Published online before print August 2, 2004, doi: 10.1161/01.CIR.0000138973.55605.38
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2004;110:776-783.)
© 2004 American Heart Association, Inc.
Original Articles |
Mineralocorticoid Receptor Antagonism Prevents the Electrical Remodeling That Precedes Cellular Hypertrophy After Myocardial Infarction
From INSERM U637-EA3759 (E.P., B.-G.K., P.B., S.R., A.M.G., J.-P.B.), IFR3, Montpellier, France, and the Division of Endocrinology and Diabetology and Laboratory of Clinical Chemistry (N.L., M.F.R.), University Hospital, Geneva, Switzerland.
Correspondence to Jean-Pierre Benitah, INSERM U637–EA3759, CHU A. de Villeneuve, 34295 Montpellier, France. E-mail benitah{at}montp.inserm.fr
Received October 28, 2003; de novo received January 29, 2004; revision received April 15, 2004; accepted April 16, 2004.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background— Cardiac hypertrophy underlies arrhythmias and sudden death, for which mineralocorticoid receptor (MR) activity has recently been implicated. We sought to establish the sequence of ionic events that link the initiating insult and MR to hypertrophy development.
Methods and Results— Using whole-cell, patch-clamp and quantitative reverse transcription–polymerase chain reaction techniques on right ventricular myocytes of a myocardial infarction (MI) rat model, we examined the cellular response over time. One week after MI, no sign of cellular hypertrophy was found, but action potential duration (APD) was lengthened. Both an increase in Ca2+ current (ICa) and a decrease in K+ transient outward current (Ito) underlay this effect. Consistently, the relative expression of mRNA coding for the Ca2+ channel 
1C subunit (Cav1.2) increased, and that of the K+ channel Kv4.2 subunit decreased. Three weeks after MI, AP prolongation endured, whereas cellular hypertrophy developed. ICa density, Cav1.2, and Kv4.2 mRNA levels regained control levels, but Ito density remained reduced. Long-term treatment with RU28318, an MR antagonist, prevented this electrical remodeling. In a different etiologic model of abdominal aortic constriction, we confirmed that APD prolongation and modifications of ionic currents precede cellular hypertrophy.
Conclusions— Electrical remodeling, which is triggered at least in part by MR activation, is an initial, early cellular response to hypertrophic insults.
Key Words: hypertrophy • action potentials • ion channels • remodeling • hormones
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Hypertrophy represents the common heart response to a variety of intrinsic or extrinsic physiological or pathological stimuli.1 Hypertrophy precedes and is part of overt heart failure2 and is a key factor in primary heart diseases. The hypertrophied heart shows remodeling of its metabolic, biochemical, and electrophysiological properties1 and is an independent risk factor for ventricular arrhythmias and sudden death.3 In this regard, recent clinical studies have shown that mineralocorticoid receptor (MR) antagonists reduce mortality and morbidity in patients with ventricular hypertrophy.4 The rationale for those studies came from the so-called aldosterone breakthrough in long-term angiotensin-converting-enzyme inhibition therapy.5 The presence of cardiac MRs6,7 suggests that they have local regulatory roles. The mechanisms of this action in cardiac remodeling are not fully understood. The antiarrhythmogenic benefits of MR antagonists might be linked to their role in ameliorating reactive fibrosis8,9 and/or, alternatively, to their electrophysiological effects. Recently, we showed that aldosterone treatment of isolated myocytes mimics the electrophysiological changes that occur during cardiac remodeling.10,11
Irrespective of etiology, the common electrophysiological feature of the hypertrophied cardiomyocyte is action potential duration (APD) prolongation, which is involved in a higher propensity to arrhythmias.12 The change in cardiac repolarization stems from an imbalance of repolarizing and depolarizing ionic currents. However, the downregulation of the outward K+ current, especially the transient one (Ito), and/or the upregulation of the L-type Ca2+ current (ICa) are still controversial.13 Changes may arise not only from the specific etiology and animal models used but also from the stage of the disease.14 Moreover, alteration of ion channels is thought to be an end-organ response that accompanies structural hypertrophy, resulting from global protein synthesis stimulation or fetal gene reprogramming.1 However, temporal dissociation of electrical remodeling and structural hypertrophy has been reported.15,16 Moreover, ionic remodeling might be a primary factor in triggering cardiac hypertrophy.17 Accordingly, electrical remodeling could be independent of mechanical overload, and a specific signal must initiate the remodeling.
In the present study, we analyzed the electrical characteristics of rat myocytes at different stages after myocardial infarction (MI). We show that electrical remodeling precedes cellular hypertrophy. APD lengthened significantly, ICa was upregulated, and Ito was downregulated already at 1 week after MI. Changes in current were matched by changes in mRNA levels. Cellular hypertrophy was evident only 3 weeks after surgery. Moreover, we observed that treatment of post-MI rats with RU28318 prevented early electrical remodeling. In a different model, left ventricular (LV) compensated hypertrophy induced by abdominal constriction, we confirmed that AP prolongation and modifications of ionic currents precede cellular hypertrophy.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animal Models
Myocardial Infarction
MI was induced in 250- to 280-g male Wistar rats (Janvier, Le Genest Saint Isle, France) by left coronary artery ligation.18 Only post-MI hearts that showed a transmural scar were used (always >4: number of parts occupied by the scar from a total of 6, as assessed by visual division of the LV free wall).
Abdominal Aortic Constriction
LV hypertrophy was induced in 150- to 180-g male Wistar rats by abdominal aorta constriction (AC).19 Age-matched, sham-operated animals were used as controls.
RU28318 Treatment
An osmotic minipump (Alzet 2ML4) was implanted subcutaneously at the time of surgery to deliver 50 µg/h RU28318, provided by Aventis (France).
Cell Isolation and Recording Techniques
Animals were euthanized 1 and 3 weeks after surgery with intraperitoneal injection of sodium pentobarbital (50 mg · kg–1). No apparent signs of failure (pulmonary congestion or chamber dilatation) were observed. Ventricular myocytes were isolated enzymatically.11 This investigation conformed to the European Community guide for the care and use of laboratory animals (French decree no. 87/848 of October 19, 1987).
Cellular hypertrophy was monitored by 2-photon microscopy (Zeiss LSM 510 NLO) to calculate cell volume (VC), and the whole-cell patch-clamp technique was used to measure membrane capacitance (Cm),19 an electrical index of membrane surface area. To measure VC, the voltage-sensitive dye 1-(3-sulfonatopropyl)-8-[b-[2-(di-n-butylamino)-6-naphthyl]vinyl]pyridium betaine (di-4-ANEPPS)–loaded cells were illuminated at 840 nm with a mode-locked Ti:sapphire laser (Mira 900, Coherent) and recorded in 3D. Images of spherical beads (Molecular Probes) were recorded under the same conditions to calculate the point spread function. Deconvolution was performed with Huygens (Bitplane AG). VC was estimated by the myocyte cross-sectional area at the center multiplied by the deconvoluted image thickness.
AP and whole-cell current were monitored at 0.1 Hz with an Axopatch 1D amplifier and recorded with pCLAMP-7 (Axon Instruments) at 23°C to 25°C. Series resistance was electronically compensated (40% to 60%). AP, Ito, and ICa were measured with protocols and solutions previously described.11,20
RT-PCR and Real-Time PCR
Total RNA was extracted from isolated cardiomyocytes by a Trizol method (InVitrogen), and its integrity was analyzed by electrophoresis with a chip-based RNA analysis system (Agilent Technologies). To obtain cDNA, 200 ng total RNA was reverse-transcribed with use of the Taqman Gold reverse transcription–polymerase chain reaction (RT-PCR) kit (Applied Biosystems). Real-time PCR analysis was done with an iCycler iQ detection system (Bio-Rad) in a master mix that contained specific primers, as described elsewhere (400 nmol/L for Cav1.221 and cyclophilin22; 500 nmol/L for Kv4.223), AmpliTaq Gold DNA polymerase, and Taqman probes (100 nmol/L) tagged at the 5' end with the fluorescent molecule 6-carboxyfluorescein (5'-FAM) containing the fluorescent quencher moiety 6-carboxytetramethylrhodamine (3'-TAMRA) in 3'. Each measurement was performed in triplicate.
Statistics
Data are presented as mean±SEM and were analyzed with either an unpaired t test or ANOVA. P<0.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Ionic Channel Remodeling Precedes Cellular Hypertrophy After MI
To understand the sequence of events that link the initial insult to hypertrophy, we examined the cellular response over time in post-MI hearts (12 versus 7 animals for 1 week and 12 versus 12 animals for 3 weeks; post-MI versus sham, respectively). To ensure that electrophysiological alteration was assessed in noninfarcted tissue exclusively, only myocytes isolated from the right ventricles (RVs) were used. This procedure eliminates artifacts due to ischemia or apoptosis and thus, deals with reactive hypertrophy.24 After LV infarction, RV hypertrophy, an important determinant in the prognosis of heart failure,25 is also observed26,27 and might be independent of mechanical factors.28
One week after surgery, VC (Figure 1A) and Cm (see below) were similar in myocytes isolated from post-MI and sham-operated rats, indicating that cellular hypertrophy had not occurred at this stage. Three weeks after MI, myocytes were hypertrophied: VC (Figure 1D) and Cm (see below) were increased significantly. In contrast, the AP was prolonged already after 1 week (Figure 1B), and this lengthening was maintained with hypertrophy development (Figure 1E). APDs were consistently lengthened from 20% of repolarization 1 and 3 weeks after MI (Figure 1C and 1F, respectively). The zero-current potential (ER) and AP amplitude were similar among all groups (data not shown).
|
To determine the ionic basis involved in this APD prolongation, we examined ICa and Ito. After 1 week, ICa amplitudes were substantially larger in post-MI than in sham myocytes (inserts in Figure 2A). Normalized to Cm, the increase of ICa densities was statistically significant in the –10- to +20-mV voltage range (Figure 2A). No changes in voltage-dependent availability were observed (Figure 2B). Neither the potential of half-inactivation (V0.5: –25.4±1.7 versus –24.8±1.4 mV for 5 post-MI versus 5 sham, respectively) nor the slope factor (k: –7.8±1.4 versus –8.5±1.6 for post-MI versus sham, respectively) was changed. However, a significant acceleration of activation rates was observed in 1-week post-MI myocytes (Figure 2C). Over the –10- to +20-mV range, the time to peak values (tpeak), determined as the time from onset of depolarization to the time of maximal current amplitude, were significantly reduced. The inactivation kinetics were determined by fitting the decay phase of the current traces to a biexponential function. The fast time constants were significantly smaller in post-MI myocytes (in the –10- to +20-mV voltage range), whereas the slow ones were not affected (Figure 2D). The faster rates of activation and inactivation could be correlated to the increase in ICa.29 In 3-week post-MI myocytes, ICa density and kinetic properties had returned to control values (Figure 2E through 2H). Neither parameter of the availability curves was altered (in mV: –24.0±1.2 and –6.5±0.7 in 7 post-MI myocytes versus –25.5±0.8 and –8.9±1.1 in 7 sham myocytes for V0.5 and k, respectively; Figure 2F). The time courses of activation or inactivation were not affected 3 weeks after MI (Figure 2G and 2H).
|
One week after MI, Ito amplitudes were reduced (inserts in Figure 3A) and then returned to normal 3 weeks after MI (inserts in Figure 3E). Ito densities were significantly decreased from 0 mV in post-MI myocytes (Figure 4A and 4E). There was no change in the voltage- and time-dependent properties of Ito. The availability curves of Ito were not altered (Figure 4B and 4F); V0.5 (in mV) and k values were increased: at week 1, they were –7.9±0.8 versus –9.0±0.6, and –7.3±0.7 versus –6.4±0.5, 17 post-MI versus 14 sham, respectively, and at week 3, they were –9.1±0.8 versus –9.6±0.6 mV, and –8.3±0.7 versus –7.5±0.6, 20 post-MI versus 21 sham, respectively. Furthermore, activation and inactivation rates were unchanged. The tpeak values were not different in any group (Figure 3C and 3G). The time constants of inactivation, best fitted by a monoexponential function, were not altered (Figure 3D and 3H).
|
|
To investigate the molecular mechanisms of the changes in ICa and Ito densities after MI, the expression level of mRNA corresponding to the -subunits of Cav1.2 and Kv4.2, respectively, were quantitatively assessed by real-time RT-PCR. Data were normalized to the amount of mRNA coding for cyclophilin present in the same cell extracts. When expressed as a percentage of the mean amount of mRNA found in sham-operated cells in each experiment, we observed after 1 week a 24% increase in Cav1.2 mRNA (Figure 4A) and a 39% decrease in Kv4.2 mRNA (Figure 4B). By 3 weeks, molecular levels of both channels returned to their respective control levels (Figure 4C and 4D).
MR Activation Contributes to Electrical Remodeling in Post-MI Myocytes
To examine whether inappropriate activation of the MR plays a role during the early response to hypertrophy, we investigated the effect of the MR antagonist RU28318 on animals subjected to MI or sham operation (in 6 versus 5 animals at 1 week and in 4 versus 4 animals at 3 weeks, MI versus sham, respectively). Although it interacts in vitro with the glucocorticoid receptor, RU28318 has been used as a selective MR antagonist because it is rapidly converted in vivo into its 
-lactone form, which is highly selective for MR.30 Infarct size was similar in the post-MI treated groups compared with untreated groups. RU28318 treatment did not have any effect on Cm after 1 week (Figure 2A), whereas it blunted the increase in Cm in post-MI myocytes 3 weeks after surgery. RU28318 also prevented lengthening of the APD (Figure 5B). AP area, evaluated by integration of voltage variation over time, increased significantly, reflecting APD lengthening in post-MI myocytes, because neither AP amplitude nor ER was modified. At both weeks 1 and 3, RU28318 treatment blunted the AP prolongation. The ICa density-voltage relations were fitted with a function to estimate the maximal conductance (GmaxICa).10 The significant increase of GmaxICa in the 1-week post-MI group was blunted by RU28318 treatment, which did not have any effect on GmaxICa in the sham group or in the myocytes 3 weeks after MI (Figure 5C). The effect of RU28318 treatment on Ito was determined on slope conductances (GsIto) estimated by linear fitting of the current density–voltage relations from +10 to +60 mV. Compared with sham-operated groups, mean GsIto was decreased significantly after MI at 1 and 3 weeks (Figure 2D). This effect was prevented by treatment with RU28318, which also blunted Cav1.2 and Kv4.2 mRNA alterations (data not shown).
|
AC Alters Ionic Currents Before Cellular Hypertrophy Develops
To investigate whether early electrical remodeling is specific to the post-MI model, we examined the well-established AC model19 by using approaches similar to those in the post-MI model. To minimize electrophysiological heterogeneity, we selected cells from the LV apex.19 Hypertrophy was not evident until 3 weeks after surgery (heart weight—to—body weight ratios [in mg/g] of AC versus sham-operated rats, respectively, were 4.67±0.1 [n=8] versus 4.61±0.1 [n=10] at week 1 and 5.10±0.1 [n=12] versus 4.51±0.1 [n=11] at week 3; P<0.005). Whereas there was no change in Cm or VC at week 1 (Figure 6A), significant increases were observed 3 weeks after AC (Figure 6D). As in the post-MI model, AC myocytes also showed AP prolongation after 1 week, whereas no change in ER or AP amplitude was detected. At week 1, an increase in ICa and a decrease in Ito (Figure 6A through 6C) might explain the AP prolongation. No changes in ICa or Ito activation or inactivation were observed (data not shown). This could indicate an increase in the number of Ca2+ channels and a decrease in the number of Ito channels. Consistently, the increase in ICa induced by ß-adrenergic stimulation was similar in sham and AC animals. At 0 mV, 1 µmol/L isoproterenol increased ICa by 175±20% (n=5) versus 174±10% (n=11) in AC versus sham myocytes, respectively. Three weeks after AC, cellular hypertrophy had normalized the elevated ICa values to control levels, whereas Ito density remained reduced.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Cardiac hypertrophy develops as an adaptation to chronic insults. Here we show that electrical remodeling takes place before cellular hypertrophy develops, indicating that these alterations may be independent of mechanical overload. We demonstrate that the mineralocorticoid system, an important component of the neurohormonal reaction, plays an important role in electrical remodeling after MI.
Our results are consistent with published work on electrical remodeling studied at different periods during the development of hypertrophy.12,13,19,24 Most importantly, our data show that electrical remodeling occurs before cellular hypertrophy development. AP prolongation at the early stages of cardiac hypertrophy may be linked to the upregulation of ICa and the downregulation of Ito. Later, once cellular hypertrophy is established, only reduced Ito persists, whereas ICa values regain control levels. After 3 weeks, the decrease in repolarizing Ito would result in AP prolongation. This repolarization rate slowing would enhance ICa activation, which in turn modulates APD.31 This hypothesis does not exclude that concomitant changes in other currents may also be involved in AP prolongation.13 The reported changes in ICa and Ito are rather controversial. A downregulation in Ito is generally reported, whereas an increased, a decreased, or an unchanged ICa have been described.13,14,32 These discrepancies may reflect differences in etiology, species, nature of analyses, experimental conditions, and even more important, the stage of disease.14 Our data support the last hypothesis, because they show that ICa increases at early stages and returns to control values once cellular hypertrophy becomes established. Whereas we observed a downregulation of Kv4.2 genes and currents before manifest hypertrophy occurred, only the Ito density decrease persisted with cellular hypertrophy. We suggest that this might reflect a Ca2+ dependence on Ito regulation, as has been noted for aldosterone regulation.11 After 3 weeks, when ICa regained control levels, the absence of a net regulation of the Kv4.2 gene and current magnitude rendered a decrease in density related to the increase in cell size. However, we cannot exclude the possibility that other processes, such as alterations of protein trafficking, come into play.
Taken together, our results show that electrical remodeling precedes cellular hypertrophy, independently of the so-called mechanoconversion,1 and might be one of the primary factors.14,17,32 In this regard, calcineurin, which triggers the hypertrophic response,33 is a Ca2+-dependent phosphatase. Hence, an increase in Ca2+ signaling must precede calcineurin activation to initiate hypertrophy. In the present work, using 2 different models of cardiac hypertrophy, we have shown that AP prolongation, which enhances Ca2+ influx, precedes cardiac hypertrophy. This early enhancement may be responsible for initiating the hypertrophic response. For example, cardiac-specific overexpression of L-type Ca2+ channels resulted in an increased Ca2+ influx and enhanced basal contractility in mice at 8 weeks of age34 and progressed to cardiomyopathy by 8 months of age.17 The signal that induces the increase in L-type Ca2+ channel gene transcription might be at the origin of hypertrophy. We thus suggest that early after an insult, there are neurohormonal signals that induce the Ca2+ influx increase and activate gene transcription, thereby triggering cardiac hypertrophy.
The role of inappropriate MR activation, as an independent contributor to cardiovascular injury, has been suggested by numerous studies. Collectively, different animal35 and clinical4 studies have emphasized the pathophysiological cardiac role of MRs. One of the more striking results of the resurgent use of the aldosterone-blocking agent spironolactone or its analogue eplerenone to treat patients with systolic LV dysfunction has been a reduction in the incidence of arrhythmias, which have been mainly related to fibrosis.4,8,9,35 However, other protective mechanisms have been underscored. Aldosterone is the major regulator of body ion homeostasis. In this regard, we recently established in vitro that aldosterone decreases Ito secondary to enhanced Ca2+ signaling,11 which probably arises from the aldosterone-induced upregulation of ICa.10 In the present study, the MR antagonist RU28318 blunted early electrical remodeling. Moreover, spironolactone is also a powerful blocker of ICa on vascular smooth muscle cells.36 We suggest that, besides fibrinogenesis, MR activation has a crucial role in electrical remodeling early after myocardial insult and before morphological remodeling. These early changes in ionic currents might open new therapeutic perspectives.
|
Acknowledgments |
|---|
Research support was provided by INSERM, the Novartis Foundation, and the Swiss National Science Foundation. Drs Kerfant and Richard were supported by a grant from the Fondation pour la Recherche Médicale. Drs Richard and Gómez are CNRS scientists. We thank R. Perrier for technical support and Pr A. Pappano for careful reading of the manuscript and helpful discussion.
|
Footnotes |
|---|
*The first 2 authors contributed equally to this work.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Swynghedauw B. Molecular mechanisms of myocardial remodeling. Physiol Rev. 1999; 79: 215–262.
2. Braunwald E, Bristow MR. Congestive heart failure: fifty years of progress. Circulation. 2000; 102 (suppl 4): 14–23.
3. Kannel WB, Abbott RD. A prognostic comparison of asymptomatic left ventricular hypertrophy and unrecognized myocardial infarction: the Framingham Study. Am Heart J. 1986; 111: 391–397.[CrossRef][Medline] [Order article via Infotrieve]
4. Pitt B. Aldosterone blockade in patients with systolic left ventricular dysfunction. Circulation. 2003; 108: 1790–1794.
5. Struthers A. Aldosterone escape during ACE inhibitor therapy in chronic heart failure. Eur Heart J. 1995; 16 (suppl N): 103–106.
6. Lombes M, Farman N, Bonvalet J, et al. Identification and role of aldosterone receptors in the cardiovascular system. Ann Endocrinol (Paris). 2000; 61: 41–46.[Medline] [Order article via Infotrieve]
7. Young M, Funder J. Mineralocorticoid receptors and pathophysiological roles for aldosterone in the cardiovascular system. J Hypertens. 2002; 20: 1465–1468.[CrossRef][Medline] [Order article via Infotrieve]
8. Lijnen P, Petrov V. Induction of cardiac fibrosis by aldosterone. J Mol Cell Cardiol. 2000; 32: 865–879.[CrossRef][Medline] [Order article via Infotrieve]
9. Funder J. Mineralocorticoids and cardiac fibrosis: the decade in review. Clin Exp Pharmacol Physiol. 2001; 28: 1002–1006.[CrossRef][Medline] [Order article via Infotrieve]
10. Benitah JP, Vassort G. Aldosterone upregulates Ca2+ current in adult rat cardiomyocytes. Circ Res. 1999; 8512: 1139–1145.
11. Benitah JP, Perrier E, Gomez AM, et al. Effects of aldosterone on transient outward K+ current density in rat ventricular myocytes. J Physiol. 2001; 537 (pt 1): 151–160.
12. Marban E. Cardiac channelopathies. Nature. 2002; 415: 213–218.[CrossRef][Medline] [Order article via Infotrieve]
13. Armoundas A, Wu R, Juang G, et al. Electrical and structural remodeling of the failing ventricle. Pharmacol Ther. 2001; 92: 213–230.[CrossRef][Medline] [Order article via Infotrieve]
14. Benitah JP, Kerfant BG, Vassort G, et al. Altered communication between L-type calcium channels and ryanodine receptors in heart failure. Front Biosci. 2002; 7: e263–e275.[Medline] [Order article via Infotrieve]
15. Schoenmakers M, Ramakers C, van Opstal JM, et al. Asynchronous development of electrical remodeling and cardiac hypertrophy in the complete AV block dog. Cardiovasc Res. 2003; 59: 351–359.
16. Peschar M, Vernooy K, Vanagt WY, et al. Absence of reverse electrical remodeling during regression of volume overload hypertrophy in canine ventricles. Cardiovasc Res. 2003; 58: 510–517.
17. Muth JN, Bodi I, Lewis W, et al. A Ca2+-dependent transgenic model of cardiac hypertrophy: a role for protein kinase C. Circulation. 2001; 103: 140–147.
18. Gomez AM, Guatimosim S, Dilly KW, et al. Heart failure after myocardial infarction: altered excitation-contraction coupling. Circulation. 2001; 104: 688–693.
19. Benitah JP, Gomez AM, Bailly P, et al. Heterogeneity of the early outward current in ventricular cells isolated from normal and hypertrophied rat hearts. J Physiol. 1993; 469: 111–138.
20. Gómez AM, Kerfant BG, Vassort G. Microtubule disruption modulates Ca2+ signaling in rat cardiac myocytes. Circ Res. 2000; 86: 30–36.
21. Martin DJ, McClelland D, Herd MB, et al. Gabapentin-mediated inhibition of voltage-activated Ca2+ channel currents in cultured sensory neurones is dependent on culture conditions and channel subunit expression. Neuropharmacology. 2002; 42: 353–366.[CrossRef][Medline] [Order article via Infotrieve]
22. Harrison DC, Medhurst AD, Bond BC, et al. The use of quantitative RT-PCR to measure mRNA expression in a rat model of focal ischemia: caspase-3 as a case study. Brain Res Mol Brain Res. 2000; 75: 143–149.[Medline] [Order article via Infotrieve]
23. Tkatch T, Baranauskas G, Surmeier DJ. Kv4.2 mRNA abundance and A-type K+ current amplitude are linearly related in basal ganglia and basal forebrain neurons. J Neurosci. 2000; 20: 579–588.
24. Huang B, Qin D, El-Sherif N. Early down-regulation of K+ channel genes and currents in the postinfarction heart. J Cardiovasc Electrophysiol. 2000; 11: 1252–1261.[CrossRef][Medline] [Order article via Infotrieve]
25. Yu CM, Sanderson JE, Chan S, et al. Right ventricular diastolic dysfunction in heart failure. Circulation. 1996; 93: 1509–1514.
26. Pfeffer MA, Pfeffer JM, Fishbein MC, et al. Myocardial infarct size and ventricular function in rats. Circ Res. 1979; 44: 503–512.
27. Sethi R, Dhalla KS, Beamish RE, et al. Differential changes in left and right ventricular adenylyl cyclase activities in congestive heart failure. Am J Physiol. 1997; 272 (pt 2): H884–H893.[Medline] [Order article via Infotrieve]
28. Nahrendorf M, Hu K, Fraccarollo D, et al. Time course of right ventricular remodeling in rats with experimental myocardial infarction. Am J Physiol. 2003; 284: H241–H248.
29. Delgado C, Artiles A, Gomez AM, et al. Frequency-dependent increase in cardiac Ca2+ current is due to reduced Ca2+ release by the sarcoplasmic reticulum. J Mol Cell Cardiol. 1999; 31: 1783–1793.[CrossRef][Medline] [Order article via Infotrieve]
30. Kim PJ, Cole MA, Kalman BA, et al. Evaluation of RU28318 and RU40555 as selective mineralocorticoid receptor and glucocorticoid receptor antagonists, respectively: receptor measures and functional studies. J Steroid Biochem Mol Biol. 1998; 67: 213–222.[CrossRef][Medline] [Order article via Infotrieve]
31. Sah R, Ramirez RJ, Backx PH. Modulation of Ca2+ release in cardiac myocytes by changes in repolarization rate: role of phase-1 action potential repolarization in excitation-contraction coupling. Circ Res. 2002; 90: 165–173.
32. Benitah J-P, Gomez A-M, Virsolvy A, et al. New perspectives on the key role of calcium in the progression of heart disease. J Muscle Res Cell Motil. 2003; 24: 277–285.[CrossRef]
33. Molkentin JD, Lu JR, Antos CL, et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998; 93: 215–228.[CrossRef][Medline] [Order article via Infotrieve]
34. Muth JN, Yamaguchi H, Mikala G, et al. Cardiac-specific overexpression of the 1 subunit of the L-type voltage-dependent Ca2+ channel in transgenic mice: loss of isoproterenol-induced contraction. J Biol Chem. 1999; 274: 21503–21506.
35. Firsov D, Muller OG. Aldosterone action in the heart. Pflugers Arch. 2003; 446: 328–333.[CrossRef][Medline] [Order article via Infotrieve]
36. Mironneau J. Calcium channel antagonist effects of spironolactone, an aldosterone antagonist. Am J Cardiol. 1990; 65: 7K–8K.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  B. Martin-Fernandez, M.ķa Miana, N. De las Heras, G. Ruiz-Hurtado, M.ķa Fernandez-Velasco, M. Bas, S. Ballesteros, V. Lahera, V. Cachofeiro, and C. Delgado Cardiac L-type calcium current is increased in a model of hyperaldosteronism in the rat Exp Physiol, June 1, 2009; 94(6): 675 - 683. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Gomez, A. Rueda, Y. Sainte-Marie, L. Pereira, S. Zissimopoulos, X. Zhu, R. Schaub, E. Perrier, R. Perrier, C. Latouche, et al. Mineralocorticoid Modulation of Cardiac Ryanodine Receptor Activity Is Associated With Downregulation of FK506-Binding Proteins Circulation, April 28, 2009; 119(16): 2179 - 2187. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. K. Mork, I. Sjaastad, O. M. Sejersted, and W. E. Louch Slowing of cardiomyocyte Ca2+ release and contraction during heart failure progression in postinfarction mice Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H1069 - H1079. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Pitt, A. Ahmed, T. E. Love, H. Krum, J. Nicolau, J. S. Cardoso, A. Parkhomenko, M. Aschermann, R. Corbalan, H. Solomon, et al. History of Hypertension and Eplerenone in Patients With Acute Myocardial Infarction Complicated by Heart Failure Hypertension, August 1, 2008; 52(2): 271 - 278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Fraccarollo, P. Galuppo, S. Schraut, S. Kneitz, N. van Rooijen, G. Ertl, and J. Bauersachs Immediate Mineralocorticoid Receptor Blockade Improves Myocardial Infarct Healing by Modulation of the Inflammatory Response Hypertension, April 1, 2008; 51(4): 905 - 914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Sartorio, D. Fraccarollo, P. Galuppo, M. Leutke, G. Ertl, I. Stefanon, and J. Bauersachs Mineralocorticoid Receptor Blockade Improves Vasomotor Dysfunction and Vascular Oxidative Stress Early After Myocardial Infarction Hypertension, November 1, 2007; 50(5): 919 - 925. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Pitt Promise of Mineralocorticoid Receptor Blockade in Asymptomatic Left Ventricular Dysfunction Hypertension, September 1, 2007; 50(3): 461 - 462. [Full Text] [PDF]
|
|
|
|
|
|
B. Pitt and G. S. Pitt Added Benefit of Mineralocorticoid Receptor Blockade in the Primary Prevention of Sudden Cardiac Death Circulation, June 12, 2007; 115(23): 2976 - 2982. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nattel, A. Maguy, S. Le Bouter, and Y.-H. Yeh Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial Fibrillation Physiol Rev, April 1, 2007; 87(2): 425 - 456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Antoons, P. G. A. Volders, T. Stankovicova, V. Bito, M. Stengl, M. A. Vos, and K. R. Sipido Window Ca2+ current and its modulation by Ca2+ release in hypertrophied cardiac myocytes from dogs with chronic atrioventricular block J. Physiol., February 15, 2007; 579(1): 147 - 160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Boixel, B. Gavillet, J.-S. Rougier, and H. Abriel Aldosterone increases voltage-gated sodium current in ventricular myocytes Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2257 - H2266. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Pitt, M. Gheorghiade, F. Zannad, J. L. Anderson, D. J. van Veldhuisen, A. Parkhomenko, R. Corbalan, E. Q. Klug, R. Mukherjee, H. Solomon, et al. Evaluation of eplerenone in the subgroup of EPHESUS patients with baseline left ventricular ejection fraction <=30% Eur J Heart Fail, May 1, 2006; 8(3): 295 - 301. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Pereira, J. Matthes, I. Schuster, H. H. Valdivia, S. Herzig, S. Richard, and A. M. Gomez Mechanisms of [Ca2+]i Transient Decrease in Cardiomyopathy of db/db Type 2 Diabetic Mice Diabetes, March 1, 2006; 55(3): 608 - 615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Perrier, S. Richard, Y. Sainte-Marie, B. C. Rossier, F. Jaisser, E. Hummler, and J.-P. Benitah A direct relationship between plasma aldosterone and cardiac L-type Ca2+ current in mice J. Physiol., November 15, 2005; 569(1): 153 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shah, F. G. Akar, and G. F. Tomaselli Molecular Basis of Arrhythmias Circulation, October 18, 2005; 112(16): 2517 - 2529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Pitt, H. White, J. Nicolau, F. Martinez, M. Gheorghiade, M. Aschermann, D. J. van Veldhuisen, F. Zannad, H. Krum, R. Mukherjee, et al. Eplerenone Reduces Mortality 30 Days After Randomization Following Acute Myocardial Infarction in Patients With Left Ventricular Systolic Dysfunction and Heart Failure J. Am. Coll. Cardiol., August 2, 2005; 46(3): 425 - 431. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Laleve, M. C. Rebsamen, S. Barrere-Lemaire, E. Perrier, J. Nargeot, J.-P. Benitah, and M. F. Rossier Aldosterone increases T-type calcium channel expression and in vitro beating frequency in neonatal rat cardiomyocytes Cardiovasc Res, August 1, 2005; 67(2): 216 - 224. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||