner, R., and Kaley, G.: Prostaglandins and local circulatory control, Fed. Proc. 35:2367, 1976. DeBono, E.. Lee, G. de J., Mottram. F. R., Pickering, G. W., Brown,J.J., Keen, H., Peart, W. S., and Sanderson, P. H.: The action of angiotensin in man, Clin. Sci. 25:123. 1963. Terragno. N. A .. Terragno, D. A., Pacholczyk, D., and McGiff, J. C.: Prostaglandins and the regulation of uterine blood How in pregnancy, Nature (Lond.) 249:57. 1974. Speroff, L., Haning, R. V., and Levin, R. M.: The effect of angiotensin II and indomethacin on uterine artery blood How in pregnant monkeys, Obstet. Gynecol. 50: 611, 1977. Everett, R. B., Worley, R.J., MacDonald, P. C., and Gam, l\. F.: Effect of prostaglandin synthetase inhibitors on pressor response to angiotensin II in human pregnancy . .J. Clin. Endocrinol. Metab. 46:1007, 1978. Speroff, L.: An essay: prostaglandins and toxaemia of pregnancy, Prostaglandins 3:721, 197~.