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Department of Medicine, University of Toronto, Toronto, Canada M5S 1A1
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We examined the effect of oral contraceptive (OC) usage on the renin angiotensin system (RAS) in two related experiments. In the first experiment, subjects were 34 healthy, normotensive, premenopausal women, 15 OC users and 19 OC nonusers, mean age 25 ± 1 yr, ingesting a controlled sodium diet. We assessed arterial pressure, glomerular filtration rate, effective renal plasma flow, renal vascular resistance (RVR), and filtration fraction (FF) using inulin and p-aminohippurate clearance techniques, both at baseline and in response to the ANG II receptor blocker losartan. In the second experiment, in similar subjects, 10 OC users and 10 nonusers, we examined circulating RAS components [angiotensinogen, ANG II, aldosterone, plasma renin activity (PRA), and active renin] in response to incremental lower body negative pressure (LBNP), to determine whether renin secretion is suppressed by OC usage. OC users exhibited elevations in systolic blood pressure, RVR, and FF compared with nonusers, which were partially corrected by losartan. In the LBNP phase of the study, baseline measures of PRA, angiotensinogen, ANG II, and aldosterone were all increased in the OC group compared with the control group. Active renin levels did not differ between groups. Incremental LBNP resulted in increased circulating levels of RAS components in both groups. We conclude that the RAS is activated in women using OCs. There was no evidence that decreases in renin secretion result in normalization of the RAS as a whole.
angiotensin II; losartan; arterial blood pressure; filtration fraction; lower body negative pressure
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ORAL CONTRACEPTIVE (OC) medications have been in widespread use for more than thirty years. Synthetic estrogens contained in OCs have well-documented effects on the renin angiotensin system (RAS) (4). A promoter region in the angiotensinogen gene is responsive to estrogen (7), and exogenous estrogen administration raises plasma, hepatic, and renal concentrations of angiotensinogen and thus has the potential to elevate plasma concentrations of ANG II, the effector substance of the RAS. The ingestion of ethinyl estradiol (15 µg/day) as part of a combined OC leads to an increase in plasma angiotensinogen, which is only slightly less than that seen during pregnancy (19). Studies of the impact of exogenous estrogen on the circulating RAS have suggested both activation (5, 24) and suppression (23). The few studies examining the renal hemodynamic consequences of OCs have provided contradictory information. An early study by Hollenberg and colleagues (9) found a significant reduction in effective renal plasma flow (ERPF) in OC users and a negative correlation between plasma ANG II and ERPF. A more recent study by Ribstein and colleagues (21) was unable to implicate activation of the RAS in women with OC-induced hypertension. It has been suggested that the low incidence of RAS-mediated hypertension in OC users (10, 30) can be explained by a counterregulatory blunting of renin secretion (20).
Our objectives for this set of experiments were therefore twofold. First, although it is well known that synthetic estrogens increase plasma angiotensinogen, their effect on the activity of the RAS as a whole is more controversial. We therefore examined renal and peripheral hemodynamic function, both at baseline and in response to the ANG II blocker losartan, in two groups of young healthy normotensive women. The first group of women served as a control group. The second group consisted of women who were OC users. We hypothesized that activation of the RAS would be reflected by the renal and systemic hemodynamic responses to ANG II receptor blockade in the OC group compared with the control group. Our second objective was to test the hypothesis that OC usage blunts renin secretion. Women from each of the control and the OC groups were subjected to incremental lower body negative pressure (LBNP) to activate the RAS (8, 18).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study 1 protocol.
Thirty-four healthy premenopausal women were recruited to participate
in this study, 15 OC users and 19 OC nonusers, mean age 25 ± 1 yr. All were normotensive, nonobese, nonsmokers, and on no medications
except for the birth-control pill. The OC users had been on treatment
for at least three cycles before the study. Pregnancy was ruled out in
nonusers by a negative 
-human chorionic gonadotropin test prior to
enrollment. The study was performed with the approval of the
University of Toronto Human Subjects Review Committee and with the
informed written consent of each subject.
1 · day1) for 7 days
prior to the study. Compliance was assessed by measurement of 24-h
urine sodium and urea excretion 1 day before the study. Subjects were
considered properly prepared for the study if the excretion of sodium
was 1.5-2 mmol · kg1 · 24 h1. No subjects were excluded on this basis. All OC
nonusers were studied in the follicular phase of the menstrual cycle.
All OC users were studied between days 7 and 21 of their cycle, a period in which they were ingesting 30 µg ethinyl
estradiol. No other effort was made to control OC compound. On the day
of testing, subjects reported to the Renal Physiology Laboratory of the
Toronto General Hospital. All studies were conducted at 0830, after an overnight fast, with the subjects lying supine in a warm quiet room.
An 18-gauge peripheral venous cannula was inserted into an antecubital
vein for infusions of inulin and p-aminohippurate (PAH), and
another cannula was placed in the opposite arm for blood sampling. Each
subject voided and then drank sufficient water in the first 45 min to
induce a water diuresis. Approximately 200 ml were ingested in each
hour of the protocol to maintain an adequate urine output for
collection of spontaneously voided samples. Baseline blood samples were
collected for inulin blank and hematocrit (Hct) and urine for inulin
blank. Hemodynamic parameters [mean arterial pressure (MAP), heart
rate] were measured throughout the study by an automated
sphygmomanometer (Dinamapp) and were recorded in each one-half hour of
the protocol. Renal hemodynamics were measured using inulin and PAH
clearance techniques as described previously (13, 15).
Briefly, three timed urine collections of 20-min duration each were
obtained for determination of baseline glomerular filtration rate (GFR)
and ERPF. At the end of this period, losartan (Cozaar, Merck, Sharpe,
and Dohne) was administered at a subdepressor dose of 25 mg (14,
16). During each hour, for 3 h, blood was collected for
inulin, PAH, and Hct, and urine was collected for inulin, PAH, and
urine sodium excretion.
Study 2 protocol.
Twenty subjects (10 OC users and 10 OC nonusers) participated in the
second study. Their demographic data were similar to those in the first
study. After a similar preparatory phase, they presented to the Renal
Physiology Laboratory. After the insertion of an 18-gauge catheter into
an antecubital vein for blood sampling, each subject was positioned in
the LBNP chamber that encased the body below the waist. The chamber was
sealed at the iliac crest and connected to a vacuum source controlled
by rheostat. Incremental LBNP was then used to activate the RAS by
unloading arterial baroreceptors (8, 18). Blood was
sampled at baseline for plasma norepinephrine, angiotensinogen, ANG II,
plasma renin concentration (PRC), plasma renin activity (PRA), and
aldosterone. LBNP at 
15 mmHg was then applied for 15 min. This level
of negative pressure normally results in unloading of cardiopulmonary
baroreceptors without changes in heart rate or arterial pressure. At
the end of this period, blood was sampled for the above parameters.
LBNP at 25 was then applied for 15 min. This level of negative
pressure results in arterial baroreceptor unloading and RAS activation.
At the end of this period, blood was again sampled. LBNP at 40 mmHg
was then applied for 15 min, resulting in further RAS activation. Blood
was again sampled at the end of this period and at the end of a
subsequent 15-min recovery period.
Sample collection and analytic methods.
Blood samples collected for inulin and PAH determinations were
immediately centrifuged at 300 rpm for 10 min at 4°C. Plasma was
separated, placed on ice, and then stored at 70°C before the assay.
Inulin concentrations in plasma and urine were measured by a modified
method of Walser et al. (29) and PAH concentration by a
spectrophotometric method according to Brun (1). The mean of the final two clearance periods represent GFR and ERPF, expressed per 1.73 m2. Filtration fraction (FF) represented the ratio
of GFR to ERPF. Renal blood flow (RBF) was calculated by dividing the
ERPF by (1 Hct). Renal vascular resistance (RVR) was derived by
dividing MAP by the RBF. Urine sodium concentration was measured by a
flame photometry method.
70°C until analysis. On the day of analysis
plasma samples were extracted on phenylsilysilica columns. A
competitive radioimmunoassay kit supplied by Buhlmann Laboratories was
used to measure the extracted ANG II. Aldosterone was measured by
radioimmunoassay, using the Coat-A-Count system. Angiotensinogen was
measured indirectly by converting endogenous angiotensinogen to ANG I
and then quantitating the amount of ANG I by radioimmunoassay.
Conversion was done by incubating the plasma with an excess amount of
exogenous renin at 37°C for 18 h. After measuring the produced
ANG I, the endogenous ANG I obtained prior to incubation was subtracted
(28). Active plasma renin was measured by two-site
immunoradiometric assay where two monoclonal antibodies to human active
renin are used. One antibody was coupled to biotin, whereas the second
was radiolabeled for detection. The sample containing active renin was
incubated simultaneously with both antibodies to form a complex. The
radioactivity of this complex was directly proportional to the amount
of immunoreactive renin present in the sample (25).
Statistical analysis. Results are presented as means ± SE. Between group baseline differences were determined using nonparametric methods (Wilcoxin rank sums). Within-subject and between-group differences in the responses to losartan and to incremental LBNP were determined by repeated measures ANOVA and Bonferroni correction. All statistical analyses were performed using the statistical package SAS (SAS Institute, Cary, NC).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Baseline characteristics.
The baseline characteristics of the two groups are shown in Table
1. There were no significant
differences in age, body mass index, or 24-h urea excretion and
calculated protein intake. Systolic blood pressure (SBP) was
significantly higher in the OC user group, as was 24-h urine sodium
excretion, corrected for body weight. Hct was significantly higher in
the control group.
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Renal and systemic hemodynamic responses to losartan.
The responses of MAP, SBP, diastolic blood pressure, GFR, ERPF, RBF,
and RVR to losartan in the two groups are shown in Table 2. The OC users exhibited values for SBP,
MAP, FF, and RVR that were significantly higher than those obtained in
nonusers. The OC users demonstrated a significant decline in SBP, FF,
and RVR in response to losartan (Fig. 1),
whereas nonusers remained at baseline. GFR and urinary sodium excretion
did not differ between groups at baseline or in response to losartan.
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RAS responses to incremental LBNP.
The responses of plasma norepinephrine, ANG II, PRC, PRA,
angiotensinogen and aldosterone in the two groups are shown in Table 3. As can be seen ANG II, PRA,
angiotensinogen, and aldosterone were significantly increased at
baseline in the OC group. PRC was not significantly different between
groups. Incremental LBNP resulted in increases in most RAS components,
which were not significantly different between groups (Fig.
2).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In this report we studied renal and peripheral hemodynamic function, both at baseline and in response to the ANG II blocker losartan, in healthy normotensive women who were users of OC medications. In addition, we examined the responses of RAS components to incremental LBNP, a known stimulus to RAS activation (8, 18). Our rationale was that OC users are known to have increases in plasma angiotensinogen levels, but the activity of the RAS as a whole in OC users is poorly understood. Our key findings were 1) renal and peripheral hemodynamic differences were discernible between groups at baseline, with OC users displaying minor but significant increases in SBP, RVR, and FF; 2) these differences were at least partially abolished by ANG II blockade; 3) plasma levels of RAS components were significantly elevated in OC users, and PRC was not suppressed; and 4) the response of RAS components to LBNP was not different between groups.
Numerous investigators have used animal models to investigate the relationship between hormonal contraceptives and the RAS. Fowler and colleagues (6) demonstrated markedly elevated angiotensinogen values in female Sprague-Dawley rats treated with mestranol (a synthetic estrogen). Blood pressure in this group of rats was also significantly elevated compared with control rats and unresponsive to ANG II blockade. Byrne et al. (2) made female Sprague-Dawley rats hypertensive with ethinyl estradiol and found an increase in all parameters of the RAS, but, in contrast to Fowler et al. (6), there was a significant antihypertensive effect of enalapril. Similar contradictory results have been described in human studies. Oelkers (20) found that usage of combined OCs resulted in a dramatic increase in angiotensinogen but only marginally increased PRA and ANG II. He postulated a "short loop feedback inhibition" of renin secretion by the slightly raised ANG II level and thus potentially a blunting of the activity of the RAS. Ribstein et al. (21) examined components of the RAS in women with OC-associated hypertension and compared them to women with essential hypertension. Captopril-induced changes in blood pressure were similar in both groups, suggesting no clear role for activation of the RAS in OC-induced hypertension.
In our study, it was evident that SBP was significantly elevated in OC users, although levels remained well within the normal range. RVR was also higher in OC users and in conjunction with the significantly augmented FF, indicates that most of the renal effect of OC usage appears to be at the efferent arteriole, which would normally result in an increased intraglomerular pressure with its attendant deleterious effects. We interpret the fact that a subdepressor dose of losartan resulted in a significant reduction in blood pressure, along with significant decreases in FF and RVR in OC users, to support the hypothesis that OC use activates the RAS and impacts on renal and systemic hemodynamic function. A few other studies exist that have examined the renal impact of OC usage. In an early study, Hollenberg and colleagues (9) reported a significant activation of the RAS in healthy young women using OCs, with a negative correlation between the increased ANG II levels and reduced RBF. In the previously cited study by Ribstein and colleagues (21), it was reported that normotensive OC users had significantly elevated SBP, RVR, PRA, and albuminuria when compared with nonusers.
In the second experiment, we demonstrated significantly higher plasma concentrations of ANG II, PRA, angiotensinogen, and aldosterone in OC users. As mentioned previously it has been proposed that changes in angiotensinogen are usually accompanied by reductions in renin secretion because of a negative feedback loop (3, 13, 20) and that plasma concentrations of ANG II are usually normal (5). Our observations suggest that this feedback loop was not operative in our subjects, in that PRC was similar in both groups, despite large differences in angiotensinogen, and ANG II and PRA levels were markedly elevated. Moreover, incremental LBNP resulted in similar increases in RAS components in both groups, indicating that renin synthesis and secretion are not blunted in OC users. Significant differences between groups in the response to LBNP were detected in the cases of PRA and aldosterone, with the OC users actually displaying augmented release. These observations call into question the theory that the direct hemodynamic effects of high angiotensinogen levels are mitigated by a decrease in renin release.
Potential confounding variables that might have impacted on RAS
function included differences in sodium and protein intake among the
groups. To ensure against this each subject in the prestudy phase of
each experiment was counseled to adhere to a controlled sodium and
protein diet and compliance was verified by 24-h urine collections
(16, 17). In the losartan phase of the study, although
both users and nonusers were considered sodium replete with values 
2
mmol/kg sodium excretion, OC users exhibited significantly augmented
excretion rates compared with nonusers. This may reflect an enhanced
extracellular fluid (ECF) volume or a "pressure natriuresis" that
serves as a negative feedback on the sodium retention stimulated by
high ANG II levels. In addition, the progestin component of the OC is
known to antagonize the action of aldosterone on the distal tubule of
the kidney and thus increase sodium excretion (12).
However, it is unlikely that this disparity in sodium excretion between
groups affected our results, as ECF volume expansion should suppress
rather than activate the RAS, and despite this, the OC users displayed
elevated values for circulating RAS components. This finding confirms
that ECF volume contraction was not the cause for RAS activation in the
OC users. It is known that protein intake can affect renal hemodynamic
function and PRA in humans (21, 26). However, all subjects
in the current study consumed similar protein content diets and 24-h
urea excretion and calculated protein intake was not different in the
two groups. Therefore, a difference in protein intake can be excluded
as a confounding variable. Another possible limitation is that we
failed to control for the progesterone component in the OC preparations
ingested by our subjects. Therefore, it is impossible to determine
whether observed effects were due to the estrogen or progesterone
component. Observations made on either component separately, however,
may be inappropriate because they can act synergistically and
antagonistically (29)
These findings might cause one to speculate on what factors are
protecting OC users from the well-known deleterious effects of ANG II
on the initiation of hypertension and progressive renal and cardiac
disease. Most women experience small elevations in blood pressure
(1-3 mmHg diastolic and 5 mmHg systolic) while taking OCs
(30), but significant hypertension develops in only a
small fraction of patients and appears to be related to duration of use
and is usually reversible with discontinuation (10). Although the current study demonstrated some hemodynamic impact, which
could be attributed to RAS activation, the effects were minor given the
extreme elevation in ANG II. We have shown that the operative
protective feature does not appear to be a decrease in renin release.
The possibility exists that high synthetic estrogen levels are
modifying the ANG II response in some way. In a recent study by
Krishnamurthi and colleagues (11), -estradiol
replacement in ovariectomized rats significantly decreased ANG type 1 receptor expression in the adrenal and the pituitary via modulation of the of the 5' leader sequence of the receptor mRNA. In a study from
this laboratory (16) we demonstrated that the renal
hemodynamic response to graded ANG II infusion is correlated with
estrogen plasma concentrations, with higher levels predicting a blunted ERPF response. A similar mechanism may also account for the observed responses in the present set of experiments.
In summary, this series of experiments suggests that sodium-replete users of OC compounds exhibit hormonal and hemodynamic evidence of activation of the RAS but only trivial changes in renal and peripheral hemodynamic function considering the extreme elevation in circulating RAS components.
Perspectives
This work has broad public health implications. Activation of the RAS by OCs should be concerning for women with preexisting renal or cardiac disease and/or hypertension. The deleterious hemodynamic and mitogenic effects of ANG II are well known. The fact that a group of normal healthy women using OCs displayed increased arterial pressure and FF suggests that OC users with preexisting renal disease may exhibit a physiological profile that may be considered condusive to the development of progressive renal failure. However, looked at in another way, our data demonstrate that at least in the case of the hemodynamic response the observed changes are minor, suggesting that there is a factor protecting normal, healthy women from the adverse impact of elevated plasma ANG II. Any modulating of the mitogenic properties of ANG II cannot be discerned from our present data, but it is possible that protection may also exist in this aspect of the ANG II response. It is tempting to speculate that estrogen itself underlies this protective mechanism. Whether this is by modulation of the ANG II type 1 receptor by synthetic estrogens, by a postreceptor effect, or by activation of a counterregulatory system such as the nitric oxide pathway is not known. The elucidation of the physiological mechanisms whereby OC users are protected from the deleterious effects of ANG II deserves further study. Indeed, these findings may have therapeutic implications in that they may translate into rational treatments for hypertension and for the prevention of progressive microvascular and macrovascular diseases.| |
ACKNOWLEDGEMENTS |
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This work was supported by an operating grant from the Heart and Stroke Foundation of Canada to Drs. J. A. Miller, D. C. Cattran, and J. S. Floras. J. S. Floras holds a Career Investigator Award from the Heart and Stroke Foundation of Ontario.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. A. Miller, Toronto General Hospital, 11EN-221, 200 Elizabeth St., Toronto, Ontario, Canada M5G 2C4 (E-mail: judith.miller{at}utoronto.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 28 July 2000; accepted in final form 30 October 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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)
and in nonusers of OC (
). *P < 0.05 vs. OC nonusers baseline values. **P < 0.05 vs
baseline.