|
|
|
| Effects of Dantrolene on calcium handling of ventricular myocytes and cardiac function in rats with chronic heart failure |
| HU Dongdong LIU Tao SHI Shaobo HUANG Yan LIANG Sa HU Dan |
| Department of Cardiology, People′s Hospital of Wuhan University Cardiovascular Research Institute of Wuhan University Hubei Key Laboratory of Cardiology, Hubei Province, Wuhan 430060, China |
|
|
|
Abstract Objective To discuss the effects of Dantrolene (DTL) on calcium handling of ventricular myocytes and cardiac function in rats with chronic heart failure (CHF). Methods According to the random number table method, 57 adult male SD rats were assigned to control group, CHF group and intervention group (n = 19), which were given normal saline, Isoproterenol (ISO), and ISO+DTL, for 2 weeks. Two-week later, the hemodynamic parameters and serum B-type natriuretic peptide (BNP) level were measured. The ventricular myocytes were isolated, then the cell contractility was automatically detected by the video edge-detector system. The calcium transient (CaT） and sarcoplasmic reticulum (SR) calcium content ([Ca2+]SR) were recorded by loading cardiomyocytes with Fura-2 AM. The protein levels of ryanodine receptor 2 (RyR2), SR Ca2+-ATPase (SERCA2a) and phospholamban (PLB) were detected by Western blot. Results Compared with control group, left ventricular end diastolic pressure (LVEDP), serum BNP level, diastolic intracellular Ca2+ level ([Ca2+]i) were significantly increased in CHF group (P < 0.01), decay time constant (tau) of CaT, time to peak (TP) of cell contraction, time to 50% cell relaxation (TR50) were significantly extended in CHF group (P < 0.01), while left ventricular end systolic pressure (LVESP), ±dP/dtmax, cell shortening percentage, CaT amplitude, [Ca2+]SR, the protein levels of RyR2 and SERCA2a were significantly decreased in CHF group (P < 0.01). Compared with CHF group, LVEDP, serum BNP level, [Ca2+]i, decay time constant of CaT were significantly decreased in intervention group (P < 0.01), decay time constant of CaT, TP of cell contraction, TR50 were significantly shortened in intervention group (P < 0.01), whereas, LVESP, ±dP/dtmax, cell shortening percentage, CaT amplitude, [Ca2+]SR, the protein level of RyR2 and SERCA2a were markedly increased in intervention group (P < 0.05 or P < 0.01). Conclusion DTL treatment can improve cardiac function in rats with CHF, which may be related to the repair of calcium handling of ventricular myocytes by DTL.
|
|
|
|
|
|
[1] Perreault CL，Meuse AJ，Bentivegna LA，et al. Abnormal intracellular calcium handling in acute and chronic heart failure：role in systolic and diastolic dysfunction [J]. Eur Heart J，1990，11（Suppl C）：8-21.
[2] Denham NC，Pearman CM，Caldwell JL，et al. Calcium in the pathophysiology of atrial fibrillation and heart failure [J]. Front Physiol，2018，9：1380.
[3] Roe AT，Frisk M，Louch WE，et al. Targeting cardiomyocyte Ca2+ homeostasis in heart failure [J]. Curr Pharm Des，2015，21（4）：431-448.
[4] H?覬ydal MA，Kirkeby-Garstad I，Karevold A，et al. Human cardiomyocyte calcium handling and transverse tubules in mid-stage of post-myocardial-infarction heart failure [J]. ESC Heart Fail，2018，5（3）：332-342.
[5] Avula UMR，Hernandez JJ，Yamazaki M，et al. Atrial infarction-induced spontaneous focal discharges and atrial fibrillation in sheep：role of dantrolene- sensitive aberrant ryanodine receptor calcium release [J]. Circ Arrhythm Electrophysiol，2018，11（3）：e005659.
[6] Hartmann N，Pabel S，Herting J，et al. Antiarrhythmic effects of dantrolene in human diseased cardiomyocytes [J]. Heart Rhythm，2017，14（3）：412-419.
[7] Acsai K，Nagy N，Marton Z，et al. Antiarrhythmic potential of drugs targeting the cardiac ryanodine receptor Ca2+ release channel：case study of dantrolene [J]. Curr Pharm Des，2015，21（8）：1062-1072.
[8] 梁飒，刘韬，石少波，等.抑制钙敏感受体对慢性心力衰竭大鼠室性心律失常易感性的影响[J].中华心律失常学杂志，2018，22（1）：69-75.
[9] 侯果，邱璇，王能，等.肾去交感神经术对慢性心力衰竭大鼠心肌纤维化及结缔组织生长因子表达的影响[J].医学研究杂志，2016，45（1）：79-83.
[10] 刘韬，石少波，黄燕，等.儿茶酚抑素对心肌梗死大鼠心室肌细胞钙转运及室性心律失常的影响[J].中国病理生理杂志，2019，35（12）：2128-2134.
[11] Nassal MM，Wan X，Laurita KR，et al. Atrial SERCA2a Overexpression has no effect on cardiac alternans but promotes arrhythmogenic SR Ca2+ triggers [J]. PLoS One，2015，10（9）：e0137359.
[12] Zhou WP，Li F，Wu JJ，et al. Calcium-handling abnormalities underlying atrial arrhythmogenesis in a Fontan operation canine model [J]. World J Pediatr，2018，14（6）：576-584.
[13] Zheng A，Yi H，Li F，et al. Changes in gut microbiome structure and function of rats with isoproterenol-induced heart failure [J]. Int Heart J，2019，60（5）：1176-1183.
[14] Yuan J，Hong H，Zhang Y，et al. Chrysophanol attenuated isoproterenol-induced cardiac hypertrophy by inhibiting Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway [J]. Cell Biol Int，2019，43（6）：695-705.
[15] Aluja D，Inserte J，Penela P，et al. Calpains mediate isoproterenol-induced hypertrophy through modulation of GRK2 [J]. Basic Res Cardiol，2019，114（3）：21.
[16] Wescott AP，Jafri MS，Lederer WJ，et al. Ryanodine receptor sensitivity governs the stability and synchrony of local calcium release during cardiac excitation-contraction coupling [J]. J Mol Cell Cardiol，2016，92：82-92.
[17] Lu L，Zheng Q，Xia L，et al. Spatial remodelling of calcium release units may impair cardiac electro-mechanical function：a simulation study [J]. Comput Biol Med，2019， 108：234-241.
[18] Bers DM. Cardiac excitation-contraction coupling [J]. Nature，2002，415（6868）：198-205.
[19] Abi-Samra F，Gutterman D. Cardiac contractility modulation：a novel approach for the treatment of heart failure [J]. Heart Fail Rev，2016，21（6）：645-660.
[20] Zhang Y，Jiao L，Sun L，et al. LncRNA ZFAS1 as a SERCA2a inhibitor to cause intracellular Ca2+ overload and contractile dysfunction in a mouse model of myocardial infarction [J]. Circ Res，2018，122（10）：1354-1368. |
|
|
|
