SK channel blockade prevents hypoxia-induced ventricular arrhythmias through inhibition of Ca 2+/voltage uncoupling in hypertrophied hearts
SK channel blockade prevents hypoxia-induced ventricular arrhythmias through inhibition of Ca 2+/voltage uncoupling in hypertrophied hearts
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SK 通道阻断通过抑制肥大心脏中的 Ca 2 /电压解偶联来预防缺氧引起的室性心律失常
DOI：
10.1152/ajpheart.00777.2020
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Anzai Toshihisa
中科院分区：
文献类型：
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作者：
Takahashi Masayuki;Yokoshiki Hisashi;Mitsuyama Hirofumi;Watanabe Masaya;Temma Taro;Kamada Rui;Hagiwara Hikaru;Takahashi Yumi;Anzai Toshihisa
室性心律失常（VA）是左心室（LV）肥大和/或急性缺血患者死亡的主要原因。我们假设，apamin，小电导Ca 2+激活的K+（SK）通道的阻滞剂，改变Ca 2+处理，并在心室肌中表现出抗心肌炎作用。自发性高血压大鼠被用作左室肥厚的模型。在Langendorff灌流系统上进行了全脑缺氧（GH）时膜电位（Vm）和细胞内钙（Cai）的双重光学标测。GH期间大多数起搏诱导的VA由触发活动引发。apamin（100 nmol/L）预处理可显著抑制VA诱导的细胞凋亡。与SK通道阻断剂（apamin和NS 8593）相比，非SK通道阻断剂（格列本脲和4-AP）没有表现出抗肿瘤作用。Apamin不仅阻止动作电位时程（APD 80）缩短，（−18.7 [95%置信区间，−35.2至−6.05] ms vs. −2.75 [95% CI，−10.45至12.65] ms，P= 0.04），而且钙瞬变持续时间（CaTD 80）延长（14.52 [95% CI，8.8-20.35] ms vs. 3.85 [95% CI，−3.3至12.1] ms，P< 0.01），从而降低CaTD 80 − APD 80，这表示“Cai/Vmun偶联”（33.22 [95% CI，22-48.4] ms vs. 6.6 [95% CI，0-14.85] ms，P< 0.01）。Cai/Vmun偶联的降低归因于apamin对舒张期Cai增加的抑制和Ca 2+衰减常数的延长。Na+/K+泵抑制剂哇巴因（ouabain）的加入可消除apamin引起的VA诱导和AP/CaTs参数变化的抑制作用。Apamin减弱APD缩短，Ca 2+处理异常，和Cai/Vmuncoupling，导致抑制VA发生在缺氧hypertrophied hearts.NEW & NOTEWORTHY我们证明，缺氧诱导的室性心律失常主要是由钙2+负载触发活动在hypertrophied心脏。阻断小电导Ca 2+激活的K+通道，特别是“apamin”，不仅缓解动作电位时程缩短，而且缓解Ca 2+处理异常，最明显的是“Ca 2 +/电压解偶联”，从而显示出抗心律失常作用。
Ventricular arrhythmia (VA) is the major cause of death in patients with left ventricular (LV) hypertrophy and/or acute ischemia. We hypothesized that apamin, a blocker of small-conductance Ca2+-activated K+(SK) channels, alters Ca2+handling and exhibits anti-arrhythmic effects in ventricular myocardium. Spontaneous hypertensive rats were used as a model of LV hypertrophy. A dual optical mapping of membrane potential (Vm) and intracellular calcium (Cai) was performed during global hypoxia (GH) on the Langendorff perfusion system. The majority of pacing-induced VAs during GH were initiated by triggered activities. Pretreatment of apamin (100 nmol/L) significantly inhibited the VA inducibility. Compared with SK channel blockers (apamin and NS8593), non-SK channel blockers (glibenclamide and 4-AP) did not exhibit anti-arrhythmic effects. Apamin prevented not only action potential duration (APD80) shortening (−18.7 [95% confidence interval, −35.2 to −6.05] ms vs. −2.75 [95% CI, −10.45 to 12.65] ms,P= 0.04) but also calcium transient duration (CaTD80) prolongation (14.52 [95% CI, 8.8–20.35] ms vs. 3.85 [95% CI, −3.3 to 12.1] ms,P< 0.01), thereby reducing CaTD80− APD80, which denotes “Cai/Vmuncoupling” (33.22 [95% CI, 22–48.4] ms vs. 6.6 [95% CI, 0–14.85] ms,P< 0.01). The reduction of Cai/Vmuncoupling was attributable to less prolonged Ca2+decay constant and suppression of diastolic Caiincrease by apamin. The inhibition of VA inducibility and changes in APs/CaTs parameters caused by apamin was negated by the addition of ouabain, an inhibitor of Na+/K+pump. Apamin attenuates APD shortening, Ca2+handling abnormalities, and Cai/Vmuncoupling, leading to inhibition of VA occurrence in hypoxic hypertrophied hearts.NEW & NOTEWORTHYWe demonstrated that hypoxia-induced ventricular arrhythmias were mainly initiated by Ca2+-loaded triggered activities in hypertrophied hearts. The blockades of small-conductance Ca2+-activated K+channels, especially “apamin,” showed anti-arrhythmic effects by alleviation of not only action potential duration shortening but also Ca2+handling abnormalities, most notably the “Ca2+/voltage uncoupling.”