Modulation of rate by autonomic agonists in SAN cells involves changes in diastolic depolarization and the pacemaker current
Modulation of rate by autonomic agonists in SAN cells involves changes in diastolic depolarization and the pacemaker current
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DOI：
10.1016/j.yjmcc.2007.04.017
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发表时间：
2007-07-01
影响因子：
5
通讯作者：
DiFrancesco, Dario
中科院分区：
文献类型：
--
作者：
Bucchi, Annalisa;BaruSCotti, Mad;DiFrancesco, Dario
已经提出了两种不同的细胞内机制来影响心脏起搏器细胞的放电速率：一种涉及第二信使cAMP对I-f电流的调节，另一种依赖于活动期间SR Ca2+瞬态的破坏或改变。虽然这两种机制都是适当的自动性和自主速率控制所必需的，但每种机制对起搏的具体贡献仍存在争议。我们研究了两个过程是否可以根据速率调制过程中对动作电位特征的潜在不同影响进行分离。为了确定特异性的I-f介导效应，我们使用了选择性I-f阻滞剂伊瓦布雷定，发现伊瓦布雷定（3 μ M）通过选择性地降低（-31.9%）早期舒张去极化（EDD）的陡峭程度来减缓速率（- 16.2%）。另一方面，ryanodine （3 μ M）用于评估SR Ca2+瞬态消除的效果，通过去极化起飞电位（TOP, 18）减缓了速率（-31.3%）。1%)而不影响EDD。因此，我们使用这两个参数来识别基于i -f或SR Ca2+瞬态的过程，并分析了rp -cAMP （50 VM）对动作电位特征的影响，rp -cAMP是一种直接激活f通道的膜透性cAMP类似物；我们发现Rp-cAMPs在不改变TOP的情况下通过增加EDD（+42.3%）来加速速率。最后，通过毒蕈碱（ACh 0.01 PM）或J -肾上腺素能（Iso 1 μ M）刺激实现速率调节；在这两种情况下，速率变化与EDD （ACh, - 29.3%和Iso， +47.6%）的改变有关，而与TOP无关。我们得出结论，自主神经激动剂诱导的EDD的速率相关变化是由If介导的，而不是由涉及SR Ca2+瞬态的过程介导的。(C) 2007爱思唯尔公司版权所有。
Two distinct intracellular mechanisms have been proposed to affect the firing rate of cardiac pacemaker cells: one involves modulation of the I-f current by the second messenger cAMP, and one relies upon disruption or alteration of SR Ca2+ transients during activity. Although both mechanisms are necessary for proper automaticity and autonomic rate control, the specific contribution of each to pacemaking is still debated. We investigated if the two processes can be separated based on potentially different effects on action potential characteristics during rate modulation. To identify specific I-f-mediated effects, we used the selective I-f blocker ivabradine and found that ivabradine (3 mu M) slows rate (- 16.2%) by selectively reducing (-31.9%) the steepness of early diastolic depolarization (EDD). On the other hand ryanodine (3 mu M), used to evaluate the effects of abolishment of SR Ca2+ transients, slowed rate (-31.3%) by depolarizing the take-off potential (TOP, 18. 1 %) without affecting EDD. We therefore used these two parameters to identify I-f-based or SR Ca2+ transients-based processes and analyzed the effects on action potential's characteristics of Rp-cAMPs (50 VM), a membrane permeable cAMP analogue directly activating f-channels; we found that Rp-cAMPs accelerates rate by increasing EDD (+42.3%) without modifying TOP. Finally, rate modulation was achieved by muscarinic (ACh 0.01 PM) or J beta-adrenergic (Iso 1 mu M) stimulation; in both cases, rate changes were associated with modifications of EDD (ACh, - 29.3% and Iso, +47.6%) and not of TOP. We conclude that rate-related changes in the EDD induced by autonomic agonists are mediated by If and not by processes involving SR Ca2+ transients. (C) 2007 Elsevier Inc. All rights reserved.