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Original Studies |
Institute of Clinical Pharmacology, University Hospital of Mannheim, Faculty for Clinical Medicine Mannheim, University of Heidelberg, 68167 Mannheim, Germany
Address all correspondence and requests for reprints to: Martin Wehling, M.D., Institute of Clinical Pharmacology, Faculty of Clinical Medicine, Ruprecht Karls University of Heidelberg, Theodor Kutzer Ufer 1–3, 68167 Mannheim, Germany. E-mail: martin.wehling{at}upha.ma.uni-heidelberg.de
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Abstract |
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We conducted a randomized, double blind, 8-fold cross-over trial on 18
healthy male volunteers. After pretreatment with the ß-blocking agent
esmolol, the ß-agonist dobutamine, the 
1-agonist
phenylephrine, or placebo, placebo (0.9% NaCl) or aldosterone (0.5 mg)
was injected. After aldosterone injection the peak plasma levels were
supraphysiological, reaching nanomolar concentrations. Primary target
variables were differences in changes in mean arterial blood pressure,
systemic vascular resistance, and cardiac output depending on the
pretreatment. Cardiovascular parameters were measured by impedance
cardiography during the maintained infusion of the adrenergic
modulators for 45 min.
Comparing pretreatments, diverse acute, and thus nongenomic, effects of aldosterone on mean arterial blood pressure were observed. After esmolol pretreatment, aldosterone caused an increase in mean arterial blood pressure by 4.1%, whereas after dobutamine pretreatment mean arterial blood pressure decreased by 1.6%, and the difference was statistically significant (P < 0.01). These effects were significant (P < 0.005) for the first 12 min, underlining their nongenomic nature. Our data support the hypothesis that aldosterone, via nongenomic mechanisms, has diverse effects on the cardiovascular system that depend on the preexisting adrenergic state. Furthermore, aldosterone blunts the blood pressure-lowering effect of the ß-blocking agent esmolol by a nongenomic mechanism.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Over the last 10 yr, however, convincing evidence of direct nongenomic vascular effects of aldosterone has been provided. These nongenomic effects cause a rise in systemic vascular resistance (9, 10) and thus might have a pathophysiological role in human hypertension and cardiac failure.
Rapid nongenomic aldosterone effects are characterized by their rapid onset of action (within minutes), their insensitivity to inhibitors of transcription (e.g. actinomycin D) and protein synthesis (e.g. cycloheximide), and their insensitivity to antagonists of the classical mineralocorticoid receptor (e.g. spironolactone) (for review, see Ref. 11).
Nongenomic aldosterone effects have been extensively characterized in vitro. After binding to a putative membrane receptor (12), a second messenger cascade involving inositol 1,4,5-triphosphate (13), diacylglycerol, and protein kinase (14) is activated. In vascular smooth muscle cells and porcine aortic endothelial cells a rapid increase in intracellular Ca2+ has been demonstrated (15, 16). Recently, we showed an increase in intracellular cAMP levels within 1 min in porcine coronary vascular smooth muscle cells, leading to an increased phosphorylation of CREB (cAMP-response element binding protein); furthermore, synergistic effects of aldosterone and isoproterenol on CREB phosphorylation could be demonstrated (17). These data support the concept of a cross-talk of adrenergic signaling and steroid action at the molecular level through cAMP.
In addition to these in vitro data, nongenomic aldosterone effects have been shown in humans in vivo. Klein and Henk (18) demonstrated an increase in systemic vascular resistance 5 min after the injection of 0.5 mg aldosterone in humans. Recent studies using modern invasive (9) and noninvasive (10) methods have confirmed the latter data. In addition to the early vasoconstrictor effect of aldosterone, a pronounced postprandial vasodilation could be demonstrated after the administration of this steroid (10), suggesting that the preexisting sympatho-vagal balance might influence the direction and intensity of nongenomic aldosterone effects. The concept of an interaction between the adrenergic system and RAAS has also been supported by the fact that aldosterone blunts human baroreceptor sensitivity (19), an effect that is also of nongenomic origin (Schmidt et al., submitted for publication).
In this study we address this issue by simulating different
autonomic states by infusion of the ß-agonist dobutamine, the
ß-blocking agent esmolol, and the 1agonist
phenylephrine before the injection of aldosterone. These infusions were
intended to cause a shift in systemic vascular resistance reflecting
30% of the maximal effect of the particular drug (20, 21). By measurement of the cardiovascular parameters, mean
arterial pressure (MAP), systemic vascular resistance (SVR) and cardiac
output (CO), the influence of the adrenergic state on aldosterone
effects was tested. Inversely, the effect of aldosterone infusion on
the action of the above-mentioned drugs could be observed. The
noninvasive method of impedance cardiography (ICG) was used to measure
cardiovascular parameters, and heart rate variability was determined
from digital electrocardiography (ECG) recording for assessment of
adrenergic activation.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Eighteen healthy male volunteers were enrolled in the study. All volunteers were subjected to a medical examination in the 2 weeks leading up to the study. The examination consisted of medical history, physical examination, 12-lead ECG, and determination of clinical laboratory parameters. All subjects gave their written informed consent to participation in the study.
Study procedures
The study was designed as a randomized, placebo-controlled, 8-fold cross-over trial, blinded with respect to the adrenergic modulators for the subjects and double blinded with respect to the aldosterone/placebo treatment. It was conducted in accordance with the guidelines for good clinical practice and the Declaration of Helsinki after approval by the institutional review board of the Faculty for Clinical Medicine Mannheim, University of Heidelberg (Mannheim, Germany). All 18 enrolled volunteers were randomly assigned to 8 test periods, with a minimum wash-out interval of 48 h.
Study design
Volunteers were hospitalized at 0730 h on each study day. After an overnight fast they received a light standardized breakfast containing 6 mmol potassium and 33 mmol sodium. Directly thereafter, subjects emptied their bladders, and a 3.5-h urine collection period commenced. Then, three indwelling catheters were inserted into forearm veins. One catheter was used for the continuous infusion of dobutamine, esmolol, phenylephrine, or placebo; one for aldosterone or placebo injection; and one for blood sampling. Adhesive electrodes for ICG and digital ECG were applied. During the entire test procedure volunteers remained in a supine position.
After a 30-min rest period, baseline data from ICG and digital
ECG were obtained over 12 min (Fig. 1
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Baseline values were calculated from the mean of four consecutive
measurements performed at 3-min intervals. These results will be
referred to as baseline 1. Then continuous infusion of the adrenergic
modulator was started. For titration of the effects, target changes
from baseline 1 were defined (Table 2). The initial doses were 7.5
µg/kg BW·min for dobutamine, 0.1 mg/kg BW·min after a bolus
injection of 0.2 mg/kg BW for esmolol, and 0.4 µg/kg BW·min for
phenylephrine. After 10 min, cardiovascular parameters were reassessed,
and the changes in SVR were considered. If the target change in SVR
(Table 2) had not been reached, the dose of the continuous infusion was
increased or decreased by 2.5 µg/kg BW·min for dobutamine, 0.035
mg/kg BW·min for esmolol, and 0.2 µg/kg BW·min for phenylephrine,
and the procedure was repeated without delay. After SVR was determined
to be within the target range, the dose was kept constant for another
10 min to insure steady state conditions. If the target range had not
been reached after three dose adjustments, study procedures were
continued without reaching the SVR target range, and baseline data for
impedance cardiography and digital ECG were obtained over 12 min.
Baseline values were calculated from the mean of four consecutive
measurements performed at 3-min intervals. These results will be
referred to as baseline 2. Then aldosterone (0.5 mg) or placebo was
injected over 1 min, and cardiovascular parameters were measured for 45
min (Fig. 1). Blood pressure and heart rate were measured at 3, 6, 9,
12, 15, 20, 25, 30, 35, 40, and 45 min (Omnicare CS24,
Hewlett-Packard Co., Boblingen, Germany), with the same
for ICG parameters and heart rate variability (HRV). At baseline 1 and
3 min after injection of aldosterone, blood samples for plasma
aldosterone determination were collected and immediately put on ice.
After the measurement period the subjects were under continuous
observation with ECG and blood pressure monitoring for 30 min.
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Time domain parameters of HRV, i.e. pNN50 (percentage of differences between adjacent normal RR intervals longer than 50 ms) and rMSSD (square root of the mean of squared differences between adjacent normal RR intervals), were calculated at 1-min intervals. Power spectral density for the low frequency and high frequency bands of heart rate variability was calculated by fast Fourier transformation in intervals of 256-s duration (23).
Esmolol and dobutamine are commercially available drugs [brand names Brevibloc (Baxter Deutschland GmbH, Unterschleissheim, Germany) and Dobutamin Fresenius (Fresenius AG, Bad Homburg, Germany)]. Phenylephrine was Neo-Synephrine (Sanofi-Winthrop Pharmaceuticals, Inc., Bruxelles, Belgium). Placebo was isotonic (0.9%) NaCl solution. For the sake of consistency these drugs will be referred to as pretreatment, although they were applied starting after baseline 1 until the end of the study procedure.
Aldosterone for human administration was prepared according to the original recipe of the formerly registered drug Aldocorten (Ciba-Geigy, Basel, Switzerland), which became clinically unavailable only recently. The chemical compound of medicinal purity (>98%) was supplied by Farmabios (Gropello Cairoli, Italy). The study drugs were prepared by the pharmacy of the University Hospital Munich Innenstadt. Placebo was isotonic (0.9%) NaCl solution. Aldosterone/placebo will be referred to as treatment.
Aldosterone levels in plasma were measured by a commercial magnetic affinity immunoassay (Biodata, Rome, Italy). The limit of detection of this assay is 6 pg/mL. Interassay variance is 4.1%, and intraassay variance was 3.5%.
Statistical methods
Statistical analysis used SAS software version 6.12 (SAS Institute, Inc., Cary, NC). There were no drop outs, thus allowing evaluation to be made on the complete set of volunteers, and there was no need to distinguish between intention to treat and per protocol populations. All individual data of ICG, HRV, and safety measures were analyzed descriptively by computation of means, SEMs, and confidence intervals. In the tables, the mean and SEM are shown. For statistical inference the percent change from baseline 2 was calculated for each variable and each measurement time point. Based on these percentage changes the area under the curve (AUC) over all time points (i.e. 45 min) was calculated. The corresponding AUCs for the variables MAP, SVR, and CO were the primary target variables.
The primary goal was to test for differences between effects of the pretreatments (dobutamine, esmolol, phenylephrine, and placebo) on aldosterone action. For that purpose intraindividual differences between the AUCs corresponding to aldosterone and placebo were analyzed by multifactorial ANOVA, followed by Scheffe’s test. The method of multifactorial ANOVA takes into account the multiple measurements in the cross-over design. To adjust for the number of three target variables, the level of significance was set at 0.016 (0.05/3) for primary analysis and 0.05 for subsidiary post-hoc analysis. As a secondary target, the AUCs of intraindividual differences were used to assess aldosterone effects for each pretreatment. This was done using a special t test appropriate for cross-over designs. The SEs given in the figures were estimated as pooled SE, based on the sampling error adjusted for the above model.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Important clinical characteristics and demographic features are
shown in Table 1.
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Table 2
shows the primary
cardiovascular parameters SVR, MAP, and CO before administration of
dobutamine, esmolol, and phenylephrine (baseline 1) and after titration
as described above (baseline 2). All values are means of four
measurements performed during the 12-min baseline periods. The shift in
SVR between baseline 1 and baseline 2 was in the intended range.
Furthermore, dobutamine and phenylephrine increased MAP by 13.5% and
6.0%, respectively, whereas esmolol caused a slight decrease in MAP of
4.2%. CO was increased only by dobutamine.
Changes in the parameters of heart rate variability reflect the
intended modulation of the sympatho-vagal balance. After dobutamine
pretreatment measures of vagal tone as pNN50, rMSSD, and the power in
the high frequency band (HF) decreased, whereas they increased
slightly, apart from HFs, after esmolol treatment. After phenylephrine
pretreatment a vagal reaction was observed (Table 3).
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Mean arterial pressure. Figure 2 shows the percent differences between
aldosterone and placebo effects for the different pretreatments.
Whereas aldosterone does not influence MAP after placebo pretreatment,
it causes an approximately 4.1% higher MAP compared with placebo after
esmolol pretreatment (P = 0.0049, by t test
for the cross-over design). During dobutamine (mean change, -1.6%)
and phenylephrine (0%), MAP is not altered by aldosterone compared
with placebo.
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) and for esmolol compared with
dobutamine (P < 0.05, by Scheffe’s test) and
phenylephrine (P < 0.05, by Scheffe’s test) during
the first 12 min after aldosterone injection (Fig. 4). In this very early time frame after
aldosterone/placebo injection a slight decrease in MAP was seen with
phenylephrine (mean change, -1.1%), which was not evident for the
entire 45-min period.
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Changes in the parameters CO and SVR are shown in Figs. 5 and 6. On
the one hand, CO decreased after aldosterone injection with dobutamine
(mean change, -3.2%) and remained stable with esmolol (+0.3%)
pretreatment. On the other hand, SVR showed a stronger tendency to
increase with esmolol pretreatment (+4.0%) than with dobutamine
(+1.0%) pretreatment (Fig. 7A). These
changes did not reach statistical significance, but they were the base
of the significant changes in MAP described above. Further analysis
(Fig. 7B) showed that the CO-lowering effect was mainly due to a 3.8%
decrease in HR.
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Aldosterone induced no significant change in any parameter of HRV.
Urine tests
Results of laboratory urine tests of sodium, potassium,
creatinine, and urea are shown in Table 4. Concerning these data, no
statistically significant differences between treatment periods were
found.
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Plasma aldosterone levels very slightly increased during
titration, but changes were not statistically significant. No
differences in aldosterone levels occurred 3 min after injection across
pretreatments. Plasma concentrations 3 min after injection were
comparable to previously published values (10) (Table 5).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The concept of the study was to pharmacologically induce different
basal activation levels of the autonomic nervous, especially the
adrenergic system. For this purpose esmolol and dobutamine were used as
modulators of the ß-adrenergic system and phenylephrine as a pure
1-agonist. The main reason for choosing these
drugs was their short elimination half-life, providing an excellent
opportunity to titrate their effects. For the same reason dobutamine
was preferred over orciprenaline, which would have been advantageous
because of its ß2 selectivity, but has a
half-life of approximately 90 min. Furthermore, esmolol and dobutamine
are almost ideal counterparts, as they have comparable receptor
selectivity plus the negligible 2-antagonistic
effects of dobutamine. As reflected by the measures of HRV listed in
Table 3, esmolol and dobutamine showed the intended shift in
sympathetic activation. However, phenylephrine caused an obvious
counterregulatory vagal activation, and thus the data obtained from the
phenylephrine periods are difficult to interpret.
The plasma aldosterone concentrations reached after iv application of
0.5 mg aldosterone are supraphysiological, but are still far lower than
concentrations expected to induce nonspecific membrane effects (
10
µmol/L) (11). Furthermore, there is evidence for the
local production of aldosterone in the rat heart, and local aldosterone
levels were estimated to be approximately 20-fold higher in heart
tissue in rats than in plasma (26). In addition, in rats
there is evidence for aldosterone synthesis in blood vessels
(27). Thus, tissue levels rather than plasma aldosterone
levels might be important to assess cardiovascular aldosterone actions.
Therefore, the high plasma levels following the aldosterone bolus
injection might be necessary to reach adequate physiological tissue
levels to produce the effects shown here.
Indeed, the data provided here show modulation of rapid nongenomic aldosterone effects on SVR, CO, and blood pressure by the adrenergic system; opposite effects occur after and during ß-agonist activity compared with ß-antagonist administration. During the ß-antagonist phase, aldosterone increases MAP, and during ß-agonist activation aldosterone decreases MAP. Notably, these effects were detected within 12 min, a time frame that allows only nongenomic effects to occur.
Although the results of the changes in CO and SVR are not
statistically significant, they seem to be useful in explaining the
significant effect observed for MAP. The analysis of these data shows
that an aldosterone-induced increase in SVR during ß-antagonist
administration and a fall in CO during ß-agonist activation underlie
these effects on MAP. In both cases the rapid nongenomic aldosterone
effect antagonizes the underlying effect shown in Table 2. In the case
of esmolol, the effect on blood pressure is almost completely
reversed.
It has been shown in vitro that aldosterone increases intracellular calcium in vascular smooth muscle cells (VSMC) by rapid nongenomic effects (16). An increase in intracellular calcium in VSMC leads to vasoconstriction and as a consequence to an increase in SVR. This effect has also been detected in vivo (9, 10).
ß2-Agonist activation in VSMC as in this study induced by dobutamine leads to an increase in cAMP via G protein-coupled activation of adenylate cyclase. This causes a decrease in intracellular calcium and consequent vasodilation. The opposite is true after blocking the ß2-receptor, e.g. with esmolol, as documented in our study by the increase in SVR during initial titration. Aldosterone given in addition to these interventions increases SVR more markedly after ß2-blockade than after ß2-agonist activation. This indicates an additive effect of aldosterone in terms of vasoconstriction and gives part of the explanation for the differential aldosterone effect on MAP after pretreatment with dobutamine and esmolol. Another part of the explanation may lie in the effect of aldosterone on CO. After ß-agonist activation, aldosterone lowers CO and has almost no effect during ß-blockade. To differentiate chronotropic from inotropic effects as possibly responsible, a post-hoc analysis of the parameters HR and SV as determinants of CO was performed. As mentioned above in the case of SVR and CO, these effects were also not statistically significant, but may be useful to explain the observations and to form new hypotheses for future research.
The urine data show no difference in the excretion of sodium, potassium, creatinine, and urea among the different treatment periods. This is in line with the results of a former study of nongenomic aldosterone effects that also showed no aldosterone effect on urinary sodium and potassium excretion after a single injection of 0.05 or 0.5 mg aldosterone during a collection period of 8 h (10).
To date, instant nongenomic effects of aldosterone on in vivo electrolyte homeostasis have not been described, although they potentially exist. Given that the electrolyte balance remained unaffected by aldosterone, it is unlikely that the observed effect on MAP and SVR are related to net shifts in sodium and potassium. However, transient electrolyte movements between intra- and extracellular compartments cannot be excluded. The fact that no differences in sodium and potassium excretion occurred renders it unlikely that dobutamine or esmolol caused a relevant shift in sodium or potassium balance in this study.
The data from healthy volunteers presented here may be of clinical importance, but their significance in a clinical context should not be overstated. Clearly, cardiogenic shock and hypertension are pathophysiologically extremely complex. Any experimental setting, including the one presented, can only inadequately mimic the complexity of these conditions. Nevertheless, the data presented suggest that in both situations high aldosterone levels could potentially be harmful to the patient. Aldosterone may antagonize the intended effects of ß-agonists (i.e. increasing CO in cardiogenic shock) and ß-antagonists (i.e. lowering blood pressure in hypertension). Notably, these effects are rapid and thus nongenomic and would not be expected to be blocked by spironolactone. However, in a recent finding, RU28318, a weak competitor of the classical mineralocorticoid receptor, has been shown to block the rapid effects of aldosterone (28). This compound is characterized by an open E ring, a structural component that is shared by the in vivo metabolite of spironolactone. Therefore, spironolactone may be able to block nongenomic aldosterone effects in vivo.
In conclusion, this study provides in vivo evidence of rapid nongenomic aldosterone effects and an interaction with the adrenergic system. Given the deleterious long-term effects of adrenergic stimulation on the cardiovascular system and their synergistic support by aldosterone, future therapeutic strategies should emphasize antimineralocorticoid intervention. The conditions under which classical mineralocorticoid receptor antagonists can block some or all of the rapid effects of aldosterone in vivo and an understanding of their potential mechanisms of action in hypertension and heart failure await further studies.
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Acknowledgments |
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Footnotes |
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Received January 19, 2000.
Revised August 21, 2000.
Revised October 18, 2000.
Accepted October 23, 2000.
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