Published online before print September 6, 2005, doi: 10.1161/01.HYP.0000182661.98259.4f
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2005;46:701.)
© 2005 American Heart Association, Inc.
Original Articles |
Nongenomic Effects of Aldosterone in the Human Heart
Interaction With Angiotensin II
From the Departments of Pharmacology (W.C., I.M.G., R.d.V., W.W.B., A.H.J.D.) and Thoracic Surgery and Heart Valve Bank (J.P.v.K.), Erasmus MC, Rotterdam, The Netherlands.
Correspondence to Dr A.H Jan Danser, Department of Pharmacology, Room EE1418b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail a.danser{at}erasmusmc.nl
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Aldosterone exerts rapid "nongenomic" effects in various nonrenal tissues. Here, we investigated whether such effects occur in the human heart. Trabeculae and coronary arteries obtained from 57 heart valve donors (25 males; 32 females; 17 to 66 years of age) were mounted in organ baths. Aldosterone decreased contractility in atrial and ventricular trabeculae by maximally 34±3% and 15±4%, respectively, within 5 to 15 minutes after its application. The protein kinase C (PKC) inhibitor chelerythrine chloride, but not the mineralocorticoid receptor antagonists spironolactone and eplerenone, blocked this effect. Aldosterone also relaxed trabeculae that were prestimulated with angiotensin II (Ang II), and its negative inotropic effects were mimicked by hydrocortisone (at 10-fold lower potency) but not 17ß-estradiol. Aldosterone concentrations required to reduce inotropy were present in failing but not in normal human hearts. Previous exposure of coronary arteries to 1 µmol/L aldosterone or 17ß-estradiol (but not hydrocortisone) doubled the maximum contractile response (Emax) to Ang II.
Emax correlated with extracellular signal-regulated kinase (ERK) 1/2 phosphorylation (P<0.01). Spironolactone and eplerenone did not block the potentiating effect of aldosterone. Studies in porcine renal arteries showed that potentiation also occurred at pmol/L aldosterone levels but not at 17ß-estradiol levels <1 µmol/L. Aldosterone did not potentiate the 
1-adrenoceptor agonist phenylephrine. In conclusion, aldosterone induces a negative inotropic response in human trabeculae (thereby antagonizing the positive inotropic actions of Ang II) and potentiates the vasoconstrictor effect of Ang II in coronary arteries. These effects are specific and involve PKC and ERK 1/2, respectively. Furthermore, they occur in a nongenomic manner, and require pathological aldosterone concentrations.
Key Words: aldosterone • mineralocorticoids • angiotensin • human
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The steroid hormone aldosterone is synthesized in the adrenal cortex in response to angiotensin II (Ang II). The primary cardiovascular effect of aldosterone has traditionally been ascribed to regulation of electrolyte homeostasis and extracellular fluid volume by promotion of sodium retention and potassium excretion in the renal collecting duct. The mechanism underlying this effect is of "genomic" nature (ie, it involves binding to the intracellular mineralocorticoid receptor [MR], followed by translocation of the steroid–receptor complex to the nucleus, where this complex acts as a transcription factor).
Two large clinical trials in patients with heart failure have recently shown that MR antagonists improve morbidity and mortality on top of angiotensin-converting enzyme inhibition.1,2 Because these beneficial effects could not be attributed solely to blockade of the renal MR-mediated effects on blood pressure, it has been proposed that aldosterone also exerts actions in extrarenal tissues. Evidence for this concept is now readily available. The nonrenal actions of aldosterone include inotropic effects in the heart and vasoconstrictor as well as vasodilator effects in various vascular beds.3–7 Unexpectedly, these effects occurred within minutes rather than hours and could not always be blocked by MR antagonists. Consequently, they are now known as "nongenomic" effects of aldosterone. Some of these nongenomic effects might in fact be exerted by aldosterone that has been synthesized locally in the heart or vessel wall, although not all studies agree on this possibility.8–10
The majority of the data on the nongenomic actions of aldosterone have been obtained in animals. It was the aim of the present study to investigate the nongenomic effects of aldosterone in the human heart, focusing on trabeculae and coronary arteries. To determine the specificity of the effects of aldosterone, we also assessed the effects of 17ß-estradiol and hydrocortisone. Furthermore, because aldosterone exerts its effects, at least in part, via Ang II or Ang II type 1 (AT1) receptors,7,11 and vice versa,10 we evaluated the interaction with Ang II in our experimental setup. Finally, we looked into the mediators of the effects of aldosterone in this study, focusing on those that have already been coupled to the nongenomic actions of aldosterone (protein kinase C [PKC], Ca2+, NO, and mitogen-activated protein kinases),3,6,7,10,12 and we determined the aldosterone levels in normal and failing human hearts to put our findings into a physiological perspective.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Tissue Collection
All studies were approved by the ethics committee of the Erasmus MC. Human trabeculae, human coronary arteries (HCAs), and left ventricular tissue were obtained from 57 heart-beating organ donors (25 men and 32 women; 46±1 years of age [range 17 to 66]) who died of noncardiac causes (46 cerebrovascular accident, 5 head trauma, and 6 brain hypoxia) <24 hours before the heart was taken to the laboratory. Hearts were provided by the Rotterdam Heart Valve Bank after removal of the heart valves. Hearts were stored in an ice-cold sterile organ-protecting solution after circulatory arrest. After arrival at the laboratory, right atrial and left ventricular trabeculae of
1-mm thickness were dissected and mounted in organ baths.13 The trabeculae were paced at 1 Hz using electrical field stimulation. Resting tension was set at 750 mg and 1950 mg for atrial and ventricular trabeculae, respectively. Changes in contraction were recorded with a force transducer. HCAs were removed and stored overnight at 4°C, cut into segments of 4-mm length, and suspended on stainless steel hooks in organ baths.13 Resting tension was set at 1.5 g. Left ventricular tissue pieces (5 to 10 g) were dissected from the heart and frozen at –70°C. Left ventricular tissue (3 to 5 g) was also obtained from 11 subjects (10 men and 1 woman; 48±4 years of age [range 30 to 64]) with end-stage dilated cardiomyopathy undergoing cardiac transplantation.14 Porcine renal arteries (PRAs) were removed from kidneys obtained at the slaughterhouse. Vessels were stored overnight and suspended in organ baths as described above. Resting tension was set at 2 g.
Trabeculae Studies
Trabeculae were allowed to equilibrate for 
60 minutes, and organ bath fluid was refreshed every 15 minutes during this period. Next, a concentration-response curve (CRC) to norepinephrine was constructed to verify the viability of the tissue. After several washouts and stabilization at baseline contractile force, CRCs to aldosterone, spironolactone, eplerenone (a gift of Pfizer), hydrocortisone, their solvent (ethanol), or 17ß-estradiol (dissolved in water) were constructed, either at baseline or after prestimulation with forskolin (dissolved in dimethylsulfoxide [DMSO]) or Ang II. To investigate the mechanism of the aldosterone-induced effects, CRCs to aldosterone were also constructed after preincubation with spironolactone, eplerenone, the NO synthase inhibitor N
-nitro-L-arginine methyl ester (L-NAME), the NO scavenger hydroxocobalamin (dissolved in methanol), the guanylyl cyclase inhibitor ODQ, the PKC inhibitor chelerythrine chloride (dissolved in DMSO), the intracellular Ca2+ blocker thapsigargin (dissolved in ethanol), or solvent. At the end of each experiment, viability was verified with norepinephrine.
Vessel Studies
Viability was evaluated as described previously.13 Next, segments were preincubated for 30 minutes with or without aldosterone, 17ß-estradiol, spironolactone, eplerenone, or L-NAME, and CRCs to Ang II, aldosterone, hydrocortisone, 17ß-estradiol, solvent (ethanol), or phenylephrine were constructed. Ang II CRCs were also constructed after completion of the CRCs to aldosterone, hydrocortisone, 17ß-estradiol, or solvent (ethanol) without refreshing the organ bath fluid in between. To determine Ang II–induced extracellular signal-regulated kinase (ERK) 1/2 activation, segments were collected and frozen at –80°C within 10 minutes after exposure to the highest Ang II concentration.
Biochemical Measurements
To determine ERK 1/2 phosphorylation, frozen HCA segments were homogenized in Nonidet P-40 lysis buffer and kept on ice for 1 hour. Next, they were centrifuged at 14 000g for 15 minutes at 4°C, and the supernatants were collected and stored at –80°C until further analysis. Protein was determined using the Bradford assay. Western blotting was performed with 20 µg protein using phospho-ERK 1/2 and ERK antibodies (Westburg; 1:2000). Peroxidase-conjugated secondary antibodies were from Pierce (1:5000). Blots were developed with the chemiluminescence substrate and visualized on Kodak films. For semiquantification, the band obtained with Ang II alone was defined as 100%.
Aldosterone was measured by solid-phase radioimmunoassay (Diagnostic Products Corporation) after its extraction from left ventricular tissue. In short, tissue was homogenized 1:2 in methanol. The supernatant was collected after a 15-minute centrifugation at 3000 rpm at 4°C, vacuum dried, and dissolved in water. The detection limit was 10 pg/g wet weight.
Total renin (ie, renin plus prorenin) was measured by immunoradiometric assay in homogenized tissue after treatment with acid and plasmin to activate prorenin.14
Data Analysis
Data are expressed as mean±SEM or geometric mean and range, and n refers to the patient number. Trabeculae showing <25 mg response to norepinephrine at the start or end of the experiment were excluded from analysis. CRCs were analyzed as described previously to obtain pEC50 (=–log[EC50]) values.13 Aldosterone levels below the detection limit were taken to be equal to the detection limit. Statistical analysis was by Mann–Whitney U test for unpaired observations, paired t test, or 1-way ANOVA, followed by post hoc evaluation according to Tukey. P<0.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Trabeculae Studies
Baseline contractile forces were 164±11 mg and 233±15 mg in atrial (n=29) and ventricular (n=15) trabeculae, respectively. Norepinephrine increased contractile force in both types of trabeculae in a concentration-dependent manner (pEC50 6.2±0.1 and 6.1±0.1, respectively). The contractile response to 10 µmol/L norepinephrine at the end of the experiment was not different from that at the start (+208±16% versus +205±11% in atrial trabeculae and +196±20% versus +198±20% in ventricular trabeculae). This indicates that tissue viability did not decrease during the course of the experiment.
Aldosterone (pEC50 8.3±0.1; n=25) and hydrocortisone (pEC50 7.6±0.2; n=5; P<0.01 versus aldosterone), but not 17ß-estradiol (n=4), reduced contractility in atrial trabeculae (Figure 1). The effects of aldosterone occurred within 5 to 15 minutes after its application. Aldosterone also reduced contractility in ventricular trabeculae (pEC50 8.1±0.5; n=7), although its effects in this preparation were more modest than in atrial trabeculae. The effects of spironolactone in atrial (pEC50 8.2±0.4; n=7) and ventricular (pEC50 8.7±0.1; n=6) trabeculae were comparable to those of aldosterone. Eplerenone did not exert effects in either atrial (n=7) or ventricular (n=4) trabeculae, nor did solvent (n=4 and 6, respectively). In atrial trabeculae, the negative inotropic effect of aldosterone after prestimulation with either forskolin (n=6) or Ang II (n=6) was identical to that at baseline. Aldosterone also relaxed forskolin-prestimulated ventricular trabeculae (n=6). Without aldosterone, the forskolin-induced increase in contractility remained stable for 45 minutes (ie, the time required to construct an aldosterone CRC).
|
Spironolactone (n=7), eplerenone (n=5), L-NAME (n=5), hydroxocobalamin (n=5), ODQ (n=4), thapsigargin (n=5), and solvent (methanol [n=4] or DMSO [n=5]) did not affect the aldosterone-induced negative inotropic effects (Figure 2), and with the exception of spironolactone (see above), none of these inhibitors affected baseline contractility. In contrast, chelerythrine chloride (n=7) not only blocked the effect of aldosterone, but tended to reverse it into a positive inotropic (P=NS) response. Chelerythrine chloride did not affect baseline contractility.
|
) or presence (•) of spironolactone (SPIRO; 10 µmol/L), eplerenone (EPLE; 1 µmol/L), L-NAME (100 µmol/L), ODQ (10 µmol/L), hydroxocobalamin (HC; 200 µmol/L), chelerythrine chloride (CHEL; 1 µmol/L), thapsigargin (THAPS; 1 µmol/L), or solvent (methanol or DMSO). Data (mean±SEM of 4 to 7 experiments) were obtained in a paired setup and have been expressed as percent change from baseline contractile force. *P<0.05 vs control.
Vessel Studies
Ang II concentration-dependently constricted HCAs (pEC50 7.5±0.5; maximum contractile response [Emax] 29±7%; n=13; Figure 3). Aldosterone (n=11), hydrocortisone (n=11), 17ß-estradiol (n=10), or solvent (ethanol; n=5), at concentrations ranging from 1 pmol/L to 1 µmol/L, did not affect baseline contractility in HCAs (data not shown). However, when constructing an Ang II CRC after exposure to aldosterone or 17ß-estradiol (without refreshing the organ bath fluid), Emax doubled to 55±11% and 51±14%, respectively (P<0.05 versus control for both), with no change in pEC50 (7.5±0.2 versus 7.5±0.2; Figure 3). Hydrocortisone tended to induce a similar potentiation (P=NS; Figure 3), whereas ethanol was without effect. Neither spironolactone (n=8) nor eplerenone (n=8) blocked the effect of aldosterone (Figure 3). The amount of phosphorylated ERK 1/2 tended to be increased in the presence of 1 µmol/L aldosterone, hydrocortisone, and 17ß-estradiol (P=NS versus Ang II alone; n=6 for all; Figure 4), with no change in the total amount of ERK 1/2. The increase in ERK 1/2 phosphorylation was limited to vessel segments displaying a large increase in Emax, as evidenced by the significant correlation between Emax and ERK 1/2 phosphorylation (r=0.56; P<0.01; Figure 4).
|
|
), or 17ß-estradiol (
).The effects of aldosterone, 17ß-estradiol, and hydrocortisone toward Ang II could be reproduced in PRAs: none of these steroids affected baseline contractility at concentrations ranging from 1 pmol/L to 1 µmol/L, and only previous exposure to aldosterone and 17ß-estradiol increased the Ang II Emax (n=9; Figure 5). Therefore, PRAs were used to test whether the effects of aldosterone and 17ß-estradiol could also be observed at lower concentrations. Preincubation with 17ß-estradiol concentrations <1 µmol/L did not result in potentiation (n=7; data not shown). In contrast, the effects of aldosterone could be mimicked at concentrations as low as 1 nmol/L (n=10; P<0.05) or, in the presence of L-NAME, 1 pmol/L (n=4; P<0.05; Figure 5). Furthermore, the potentiating effects were specific for Ang II because preincubation with 1 nmol/L aldosterone did not affect the phenylephrine CRC (n=4; Figure 5).
|
Aldosterone Levels in the Human Heart
Aldosterone levels in failing hearts (184 [range 10 to 4710] pg/g; n=11) were 10-fold higher (P<0.02) than in normal hearts (26 [range 10 to 481] pg/g; n=12). This parallels our previous observations on cardiac renin.14 In fact, the levels of renin in the heart correlated significantly with those of aldosterone (r=0.71; P<0.05; Figure 6).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present study is the first to demonstrate nongenomic actions of aldosterone in the human heart. Aldosterone exerted a negative inotropic effect in atrial and ventricular trabeculae at baseline and after prestimulation with the adenylyl cyclase activator forskolin. This effect was long lasting and, unlike the short-lasting negative inotropic effect of bradykinin,15 did not involve the NO–cGMP pathway. The PKC inhibitor chelerythrine chloride fully blocked the aldosterone-induced negative inotropy, suggesting that it is mediated via the diacylglycerol–PKC signal transduction pathway. Patch clamp studies in rabbit ventricular myocytes have revealed that aldosterone affects Na+-K+ pump activity via
PKC,12 thereby providing a mechanism for the negative inotropic response to aldosterone. The modest effect of aldosterone in ventricles is in agreement with the fact that atria have fewer sodium pumps than ventricles16 because low expression enhances inotropic sensitivity. The lack of effect of MR antagonists suggests that the inotropic effects of aldosterone occur in an MR-independent manner. In fact, as in the isolated perfused rat heart,4,5 spironolactone exerted an inotropic effect that was comparable to that of aldosterone, whereas the more selective MR antagonist eplerenone did not. This further supports the MR independency of the effects of aldosterone and spironolactone. However, importantly, aldosterone and spironolactone exerted positive inotropy in the rat heart,4,5 as opposed to the negative inotropy observed here and in rabbit cardiomyocytes.12 Although this may relate to species differences, alternative explanations must be considered. First, inotropic effects in isolated trabeculae do not necessarily parallel inotropic effects in intact hearts because the latter also reflect responses on coronary flow. Second, similar diametrically differing effects of aldosterone have been observed on flow, either because such effects involve different cells or because different second messengers are activated depending on the experimental circumstances.5,6,12,17 Finally, the consequences of PKC-induced regulation of Na+-K+ pump activity are tissue specific and range from stimulation to inhibition or no change.12,18
Hydrocortisone mimicked the inotropic effects of aldosterone at lower potency. This underlines the specificity of the aldosterone effect. However, because glucocorticoids circulate at levels that are several orders of magnitude higher than those of aldosterone, the inotropic effects of aldosterone and glucocorticoids may occur simultaneously in vivo.
The aldosterone levels in failing human hearts were found to be up to 5000 pg/g (corresponding with 15 nmol/L), that is, high enough to allow the inotropic effects of aldosterone to occur under pathological conditions in vivo. The levels in normal hearts (25 pg/g or <0.1 nmol/L) appeared to be too low to exert inotropic effects. Although the origin of aldosterone in the heart is still under debate,8 our observation that the cardiac aldosterone levels correlate with the cardiac levels of renin (which is exclusively of renal origin14), combined with previous findings on cardiac extraction of aldosterone,19 suggest that at least some cardiac aldosterone is of extracardiac origin.
The high renin levels in failing human hearts will result in high local Ang II levels.20 In agreement with previous studies,21 Ang II was found to induce a modest (compared with norepinephrine) positive inotropic effect. Aldosterone counteracted this effect. This observation contrasts with the aldosterone-induced potentiation of the vasoconstrictor effect of Ang II in HCAs. Hydrocortisone and 17ß-estradiol similarly potentiated constriction, although significance was reached for 17ß-estradiol only. The magnitude of potentiation (ie, the increase in Emax) correlated with the increase in the level of phosphorylated ERK 1/2, in full agreement with a previous study on steroid–Ang II interaction in rat aortic vascular smooth muscle cells.7 None of the steroids applied in the present study exerted a constrictor or dilator effect of its own, and the Ang II–potentiating effects became apparent only after constructing a CRC to the steroid. Such construction requires 30 to 60 minutes, a time interval that is insufficient to allow the AT1 receptor upregulation that underlies the Ang II potentiation after a 24- to 48-hour exposure to aldosterone and glucocorticoids.11,22
Studies in HCA smooth muscle cells have already indicated that Ang II is capable of activating MR-mediated gene expression in an aldosterone-independent manner (suggesting MR activation by post-translational modifications such as phosphorylation).10 The present data extend this observation by demonstrating functional synergy when applying aldosterone together with Ang II. This synergy did not depend on MR activation, was selective, and occurred at physiological aldosterone levels.
In the rat aorta,3 as well as the human forearm,6 aldosterone has been reported to enhance vasoconstriction and vasodilation. The latter was endothelium dependent, whereas the former could only be observed during NO synthase blockade. The absence of aldosterone-induced vasodilation in HCAs may relate to our inability to observe endothelial NO release in these vessels.23
Limited NO release could also underlie the absence of a vasodilator response to 17ß-estradiol in HCAs. Despite the higher incidence of stroke, myocardial infarction, and dementia in postmenopausal women taking hormone replacement therapy,24 virtually all in vitro studies published so far claim that estrogen induces vasodilation through endothelium-dependent or endothelium-independent mechanisms.24 An alternative explanation for the absence of estrogen-induced vasodilation in HCAs, at least in women, is the change in estrogen receptor cellular localization during perimenopause.25 Furthermore, estrogen inactivates reactive oxygen species like the vasodilator H2O226,27 and alters the AT1/AT2 receptor ratio.28,29 Both phenomena will directly affect Ang II–induced vasoconstriction.
Perspectives
Aldosterone induces a negative inotropic response in human trabeculae (thereby antagonizing the positive inotropic actions of Ang II) and potentiates the vasoconstrictor effect of Ang II in HCAs. These effects occur in a rapid, nongenomic manner, independently of MR, and involve PKC and ERK 1/2, respectively. Combined with the nonhemodynamic effects of aldosterone in cardiac tissue, which result in inflammation and fibrosis,5,30 these data shed light on the wide variety of actions of aldosterone in the heart. Future studies should now address which receptor mediates the nongenomic cardiac effects of aldosterone and to what degree these effects occur in failing hearts. In view of the comparable beneficial effects of spironolactone and eplerenone in heart failure,1,2 such studies should also critically evaluate the physiological importance of the negative inotropic effect of spironolactone. The many nongenomic, non–MR-mediated effects of aldosterone suggest that aldosterone synthase inhibitors may yield effects on top of MR blockade.
Received May 31, 2005; first decision June 22, 2005; accepted July 28, 2005.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 341: 709–717.
2. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309–1321.
3. Liu SL, Schmuck S, Chorazcyzewski JZ, Gros R, Feldman RD. Aldosterone regulates vascular reactivity: short-term effects mediated by phosphatidylinositol 3-kinase-dependent nitric oxide synthase activation. Circulation. 2003; 108: 2400–2406.
4. Barbato JC, Mulrow PJ, Shapiro JI, Franco-Saenz R. Rapid effects of aldosterone and spironolactone in the isolated working rat heart. Hypertension. 2002; 40: 130–135.
5. Chai W, Garrelds IM, Arulmani U, Schoemaker RG, Lamers JMJ, Danser AHJ. Genomic and nongenomic effects of aldosterone in the rat heart: why is spironolactone cardioprotective? Br J Pharmacol. 2005; 145: 664–671.[CrossRef][Medline] [Order article via Infotrieve]
6. Schmidt BMW, Oehmer S, Delles C, Bratke R, Schneider MP, Klingbeil A, Fleischmann EH, Schmieder RE. Rapid nongenomic effects of aldosterone on human forearm vasculature. Hypertension. 2003; 42: 156–160.
7. Mazak I, Fiebeler A, Müller DN, Park JK, Shagdarsuren E, Lindschau C, Dechend R, Viedt C, Pilz B, Haller H, Luft FC. Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cells. Circulation. 2004; 109: 2792–2800.
8. Gomez-Sanchez EP, Ahmad N, Romero DG, Gomez-Sanchez CE. Origin of aldosterone in the rat heart. Endocrinology. 2004; 145: 4796–4802.
9. Takeda Y, Miyamori I, Yoneda T, Iki K, Hatakeyama H, Blair IA, Hsieh FY, Takeda R. Production of aldosterone in isolated rat blood vessels. Hypertension. 1995; 25: 170–173.
10. Jaffe IZ, Mendelsohn ME. Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res. 2005; 96: 643–650.
11. Xiao F, Puddefoot JR, Barker S, Vinson GP. Mechanism for aldosterone potentiation of angiotensin II-stimulated rat arterial smooth muscle cell proliferation. Hypertension. 2004; 44: 340–345.
12. Mihailidou AS, Mardini M, Funder JW. Rapid, nongenomic effects of aldosterone in the heart mediated by epsilon protein kinase C. Endocrinology. 2004; 145: 773–780.
13. Tom B, Garrelds IM, Scalbert E, Stegmann APA, Boomsma F, Saxena PR, Danser AHJ. ACE-versus chymase-dependent angiotensin II generation in human coronary arteries: a matter of efficiency? Arterioscler Thromb Vasc Biol. 2003; 23: 251–256.
14. Danser AHJ, van Kesteren CAM, Bax WA, Tavenier M, Derkx FHM, Saxena PR, Schalekamp MADH. Prorenin, renin, angiotensinogen, and angiotensin-converting enzyme in normal and failing human hearts. Evidence for renin binding. Circulation. 1997; 96: 220–226.
15. Tom B, de Vries R, Saxena PR, Danser AHJ. Negative inotropic effect of bradykinin in porcine isolated atrial trabeculae: role of nitric oxide. J Hypertens. 2001; 19: 1289–1293.[Medline] [Order article via Infotrieve]
16. McDonough AA, Velotta JB, Schwinger RH, Philipson KD, Farley RA The cardiac sodium pump: structure and function. Basic Res Cardiol. 2002; 97 (suppl 1): I19–I24.[Medline] [Order article via Infotrieve]
17. Barbato JC, Rashid S, Mulrow PJ, Shapiro JI, Franco-Saenz R. Mechanisms for aldosterone and spironolactone-induced positive inotropic actions in the rat heart. Hypertension. 2004; 44: 751–757.
18. Therien AG, Blostein R. Mechanisms of sodium pump regulation. Am J Physiol Cell Physiol. 2000; 279: C541–C566.
19. Hayashi M, Tsutamoto T, Wada A, Tsutsui T, Ishii C, Ohno K, Fujii M, Taniguchi A, Hamatani T, Nozato Y, Kataoka K, Morigami N, Ohnishi M, Kinoshita M, Horie M. Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. Circulation. 2003; 107: 2559–2565.
20. van Kats JP, Duncker DJ, Haitsma DB, Schuijt MP, Niebuur R, Stubenitsky R, Boomsma F, Schalekamp MADH, Verdouw PD, Danser AHJ. Angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade prevent cardiac remodeling in pigs after myocardial infarction: role of tissue angiotensin II. Circulation. 2000; 102: 1556–1563.
21. Holubarsch C, Hasenfuss G, Schmidt-Schweda S, Knorr A, Pieske B, Ruf T, Fasol R, Just H. Angiotensin I and II exert inotropic effects in atrial but not in ventricular human myocardium. An in vitro study under physiological experimental conditions. Circulation. 1993; 88: 1228–1237.
22. Ullian ME, Walsh LG, Morinelli TA. Potentiation of angiotensin II action by corticosteroids in vascular tissue. Cardiovasc Res. 1996; 32: 266–273.
23. van Esch JHM, Tom B, Dive V, Batenburg WW, Georgiadis D, Yiotakis A, van Gool JMG, de Bruijn RJA, de Vries R, Danser AHJ. Selective angiotensin-converting enzyme C-domain inhibition is sufficient to prevent angiotensin I-induced vasoconstriction. Hypertension. 2005; 45: 120–125.
24. Reckelhoff JF. Sex steroids, cardiovascular disease, and hypertension: unanswered questions and some speculations. Hypertension. 2005; 45: 170–174.
25. Wynne FL, Payne JA, Cain AE, Reckelhoff JF, Khalil RA. Age-related reduction in estrogen receptor-mediated mechanisms of vascular relaxation in female spontaneously hypertensive rats. Hypertension. 2004; 43: 405–412.
26. Orshal JM, Khalil RA. Gender, sex hormones, and vascular tone. Am J Physiol Regul Integr Comp Physiol. 2004; 286: R233–R249.
27. Schuijt MP, Tom B, de Vries R, Saxena PR, Sluiter W, van Kats JP, Danser AHJ. Superoxide does not mediate the acute vasoconstrictor effects of angiotensin II: a study in human and porcine arteries. J Hypertens. 2003; 21: 2335–2344.[Medline] [Order article via Infotrieve]
28. Batenburg WW, Garrelds IM, Bernasconi CC, Juillerat-Jeanneret L, van Kats JP, Saxena PR, Danser AHJ. Angiotensin II type 2 receptor-mediated vasodilation in human coronary microarteries. Circulation. 2004; 109: 2296–2301.
29. Silva-Antonialli MM, Tostes RCA, Fernandes L, Fior-Chadi DR, Akamine EH, Carvalho MHC, Fortes ZB, Nigro D. A lower ratio of AT1/AT2 receptors of angiotensin II is found in female than in male spontaneously hypertensive rats. Cardiovasc Res. 2004; 62: 587–593.
30. Sun Y, Zhang J, Lu L, Chen SS, Quinn MT, Weber KT. Aldosterone-induced inflammation in the rat heart: role of oxidative stress. Am J Pathol. 2002; 161: 1773–1781.
This article has been cited by other articles:
 |
|
 |
|
  S. Bunda, Y. Wang, T. F. Mitts, P. Liu, S. Arab, M. Arabkhari, and A. Hinek Aldosterone Stimulates Elastogenesis in Cardiac Fibroblasts via Mineralocorticoid Receptor-independent Action Involving the Consecutive Activation of G{alpha}13, c-Src, the Insulin-like Growth Factor-I Receptor, and Phosphatidylinositol 3-Kinase/Akt J. Biol. Chem., June 12, 2009; 284(24): 16633 - 16647. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Klotz, D. Burkhoff, I. M. Garrelds, F. Boomsma, and A.H.J. Danser The impact of left ventricular assist device-induced left ventricular unloading on the myocardial renin-angiotensin-aldosterone system: therapeutic consequences? Eur. Heart J., April 1, 2009; 30(7): 805 - 812. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Maggio and M. Segal Differential Corticosteroid Modulation of Inhibitory Synaptic Currents in the Dorsal and Ventral Hippocampus J. Neurosci., March 4, 2009; 29(9): 2857 - 2866. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. R. Palmer, A. P. Pilbrow, C. M. Frampton, T. G. Yandle, L. Skelton, M. G. Nicholls, and A. M. Richards Plasma aldosterone levels during hospitalization are predictive of survival post-myocardial infarction Eur. Heart J., October 2, 2008; 29(20): 2489 - 2496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Mulder, V. Mellin, J. Favre, M. Vercauteren, I. Remy-Jouet, C. Monteil, V. Richard, S. Renet, J. P. Henry, A. Y. Jeng, et al. Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: a comparison with spironolactone Eur. Heart J., September 1, 2008; 29(17): 2171 - 2179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.C. Montezano, G.E. Callera, A. Yogi, Y. He, R.C. Tostes, G. He, E.L. Schiffrin, and R.M. Touyz Aldosterone and Angiotensin II Synergistically Stimulate Migration in Vascular Smooth Muscle Cells Through c-Src-Regulated Redox-Sensitive RhoA Pathways Arterioscler. Thromb. Vasc. Biol., August 1, 2008; 28(8): 1511 - 1518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Yamada, M. Kushibiki, T. Osanai, H. Tomita, and K. Okumura Vasoconstrictor effect of aldosterone via angiotensin II type 1 (AT1) receptor: possible role of AT1 receptor dimerization Cardiovasc Res, July 1, 2008; 79(1): 169 - 178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. W. Krug, S. Kopprasch, C. G. Ziegler, S. Dippong, R. A. Catar, S. R. Bornstein, H. Morawietz, and M. Gekle Aldosterone Rapidly Induces Leukocyte Adhesion to Endothelial Cells: A New Link Between Aldosterone and Arteriosclerosis? Hypertension, November 1, 2007; 50(5): e156 - e157. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Bunda, P. Liu, Y. Wang, K. Liu, and A. Hinek Aldosterone Induces Elastin Production in Cardiac Fibroblasts through Activation of Insulin-Like Growth Factor-I Receptors in a Mineralocorticoid Receptor-Independent Manner Am. J. Pathol., September 1, 2007; 171(3): 809 - 819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Maggio and M. Segal Striking Variations in Corticosteroid Modulation of Long-Term Potentiation along the Septotemporal Axis of the Hippocampus J. Neurosci., May 23, 2007; 27(21): 5757 - 5765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Chai, I. M. Garrelds, R. de Vries, and A.H. Jan Danser Cardioprotective Effects of Eplerenone in the Rat Heart: Interaction With Locally Synthesized or Blood-Derived Aldosterone? Hypertension, April 1, 2006; 47(4): 665 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Schiffrin Effects of Aldosterone on the Vasculature Hypertension, March 1, 2006; 47(3): 312 - 318. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||