Autocrine A2 in the T-System of Ventricular Myocytes Creates Transmural Gradients in Ion Transport: A Mechanism to Match Contraction with Load?
Autocrine A2 in the T-System of Ventricular Myocytes Creates Transmural Gradients in Ion Transport: A Mechanism to Match Contraction with Load?
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DOI：
10.1016/j.bpj.2014.04.042
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发表时间：
2014-06-03
影响因子：
3.4
通讯作者：
Kim, Jeremy H.
中科院分区：
文献类型：
--
作者：
Gao, Junyuan;Sun, Xiurong;Kim, Jeremy H.
钠钾泵电流（l(p)）、瞬态外向钾离子电流（I-to）和钙离子电流（I-CaL）的跨壁异质性在调节心室心肌的电和收缩活动中起重要作用。先前的研究表明血管紧张素II （A2）可能决定I-to的跨壁梯度，但A2对I和I- cal的影响尚不清楚。在这项研究中，肌细胞被分离。从心外膜和。心内膜。我们发现I-p和Ito都有单调梯度，ENDO的电流最低。当AT(1)Rs被抑制时，EPI电流不受影响，但ENDO电流增加，提示内源性细胞外A2抑制ENDO中这两种电流。A2对i -p和i -to的抑制产生的K-0.5值基本相同，因此它们可能受到相同的机制调节。(1) r介导的I-p或I-to的抑制或I-caL的刺激在离体肌细胞中持续数小时，表明A2像t系统一样持续自分泌进入受限扩散室。缩管使EPI I-p降至低ENDO值，消除了A2敏感性，因此t系统管腔可能确实是受限扩散室。这些研究表明，33-50%的IF、57-65%的I-to和相当一部分I-caL存在于t小管膜中，在t小管膜中，它们受A2自分泌进入t系统管腔和AT(1)Rs激活的跨壁调节。增加的AT(1)R激活调节这些电流的方向，预计会增加收缩性。内源性A2激活AT(1)Rs从EPI到ENDO单调增加，其方式类似于报道的心室充满血液时被动张力的增加。因此，我们假设负载是调节AT(1)Rs的a2激活的信号，AT(1)Rs产生与负载梯度相匹配的收缩梯度。
Transmural heterogeneities in Na/K pump current (l(p)), transient outward K+-current (I-to), and Ca2+-current (I-CaL) play an important role in regulating electrical and contractile activities in the ventricular myocardium. Prior studies indicated angiotensin II (A2) may determine the transmural gradient in I-to, but the effects of A2 on I, and I-caL were unknown. In this study, myocytes were isolated. from five muscle layers between epicardium and. endocardium. We found a monotonic gradient in both I-p and Ito, with the lowest currents in ENDO. When AT(1)Rs were inhibited, EPI currents were unaffected, but ENDO currents increased, suggesting endogenous extracellular A2 inhibits both currents in ENDO. I-p-and I-to-inhibition by A2 yielded essentially the same K-0.5 values, so they may both be regulated by the same mechanism. A2/AT(1) R-mediated inhibition of I-p or I-to or stimulation of I-caL persisted for hours in isolated myocytes, suggesting continuous autocrine secretion of A2 into a restricted diffusion compartment, like the T-system. Detubulation brought EPI I-p to its low ENDO value and eliminated A2 sensitivity, so the T-system lumen may indeed be the restricted diffusion compartment. These studies showed that 33-50% of IF, 57-65% of I-to, and a significant fraction of I-caL reside in T-tubule membranes where they are transmurally regulated by autocrine secretion of A2 into the T-system lumen and activation of AT(1)Rs. Increased AT(1)R activation regulates each of these currents in a direction expected to increase contractility. Endogenous A2 activation of AT(1)Rs increases monotonically from EPI to ENDO in a manner similar to reported increases in passive tension when the ventricular chamber fills with blood. We therefore hypothesize load is the signal that regulates A2-activation of AT(1)Rs, which create a contractile gradient that matches the gradient in load.