A low-dose β1-blocker in combination with milrinone improves intracellular Ca2+ handling in failing cardiomyocytes by inhibition of milrinone-induced diastolic Ca2+ leakage from the sarcoplasmic reticulum.
A low-dose β1-blocker in combination with milrinone improves intracellular Ca2+ handling in failing cardiomyocytes by inhibition of milrinone-induced diastolic Ca2+ leakage from the sarcoplasmic reticulum.
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DOI：
10.1371/journal.pone.0114314
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Yano M
中科院分区：
文献类型：
--
作者：
Kobayashi S;Susa T;Ishiguchi H;Myoren T;Murakami W;Kato T;Fukuda M;Hino A;Suetomi T;Ono M;Uchinoumi H;Tateishi H;Mochizuki M;Oda T;Okuda S;Doi M;Yamamoto T;Yano M
本研究的目的是研究在米力农中加入低剂量β1受体阻滞剂是否能改善衰竭心肌细胞的心功能及其潜在的心脏保护机制。低剂量β1受体阻滞剂和米力农联合使用如何影响心力衰竭细胞内Ca 2+处理的分子机制尚不清楚。我们研究了米力农和兰地洛尔对正常和衰竭犬心肌细胞胞内钙瞬变（Ca 2 + transient，CaT）、细胞缩短（cell shortening，CS）、舒张期钙火花（diastolic Ca 2 + sparks，CaSF）频率和肌浆网钙浓度（{Ca 2 +}SR）的影响，并采用免疫印迹法测定兰尼碱受体（RyR 2）和受磷蛋白（phospholamban，PLB）的磷酸化水平。与正常心肌细胞相比，衰竭心肌细胞中CaSF显著增加，CaT和CS峰值显著降低。单独给药米力农可轻微增加CaT和CS峰值，而CaSF显著增加，同时{Ca 2 +} SR略有增加。以不抑制心肌细胞功能的剂量向衰竭心肌细胞联合给药β1-阻滞剂兰地洛尔可显著降低CaSF，同时{Ca 2 +}SR进一步增加，与单独给药米力农相比，CaT和CS峰值改善。兰地洛尔抑制RyR 2（Ser 2808）的过度磷酸化，但对磷酸化PLB（Ser 16和Thr 17）的水平没有影响。低剂量兰地洛尔可显著抑制在固定起搏频率（0.5 Hz）下衰竭心肌细胞CaT和CS的交替。低剂量β1受体阻滞剂联合米力农可改善衰竭心肌细胞的心功能，显然是通过抑制RyR 2磷酸化，而不是PLB，以及随后的舒张期Ca 2+渗漏。
The purpose of this study was to investigate whether adding a low-dose β1-blocker to milrinone improves cardiac function in failing cardiomyocytes and the underlying cardioprotective mechanism. The molecular mechanism underlying how the combination of low-dose β1-blocker and milrinone affects intracellular Ca2+ handling in heart failure remains unclear. We investigated the effect of milrinone plus landiolol on intracellular Ca2+ transient (CaT), cell shortening (CS), the frequency of diastolic Ca2+ sparks (CaSF), and sarcoplasmic reticulum Ca2+ concentration ({Ca2+}SR) in normal and failing canine cardiomyocytes and used immunoblotting to determine the phosphorylation level of ryanodine receptor (RyR2) and phospholamban (PLB). In failing cardiomyocytes, CaSF significantly increased, and peak CaT and CS markedly decreased compared with normal myocytes. Administration of milrinone alone slightly increased peak CaT and CS, while CaSF greatly increased with a slight increase in {Ca2+}SR. Co-administration of β1-blocker landiolol to failing cardiomyocytes at a dose that does not inhibit cardiomyocyte function significantly decreased CaSF with a further increase in {Ca2+}SR, and peak CaT and CS improved compared with milrinone alone. Landiolol suppressed the hyperphosphorylation of RyR2 (Ser2808) in failing cardiomyocytes but had no effect on levels of phosphorylated PLB (Ser16 and Thr17). Low-dose landiolol significantly inhibited the alternans of CaT and CS under a fixed pacing rate (0.5 Hz) in failing cardiomyocytes. A low-dose β1-blocker in combination with milrinone improved cardiac function in failing cardiomyocytes, apparently by inhibiting the phosphorylation of RyR2, not PLB, and subsequent diastolic Ca2+ leak.
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影响因子：
64.5
作者：
Marx, SO;Reiken, S;Marks, AR
通讯作者：
Marks, AR
影响因子：
2.8
作者：
Ikeshita, Kazutoshi;Nishikawa, Kiyonobu;Asada, Akira
通讯作者：
Asada, Akira
影响因子：
13.5
作者：
Györke S;Carnes C
通讯作者：
Carnes C
影响因子：
24
作者：
Hirashiki, A;Izawa, H;Yokota, M
通讯作者：
Yokota, M
影响因子：
--
作者：
KIHARA, Y;MORGAN, JP
通讯作者：
MORGAN, JP