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(Hypertension. 2002;40:124.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Mineralocorticoid and Angiotensin Receptor Antagonism During Hyperaldosteronemia

Anastasia S. Mihailidou; Mahidi Mardini; John W. Funder; Matthew Raison

From the Department of Cardiology, Royal North Shore Hospital (A.S.M., M.M., M.R.), Sydney, Australia; The University of Sydney (A.S.M., M.M.), Sydney, Australia; and Baker Medical Research Institute (J.W.F.), Melbourne, Australia.

Correspondence to Dr Anastasia Susie Mihailidou, Department of Cardiology, Royal North Shore Hospital, Pacific Highway, St. Leonards, Sydney, NSW, Australia 2065. E-mail amihaili{at}doh.health.nsw.gov.au

	Abstract

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Elevated aldosterone levels induce a spironolactone-inhibitable decrease in cardiac sarcolemmal Na⁺-K⁺ pump function. Because pump inhibition has been shown to contribute to myocyte hypertrophy, restoration of Na⁺-K⁺ pump function may represent a possible mechanism for the cardioprotective action of mineralocorticoid receptor (MR) blockade. The present study examines whether treatment with the angiotensin type 1 receptor antagonist losartan, with either spironolactone or eplerenone, has additive effects on sarcolemmal Na⁺-K⁺ pump activity in hyperaldosteronemia. New Zealand White rabbits were divided into 7 different groups: controls, aldosterone alone, aldosterone plus spironolactone, aldosterone plus eplerenone, aldosterone plus losartan, aldosterone plus losartan and spironolactone, and aldosterone plus losartan and eplerenone. After 7 days, myocytes were isolated by enzymatic digestion. Electrogenic Na⁺-K⁺ pump current (I_p), arising from the 3:2 Na⁺:K⁺ exchange ratio, was measured by the whole-cell patch clamp technique. Elevated aldosterone levels lowered I_p; treatment with losartan reversed aldosterone-induced reduced pump function, as did MR blockade. Coadministration of spironolactone or eplerenone with losartan enhanced the losartan effect on pump function to a level similar to that measured in rabbits given losartan alone in the absence of hyperaldosteronemia. In conclusion, hyperaldosteronemia induces a decrease in I_p at near physiological levels of intracellular Na⁺ concentration. Treatment with losartan reverses this aldosterone-induced decrease in pump function, and coadministration with MR antagonists produces an additive effect on pump function, consistent with a beneficial effect of MR blockade in patients with hypertension and congestive heart failure treated with angiotensin type 1 receptor antagonists.

Key Words: aldosterone • ion transport • hypertrophy • sodium-potassium pump • myocytes • rabbits

	Introduction

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Elevated plasma aldosterone levels represent a marker of poor prognosis in patients with heart failure.¹ Although ACE inhibitors (ACEI) are commonly used in the treatment of heart failure and hypertension, continuous ACEI administration does not produce a sustained decrease in plasma aldosterone levels^2,3; aldosterone levels are similarly elevated during angiotensin (Ang) II receptor blockade.⁴ The recent Randomized Aldactone Evaluation Study (RALES) demonstrated that adding spironolactone, a mineralocorticoid receptor (MR) antagonist, to standard therapy including an ACEI significantly reduced morbidity and mortality in patients with moderate to severe heart failure.⁵ Similarly, combining spironolactone with an ACEI has a beneficial effect on left ventricular hypertrophy in patients with essential hypertension.⁶ The physiological mechanisms underlying the cardioprotective action of MR blockade remain to be established.

We have recently reported that elevated levels of aldosterone induce a spironolactone-inhibitable decrease in cardiac sarcolemmal Na⁺-K⁺ pump function.⁷ Pump inhibition activates key growth-related genes in cardiac myocytes⁸ and contributes to myocyte hypertrophy.^9,10 Restoration of Na⁺-K⁺ pump function may represent a possible mechanism for the cardioprotective action of MR blockade; another potential mechanism is an interaction between MR antagonist and ACEI treatment. Previous studies from our laboratory have shown that treatment with either ACEI or Ang II antagonists stimulates Na⁺-K⁺ pump activity.^11–13

Until recently, spironolactone was the only MR antagonist available. Spironolactone has relatively high affinity for androgen and progesterone receptors; in contrast, the new MR antagonist eplerenone has much higher selectivity for MRs.¹⁴ In the present study, we examined whether eplerenone reproduces the effect of spironolactone on aldosterone-induced decreased pump function, and whether combined treatment with spironolactone or eplerenone plus an Ang II antagonist, losartan, may have additive effects on cardiac sarcolemmal Na⁺-K⁺ pump activity in hyperaldosteronemia.

Aldosterone (50 µg/kg body weight per day) was administered to rabbits via implanted osmotic minipumps,⁷ producing plasma levels similar to those often seen in human heart failure. Eplerenone and losartan were administered by gavage; spironolactone, by minipump. Aldosterone-treated rabbits received losartan alone, eplerenone alone, or losartan in combination with spironolactone or eplerenone. We measured Na⁺-K⁺ pump current (I_p) in isolated ventricular myocytes using the whole-cell patch clamp technique. Both eplerenone and losartan reversed the aldosterone-induced decrease in cardiac sarcolemmal Na⁺-K⁺ pump function. Coadministration of eplerenone or spironolactone with losartan produced an additive effect on pump function, evidence for a synergy between angiotensin receptor and MR blockade.

	Methods

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Treatment Protocols
A total of 79 male New Zealand White rabbits (2.5 to 3.0 kg; age, 12 to 14 weeks) were maintained on standard chow and free access to tap water. Rabbits were allocated to 7 different treatment groups: controls, aldosterone alone, or combined with eplerenone, losartan alone, and aldosterone plus losartan and either spironolactone or eplerenone. All treatments were administered for 7 days. Aldosterone (50 µg/kg body weight per day) and spironolactone (200 µg/kg body weight per day) were administered by osmotic minipumps.⁷ The dose of losartan (25 mg/kg body weight per day) was based on previous studies from our laboratory.^11,13 Eplerenone (5 mg/kg body weight) was given twice a day to achieve a total dose of 10 mg/kg body weight per day. Eplerenone and losartan in capsules were administered by gavage. Experimental protocols were approved by the institutional ethics committee at Royal North Shore Hospital.

Intraarterial blood pressure was measured as previously described.¹⁵ Changes in systolic blood pressure (SBP) relative to baseline are reported, to control for the effect of the anesthetic. Serum concentrations of Na⁺, K⁺, Mg²⁺, and plasma levels of aldosterone and Ang II were measured at baseline and before euthanasia. Serum levels of K⁺ and pump current data from rabbits treated with spironolactone alone or in combination with aldosterone have been previously reported⁷ but have been included to facilitate comparison. Plasma levels of noradrenaline (NAd) were measured in control and aldosterone treated rabbits.

Measurement of Na⁺-K⁺ Pump Current
After 7 days of treatment, rabbits were anesthetized with ketamine (50 mg/kg) and xylazine hydrochloride (20 mg/kg) given intramuscularly. Single myocytes from either ventricle were isolated and voltage clamped with wide-tipped (4 to 5 µm) patch pipettes with resistances of 0.9 to 1.1 M; measurement of I_p, composition of superfusates, and pipette solutions have been previously described.⁷ Reported currents are normalized for membrane capacitance and, thus, for cell size. Membrane capacitance was determined by measuring the transient current response to 10-mV hyperpolarizing voltage steps applied from a holding potential of -80 mV. The charge transferred during each voltage pulse was derived by integrating the capacitive current with respect to time. Membrane capacitance was then calculated by dividing the charge transferred by the voltage step of 10 mV.

Reagents and Chemicals
Aldosterone, spironolactone, and ouabain were purchased from Sigma Chemical Company. Losartan was kindly donated by Merck, USA and eplerenone by Pharmacia, Chicago, Ill. Tetramethylammonium chloride was purum grade from Fluka, and other chemicals were analytical grade from BDH Laboratory Supplies.

Statistical Analysis
Results are expressed as mean±SE. Statistical comparisons were by unpaired and paired Student’s t test and by 1-way ANOVA followed by Dunnett’s test, with statistical significance set at P<0.05.

	Results

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The dose of 50 µg/kg body weight per day aldosterone produces increases in plasma levels of aldosterone similar to those in clinical hyperaldosteronemia.⁷ Body weight and heart weight were measured in control and aldosterone-treated rabbits, and heart/body weight ratio was calculated. Body weight in control rabbits (2.72±0.06 to 2.82±0.07 kg; n=15) and rabbits infused with aldosterone (2.78±0.07 to 2.85±0.08 kg; n=18) were similar over the 7-day period. In contrast, rabbits treated with aldosterone had significantly larger hearts (7.76±0.20 g) than did control rabbits (6.71± 0.20 g), and heart:body weight ratio in rabbits infused with aldosterone was significantly higher (2.68±0.05 versus 2.50±0.05 g/kg; P=0.01). There were similar increases in membrane capacitance, an index of cell surface area.¹⁶ Cells were included in this study exclusively by whether they could be successfully patch clamped. The capacitances of myocytes from control rabbits and from rabbits infused with aldosterone were 138.5±4.6 pF (n=40) and 150.3±3.5 pF (n=50), P<0.05.

We also measured plasma levels of NAd. Levels of NAd did not change over the 7-day period in control rabbits (9.5±2.6 to 6.3±2.0 nmol/L), whereas levels were significantly lower in aldosterone-treated rabbits over the same period (7.7±1.5 to 1.4±0.8 nmol/L). To determine an effective and safe dose of eplerenone, we treated rabbits with a total dose of 10, 20, or 50 mg/kg body weight per day of eplerenone for 7 days. Table 1 summarizes the effect of each dose on SBP and on serum levels of K⁺ and I_p. All doses were well tolerated, and no hyperkalemia was found at any dose. Only at the highest dose of eplerenone were there significant changes in SBP and I_p, and for subsequent studies, we used 10 mg/kg body weight per day.

View this table: [in this window] [in a new window]   Table 1. Eplerenone and SBP, Serum Levels of K+, and Ip

Plasma concentrations of aldosterone were measured in the different treatment groups at the time of minipump implantation and immediately before the rabbits were euthanized. There was an approximate 3-fold increase in plasma aldosterone levels, similar in all cotreatment groups. Plasma concentrations of Ang II were measured in control, aldosterone-treated, and aldosterone-treated rabbits receiving losartan and eplerenone. Plasma concentrations of Ang II were significantly decreased in aldosterone-treated rabbits compared with controls (mean change, -49±10 pg/mL [n=9] and 10±5 pg/mL [n=7], respectively). Cotreatment with losartan plus eplerenone blunted the effect of infused aldosterone on plasma levels of Ang II (-6±7 pg/mL, n=7).

SBP measured in 4 rabbits infused with aldosterone was higher than SBP in 5 control rabbits (BP, 8±3 versus 0±1 mm Hg, respectively); in the present study, we did not measure the effect of cotreatment with spironolactone. Cotreatment of 5 aldosterone-infused rabbits with low-dose eplerenone did not reverse the aldosterone effect (BP, 6±1 mm Hg), whereas cotreatment with losartan lowered blood pressure (BP, -6±2 mm Hg, n=4), with similar levels in aldosterone-infused rabbits receiving losartan plus eplerenone (BP -8±1 mm Hg, n=7). Aldosterone-treated rabbits receiving spironolactone and losartan showed a significant decrease in blood pressure (BP -3±2 mm Hg, n=7) compared with that of rabbits receiving aldosterone alone.

Effect of Treatment on Serum Concentrations of Na⁺, K⁺, and Mg²⁺
The effect of treatment on serum Na⁺ is shown in Table 2. Although changes are small, infusion of aldosterone produced significant increases in serum Na⁺ compared with control, which persisted in aldosterone-treated rabbits receiving spironolactone, eplerenone, or losartan. In contrast, cotreatment with spironolactone or eplerenone plus losartan abolished the aldosterone-induced increase in serum Na⁺. As in our previous study, a significant decrease in serum K⁺ was measured in aldosterone-treated rabbits (Table 2). Decreased serum K⁺ persisted, despite cotreatment with eplerenone or spironolactone and/or losartan. Because hypomagnesemia often accompanies hypokalemia, we examined whether there was also evidence of lower serum Mg²⁺ in aldosterone-treated rabbits. Infusion of aldosterone produced a decrease in serum Mg²⁺ (Table 2), with eplerenone restoring serum Mg²⁺ to control levels. Although baseline levels were lower in aldosterone-treated rabbits receiving eplerenone plus losartan, serum levels Mg²⁺ did not change over the same period.

View this table: [in this window] [in a new window]   Table 2. Serum Concentrations of Na+, K+, and Mg2+ Before and After (Post-Rx) Treatment

Effect of Treatment on I_p
We measured I_p in isolated myocytes after 7 days of treatment using a Na⁺ concentrate in the pipette solution of 10 mmol/L. Figure 1 shows representative recordings of membrane currents during measurement of I_p in myocytes from control rabbits and from rabbits treated with aldosterone, aldosterone plus losartan and spironolactone, and aldosterone plus losartan and eplerenone. Absolute I_p is dependent on the number of functional pump units in the cell, and this, in turn, is a function of cell surface area. Because cell membrane capacitance (C_m) is a proportional measure of cell surface area,¹⁶ absolute I_p was adjusted for C_m to obtain a standardized measure of pump activity. We previously showed that spironolactone had no direct effect on I_p; low-dose eplerenone similarly has no direct effect on I_p (Table 1). In separate experiments, we examined the effect of treatment with losartan on I_p of myocytes from rabbits not treated with aldosterone. Figure 2A shows mean I_p values and includes the spironolactone and eplerenone data to facilitate comparison. Mean I_p of myocytes isolated from rabbits treated with losartan was significantly higher than in controls, in agreement with previously reported stimulatory effect of losartan on I_p from our laboratory^11,13.

View larger version (20K): [in this window] [in a new window]   Figure 1. Representative recordings of holding currents (Ih). Myocytes were voltage clamped at -40 mV with patch pipettes containing Na+ in a concentration of 10 mmol/L. BaCl2 was used to inhibit K+ channels, and Ip was defined as the shift in Ih induced by 100 µmol/L ouabain. Cells with a similar capacitance (Cm) were chosen to facilitate comparisons. Ih of myocytes from rabbits treated with vehicle (control), aldosterone (Ald), or aldosterone combined with losartan (Ald/Los) plus spironolactone (Ald/Los/SP) or eplerenone (Ald/Los/EPL) is shown. Na+-K+ pump current, Ip, was determined by sampling Ih at 10-second intervals over a 50-second period before and during superfusion of ouabain. Difference in mean values of the sampled currents defined Ip for each cell.

View larger version (21K): [in this window] [in a new window]   Figure 2. A, Effect of treatment on normalized Na+-K+ pump current (Ip). Bars indicate mean Ip of myocytes from control rabbits and rabbits treated with losartan (Los). Data for myocytes from rabbits treated with spironolactone (SP, previously reported7) and eplerenone (EPL, 10 mg/kg body weight per day), shown in Table 1, are included here to facilitate comparison. B, Cotreatment and Ip. Bars indicate mean Ip of myocytes from control rabbits and rabbits treated with aldosterone (Ald), aldosterone plus eplerenone (Ald+EPL), aldosterone plus losartan (Ald+Los), or combined with spironolactone (Ald/Los/SP) or with eplerenone (Ald/Los/EPL). Mean Ip from rabbits treated with aldosterone and spironolactone (Ald+SP) have been previously reported7 but are included to facilitate comparison. Rabbit number in each group is indicated by n; cell number, by parentheses. *Statistically significant difference in mean Ip in cells from control and treated rabbits.

Figure 2B summarizes the effect of cotreatment. Mean I_p of myocytes from aldosterone-treated rabbits was significantly lower compared with control; cotreatment with eplerenone reversed this aldosterone-induced decrease in I_p, paralleling the effect of spironolactone previously reported⁷. Similarly, cotreatment with losartan reversed the aldosterone-induced decrease in I_p. Coadministration of spironolactone or eplerenone plus losartan during hyperaldosteronemia enhanced the losartan effect on pump function to a level similar to that measured in rabbits given losartan alone in the absence of hyperaldosteronemia.

	Discussion

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The present study shows that losartan and eplerenone have effects similar to spironolactone in hyperaldosteronemia, restoring aldosterone-induced decreased cardiac Na⁺-K⁺ pump function to control levels. Coadministration of spironolactone or eplerenone with losartan has an additive effect on Na⁺-K⁺ pump function, suggesting an interaction between angiotensin receptor and MR blockade on pump function that has not been previously described. Low doses of both spironolactone and eplerenone were used, and no hyperkalemia was observed in rabbits receiving losartan alone.

Infusion of aldosterone produced an 3-fold increase in plasma levels, maintained in all cotreatment groups and comparable to clinical hyperaldosteronemia; similarly, the changes in serum concentrations of Na⁺, K⁺, and Mg²⁺ in aldosterone-infused rabbits were comparable to those reported in clinical hyperaldosteronemic states. Rabbits infused with aldosterone had increased serum Na⁺, persisting during treatment with spironolactone, eplerenone, or losartan. In contrast, combined treatment with losartan plus spironolactone or eplerenone blunted the increase in serum Na⁺. However, changes in serum levels of electrolytes might not always reflect intracellular levels. Spironolactone had no effect on aldosterone-induced increased serum levels of Na⁺, although we have previously shown that it reverses aldosterone-induced increased intracellular Na⁺.⁷

MR antagonists are not commonly used in combination with ACEI for fear of serious hyperkalemia. Despite this concern, cotreatment with losartan plus low-dose spironolactone or eplerenone in the present study did not produce hyperkalemia or reverse aldosterone-induced hypokalemia. Because K⁺ depletion has been reported to affect cardiac Na⁺-K⁺ pump function,¹⁷ the possibility that K⁺ deficiency accounts for the decrease in pump current should be considered. In our previous study,⁷ aldosterone-induced reduced serum levels of K⁺ similar to those of the present study did not result in reduced K⁺ content in the myocardium or skeletal muscle, which contains 75% of the total body K⁺ content. An effect of aldosterone on K⁺ balance is associated with a decrease in abundance of Na⁺-K⁺ pump units. We did not find such a decrease in cardiac or skeletal muscle in our previous study.⁷ Finally, it should be noted that K⁺ depletion in rabbits has been reported to increase rather than decrease electrogenic pump activity in cardiac myocytes.¹⁸ It is important to emphasize that in the present study, coadministration of spironolactone or eplerenone with losartan enhanced the losartan effect on cardiac Na⁺-K⁺ pump function without having any effect on aldosterone-induced decrease in serum K⁺, evidence for an action of spironolactone and eplerenone independent of any diuretic effect. Though basal serum Mg²⁺ varied between groups, only in the aldosterone-alone group were levels significantly different at 7 days, a difference reversed in either treatment group.

Aldosterone infusion in the present study decreased circulating Ang II levels, in agreement with previous studies^19,20 and confirming a reciprocal interaction between the 2 hormones.²¹ The effect of losartan to reverse aldosterone-induced decreased pump function might involve an aldosterone-induced increase in angiotensin type 1 (AT₁) receptor density, although the evidence is conflicting. Sun and Weber¹⁹ found a low density of Ang II receptors in rat heart, and although they report an increase in Ang II binding after aldosterone administration, their results are expressed as a percentage of control rather than absolute figures. Robert et al²⁰ interpret their findings to suggest that activation of AT₁ receptors mediates the cardiac effects of aldosterone. It is important to note that in both these studies, aldosterone infusion was supplemented with high salt in the drinking water. High sodium intake has been shown to decrease circulating aldosterone and to significantly increase cardiac AT₁ receptor mRNA in normotensive Wistar-Kyoto rats.²² In addition, previous studies^23,24 showed that ACEI and AT₁ receptor blockade did not block the effects of aldosterone/salt on cardiac fibrosis. In the present study, aldosterone was infused alone without high salt in the drinking water.

Previous studies from our laboratory have shown that treatment with hydralazine had no effect on pump function, despite a significant reduction in blood pressure;¹¹ therefore, the effect of losartan is unlikely to reflect solely a reduction in blood pressure. Similarly, low-dose eplerenone in the present study restored pump function without affecting aldosterone-induced increased blood pressure. An increase in the apparent affinity of the pump for intracellular Na⁺ by losartan¹³ is therefore the most likely mechanism. Aldosterone has also been reported to block NAd uptake in the heart,²⁵ with increased plasma NAd found in guinea pigs receiving aldosterone/salt treatment.²⁶ In contrast, we found aldosterone treatment reduced NAd levels, perhaps reflecting the rabbits’ low salt intake. The other relevant studies have been in heart failure^1,27 rather than hyperaldosteronemia per se.

Mechanism for Additive Effect of Aldosterone Antagonists
Our results show an interaction between aldosterone and angiotensin receptor blockade on cardiac sarcolemmal Na⁺-K⁺ pump function, which has not previously been reported. This interaction may involve a change in the affinity of preexisting pumps for Na⁺ or synthesis of pump isoforms with a high affinity for Na⁺. Multiple isoforms have not been found in the rabbit,²⁸ and we have previously reported that aldosterone had no effect on the concentration of ouabain sensitive- and ouabain-insensitive isoforms of the myocardial pump.⁷ Similarly, previous studies from our laboratory found that the ACEI captopril, did not change ₁- and ₂-pump subunit mRNA.¹² In contrast, modification of the apparent affinity for Na⁺ of preexisting pumps by losartan has been shown in previous studies from our laboratory¹³ and might thus contribute to the interaction with MR blockade.

Another possible mechanism for the interaction between aldosterone and angiotensin receptor antagonists might involve protein kinase C (PKC). ACEI and Ang II receptor antagonists have been reported to prevent translocation of PKC in the heart,^29,30 and in a recent study from our laboratory, PKC was shown to mediate Ang II–mediated inhibition of pump activity.³¹ Aldosterone-induced activation of PKC in noncardiac tissue has been reported by several studies,^32,33 and a similar response in the heart might contribute in part to the aldosterone-induced inhibition of pump function observed in the present study. The effect of losartan on this aldosterone-induced pump inhibition might result from these competing effects on PKC activity. Addition of spironolactone would block the aldosterone-induced activation of PKC.

Perspectives
This is the first report of a synergy between angiotensin receptor and MR blockade on cardiac sarcolemmal Na⁺-K⁺ pump function. MR blockade prevents aldosterone-induced Na⁺-K⁺ pump inhibition and potentiates the action of losartan on pump function in hyperaldosteronemia. Because pump inhibition induces activation of key growth-related cardiac genes⁸ and generation of reactive oxygen species,³⁴ combined AT₁ receptor and MR blockade may have particular benefits in cardiac remodeling.

	Acknowledgments

 
This study was supported by the North Shore Heart Research Foundation and a grant from G.D. Searle/Monsanto/Pharmacia.

Received February 7, 2002; first decision March 5, 2002; accepted May 31, 2002.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L, for the Consensus Trial Study Group. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation. 1990; 82: 1730–1736.[Abstract/Free Full Text]

2. Pitt B. ‘Escape‘ of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther. 1995; 9: 145–149.[CrossRef][Medline] [Order article via Infotrieve]

3. Struthers AD. Aldosterone escape during ACE inhibitor therapy in chronic heart failure. J Cardiac Failure. 1996; 2: 47–54.[CrossRef][Medline] [Order article via Infotrieve]

4. McKelvie RS, Yusuf S, Pericak D, Avezum A, Burns RJ, Probstfield J, Tsuyuki RT, White M, Rouleau J, Latini R, Maggioni A, Young J, Pogue J. Comparison of candesartan, enalapril, and their combination in congestive heart failure: Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. Circulation. 1999; 100: 1056–1064.[Abstract/Free Full Text]

5. 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. N Engl J Med. 1999; 341: 709–717.[Abstract/Free Full Text]

6. Sato AS, Suzuki Y, Saruta T. Effects of spironolactone and angiotensin-converting enzyme inhibitor on left ventricular hypertrophy in patients with essential hypertension. Hypertens Res. 1999; 22: 17–22.[Medline] [Order article via Infotrieve]

7. Mihailidou AS, Bundgaard H, Mardini M, Hansen PS, Kjeldsen K, Rasmussen HH. Hyperaldosteronemia in rabbits inhibits the cardiac sarcolemmal Na⁺ -K⁺ pump. Circ Res. 2000; 86: 37–42.[Abstract/Free Full Text]

8. Komentiani P, Li J, Gnudi L, Kahn BB, Askari A, Xie Z. Multiple signal transduction pathways link Na⁺/K⁺-ATPase to growth-related genes in cardiac myocytes. J Biol Chem. 1998; 24: 15249–15256.

9. Kent RL, Hoober K, Cooper GIV. Load responsiveness of protein synthesis in adult mammalian myocardium: role of cardiac deformation linked to sodium influx. Circ Res. 1989; 64: 74–85.[Abstract/Free Full Text]

10. Huang L, Kometiani P, Xie Z. Differential regulation of Na/K-ATPase -subunit isoform gene expressions in cardiac myocytes by ouabain and other hypertrophic stimuli. J Mol Cell Cardiol. 1997; 29: 3157–3167.[CrossRef][Medline] [Order article via Infotrieve]

11. Hool LC, Whalley DW, Doohan MM, Rasmussen HH. Angiotensin-converting enzyme inhibition, intracellular Na⁺, and Na⁺-K⁺ pumping in cardiac myocytes. Am J Physiol. 1995; 268: C366–C375.[Medline] [Order article via Infotrieve]

12. Hool LC, Gray DF, Robinson BG, Rasmussen HH. Angiotensin-converting enzyme inhibitors regulate the Na⁺-K⁺ pump via effects on angiotensin metabolism. Am J Physiol. 1996; 271: C172–C180.[Medline] [Order article via Infotrieve]

13. Buhagiar KA, Hansen PS, Gray DF, Mihailidou AS, Rasmussen HH. Angiotensin regulates the selectivity of the Na⁺-K⁺ pump for intracellular Na⁺. Am J Physiol. 1999; 277: C461–C468.[Medline] [Order article via Infotrieve]

14. Rabasseda X, Silvestre J, Castaner J. Eplerenone: antihypertensive treatment of heart failure: aldosterone antagonist. Drugs Future. 1999; 24: 488–501.[CrossRef]

15. Mardini M, Mihailidou AS, Wong A, Rasmussen HH. Cyclosporine and FK506 differentially inhibit the sarcolemmal Na⁺-K⁺ pump. J Pharmacol Exp Ther. 2001; 297: 804–810.[Abstract/Free Full Text]

16. Fozzard HA, January CT, Makielski JC. New studies of the excitatory sodium currents in heart muscle. Circ Res. 1985; 56: 475–485.[Abstract/Free Full Text]

17. Nørrgard A, Kjeldsen K, Hansen O. K⁺-dependent 3-O-methylfluorescein phosphatase activity in crude homogenate of rodent heart ventricle: effect of K⁺ depletion and changes in thyroid status. Eur J Pharmacol. 1985; 113: 373–382.[CrossRef][Medline] [Order article via Infotrieve]

18. Shattock MJ, Matsuura H, Ward JPT. Sodium pump current measured in cardiac ventricular myocytes isolated from control and potassium depleted rabbits. Cardiovasc Res. 1994; 28: 1854–1862.[Abstract/Free Full Text]

19. Sun Y, Weber KT. Angiotensin II and aldosterone receptor binding in rat heart and kidney: response to chronic angiotensin II or aldosterone administration. J Lab Clin Med. 1993; 122: 404–411.[Medline] [Order article via Infotrieve]

20. Robert V, Heymes C, Silvestre J-S, Sabri A, Swynghedauw B, Delcayre C. Angiotensin AT₁ receptor subtype as a cardiac target of aldosterone. Hypertension. 1999; 33: 981–986.[Abstract/Free Full Text]

21. Schiffrin EL, Franks DJ, Gutkowska J. Effect of aldosterone on vascular angiotensin II receptors in the rat. Can J Physiol Pharmacol. 1985; 63: 1522–1527.[Medline] [Order article via Infotrieve]

22. Takeda Y, Yoneda T, Demura M, Miyamori I, Mabuchi H. Sodium-induced cardiac aldosterone synthesis causes cardiac hypertrophy. Endocrinology. 2000; 141: 1901–1904.[Abstract/Free Full Text]

23. Sun Y, Ratajska A, Weber KT. Inhibition of angiotensin-converting enzyme and attenuation of myocardial fibrosis by lisinopril in rats receiving angiotensin II. J Lab Clin Med. 1995; 126: 95–101.[Medline] [Order article via Infotrieve]

24. Young MJ, Funder JW. The renin-angiotensin-aldosterone system in experimental mineralocorticoid-salt–induced cardiac fibrosis. Am J Physiol. 1996; 34: E883–E888.

25. Barr CS, Lang CC, Hanson J, Arnott M, Kennedy N, Struthers AD. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol. 1995; 76: 1259–1265.[CrossRef][Medline] [Order article via Infotrieve]

26. Ramirez-Gil JF, Delcayre C, Robert V, Wassef M, Trouve P, Mougenot N, Charlemagne D, Lechat P. In vivo left ventricular function and collagen expression in aldosterone/salt-induced hypertension. J Cardiovasc Pharmacol. 1998; 32: 927–934.[CrossRef][Medline] [Order article via Infotrieve]

27. Burger AJ, Aronson D. Activity of the neurohormonal system and its relationship to autonomic abnormalities in decompensated heart failure. J Card Fail. 2001; 7: 122–128.[Medline] [Order article via Infotrieve]

28. Lancaster MK, Bennett DL, Cook SJ, O’Neill SC. Na/K pump subunit expression in rabbit ventricle and regional variations of intracellular sodium regulation. Pflügers Arch. 2000; 440: 735–739.[CrossRef][Medline] [Order article via Infotrieve]

29. Malhotra A, Reich D, Reich D, Nakouzi A, Sanghi V, Geenan DL, Buttrick PM. Experimental diabetes is associated with functional activation of protein kinase C and phosphorylation of troponin I in the heart, which are prevented by angiotensin II receptor blockade. Circ Res. 1997; 81: 1027–1033.[Abstract/Free Full Text]

30. Takeishi Y, Bhagwat A, Ball NA, Kirkpatrick DL, Periasamy M, Walsh RA. Effect of angiotensin-converting enzyme inhibition on protein kinase C and SR proteins in heart failure. Am J Physiol. 1999; 276: H53–H62.[Medline] [Order article via Infotrieve]

31. Buhagiar KA, Hansen PS, Bewick NL, Rasmussen HH. Protein kinase C contributes to regulation of the sarcolemmal Na⁺-K⁺ pump. Am J Physiol. 2001; 50: C1059–C1063.

32. Christ M, Meyer C, Sippel K, Wehling M. Rapid aldosterone signaling in vascular smooth muscle cells: involvement of phospholipase C, diaglycerol and protein kinase C. Biochem Biophys Res Comm. 1995; 213: 123–129.[CrossRef][Medline] [Order article via Infotrieve]

33. Doolan CM, Harvey BJ. Modulation of cytosolic protein kinase C and calcium ion activity by steroid hormones in rat distal colon. J Biol Chem. 1996; 271: 8763–8767.[Abstract/Free Full Text]

34. Xie Z, Kometiani P, Liu J, Li J, Shapiro JI, Askari A. Intracellular reactive oxygen species mediate the linkage of Na⁺/K⁺-ATPase to hypertrophy and its marker genes in cardiac myocytes. J Biol Chem. 1999; 274: 19323–19328.[Abstract/Free Full Text]

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