(Circulation. 1999;99:1485-1491.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Aldosterone, Not Estradiol, Is the Physiological Agonist for Rapid Increases in cAMP in Vascular Smooth Muscle Cells
From the Institute of Clinical Pharmacology, Klinikum Mannheim of the University of Heidelberg, Mannheim, Germany.
Correspondence to Martin Wehling, MD, Institute of Clinical Pharmacology, Klinikum Mannheim, Theodor Kutzer Ufer 1-3, D-68135 Mannheim, Germany. E-mail martin.wehling{at}medinn.med.uni-muenchen.de
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Steroid-induced gene regulation in the endocrine tissues and vascular wall is achieved through the interaction of specific receptor proteins and promoters of target genes. In addition to these delayed steroid actions, rapid effects of steroids have been reported in various tissues that were clearly incompatible with the classic theory of genomic steroid action.
Methods and Results—Because high doses of 17ß-estradiol have
been shown to modulate intracellular cAMP levels in vascular smooth
muscle cells, steroid-induced stimulation of adenylate
cyclase stimulation and phosphorylation of cAMP
response element binding protein was investigated in porcine
coronary artery vascular smooth muscle cells.
Aldosterone induces a 
1.5- to 2.5-fold increase in
intracellular cAMP levels (EC50 0.01 to 0.1 nmol/L)
within 1 minute, whereas 17ß-estradiol and hydrocortisone act only at
supraphysiological concentrations (10
µmol/L). Aldosterone-induced changes in intracellular
cAMP are calcium dependent; they are not blocked by
inhibitors of mineralocorticoid receptors, transcription,
or protein synthesis. In addition, aldosterone induces a
time-dependent phosphorylation of cAMP response element
binding protein with potential transcriptional importance.
Conclusions—A nongenomic modulation of vascular smooth muscle cells by aldosterone is consistent with the data that aldosterone, not estrogen, is the physiological stimulus for cAMP.
Key Words: vasculature • pharmacology • hormones • muscle, smooth
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Steroid effects in classic target tissues have been attributed to gene regulation via intracellular receptors. Regulation is achieved through the interaction of specific steroid receptor proteins and promoters of target genes. Mineralocorticoids and glucocorticoids differ markedly with regard to their physiological and clinical effects, although intracellular receptor proteins are closely related and widely promiscuous.1 2 Transcription is enhanced via a common, nonspecific consensus DNA sequence, originally designated as glucocorticoid-response element3 or hormone-responsive element. Because both receptor binding and response elements are not sufficient to confer specificity and the complexity of mineralocorticoid or glucocorticoid effects, other mechanisms such as the differential actions of receptors, including nonreceptor factors,4 differential metabolism of steroids in hormone responsive tissues as described for 17ß-hydroxy-steroid dehydrogenase,5 6 or additional nonclassic receptors, may be involved.
The existence of nongenomic effects of steroids such as those on neuronal activity (reviewed in References 7 and 87 8 ) or vasoregulation9 10 11 12 13 is supported by expanding experimental evidence and points to the involvement of such nonclassic receptors. Most of these effects can be observed within minutes after steroid exposure14 15 16 and are not blocked by inhibitors of protein synthesis, nuclear transcription, or both. The mechanisms underlying these rapid effects are not completely understood, but they may involve direct action on membrane receptors for steroids.17 18 In this context, it is remarkable that specificity, lacking those elements of steroid action as described above, may be found at the level of nongenomic steroid action.13 16
Nongenomic and genomic steroid actions may be interrelated ("cross-talk"). Neuropeptide gene transcription may be promoted by estrogen, although estrogenic response elements19 20 are not contained in these genes. The promoters of these genes do, however, contain active cAMP-response elements (CREs) and cross-talk through cAMP signaling is likely to occur. Cross-talk of adrenergic signaling through cAMP and steroid actions is further supported by the data of Nordeen et al21 and others,22 who demonstrated a synergistic transactivation of steroid-induced gene expression by the addition of 8-bromo-cAMP.
Although some of these estrogenic effects on cAMP signaling have been found at physiological estrogen concentrations, most of these actions in cardiovascular effector cells have been shown to occur only at high, micromolar concentrations of estrogens.23 24 Thus, estrogen might not be the physiological agonist for these processes. Because aldosterone has been shown to rapidly act on intracellular calcium and phosphoinositide hydrolysis in vascular smooth muscle cells at physiological concentrations,15 25 the aim of the present study was to investigate various steroids, including aldosterone and estrogen, as potential agonists affecting intracellular cAMP levels in porcine coronary vascular smooth muscle cells (PCVSMCs). To follow the sequelae of steroid-induced stimulation of adenylate cyclase, phosphorylation of CRE binding protein (CREB) was tested because it may link cAMP levels to transcription.26
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Materials
Isoproterenol and aldosterone were from Fluka. Cycloheximide, spironolactone, 17ß-estradiol, and hydrocortisone from Sigma. 3-Isobutyl-1-methylxanthine (IBMX) was from BIOMOL. All other chemicals used were of analytical grade and were from Merck AG.
Monoclonal antibodies against the 
-smooth muscle isoform of actin
and against the smooth muscle isoform of myosin were purchased from
Progen Biotechnik and Sigma. Collagenase type I was from
Worthington Biochemical. Elastase, penicillin/streptomycin, and
amphotericin B were from Boehringer Mannheim AG. Soybean
trypsin inhibitor was from Serva/Boehringer
Ingelheim. FCS was from cc-pro GmbH.
Isolation and Primary Culture of PCVSMCs
PCVSMCs were prepared enzymatically from pig coronary
arteries, with minor modifications as described
previously.15 In brief, porcine hearts were obtained from
the local slaughterhouse and transported to the laboratory within 30
minutes. Coronary arteries were dissected aseptically under a
microscope and placed in ice-cold PBS supplemented with standard
amounts of penicillin (10 U/mL)-streptomycin (10 µg/mL) and
amphotericin B (1 U/mL). After mechanical removal of the
endothelial layer of the coronary arteries, the
medial layer was stripped off with fine forceps and then underwent with
enzymatic disaggregation (1 mg/mL collagenase, 0.25 mg/mL
elastase, 0.375 mg/mL trypsin inhibitor; 85 minutes at
37°C in HEPES-buffered DMEM). The reaction was terminated with 10%
FCS. After centrifugation and washing, disaggregated
cells were cultured in nutrient mixture Ham's F-12/DMEM (1:5)
supplemented with 10% FCS and antibiotics and antimycotics under
standard conditions (37°C, 5% CO2) in
25-cm2 cell culture flasks (Falcon) without the
use of extracellular matrices. Plating efficiency was 65% to 80%
for primary culture and >95% for the splitting of passaged cells.
After 24 hours, the cultures were washed once to remove nonadherent
cells and debris and fed with fresh medium. Culture medium was
routinely changed each other day. In experiments, only early passage
cells (passages 2 to 6) were used 3 to 4 days after seeding. PCVSMCs
showed a typical hill-and-valley phenotype, and >95% of the
cells stained positive with a specific monoclonal antibody against the
-smooth muscle isoform of actin and against the smooth muscle
isoform of myosin (data not shown).
Stimulus-Induced Changes of Intracellular cAMP Levels
Experiments were conducted 3 to 4 days after cell splitting at
80% confluence and 24-hour cultivation in serum-free medium.
Initially, the incubation medium was exchanged by PSS buffer (135
mmol/L NaCl, 5 mmol/L KCl, 1.8 mmol/L
CaCl2, 0.5 mmol/L
MgCl2, 5.5 mmol/L glucose, 20 mmol/L
HEPES, pH 7.4) containing 500 µmol/L IBMX. After 30 minutes,
isoproterenol, steroids, the vehicle with corresponding ethanol
concentrations, or a combination, were added, and the reaction was
stopped at times indicated by aspiration of the buffer and transfer of
the dishes on ice. Incubation of cells with vehicle alone (up to 0.1%
ethanol in PSS buffer) did not influence intracellular cAMP levels
(data not shown). Inhibitors were added 15 or 60 minutes
before cell stimulation as indicated. cAMP was determined with a
commercial radioimmunoassay (Amersham) after ethanol extraction. Stock
solutions of all steroids (10 mmol/L) were prepared in ethanol and
stored in glass vials.
Analysis of Phosphorylation Status of CREB
After Cell Stimulation
Steroid- and isoproterenol-induced
phosphorylation of the serine-133 residue of CREB was
measured via immunoblotting, which is accepted as an
indicator of CREB activation. In brief, cells were cultured in standard
medium with 10% FCS for 3 days; 24 hours before the experiments, the
medium was exchanged, and cells were cultured serum free at 80%
confluence. Before the experiments, the incubation medium was changed
to PSS buffer containing 500 µmol/L IBMX. After 30 minutes,
various stimuli or controls (vehicle without steroids) were added and
the reaction immediately stopped at times indicated by transferring the
culture dishes on ice. The medium was aspirated, and cells lysed by
adding SDS sample buffer. After scraping the cells off the plate with a
rubber policeman, samples were heated, and aliquots were loaded on a
10% SDS-polyacrylamide gel. After electrotransfer to a PVDF
-membrane (Amersham), phosphorylated CREB was detected
through the binding of specific antibody against the
phosphorylated serine-133 residue of CREB (New England
Biolabs) and the enhanced chemoluminescence method (Phototype; New
England Biolabs). Agonist-induced changes in the
phosphorylation status were semiquantitatively
determined with densitometry (Image Master 1D; Pharmacia). The integral
of the absorbance of detected bands (Axmm) was used in calculations.
Relative values of these integrals did not substantially differ from
results obtained through calculations of peak absorbances of bands.
Statistical Analysis
Results are presented as mean±SEM. Statistical
comparisons of different conditions were made with commercial software
with the use of nonparametric tests. Friedman's
analysis was used for multiple comparisons, and
Wilcoxon test was used for single comparisons (StatView SE+
Graphics for Apple MacIntosh); probability value of <0.05 was
considered statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Effects of Aldosterone and Isoproterenol on Basal cAMP Levels
The basal cAMP level in PCVSMCs was 1.55±0.17 pmol/106 cells. Incubation of the cells with aldosterone (100 nmol/L) increased intracellular cAMP levels
1.5- to 2.5-fold within 1 minute versus control conditions
(0.0001% ethanol, P<0.05; Figure 1
). Stimulation of PCVSMCs with
isoproterenol (10 µmol/L), an -adrenoceptor stimulator,
induced a time-dependent, 6-fold increase of intracellular cAMP
levels (P<0.05). Aldosterone-induced increases
in intracellular cAMP were concentration dependent with cAMP
concentrations reaching 234% of control levels at 100 nmol/L (Figure 2). The EC50 value
of this effect is between 0.01 and 0.1 nmol/L (Figure 2). Basal
cAMP values were not affected by the addition of the vehicle (up to
0.1% ethanol) to the incubation medium.
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), with aldosterone
(100 µmol/L; 
), or with isoproterenol (10 nmol/L; 
).
Levels of intracellular cAMP were measured with a specific
radioimmunoassay (see "Methods"). Values are mean±SEM (n=5 for
isoproterenol and n=8 for control and aldosterone).
*P<0.05 vs control.
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, control). Values are mean±SEM (n=6). *P<0.05 vs
respective baseline values.
Because aldosterone-induced effects in rat vascular smooth
muscle cells seem to involve calcium signaling,15 the
influence of calcium on cAMP effects was investigated (Table 1): stimulation by
aldosterone in calcium-free buffer increased intracellular
cAMP concentrations (135% of control values; P<0.05), but
the extent was less than that in controls. Also, after preemptying of
inositol-1,4,5-trisphosphate–sensitive stores by the
Ca2+-ATPase inhibitor thapsigargin
(1 µmol/L), aldosterone-induced effects were small
but significant (124% of control values; P<0.05).
Preincubation of cells in calcium-free buffer with thapsigargin
completely abolished aldosterone-induced changes in
intracellular cAMP (Table 1; NS).
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Steroid Specificity and Inhibitors
Hydrocortisone and 17ß-estradiol significantly increased cAMP
only if concentrations as high as 10 µmol/L were used (173% or
139% of control values; P<0.05; Figure 2
).
Preincubation of cells with the inhibitors of transcription
and protein synthesis for 15 minutes did not block rapid
aldosterone-induced effects on intracellular cAMP levels:
aldosterone (100 nmol/L) stimulated intracellular cAMP
levels by 154±12% without inhibitors
(P<0.05), by 217±21% during preincubation with
actinomycin D (5 µg/mL), and by 150±19% during preincubation with
cycloheximide (20 µg/mL). Similar results were obtained after
60-minute preincubation with inhibitors, which is
considered to be a sufficient time period for inhibitors to
take effect,27 28 and subsequent stimulation of cells
with 10 nmol/L aldosterone for 1 minute (Figure 3). Incubation of PCVSMCs with
inhibitors alone did not significantly influence basal cAMP
levels.
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In addition, 15-minute incubation of cells with spironolactone (10
µmol/L), a classic antagonist of genomic
mineralocorticoid action, did not significantly blunt
aldosterone-induced effects on intracellular cAMP levels
(Figure 4; 186% versus 162% of control
values). Similar results were obtained after a 60-minute preincubation
of the cells in spironolactone (10 µmol/L):
aldosterone (10 nmol/L) significantly increased
intracellular cAMP levels from 2.58±0.10 to 4.85±0.37
pmol/105 cells without (n=8; P<0.05)
and from 2.48±0.20 to 4.89±0.60 pmol/105 cells
(n=6; P<0.05) with the continued presence of
spironolactone. Basal cAMP levels were not significantly influenced by
the preincubation of cells in spironolactone for 60 minutes.
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Phosphorylation of CREB
Stimulation of cells with isoproterenol and
aldosterone increased immunodetectable
phosphorylation of CREB within minutes, whereas the
addition of the solvent alone did not significantly influence CREB
phosphorylation (Figure 5). Levels of
phosphorylation significantly increased to 128±16%
(n=10; P<0.05) and 150±23% (n=6; P<0.05)
after stimulation of cells with 1 and 100 nmol/L
aldosterone for 10 minutes, respectively, whereas 10
µmol/L isoproterenol increased phosphorylation levels
of CREB to 409±125% of control levels (n=6; P<0.05).
Differences in phosphorylation levels correlate with
differences in the increases of intracellular cAMP after stimulation
with aldosterone or isoproterenol. Stimulation of cells
with 0.1 µmol/L estradiol did not significantly change levels of
CREB phosphorylation (111±17% versus control; n=6;
NS), whereas the stimulation with 10 µmol/L estradiol
significantly induced CREB phosphorylation within 10
minutes (174±61% versus control; n=6; P<0.05). A similar
concentration-dependent correlation between estradiol-induced increases
in cAMP and CREB phosphorylation was found for
hydrocortisone, whereas 0.1 µmol/L hydrocortisone was
ineffective (111±7% versus respective control; n=7; NS), and 10
µmol/L hydrocortisone significantly increased levels of CREB
phosphorylation versus control (147±28% versus
control; n=7; P<0.05). Coincubation of
aldosterone with increasing concentrations of isoproterenol
was performed to search for synergistic effects. After preincubation of
cells with 100 nmol/L aldosterone for 10 minutes,
isoproterenol increased phosphorylation of CREB at
10-fold lower concentrations to levels obtained in experiments
without aldosterone, suggesting an at least additive, if
not synergistic, action of isoproterenol and aldosterone
(Figure 6). Comparable sensitization of
isoproterenol (0.1 nmol/L for 5 minutes)-induced increases in pCREB
levels were found during coincubation with 10 µmol/L estradiol
or hydrocortisone (180±42% and 146±23% versus control; n=7;
P<0.05), whereas 0.1 nmol/L isoproterenol alone did not
significantly change CREB phosphorylation (114±8%;
n=21; NS). However, aldosterone induced an increase in CREB
phosphorylation during coincubation with 0.1 nmol/L
isoproterenol, even at a concentration as low as 1 nmol/L (199±0.5%;
n=11; P<0.05).
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) for times indicated. After incubation, cell lysates were
separated on 12% SDS-PAGE, and phosphorylated CREB was
detected immunologically after transfer on PVDF membranes (see
"Methods"). Bands were measured densitometrically, and data are
expressed as trace values (absorbancexmm). Values are mean±SEM (n=4).
B, Representative immunoblot demonstrating
time-dependent effects of aldosterone on
phosphorylation of CREB (pCREB). Cells were incubated
in PSS buffer alone or with aldosterone for times
indicated. Incubation conditions and methods were same as described in
A.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The main findings of the present study are that (1) aldosterone specifically increases intracellular levels of cAMP in PCVSMCs within minutes, and the effect is not blocked by inhibitors of transcription and protein synthesis; (2) the EC50 value of
0.01 to 0.1 nmol/L is close to
the free physiological plasma concentration of
aldosterone in humans29 ; (3) hydrocortisone
and 17ß-estradiol are active only at
supraphysiological concentrations; (4) CREB is
rapidly phosphorylated in response to
aldosterone but not in response to estradiol or
hydrocortisone at comparable concentrations; and (5) isoproterenol
effects occur at lower concentrations after pretreatment with
aldosterone. These effects are in line with the effects of aldosterone in vascular smooth muscle cells described previously for Ca2+, inositol-1,4,5-trisphosphate, and protein kinase C.15 16 25 They are classified as nongenomic effects because they are rapid and not inhibited by the mineralocorticoid receptor antagonist spironolactone or by inhibitors of transcription and protein synthesis. A new pathway through specific membrane receptors for aldosterone was previously suggested12 17 30 to transmit these rapid aldosterone actions. The receptors involved are clearly distinct from the cytosolic type 1 mineralocorticoid receptor,31 which does not distinguish mineralocorticoids from glucocorticoids. Radioactive binding studies in membrane preparations from human mononuclear leukocytes, porcine kidney, and porcine liver17 30 32 suggest a binding site compatible with major features of nongenomic aldosterone action (eg, specificity, low binding of spironolactone).
The interaction of steroids with specific receptors is not the only mechanism of rapid action known to date: steroid effects at supraphysiological concentrations may be induced by nonspecific membrane interactions.33 34 However, rapid aldosterone effects on cell signaling, including intracellular cAMP, CREB phosphorylation, calcium,16 and phosphoinositide hydrolysis,15 25 occur at subnanomolar physiological concentrations of aldosterone, suggesting the involvement of specific mechanisms. In contrast to rapid aldosterone actions, rapid estradiol-induced increases of cAMP in vascular smooth muscle cells of rat pulmonary artery,23 effects on calcium currents of vascular smooth muscle cells,35 and regulation of vascular tone predominantly occur at micromolar concentrations,24 36 whereas the rapid actions at physiological estradiol concentrations have been demonstrated only in cells of fetal origin37 38 39 or undifferentiated, multipotent cells.40 Because supramicromolar concentrations of estrogens are nonphysiological, perhaps even nonpharmacological, the data presented here suggest that aldosterone, but not 17ß-estradiol, is the physiological stimulus of cAMP in vascular smooth muscle cells of porcine coronary arteries.
With regard to the intracellular signaling leading to cAMP stimulation, it should be noted that free intracellular calcium has been shown to be involved in nongenomic action of aldosterone in PCVSMCs at low physiological concentrations.16 Preemptying of inositol-1,4,5-trisphosphate–sensitive stores by thapsigargin in calcium-free buffer abolished rapid effects on intracellular cAMP. These data are in line with those demonstrating dependence of cAMP-mediated contractility on modulation of intracellular calcium signaling.41 Thus, a calcium/calmodulin–dependent adenylate cyclase may be involved in aldosterone-induced effects on intracellular cAMP levels as suggested by Zhang et al.42
Increases in intracellular cAMP after stimulation with aldosterone are markedly lower than increases after stimulation with isoproterenol or forskolin. Given this, it is even more important to review evidence supporting the physiological relevance of rapid aldosterone effects. Suppression of baroreceptor discharge has been demonstrated in a canine model within 15 minutes of aldosterone injection.43 Rapid reduction of coronary flow and increases of aortic flow and cardiac output were found in an isolated rat working heart model.44 Klein and Henk45 showed rapid aldosterone effects on systemic vascular resistance in humans occurring within 5 minutes. Furthermore, in a placebo-controlled, randomized trial, rapid aldosterone-induced increases in phosphocreatine levels have been shown for calf muscle during recovery from submaximal exercise.46 Although the in vivo and in vitro effects of aldosterone alone appear small, its synergisms with other cardiovascular hormones may be physiologically important. An at least additive, if not synergistic, effect is suggested by data on the combined aldosterone/isoproterenol action shown here and by earlier data on angiotensin II/aldosterone effects on [Ca2+]i.16 Another important issue concerning the physiological relevance of rapid aldosterone effects involves a comparison of aldosterone concentrations required for rapid in vitro action with those present in vivo. Aldosterone levels producing half-maximal effects (0.01 to 0.1 nmol/L) in vitro are relatively low in terms of the normal range of circulating aldosterone plasma concentrations (0.1 nmol/L in humans29 ). Therefore, a tonic modest stimulation of the system may be present under physiological conditions. Lowering of aldosterone levels may be a protective mechanism in, for example, salt loading, by a possibly changed sensitivity to catecholamine effects. This appears to be even more relevant as the concentrations required in vitro are commonly higher than those required in vivo.
In addition to these direct or indirect rapid cardiovascular effects, nongenomic effects of aldosterone on intracellular signaling15 16 25 may modulate long-term actions of aldosterone or other steroids on the cardiovascular system through the activation of transcriptional coactivators such as CREB. This assumption is in line with data suggesting a modulation of steroid-induced gene transactivation by increases in intracellular cAMP: modulation of transcription rates after stimulation with glucocorticoids or mineralocorticoids has been demonstrated in cells transfected with glucocorticoid21 or mineralocorticoid receptors22 during coincubation with 8-bromo-cAMP. Thus, modulation of intracellular signaling may be involved in the determination of specificity of mineralocorticoid and glucocorticoid actions,22 as suggested recently.12 13
In summary, aldosterone rapidly increases intracellular cAMP levels within minutes at subnanomolar concentrations, whereas both estrogen and hydrocortisone are active only at supramicromolar concentrations. Phosphorylation of CREB by aldosterone, as a known coactivator of genomic steroid action, suggests that aldosterone may influence transcription through its rapid action on phosphorylation mechanisms. Because the half-maximal effects of aldosterone are seen at concentrations close to or even below free circulating plasma aldosterone levels, a tonic modest stimulation of this system may be the normal physiological state. Thus, changes in aldosterone plasma levels during alterations of body water or electrolyte balance may be involved in the fine tuning of vasoregulation via modulation of sensitivity to other vasoregulators such as catecholamines or angiotensin II. The development of inhibitors that block both rapid nongenomic and subsequent genomic steroid effects may be relevant in future drug developments for the treatment of important cardiovascular diseases, such as hypertension and chronic heart failure.
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Acknowledgments |
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This study was supported by a grant of the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (No. 01EC9407). We thank Elke Kirsch for expert technical assistance. Some results presented in this study are part of the doctoral thesis of Andreas Günther at the Faculty of Clinical Medicine Mannheim, University of Heidelberg.
Received July 23, 1998; revision received November 9, 1998; accepted November 18, 1998.
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