Beneficial Effects of the Dual L- and T-Type Ca2+ Channel Blocker Efonidipine on Cardiomyopathic Hamsters

Suzuki, Shinsuke; Ohkusa, Toshifumi; Ono, Katsushige; Sato, Takashi; Yoshida, Masaaki; Yano, Masafumi; Takebayashi, Satoshi; Matsuzaki, Masunori

doi:10.1253/circj.71.1970

Cited by 8 publications

(4 citation statements)

References 26 publications

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“…10,19,20 The increase in ICaT density observed in the hypertrophied RA cells in the present study might be in line with those findings. We also found that ICaT was not inhibited by approximately 100 μmol/L Ni 2+ , which contradicts previous reports that cardiac ICaT is completely blocked by a low Ni 2+ concentration (40 μmol/L), 13 although a previous report described postnatal evolution of ICaT density in rat atrial cardiomyocytes and demonstrated that rat neonatal ICaT is poorly sensitive to Ni 2+ (IC50, 160 μmol/L).…”

Section: T-type Ca Channel Current Reappears In Mct-treated Cellssupporting

confidence: 92%

Molecular and Electrical Remodeling of L- and T-Type Ca2+ Channels in Rat Right Atrium With Monocrotaline-Induced Pulmonary Hypertension

Koyama

Ono

Watanabe

et al. 2009

Circ J

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t is well known that fibrillating or hemodynamically overloaded atria are subject to cellular electrical remodeling, which is characterized by shortening of the action potential 1 and often contributes to the occurrence and persistence of atrial fibrillation (AF). AF and chronic obstructive pulmonary disease (COPD) frequently coexist and complicate treatment of both clinical conditions. 2,3 COPD patients are susceptible to secondary pulmonary hypertension (PH), and the resulting hemodynamic changes, and in addition hypoxia, hypercapnia, acid-base disorders, disturbed sympathovagal balance, and medication can lead to the development of AF. 2,3 Recent studies demonstrated that the densities of the L-type calcium (Ca 2+ ) current (ICaL), transient outward current (Ito), and voltage-dependent Na + current (INa) are decreased in experimental animal models of atrial tachycardia-related AF. [4][5][6] In contrast to tachycardia-induced ionic remodeling, several clinical and experimental studies have indicated a decrease, no change, or even an increase in the ICaL density in chronic heart failure (CHF), 1,7,8 depending on the experimental conditions. Nonetheless, it is generally agreed that a possible change in ICaL is a key factor in electrical remodeling of cardiac myocytes in CHF and/or hypertrophy. In addition, the T-type Ca 2+ channel is involved in electrical remodeling during CHF or hypertrophy. The T-type Ca 2+ channel is normally expressed in embryonic and neonatal myocytes, and in the conducting system of the adult heart, 9 and in rats it is re-expressed in pathologic conditions such as ventricular hypertrophy and post-myocardial infarction. 10 In the present study, the electrical properties of ICaL and ICaT were characterized in rat right atrial cells with monocrotaline (MCT)-induced PH, and the possible causes are discussed in relation to changes in the expression and function of Ca 2+ channel subunits. Methods AnimalsThe Animal Ethics Committee of Akita University School of Medicine, Japan, approved the study protocol. Four-week-old Wistar rats (CLEA Japan, Tokyo, Japan), weighing 140-150 g each, were treated with 500 mg MCT (Crotaline; Sigma, St Louis, MO, USA) to produce PH. A single dose of MCT 60 mg/kg was injected subcutaneously in the interscapular region. Measurement of Hemodynamic Parameters and Assessment of Right Ventricular (RV) HypertrophyRV pressure and heart rate were measured, using a pressure transducer connected to a monitor (DynaScope 5100E; Fukuda Denshi, Tokyo, Japan). Right atrial (RA) and RV hypertrophy were evaluated by measuring the ratio of the RA weight to body weight (BW), the ratio of the RV free wall weight to BW, and the ratio of the RV weight to the left ventricular free wall plus septum (LV + IVS) weight. (Received June 19, 2008; revised manuscript received September 8, 2008; accepted September 24, 2008; released online December 26, 2008) Departments of Cardiology, *Physiology, Akita University School of Medicine, Akita, Japan Mailing address: Hiroshi Ito, Department of Ca...

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Section: T-type Ca Channel Current Reappears In Mct-treated Cellssupporting

confidence: 92%

Molecular and Electrical Remodeling of L- and T-Type Ca2+ Channels in Rat Right Atrium With Monocrotaline-Induced Pulmonary Hypertension

Koyama

Ono

Watanabe

et al. 2009

Circ J

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“…Suzuki et al have clearly demonstrated that efonidipine brought significant improvement of cardiac function in cardiomyopathic hamsters (33). The strong cardioprotective effect of efonidipine in rats has also been reported by Morimoto et al (34).…”

Section: Discussionmentioning

confidence: 99%

Effect of Efonidipine on TGF-β1–Induced Cardiac Fibrosis Through Smad2-Dependent Pathway in Rat Cardiac Fibroblasts

et al. 2011

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Transforming growth factor beta-1 (TGF-β1) plays a critical role in progression of cardiac fibrosis, which may involve intracellular calcium change. We examined effects of efonidipine, a dual T-type and L-type calcium channel blocker (CCB), on TGF-β1–induced fibrotic changes in neonatal rat cardiac fibroblast. T-type and L-type calcium channel mRNAs were highly expressed in cultured cardiac fibroblasts. TGF-β1 (5 ng/mL) significantly increased Smad2 phosphorylation and [3H]-leucine incorporation, which were attenuated by pretreatment with efonidipine (10 μM). Neither R(−)efonidipine (10 μM), selective T-type CCB, nor nifedipine (10 μM), selective L-type CCB, efficaciously inhibited both TGF-β1–induced Smad2 phosphorylation and [3H]-leucine incorporation. However, both were markedly attenuated by combination of R(−)efonidipine and nifedipine, EDTA, or calcium-free medium. Pretreatment with Smad2 siRNA significantly attenuated [3H]-leucine incorporation induced by TGF-β1. These data suggest that efonidipine elicits inhibitory effects on TGF-β1– and Smad2-dependent protein synthesis through both T-type and L-type calcium channel–blocking actions in cardiac fibroblasts.

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“…Indeed, T-type channel blockers that have low LCC activity (efonidipine and mibefradil) improve cardiac function in the hamster [81,82]. However, a comparison of mibefradil and verapamil efficacy in preventing the dystrophic process in hamsters showed no benefit of mibefradil [83].…”

Section: Putative Disease Mechanismsmentioning

confidence: 99%

δ-Sarcoglycan-deficient muscular dystrophy: from discovery to therapeutic approaches

Blain

Straub

2011

Skeletal Muscle

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Mutations in the δ-sarcoglycan gene cause limb-girdle muscular dystrophy 2F (LGMD2F), an autosomal recessive disease that causes progressive weakness and wasting of the proximal limb muscles and often has cardiac involvement. Here we review the clinical implications of LGMD2F and discuss the current understanding of the putative mechanisms underlying its pathogenesis. Preclinical research has benefited enormously from various animal models of δ-sarcoglycan deficiency, which have helped researchers to explore therapeutic approaches for both muscular dystrophy and cardiomyopathy.

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Beneficial Effects of the Dual L- and T-Type Ca2+ Channel Blocker Efonidipine on Cardiomyopathic Hamsters

Cited by 8 publications

References 26 publications

Molecular and Electrical Remodeling of L- and T-Type Ca2+ Channels in Rat Right Atrium With Monocrotaline-Induced Pulmonary Hypertension

Molecular and Electrical Remodeling of L- and T-Type Ca2+ Channels in Rat Right Atrium With Monocrotaline-Induced Pulmonary Hypertension

Effect of Efonidipine on TGF-β1–Induced Cardiac Fibrosis Through Smad2-Dependent Pathway in Rat Cardiac Fibroblasts

δ-Sarcoglycan-deficient muscular dystrophy: from discovery to therapeutic approaches

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