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Cardiovascular Drugs and Therapy

, Volume 28, Issue 2, pp 137–143 | Cite as

Protective Effects of Aliskiren on Atrial Ionic Remodeling in a Canine Model of Rapid Atrial Pacing

  • Zhiqiang Zhao
  • Xinghua Wang
  • Jian Li
  • Wansong Yang
  • Lijun Cheng
  • Yan Chen
  • Tong Liu
  • Enzhao Liu
  • Kangyin Chen
  • Guangping Li
ORIGINAL ARTICLE

Abstract

Purpose

Aliskiren inhibits the activation of the renin-angiotensin system. Here, we investigated the effects of aliskiren on chronic atrial iron remodeling in the experimental canine model of rapid atrial pacing.

Methods

Twenty-eight dogs were assigned to sham (S), control paced (C), paced + aliskiren (10 mg Kg−1 d−1, A1), and paced + aliskiren (20 mg Kg−1 d−1, A2) groups. Rapid atrial pacing at 500 bpm was maintained for 2 weeks, while group S was not paced. Levels of serum angiotensin-converting enzyme and angiotensin II after pacing were determined by ELISA. Whole-cell patch-clamp technique, western blot, and RT-PCR were applied to assess atrial ionic remodeling.

Results

The density of I CaL and I Na currents (pA/pF) was significantly lower in group C compared with group S (I CaL: −4.09 ± 1.46 vs. −6.12 ± 0.58,P < 0.05; I Na: 30.48 ± 6.08 vs. 46.31 ± 4.73, P < 0.05). However, the high dose of aliskiren elevated the density of I CaL and I Na currents compared with group C (I CaL: −6.23 ± 1.35 vs. −4.09 ± 1.46, P < 0.05; I Na: 58.62 ± 16.17 vs. 30.48 ± 6.08, P < 0.01). The relative mRNA and protein expression levels of Cav1.2 and Nav1.5α were downregulated in group C respectively (Cav1.2: 0.46 ± 0.08; Nav1.5α: 0.52 ± 0.08, P < 0.01; Cav1.2: 0.31 ± 0.03; Nav1.5α: 0.41 ± 0.04, P < 0.01;), but were upregulated by aliskiren.

Conclusions

Aliskiren has protective effects on atrial tachycardia-induced atrial ionic remodeling.

Keywords

Atrial fibrillation Atrial remodeling Aliskiren Ca2+ channel Na+ channel 

Introduction

Atrial fibrillation (AF) is the most frequently encountered arrhythmia in clinical practice and no single modality is effective for all patients [1]. An improved understanding of the mechanisms underlying AF is needed for the development of novel therapeutic approaches [2]. The relationship between the renin-angiotensin system (RAS) and AF has been the focus of many studies. Our previous studies have indicated that in long-term atrial tachycardic dogs, Ang-(1–7) could prevent the action potential duration shortening, suppress the decrease in transient outward current (I TO) and L-type calcium channel (I CaL), and reduce the inducibility and duration of AF, as well as attenuate interstitial fibrosis and the angiotensin (Ang) II-mediated expression of extracellular signal-regulated kinases 1/2 (ERK1/2) [3, 4]. Voltage-gated sodium (Nav) channels initiate action potential (AP) depolarization and are responsible for propagating the AP throughout the heart [5]. Investigations of non-antiarrhythmic drugs interfering with RAS have demonstrated beneficial effects of preventing the episodes of AF in both animals and humans, suggesting a possible role for RAS as a mediator of atrial remodeling in AF.

Aliskiren is a recently developed and first clinically available direct renin inhibitor, with a molecular weight of 609.8. Aliskiren has oral bioavailability, an extended half-life [6], and ideal pharmacokinetics. Aliskiren directly inhibits renin, by decreasing the plasma renin activity (PRA) [7]. It acts by binding to the active sites of renin, preventing angiotensinogen from binding and being cleaved to form Ang I, thereby inhibiting the activation of RAS at the rate-limiting step [8, 9, 10, 11]. Aliskiren can induce phosphorylation on serine and tyrosine residues of Ang II, which are associated with Ang II, which is an independent activator of mitogen-activated protein kinase. Ang II can activate the ERK1/2 pathway, which is known to be involved in cell hypertrophy and proliferation [12].

Materials and Methods

Animal Model Preparation

The dogs used in this study were approved by the Experimental Animal Administration Committee of Tianjin Medical University and Tianjin Municipal Commission for Experimental Animal Control. The approach used to induce and maintain sustained AF in experimental dogs has been previously described [13]. In this study, 28 mongrel dogs of either gender, weighing between 11 and 15 kg, were randomly assigned to a sham group (S), control paced group (C), paced + aliskiren group (10 mg · Kg−1 · d−1, A1), and paced + aliskiren group (20 mg · Kg−1 · d−1, A2), with seven dogs in each group. The animals were anesthetized with intravenous pentobarbital sodium (30 mg · kg−1). After intubation and mechanical ventilation, a modified unipolar J pacing lead (St. Jude Medical, Saint Paul, MN, USA) was inserted through the right jugular vein and the distal end of the lead was tightly positioned in the right atrium. The initial atrial capture was verified by an external stimulator (ALC-V8, Shanghai Alcott Biotech CO.,LTD, China). Then, the proximal end of the pacing lead was connected to a programmable pacemaker (Fudan University, Shanghai, China), which was inserted into a pocket in the neck. The dogs in groups C, A1, and A2 were paced at 500 bpm (120-ms cycle length) with 0.2-ms square-wave pulses at twice-threshold current for 2 weeks. The electrocardiogram (ECG) was monitored after 24 h in conscious dogs and then every other day to ensure continuous 1:1 atrial capture. The dogs in group S were without pacing and were studied 2 weeks after pacemaker insertion. Groups A1 and A2 received orally 10 and 20 mg · Kg−1 · d−1 aliskiren, respectively, for 2 weeks during pacing. Systolic blood pressure was measured by carotid artery intubation during anesthesia at baseline and after 2 weeks of rapid atrial pacing. ECG and blood pressure were recorded by a multi-channel electrophysiological recorder (TOP2001, Shanghai Hong Tong Industrial Co., China).

Single-Cell Electrophysiology

Solutions

Tyrode’s solution contained (mmol/L) 136 NaCl, 5.4 KCl, 0.8 MgCl2, 1.8 CaCl2, 0.33 NaH2PO4, 10 glucose, and 10 HEPES, pH 7.4 (adjusted with NaOH). KB solution contained (mmol/L) 20 KCl, 10 KH2PO4, 10 glucose, 70 L-glutamic acid, 10 taurine, 10 EGTA, and 0.2 % bovine serum albumin, pH 7.4 (adjusted with KOH). The pipette solution used to record I CaL and I Na contained (mmol/L) 20 CsCl, 1 MgCl2, 10 EGTA, 80 aspartic acid, 80 CsOH, 0.1 Na3GTP, 5 Mg2ATP, 10 HEPES, 20 TEA-Cl, and 5 Na2phosphocreatine 4H2O, pH 7.25 (adjusted with CsOH). The extracellular solution recording I Na contained (mmol/L) 110 choline-Cl, 10 NaCl, 20 CsCl, 1 MgCl2, 1 CaCl2, 10 HEPES, and 10 glucose, pH 7.4 (adjusted with NaOH). The extracellular solution recording I CaL was the same as the Tyrode’s solution.

Atrial Cell Isolation

According to the cell isolation methods of Yue et al. [14] and Li et al. [15], a median sternotomy was performed, and the hearts were quickly excised. After cardiac excision, the hearts were immersed in Tyrode’s solution at 4 °C. The solutions used for dissection and perfusion were equilibrated with 100 % O2. The left circumflex artery was cannulated and connected to the Langendorff perfusion system filled with Tyrode’s solution free from CaCl2 and saturated with 100 % O2. The heart was perfused at 25 mL/min and the perfusion pressure was maintained at 80 mmHg. The arterial branches were ligated with silk thread to ensure adequate perfusion. The tissue was then perfused at 25 mL/min with Ca2+-free Tyrode’s solution at 37 °C for 20 min, followed by a 40-min perfusion with the same solution containing collagenase (150 U/mL, CLSII, Worthington Biochemical, Lakewood, NJ, USA), 0.5 % bovine serum albumin (Sigma Chemical Co., St. Louis, MO, USA) and 50 mM CaCl2. Softened tissue from a well-perfused region of the LA-free wall was removed with forceps, tissue pieces were washed with KB solution, and gently triturated. Cells were dispersed by gentle pipetting for 5 min in KB solution and then filtrated. After the above procedure, the myocardial cells were kept at room temperature for 60 min.

The quiescent rod-shaped cells showing clear cross striations were chosen. A small aliquot of the solution containing the isolated cells was placed in a 1-ml chamber mounted on the stage of an inverted microscope (Olympus, Tokyo, Japan). Cells were allowed to adhere to the bottom of the chamber for 10 min, and then the cells were superfused at 3 mL/min with Tyrode’s solution [4].

Data Acquisition

To record ionic currents, we used the whole-cell patch-clamp technique with Axopatch 200B amplifier (Molecular Devices, Sunnyvale, CA, USA). Borosilicate glass microelectrodes, which have a 1.5-mm outer diameter and a 1.1-mm inner diameter, were used. These microelectrodes kept tip resistance of 2.5–5 MΩ. To control for cell-size variability, currents were expressed as densities (pA/pF). Voltage command pulses were generated by a 12-bit digital-to-analog (D/A) converter (Digidata 1200, Molecular Devices) controlled by the Clampfit 10.2 software. Recordings were sampled at 10 kHz and low-pass filtered at 1–5 kHz.

Western Blotting

LA tissues from each group were prepared for western blot analysis. Protein was extracted with total protein extraction buffer. An equal amount of protein was loaded onto a 6 % SDS denaturing polyacrylamide gel, separated by electrophoresis, transferred onto a polyvinylidene fluoride membrane (Merck Millipore, Billerica, MA, USA), and incubated with the specific primary antibody overnight at 4 °C. The membranes were then washed and subsequently incubated with the secondary antibody conjugated to horseradish peroxidase. Proteins were visualized using enhanced chemiluminescence. Protein levels of I CaLα1C subunit (Cav1.2) and I Nav1.5α subunit (Nav1.5α) were expressed as the ratio against the levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Anti-GAPDH, anti-Nav1.5α, and anti-Cav1.2 antibodies were purchased from Abcam Inc. (Cambridge, UK).

RNA Isolation and RT-PCR

Specific oligonucleotide primer pairs used to amplify the Na+ and Ca2+ channel genes were designed according to sequences obtained from GeneBank. GenBank sequence numbers are NM_001002994 (Nav1.5α), AB262537.1 (Cav1.2), AF021873.2 (β-actin), and NM001003142.1 (GAPDH). The primers specific to each channel were: 5′-TGAATGTCCTCCTCGTCTG-3′ and 5′-TGTTGGTTGAAGTTGTCG-3′ (Nav1.5α, 424 bp), 5′-CCCTGCTGTGGACCTTCA-3′ and 5′-CACCTTCCGTGCTGTTGC-3′ (Cav1.2, 288 bp), 5′-CAGAGCAAGCGGGGCATC-3′ and 5′-AGGTAGTCAGTCAGGTCC-3′ (β-actin, 392 bp), and 5′-ACCACAGTCCATGCCATCAC-3′ and 5′-CACCACCTTCTTGATGTCATC-3′ (GAPDH, 261 bp). β-actin and GAPDH were included as the internal control.

Total RNA (200 ng) was used as the template for RT-PCR using a commercially available kit (TaKaRa, Shiga, Japan). The PCR consisted of 35 cycles of 94 °C for 40 s, 51 °C (Nav1.5α), 52 °C (Cav1.2, β-actin), or 55 °C (GAPDH) for 30 s, and 72 °C for 30 s. Five microliters of product were analyzed by 1 % agarose gel electrophoresis.

Statistical Analysis

All quantitative data are expressed as mean ± SEM. Statistical comparisons among groups were performed by one-way analysis of variance (ANOVA). If significant effects were indicated by ANOVA, a t test with Bonferroni’s correction or the Dunnett’s test was used to evaluate the significance of differences between individual mean values. A two-tailed P < 0.05 was considered statistically significant.

Results

Hemodynamic Parameters

There was no difference in ventricular rate between the four groups at baseline and 2 weeks following pacing. At baseline, the systolic blood pressure was normal and there was no difference between the four groups (P > 0.05). After 2 weeks of pacing, the systolic blood pressure did not change in groups S and C (P > 0.05), but there was a significant difference in groups A1 and A2 compared with groups S and C. Moreover, the systolic blood pressure (mmHg) of dogs in group A2 was lower than that in group A1 (A1: 125.8 ± 6.7 vs. A2: 116.7 ± 3.7, P < 0.05; Table 1), but the systolic blood pressure in groups A1 and A2 was still within the normal range and all animals retained a good appetite and physiological condition.
Table 1

Hemodynamic parameters before and after pacing in each group (\( \overline{x} \) ±s)

Group

Heart rate (bpm)

Systolic blood pressure (mm Hg)

Before pacing

Paced for 2 weeks

P

Before pacing

Paced for 2 weeks

P

S

197 ± 11

199 ± 17

>0.05

136.3 ± 7.5

134.3 ± 7.6

>0.05

C

197 ± 9

198 ± 12

>0.05

138.5 ± 10.0

131.5 ± 7.1

>0.05

A1

196 ± 13

198 ± 15

>0.05

136.2 ± 6.9

125.8 ± 6.7*

<0.01

A2

195 ± 12

200 ± 10

>0.05

137.3 ± 5.1

116.7 ± 3.7*△▲

<0.01

F

0.100

0.029

 

0.122

8.874

 

P

>0.05

>0.05

 

>0.05

<0.01

 

* p < 0.05 vs. corresponding value in group S, p < 0.05 vs. corresponding value in group C; p < 0.05 vs. corresponding value in group A1. S sham group, C control paced group, A1: paced + aliskiren 10 mg · Kg−1 · d−1 group, A2: paced + aliskiren 20 mg · Kg−1 · d−1 group

Levels of Serum ACE and Ang II

An ELISA kit was purchased from the Nanjing Jiancheng Bioengineering Institute, to measure the serum levels of angiotensin-converting enzyme (ACE) and Ang II in the different groups after 2 weeks. The levels of serum ACE and Ang II were significantly high in the rapid pacing group. Aliskiren significantly reduced the serum ACE and Ang II level in the rapid paced dogs (Fig. 1).
Fig. 1

ACE and Ang II levels in the four groups of canine serum. Aliskiren significantly decreases ACE and Ang II levels. a representative serum ACE levels. b representative serum Ang II levels. S sham group, C control paced group, A1, paced + aliskiren 10 mg · Kg−1 · d−1 group, A2, paced + aliskiren 20 mg · Kg−1 · d−1 group. * P < 0.01 vs. corresponding value in group S; △ P < 0.01 vs. corresponding value in group C; ▲ P < 0.01 vs. corresponding value in group A1.$ P < 0.05 vs. corresponding value in group A1

I CaL Changes and Gene Expression

Any contaminating effects of I CaL rundown were minimized by beginning all experiments 5 min after membrane rupture. Depolarizing 200-ms pulses from −40 mv to voltages with a range of −50 mv to +50 mv elicited typical I CaL. We found that the I CaL density clearly reduced by rapid atrial pacing. The maximum I CaL density peak reduced from −6.12 ± 0.58 pA/pF in group S (n = 9 cells) to −4.09 ± 1.46 pA/pF in group C (n = 10 cells; P < 0.05). After aliskiren treatment, the I CaL density was up to −4.80 ± 0.71 pA/pF and −6.23 ± 1.35 pA/pF (P < 0.05; Fig. 2a, b). Meanwhile, rapid atrial pacing downregulated the mRNA and protein expression of Cav1.2 (mRNA: 0.46 ± 0.08; protein: 0.31 ± 0.03; P < 0.01). In contrast, aliskiren significantly increased the mRNA and protein expression of Cav1.2 (relative mRNA expression in A2: 0.83 ± 0.10; P < 0.01; protein expression in A2: 0.75 ± 0.04, A1: 0.49 ± 0.05, P < 0.01; Figs. 3a, b and 4a, b).
Fig. 2

I-V curves of I CaL and I Na in the four groups. a I-V curves of I CaL obtained from dogs of the various groups. TP test potential. b Columns and error bars indicate mean ± SEM, respectively. c I-V curves of I Na obtained from dogs of the various groups. TP test potential. d Columns and error bars indicate mean ± SEM, respectively. * P < 0.01 vs. corresponding value in group S, # P < 0.05 vs. corresponding value in group S; △ P < 0.01 vs. corresponding value in group C; ▲ P < 0.01 vs. corresponding value in group A1

Fig. 3

The mRNA expression of Cav1.2 and Nav1.5α was suppressed by atrial pacing. Aliskiren markedly upregulated the mRNA expression of Cav1.2 and Nav1.5α. a representative Cav1.2 RT-PCR. c representative Nav1.5α RT-PCR. b and d Columns and error bars indicate mean ± SEM, respectively. Data are presented as relative gene expression (n = 6). * P < 0.01 vs. corresponding value in group S, # P < 0.05 vs. corresponding value in group S; △ P < 0.01 vs. corresponding value in group C; ▲ P < 0.01 vs. corresponding value in group A1

Fig. 4

The protein expression of Cav1.2 and Nav1.5α was suppressed by atrial pacing. Aliskiren markedly upregulated the protein expression of Cav1.2 and Nav1.5α. a representative images of Cav1.2 western blots; GAPDH was used as a loading control. b representative images of Nav1.5α western blots. c and d Columns and error bars indicate mean ± SEM. * P < 0.01 vs. corresponding value in group S; △ P < 0.01 vs. corresponding value in group C; ▲ P < 0.01 vs. corresponding value in group A1

I Na Changes and Gene Expression

The I-V curve relationship for I Na in each group shows the results for I Na current densities, peak I Na density is shown as a function of test potential. Any contaminating effects of I Na rundown were minimized by beginning all recordings 5 min after membrane rupture. Depolarizing 200-ms pulses from −90mV to voltages with a range of −80mV to +60mV elicited typical I Na. Rapid atrial pacing was associated with a decrease in I Na density. The maximum I Na density peak was reduced from −46.31 ± 4.73 pA/pF (n = 7 cells) in group S to −30.48 ± 6.08 pA/pF in group C (n = 9 cells; P < 0.01). After 2 weeks of treatment with a high dose of aliskiren, the maximum density peak of I Na increased to −58.62 ± 16.17 pA/pF (n = 7 cells; Fig. 2c, d; P < 0.01). The mRNA and protein expression of Nav1.5α were downregulated by rapid atrial pacing. Both low- and high-dose aliskiren upregulated the mRNA and protein expression of Nav1.5α (Fig. 3c, d, c, d).

Discussion

RAS blockade may herald a whole new era of AF management. Researchers have noted that ACE inhibitors (ACEIs) and Ang II receptor blockers (ARBs) have emerged as novel drugs for reducing the risk of AF [16]. Goette et al. [17] have indicated that an ACE-dependent increase in the amount of activated ERK1/2 in atrial interstitial cells may contribute to the development of atrial fibrosis in patients with AF. They have also reported that AF is associated with the downregulation of atrial Ang II receptor type 1 (AT1R) and the upregulation of AT2R proteins. These findings may help define the pathophysiological role of the angiotensin system in the structural remodeling of the fibrillating atria [18]. Kumagai et al. [19] have reported that the AT1R antagonist, candesartan, can prevent the promotion of AF by suppressing the development of structural remodeling. A recent meta-analysis [20] has indicated that RAS blockade therapy had significant protective effects on AF prevention. Furthermore, ACEIs had similar preventive effects as ARBs. However, whether ACEIs and ARBs should be used alone or in combined therapy is still controversial, as they all increase the serum PRA level [21]. In addition, Ang II and aldosterone are not always completely suppressed during long-term ACEI/ARB treatment. An incomplete inhibition of RAS may be responsible for the residual organ damage and adverse events. Moreover, the GISSI-AF study has revealed no statistically significant differences between the valsartan and placebo treatments in preventing atrial arrhythmia recurrences [22].

RAS has been implicated in the pathogenesis of cardiovascular diseases and, particularly, in various aspects of cardiac remodeling. Remodeling of the atria could serve as the anatomical substrate necessary for the development of AF [23]. A key component of AF-related remodeling is downregulation of I CaL protein, which reduces the atrial effective refractory period (AERP) and decreases the physiological rate adaptation of AERP [24, 25]. Calcium overload in cardiomyocytes plays an important role in initiating atrial remodeling [26, 27, 28]. SCN5A, the human gene encoding Nav1.5α, has been linked to many cardiac electrical disorders, including the congenital and acquired long QT syndrome, Brugada syndrome, slowing conduction, sick sinus syndrome, AF, and dilated cardiomyopathy [29]. In humans, the cardiac Na+ channel is responsible for the fast depolarization upstroke of the cardiac AP and is a molecular target of antiarrhythmic drugs, some of which are effective in treating atrial arrhythmias. Mutations of SCN5A may predispose patients with or without underlying heart diseases to AF, expanding the clinical spectrum of disorders of the cardiac Na+ channel to AF, representing important progress toward molecular phenotyping and directed rather than empirical therapy against this common arrhythmia [30].

The effects of aliskiren on electrophysiological remodeling in Ang II-induced cardiac injury have been explored, confirming that aliskiren can prevent atrial electrical remodeling, and decrease the arrhythmia induction and connexin 43 expression in double-transgenic rats [31]. In addition, aliskiren has been reported to be able to reduce the left ventricular mass reduction at least as effectively as other RAS blockers [32]. Our study showed for the first time that aliskiren could significantly increase ion channel gene expression and ion currents after rapid atrial pacing for 2 weeks. The following sentences outline how aliskiren may affect atrial ion currents and its tachycardia-induced alterations. ERP shortening and loss of ERP rate adaptation are the two major factors involved in tachycardia-induced remodeling and they are attributed to decreased I CaL density in the remodeled atrium [24]. Ang II can downregulate the cardiac Na+ channel through an H2O2-dependent pathway that involves NF-κB activation [33]. Na+ channel transcriptional dysregulation may contribute to the increased arrhythmic risk seen in states of RAS activation. Moreover, as previously reported, I CaL currents were suppressed by Ang II through the PKC pathway in heart cells [34].

In this study, a high dose of aliskiren completely reversed the decrease in Cav1.2 and Nav1.5α mRNA and protein expression. This effect may be achieved by preventing AERP from shortening and loss of rate adaptation. Additionally, ACE and Ang II have been reported to have close relationships with AF [35, 36]. As aliskiren can reduce their expression in atria myocardium in animal models [37, 38], it may be one of the mechanisms by which aliskiren affects ionic remodeling. Aliskiren may affect atrial ionic remodeling through other mechanisms as well, such as ameliorating oxidative stress [39] and inflammation [40], but further experiments are needed to confirm these hypothetical mechanisms.

Notes

Acknowledgments

This work was supported by the Program of Natural Science Foundation of China (No. 81370300) and China Education Ministry Colleges and Universities Special Scientific Research Foundation for Doctoral Advisor Class (No. 20121202110004).

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Zhiqiang Zhao
    • 1
  • Xinghua Wang
    • 1
  • Jian Li
    • 1
  • Wansong Yang
    • 1
  • Lijun Cheng
    • 1
  • Yan Chen
    • 1
  • Tong Liu
    • 1
  • Enzhao Liu
    • 1
  • Kangyin Chen
    • 1
  • Guangping Li
    • 1
  1. 1.Department of Cardiology, Tianjin Institute of CardiologySecond Hospital of Tianjin Medical UniversityTianjinPeople’s Republic of China

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