Makoto Nakano

Tohoku University, Sendai, Kagoshima-ken, Japan

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Publications (22)83.03 Total impact

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    ABSTRACT: Background: Heart failure (HF) is a complex clinical syndrome, resulting from structural and/or functional cardiac disease. The aim of this study was to determine whether the activity of Rho-kinase, which has been identified as an important therapeutic target of cardiovascular disease, is enhanced in HF patients. Methods and Results: Total and phosphorylated forms of myosin binding subunit (t-MBS and p-MBS), a substrate of Rho-kinase, were measured on western blotting in circulating leukocytes, and the p-MBS/t-MBS ratio was defined as an index of systemic Rho-kinase activity. First, during the time-course of acute HF (n=12), Rho-kinase activity was significantly elevated in the acute phase compared to the chronic phase (1.19±0.06 vs. 0.97±0.04, P<0.05). Next, Rho-kinase activity was examined in 30 controls and 130 chronic HF patients (cardiomyopathy, n=57; valvular heart disease, n=35; ischemic heart disease [IHD], n=33; and others, n=5). As compared with the controls, Rho-kinase activity was significantly elevated in the total HF group (1.14±0.02 vs. 0.77±0.05, P<0.0001) and in each underlying heart disease (P<0.05 each). Importantly, in the high-risk non-IHD group, Rho-kinase activity was significantly associated with plasma brain nutriuretic peptide level. Finally, p-MBS was expressed in myocardial biopsy samples (immunohistochemistry) in chronic HF patients (n=36), independent of Rho-kinase activity in leukocytes. Conclusions: Rho-kinase is activated in HF patients, suggesting that it could be a new therapeutic target of the disorder.
    Circulation Journal 07/2013; · 3.58 Impact Factor
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    ABSTRACT: Background: The functional role of the cavotricuspid isthmus (CTI) for common atrial flutter (cAFL) remains to be elucidated. In the present study, we examined whether the EnSite system (St. Jude Medical, St. Paul, MN, USA), a noncontact mapping system, is useful to evaluate the conduction properties of CTI to minimize radiofrequency (RF) ablation applications for cAFL. Methods: We enrolled 22 consecutive patients with cAFL (64.1 ± 9.5 years old, M/F 21/1) treated with the EnSite system and examined the conduction properties during cAFL and during atrial pacing. In addition, the effectiveness of the system was evaluated in comparison with the conventional ablation group (67 ± 8.9 years old, n = 15, M/F 13/2). Result: In 11 out of the 22 patients, CTI block line was achieved by fewer RF applications on a presumed single activation pathway which the EnSite system showed (point ablation [PA] group), and the remaining 11 patients needed additional linear ablation (additional ablation [AA] group). The number of RF applications in the PA group was significantly smaller than that in the conventional group. During the lower lateral right atrial pacing at a cycle length of 600 ms, the CV of the CTI in the PA group was smaller compared to that in the AA group (1.36 ± 0.61 vs 2.17 ± 0.66 m/s, P < 0.05), although the CV during cAFL (averaged cycle length 245 ± 34 ms) was not different in both groups. Conclusions: These results indicate that targeting the presumed single line identified by EnSite could be an optional therapy for cAFL RF ablation, and diverse conduction properties in CTI are related to the success rate of this procedure. (PACE 2012;00:1-8).
    Pacing and Clinical Electrophysiology 10/2012; · 1.75 Impact Factor
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    ABSTRACT: BACKGROUND: Predictors of ventricular arrhythmias (VA) in patients with cardiac sarcoidosis (CS) remain unclear. METHODS AND RESULTS: We examined 61 consecutive CS patients who were admitted to our hospital from April 2002 to March 2012 with a mean follow-up period of 45±31 months for the relationship between delayed enhancement on cardiac magnetic resonance imaging (DE-MRI) and VA or a composite endpoint, including VA, heart failure hospitalization, and cardiovascular mortality. Although there was no significant difference in baseline clinical characteristics between patients with VA and those without it, the former group was characterized as compared with the latter by lower left ventricular (LV) ejection fraction (p<0.05), larger LV systolic/diastolic dimensions (both p<0.05), and a significant association with DE-MRI (p<0.05). Furthermore, the patients with DE-MRI (n=26), as compared with those without it (n=11), had a significantly higher composite endpoint event rate (41% vs. 0%, p<0.05) and a trend toward higher VA (29% vs. 0%, p=0.12). Univariate analysis also showed that impaired LV systolic function was significantly associated with composite events on follow-up. CONCLUSIONS: These results indicate that the presence of DE-MRI is a significant predictor of VA events and poor outcome in CS patients.
    Journal of Cardiology 08/2012; · 2.30 Impact Factor
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    ABSTRACT: After the East Japan Earthquake disaster there may have been a deterioration of patients with cardiovascular diseases. We examined the data from 189 consecutive patients implanted with cardiovascular devices for the 6-month period before and after the Earthquake. In 170 patients with defibrillators, the number who experienced tachyarrhythmias increased significantly after the Earthquake (28 ± 5 vs. 34 ± 3 patients/month, P<0.05). In 74 patients with biventricular pacemakers, the number of heart failure hospitalizations significantly increased after the Earthquake (1.2 ± 1.0 vs. 2.7 ± 1.2 patients/month, P<0.05). The East Japan Earthquake disaster unfavorably affected patients implanted with defibrillators or biventricular pacemakers.
    Circulation Journal 04/2012; 76(5):1283-5. · 3.58 Impact Factor
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    ABSTRACT: Erythropoietin (EPO) is a principal regulator that promotes proliferation and terminal differentiation of erythroid progenitor cells. EPO receptors are expressed not only in hematopoietic lineage cells but also in the cardiovascular system. We performed animal experiments using transgene-rescued EPO receptor null mutant mice (EpoR-/- rescued) that express the EPO receptor exclusively in the hematopoietic cells. The results of these experiments suggest that endogenous EPO/EPO receptor system in the heart exerts cardioprotective effects against myocardial injury induced by ischemia followed by reperfusion and pressure-overload induced left ventricular dysfunction. Many animal experiments have shown that the administration of recombinant human EPO also elicits cardioprotective effects against myocardial injury induced by ischemia and reperfusion. In contrast to the promising results of these animal experiments, recent clinical trials failed to demonstrate the reduction in infarct size or improvement of cardiac function by the administration of recombinant human EPO in patients with acute myocardial infarction who underwent primary percutaneous coronary intervention. It should be tested in future clinical studies whether a relatively low dose of recombinant human EPO or its derivatives that have no erythropoietic action reduces infarct size and ameliorates cardiac dysfunction in patients with acute myocardial infarction. In this article, we review implications of anemia associated with chronic heart failure, roles of the endogenous EPO/EPO receptor system, and the effects of the administration of erythropoiesis-stimulating agents in pathologic conditions of the heart by focusing on the EPO receptor as a potential candidate of novel therapeutic targets in cardiovascular diseases.
    The Tohoku Journal of Experimental Medicine 01/2012; 227(2):83-91. · 1.37 Impact Factor
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    ABSTRACT: Although hypoxia and ischemia are known to be involved in the pathogenesis of cardiovascular disease, specific therapeutic targets still remain elusive. To address this important issue, we have performed 2 series of experimental studies, aiming at erythropoietin (Epo)/Epo receptor (EpoR) based on the following backgrounds. Epo has long been regarded as a hematopoietic hormone that acts exclusively in the proliferation and differentiation of erythroid progenitors. Although recent studies have demonstrated that EpoR is expressed in the cardiovascular system, the potential protective role of the vascular Epo/EpoR system in vivo remains to be examined. We hypothesized that the vascular Epo/EpoR system plays an important protective role against the development of cardiovascular disease. Using vascular EpoR-deficient mouse, we demonstrated that the vascular Epo/EpoR system plays a crucial role for endothelial function and vascular homeostasis. The vascular Epo/EpoR system is important for the activation of the vascular endothelial growth factor/vascular endothelial growth factor receptor-2 system, inhibits hypoxia-induced pulmonary endothelial damage and promotes ischemia-induced angiogenesis in vivo. These results indicate that the vascular Epo/EpoR system plays an important protective role against hypoxia/ischemia, demonstrating that this system is a novel therapeutic target in cardiovascular medicine.
    Journal of cardiovascular pharmacology 09/2011; 58(6):570-4. · 2.83 Impact Factor
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    ABSTRACT: Although myocardial fibrosis plays an important role in the progression of heart failure (HF), its prognostic impact still remains to be clarified. A total of 172 consecutive patients with chronic HF, who underwent cardiac catheterization and endomyocardial biopsy between January 2001 and September 2008, were examined. They were divided into 2 groups: HF with preserved ejection fraction (HFPEF; left ventricular ejection fraction [LVEF] ≥ 50%, n=81); and HF with reduced LVEF (HFREF; LVEF < 50%, n=91). The collagen volume fraction (CVF) in biopsy samples was calculated and its prognostic impact examined. Mean follow-up in the HFPEF and the HFREF groups was 41 ± 33 months and 41 ± 26 months, respectively. Although CVF was similar between the 2 groups (1.83 ± 1.54% vs. 2.07 ± 2.35%), CVF was significantly correlated with LV end-diastolic pressure in the HFREF group but not in the HFPEF group. When HF stage was adjusted, the long-term prognosis was comparable between the 2 groups. When the patients were divided into 2 groups according to median CVF, however, severe fibrosis was a significant predictor for all-cause death (P=0.014) and cardiac events (P=0.02) in the HFREF, but not in the HFPEF group. Myocardial fibrosis evaluated on biopsy samples is a useful indicator for long-term survival, suggesting that it may be an important therapeutic target as well.
    Circulation Journal 08/2011; 75(11):2605-13. · 3.58 Impact Factor
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    ABSTRACT: Triggered arrhythmias arise from delayed afterdepolarizations (DADs), with Ca(2+) waves playing an important role in their formation. In ventricular hypertrophy, however, it remains unclear how Ca(2+) waves change their propagation features and affect arrhythmogenesis. We addressed this important issue in a rat model of hypertrophy. Rats were given a subcutaneous injection of 60 mg/kg monocrotaline (MCT-rats) or solvent (Ctr-rats). After 4 weeks, MCT-rats showed high right ventricular (RV) pressure and RV hypertrophy. Trabeculae were dissected from 36 right ventricles. The force was measured using a silicon strain gauge and regional intracellular Ca(2+) ([Ca(2+)](i)) was determined using microinjected fura-2. Reproducible Ca(2+) waves were induced by stimulus trains (2 Hz, 7.5s). MCT-rats showed a higher diastolic [Ca(2+)](i) and faster and larger Ca(2+) waves (P<0.01). The velocity and amplitude of Ca(2+) waves were correlated with the diastolic [Ca(2+)](i) both in the Ctr- and MCT-rats. The velocity of Ca(2+) waves in the MCT-rats was larger at the given amplitude of Ca(2+) waves than that in the Ctr-rats (P < 0.01). The amplitude of DADs was correlated with the velocity and amplitude of Ca(2+) waves in the Ctr- and MCT-rats. The results suggest that an increase in diastolic [Ca(2+)](i) and an increase in Ca(2+) sensitivity of the sarcoplasmic reticulum Ca(2+) release channel accelerate Ca(2+) waves in ventricular hypertrophy, thereby causing arrhythmogenesis.
    Circulation Journal 04/2011; 75(6):1343-9. · 3.58 Impact Factor
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    ABSTRACT: Atrial fibrillation (AF) is the most common tachyarrhythmia. Shortening of atrial action potential duration (APD) and effective refractory period (ERP) is one of the crucial factors in the occurrence and maintenance of AF. ERP is usually shorter than APD, but ERP can be prolonged beyond action potential repolarization in some situations. It is termed as post-repolarization refractoriness (PRR) that is thought to be one of main anti-arrhythmic mechanisms of class I sodium channel blockers (SCBs). Most of anti-arrhythmic agents, including SCBs, have multi-channel blocking effects. It is unknown whether atrial PRR with SCBs is associated with the reduction of sodium channel availability. We therefore explored the relationship between the reduction of sodium channel availability with a pure SCB (pilsicainide or tetrodotoxin) and atrial PRR using the left atrial appendage from male guinea pigs (each group, n = 3~10). Employing a standard microelectrode technique, we evaluated APD measured at 90% repolarization (APD(90)) and the sodium channel availability, judged from the maximal rate of rise of action potential (Vmax). At a 500-msec basic cycle length (BCL), pilsicainide prolonged atrial ERP assessed by a single extra-stimulus in response to the decrement of the Vmax in a dose-dependent manner without affecting APD(90). Furthermore, pilsicainide increased the ERP and decreased the Vmax in a rate-dependent manner without APD(90) prolongation at a shorter BCL (200 msec). Importantly, tetrodotoxin reproduced the effects of pilsicainide on atrial ERP, APD(90), and Vmax. These results indicate that SCBs produce atrial PRR through the reduction of sodium channel availability.
    The Tohoku Journal of Experimental Medicine 01/2011; 225(1):35-42. · 1.37 Impact Factor
  • Journal of Cardiac Failure - J CARD FAIL. 01/2011; 17(9).
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    ABSTRACT: Atherosclerosis is characterized by infiltration of inflammatory cells and enhanced vasa vasorum formation, for which immunological mechanisms may be involved. OX40, a membrane-bound molecule of the tumour necrosis factor-receptor superfamily, is expressed by activated T-cells, while OX40 ligand (OX40L) is expressed in activated macrophages and endothelial cells. In this study, we thus examined whether the OX40/OX40L system is involved in the pathogenesis of atherosclerosis. We examined apolipoprotein E-deficient (ApoE(-/-)) mice and ApoE(-/-)/OX40L-double-deficient (ApoE(-/-)/OX40L(-/-)) mice fed on a high-fat diet for 8 weeks. The extent of aortic atheroma was significantly less in ApoE(-/-)/OX40L(-/-) mice compared with ApoE(-/-) mice. We also treated high-fat-fed ApoE(-/-) mice with or without MGP34 antibody (OX40L-specific neutralizing antibody) for 10 weeks. After the treatment, the extent of aortic atheroma was again significantly less in MGP34-treated mice compared with controls. Importantly, both vascular density in the aortic adventitia and vascular endothelial growth factor-induced angiogenesis in the Matrigel assay in vivo were significantly reduced in ApoE(-/-)/OX40L(-/-) mice compared with ApoE(-/-) mice. Finally, when high-fat-fed ApoE(-/-) mice were transplanted with bone marrow cells from either wild-type or OX40L(-/-) mice, the extent of aortic atheroma was comparable between the two groups. These results indicate that the vascular OX40/OX40L system plays an important role in the formation of vasa vasorum and subsequent atherosclerosis, suggesting that the vascular OX40/OX40L system might be a new therapeutic target of atherosclerosis.
    Cardiovascular Research 12/2010; 88(3):539-46. · 5.81 Impact Factor
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    ABSTRACT: Pulmonary hypertension (PH) still remains a serious disease, for which the plasma level of brain natriuretic peptide (BNP) and hemodynamic variables (eg, cardiac index: CI) are established prognostic factors. The aim of the present study was to identify new additional prognostic factors of the disorder to improve the management of PH. The study cohort comprised 136 consecutive PH patients admitted to hospital from 1974 to 2008, all of whom were closely followed every 6-12 months. During the follow-up period of 53.5+/-4.5 [SEM] months, 47 patients died of cardiopulmonary causes. The patients who were initially treated with monotherapy showed improved pulmonary hemodynamics when subsequently treated with combination therapy. Multivariate analysis showed that BNP and CI were significant and independent prognostic factors in all PH patients. However, in PH patients with low CI at diagnosis, only CI improvement by PH therapy was a significant and independent prognostic factor. Indeed, the patients with low CI at diagnosis (CI <2.5) followed by subsequent normalization in response to therapy (CI > or =2.5) showed a significantly better survival compared with those without such normalization. CI normalization in response to treatment is an independent new prognostic factor of PH in patients with low CI at diagnosis, suggesting the importance of intensive therapy to achieve CI normalization.
    Circulation Journal 09/2010; 74(9):1965-71. · 3.58 Impact Factor
  • Circulation Journal 08/2010; 74(8):1742-4. · 3.58 Impact Factor
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    ABSTRACT: Direct evidence for Rho-kinase activation in patients with pulmonary hypertension (PH) is still lacking. Rho-kinase activity in circulating neutrophils was examined by determining the ratio of phosphorylated/total forms of myosin-binding subunit, a substrate of Rho-kinase, in 40 consecutive PH patients and 40 healthy controls. Next, Rho-kinase expression and activity was examined in isolated human lung tissues (5 patients with idiopathic pulmonary arterial hypertension [IPAH], 5 controls) and vascular reactivity of isolated small human pulmonary arteries in vitro (4 IPAH, 4 controls). Rho-kinase activity in circulating neutrophils was significantly increased in the PH patients overall compared with controls (P<0.0001). Significant correlations were noted between Rho-kinase activity and the severity and duration of PAH (all P<0.05). Rho-kinase expression and activity in isolated lung tissues also were significantly increased in the IPAH patients compared with the controls (both P<0.0001). Endothelium-dependent relaxation was markedly impaired and serotonin-induced contraction (in the absence of the endothelium) markedly enhanced in the PAH patients compared with the controls, and the hypercontraction to serotonin was abolished by hydroxyfasudil, a specific Rho-kinase inhibitor. These results provide the first direct evidence for Rho-kinase activation in patients with PAH, suggesting the therapeutic importance of Rho-kinase in the disorder.
    Circulation Journal 07/2009; 73(9):1731-9. · 3.58 Impact Factor
  • Journal of Cardiac Failure - J CARD FAIL. 01/2009; 15(7).
  • Journal of Cardiac Failure - J CARD FAIL. 01/2009; 15(7).
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    ABSTRACT: Mobilization of stem cells/progenitors is regulated by the interaction between stromal cell-derived factor-1 (SDF-1) and its ligand, CXC chemokine receptor 4 (CXCR4). Statins have been suggested to ameliorate pulmonary arterial hypertension (PAH); however, the mechanisms involved, especially their effects on progenitors, are largely unknown. Therefore, we examined whether pravastatin ameliorates hypoxia-induced PAH in mice, and if so, which type of progenitors and what mechanism(s) are involved. Chronic hypoxia (10% O(2) for 5 weeks) increased the plasma levels of SDF-1 and mobilization of CXCR4(+)/vascular endothelial growth factor receptor (VEGFR)2(+)/c-kit(+) cells from bone marrow (BM) to pulmonary artery adventitia in Balb/c mice in vivo, both of which were significantly suppressed by simultaneous oral treatment with pravastatin (2 mg/kg/day). Furthermore, in vitro experiments demonstrated that hypoxia enhances differentiation of VEGFR2(+)/c-kit(+) cells into alpha-smooth muscle actin(+) cells. Importantly, pravastatin ameliorated hypoxia-induced PAH associated with a decrease in the number of BM-derived progenitors accumulating in the pulmonary artery adventitia. The expression of intercellular adhesion molecule-1 (ICAM-1) and its ligand, CD18 (beta2-integrin), were enhanced by hypoxia and were again suppressed by pravastatin. These results suggest that pravastatin ameliorates hypoxia-induced PAH through suppression of SDF-1/CXCR4 and ICAM-1/CD18 pathways with a resultant reduction in the mobilization and homing of BM-derived progenitor cells.
    Cardiovascular Research 10/2008; 81(1):226-34. · 5.81 Impact Factor
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    ABSTRACT: Aims We examined whether non-uniform muscle contraction affects delayed afterdepolarizations (DADs) by dissociating Ca2+ from myofilaments within the border zone (BZ) between contracting and stretched regions. Methods and results Force, sarcomere length (SL), membrane potential, and [Ca2+] i dynamics were measured in 31 ventricular trabeculae from rat hearts. Non-uniform muscle contraction was produced by exposing a restricted region of muscle to a jet of solution containing 20 mmol/L 2,3-butanedione monoxime (BDM). DADs were induced by 7.5 s-2 Hz stimulus trains at an SL of 2.0 µm (24°C, [Ca2+] o 2.0 mmol/L). The BDM jet enhanced DADs ( n = 6, P < 0.05) and aftercontractions ( n = 6, P < 0.05) with or without 100 µmol/L streptomycin and occasionally elicited an action potential. A stretch pulse from an SL of 2.0 µm to 2.1 or 2.2 µm during the last stimulated twitch of the trains accelerated Ca2+ waves in proportion to the increment of force by the stretch ( P < 0.01) with or without streptomycin. In the presence of 1 mmol/L caffeine, rapid shortening of the muscle after the stretch pulse increased [Ca2+] i within the BZ, whose amplitude correlated with the increment of force by the stretch ( n = 15, P < 0.01). Conclusion These results suggest that non-uniform muscle contraction can enhance DADs by dissociating Ca2+ from myofilaments within the BZ and thereby cause triggered arrhythmias.
    Cardiovascular Research 07/2008; · 5.81 Impact Factor
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    ABSTRACT: We have recently demonstrated that endogenous erythropoietin (Epo)/Epo receptor (EpoR) system plays an important protective role in hypoxia-induced pulmonary hypertension. However, it remains to be examined whether vascular EpoR system contributes to angiogenesis in response to ischemia. We examined angiogenesis in EpoR(-/-)-rescued mice that lack EpoR in most organs including cardiovascular system except erythroid-lineage cells. Two weeks after femoral artery ligation, blood flow recovery, activation of VEGF/VEGF receptor system, and mobilization of endothelial progenitor cells were all impaired in EpoR(-/-)-rescued mice as compared with wild-type (WT) mice. Bone marrow (BM) transplantation with WT-BM cells in EpoR(-/-)-rescued mice partially but significantly improved blood flow recovery after hindlimb ischemia. The extent of VEGF upregulation and the number of BM-derived cells in ischemic tissue were significantly less in EpoR(-/-)-rescued mice compared with WT mice even after BM reconstitution with WT-BM cells. Similarly, the recovery of blood flow was significantly impaired in recipient EpoR(-/-)-rescued mice that had been transplanted with WT-BM or EpoR(-/-)-rescued-BM as compared with recipient WT mice. Furthermore, the Matrigel implantation assay and aortic ring assay showed that microvessel growth in vitro was significantly reduced in EpoR(-/-)-rescued mice as compared with WT mice. These results indicate that vascular EpoR system also plays an important role in angiogenesis in response to hindlimb ischemia through upregulation of VEGF/VEGF receptor system, both directly by enhancing neovascularization and indirectly by recruiting endothelial progenitor cells and BM-derived proangiogenic cells.
    Circulation Research 04/2007; 100(5):662-9. · 11.86 Impact Factor
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    ABSTRACT: Class III antiarrhythmic agents have been widely used to suppress ventricular tachyarrhythmias in patients with heart failure because they have been shown to have positive inotropic effects as well. However, it remains to be examined whether those agents also exert positive inotropic effects in failing hearts. We addressed this important issue in a rat model of heart failure. We used Nifekalant as a representative class III antiarrhythmic agent. Four weeks after a s.c. injection of 60 mg/kg monocrotaline (MCT) or vehicle (Ctr) into rats, we obtained trabeculae from right ventricles and measured the developed force and intracellular Ca(2+) ([Ca(2+)](i)) by the fura-2 microinjection method. The sarcoplasmic reticulum (SR) Ca(2+) content was assessed by the rapid-cooling contracture (RCC) technique. MCT rats exhibited right ventricular hypertrophy induced by pressure overload. The protein expression of SR Ca(2+) ATPase type 2 (SERCA2) and the SERCA2/phospholamban ratio in MCT rats was lower with a slower decline of Ca(2+) transients and a reduced amplitude of RCCs. Nifekalant concentration-dependently increased the force, peak [Ca(2+)](i), and the amplitude of RCCs in Ctr rats but not in MCT rats with identical prolongation of the action potential. Under the SR inhibited with cyclopiazonic acid and ryanodine, Nifekalant increased the force in Ctr rats but not in MCT rats. These results indicate that the positive inotropic effects of Nifekalant is reduced in failing hearts, probably due to the depressed SR Ca(2+) uptake and reduced reserve of the trans-sarcolemmal Ca(2+) transport, warranting a caution in the antiarrhythmic therapy with a class III antiarrhythmic agent in heart failure.
    Journal of Pharmacology and Experimental Therapeutics 10/2006; 318(3):1102-7. · 3.89 Impact Factor