Reduced Inotropic Effect of Nifekalant in Failing Hearts in Rats

Endo, Hideki; Miura, Makoto; Hirose, Masao; Takahashi, Jun; Wakayama, Yuji; Sugai, Yoshinao; Kagaya, Yutaka; Watanabe, Jun; Shirato, Kunio; Shimokawa, Hiroaki

doi:10.1124/jpet.106.102780

Cited by 6 publications

(8 citation statements)

References 40 publications

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“…In addition, our previous report showed that MCT-rats exhibit a lower expression of SERCA2 protein and a relatively higher expression of NCX protein. 25 These properties of MCT-rats are consistent with past reports for the same experimental model 27,28 and for other animal models of ventricular hypertrophy. 29 Thus, we are convinced that MCT-rats can serve as a model of ventricular hypertrophy to examine the propagation features of Ca 2+ waves.…”

Section: Mct-induced Rv Hypertrophysupporting

confidence: 81%

“…The steeper slope of the relationship in the MCT-rats may be due to the increased expression of the NCX. 19, 25 In conclusion, the results of the present study suggest that an increase in diastolic [Ca 2+ ]i and an increase in the Ca 2+ sensitivity of the SR Ca 2+ release channel accelerate Ca 2+ waves in ventricular hypertrophy, thereby causing arrhythmogenesis.…”

Section: Acceleration Of Ca 2+ Wavesmentioning

confidence: 84%

“…Sprague-Dawley rats weighing 200 g received a single subcutaneous injection of 60 mg/kg MCT (MCT-rats) or an equal volume of solvent (Ctr-rats), as previously described. 25 Four weeks after the injection, 25.4% of the MCT-rats died from right-sided heart failure but none of the Ctr-rats died. The survivors were anesthetized, the right atrial and ventricular pressures were measured, and then the heart was excised for sample preparation and heart weight measurement.…”

Section: Animal Modelmentioning

confidence: 99%

“…As in our previous studies, 25 we used MCT-rats as an experimental model of pulmonary hypertension-induced RV hypertrophy. MCT is a pyrrolizidine alkaloid, and its bioactive metabolite selectively injures the vascular endothelium of lung vessels.…”

Section: Mct-induced Rv Hypertrophymentioning

confidence: 99%

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Acceleration of Ca2+ Waves in Monocrotaline-Induced Right Ventricular Hypertrophy in the Rat

Miura

Hirose

Endoh

et al. 2011

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp rrhythmias are likely to occur in diseased hearts, 1-3 and delayed afterdepolarizations (DADs) play an important role 4 in their occurrence, associated with catecholamine excess, 5 heart failure, 6 and mutations of the ryanodine receptor or calsequestrin. 7 Such diseased hearts not only exhibit an increase in diastolic intracellular Ca 2+ ([Ca 2+ ]i), 8 which causes spontaneous Ca 2+ release from the sarcoplasmic reticulum (SR), 9,10 but also exhibit nonuniform muscle contraction, 11,12 which causes Ca 2+ dissociation from the myofilaments within the border zone between contracting and stretched regions during the relaxation phase. 10,13,14 Both the Ca 2+ released from the SR and that dissociated from the myofilaments can induce Ca 2+ waves, which propagate along the myocardium by the mechanism of Ca 2+ -induced Ca 2+ release from the SR. 15 Since the velocity and amplitude of Ca 2+ waves determine the formation of DADs 16 (ie, arrhythmogenesis principally through the activation of the Na + -Ca 2+ exchange (NCX) current 16,17 ), it is still important to investigate the propagation features of the Ca 2+ waves.It has been reported that in ventricular hypertrophy, 6 clear changes occur with maladaptive remodeling of the myocardium: (1)

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Section: Mct-induced Rv Hypertrophysupporting

confidence: 81%

Section: Acceleration Of Ca 2+ Wavesmentioning

confidence: 84%

Section: Animal Modelmentioning

confidence: 99%

Section: Mct-induced Rv Hypertrophymentioning

confidence: 99%

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Acceleration of Ca2+ Waves in Monocrotaline-Induced Right Ventricular Hypertrophy in the Rat

Miura

Hirose

Endoh

et al. 2011

Circ J

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“…Heart failure can be identified by clinical symptoms that have been linked to hemodynamic indexes of right heart failure (15). Following MCT treatment, the RV action potential is prolonged (9,26,32). This is associated with decreased K ϩ channel activity, although studies disagree precisely which channels (26,27,32,41).…”

mentioning

confidence: 99%

Arrhythmogenic substrate in hearts of rats with monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy

Benoist

Stones

Drinkhill

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Benoist D, Stones R, Drinkhill M, Bernus O, White E. Arrhythmogenic substrate in hearts of rats with monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy. Am J Physiol Heart Circ Physiol 300: H2230 -H2237, 2011. First published March 11, 2011 doi:10.1152/ajpheart.01226.2010.-Mechanisms associated with right ventricular (RV) hypertension and arrhythmias are less understood than those in the left ventricle (LV). The aim of our study was to investigate whether and by what mechanisms a proarrhythmic substrate exists in a rat model of RV hypertension and hypertrophy. Rats were injected with monocrotaline (MCT; 60 mg/kg) to induce pulmonary artery hypertension or with saline (CON). Myocardial levels of mRNA for genes expressing ion channels were measured by real-time RT-PCR. Monophasic action potential duration (MAPD) was recorded in isolated Langendorff-perfused hearts. MAPD restitution was measured, and arrhythmias were induced by burst stimulation. Twenty-two to twenty-six days after treatment, MCT animals had RV hypertension, hypertrophy, and decreased ejection fractions compared with CON. A greater proportion of MCT hearts developed sustained ventricular tachycardias/fibrillation (0.83 MCT vs. 0.14 CON). MAPD was prolonged in RV and less so in the LV of MCT hearts. There were decreased levels of mRNA for K ϩ channels. Restitution curves of MCT RV were steeper than CON RV or either LV. Dispersion of MAPD was greater in MCT hearts and was dependent on stimulation frequency. Computer simulations based on ion channel gene expression closely predicted experimental changes in MAPD and restitution. We have identified a proarrhythmic substrate in the hearts of MCT-treated rats. We conclude that steeper RV electrical restitution and rate-dependant RV-LV action potential duration dispersion may be contributing mechanisms and be implicated in the generation of arrhythmias associated with in RV hypertension and hypertrophy. electrical restitution; fibrillation; action potentials INCREASED PULMONARY ARTERIAL pressure increases loading on the right ventricle (RV), which can lead to electrical, mechanical, and structural remodeling. In humans, pulmonary artery hypertension (PAH) is a disease that can be unstable and RV failure is a common outcome (4, 13, 38). The QT interval and QT dispersion of the ECG have been reported to be increased (19,20), and the shift in ECG derived ventricular gradient [reflecting action potential duration (APD) dispersion] has been related to increased RV load (17). Such changes in electrical activity have been linked to arrhythmias (1, 39), and PAH is associated with arrhythmias in patients (11). RV pathophysiology is in general understudied compared with the left ventricle (LV; Ref. 38), and the mechanisms that underlie RV changes in electrical activity in response to hypertension are not well understood.The monocrotaline (MCT)-induced model of pulmonary arterial hypertension and RV hypertrophy is well established (e.g., Refs. 14, 23). MCT is a pyrrolizidine alkaloid from...

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