Differential K(ATP) channel pharmacology in intact mouse heart.
Differential K(ATP) channel pharmacology in intact mouse heart.
复制标题
DOI：
10.1016/j.yjmcc.2009.08.026
复制
发表时间：
2010-01
影响因子：
5
通讯作者：
Nichols, Colin G.
中科院分区：
文献类型：
--
作者：
Glukhov, Alexey V.;Flagg, Thomas P.;Fedorov, Vadim V.;Efimov, Igor R.;Nichols, Colin G.
传统上，心脏肌膜 KATP 通道被认为由 Kir6.2 (KCNJ11) 和 SUR2A (ABCC9) 亚基组成。然而，强有力的证据表明，SUR1（磺酰脲类受体 1 型，ABCC8）亚基也在心脏中表达，并且它们在心房中发挥着重要的功能作用。为了进一步研究这一点，我们评估了同种型特异性钾通道开放药物二氮嗪（特定于 SUR1>SUR2A）和吡那地尔（SUR2A>SUR1）对野生型小鼠（WT，n=6）、SUR1−/−（n=6）和 Kir6.2−/− 小鼠（n=5）的完整心脏的影响。通过兰根多夫灌注心脏后表面的光学测绘来估计心房和心室的动作电位持续时间（APD）。为了确认两种开启剂的心房效应，在 WT (n=4) 和 SUR1−/− (n=3) 小鼠中绘制了分离的心房制剂图。玻璃微电极技术也用于验证光学动作电位。在 WT 心脏中，二氮嗪 (300 µM) 降低心房的 APD（从 33.8±1.9 ms 降至 24.2±1.1 ms，p<0.001），但对心室没有影响（APD 分别为 60.0±7.6 ms 与 60.8±7.5 ms，NS），这与 SUR1 的心房特异性作用一致。 SUR1 的缺失导致二氮嗪在 SUR1−/− 心房中的功效丧失（APD 分别为 36.8±1.9 ms 和 36.8±2.8 ms，NS）。相比之下，吡那地尔 (300 µM) 显着降低了 WT 和 SUR1−/− 心脏中的心室 APD（WT 中从 60.0±7.6 ms 降至 29.8±3.5 ms，p<0.001；SUR1−/− 中从 63.5±2.1 ms 降至 24.8±3.8 ms，p<0.001），但没有降低任一心脏中心房 APD。 WT或 SUR1−/− 心。格列本脲 (10μM) 逆转了吡那地尔对心室的影响，并将 APD 恢复至对照值。 Kir6.2−/− 心脏中 Kir6.2 亚基的缺失导致两种开启器的功效丧失（对于对照的心房和心室与二氮嗪和 分别为吡那地尔）。总的来说，这些结果表明，在同一只小鼠心脏中，由于 SUR1 在形成心房通道方面占主导地位，导致心房和心室中 KATP 药理学存在显着差异，导致钾通道开放剂对两个心室中的 APD 产生不同的影响。
Classically, cardiac sarcolemmal KATP channels have been thought to be composed of Kir6.2 (KCNJ11) and SUR2A (ABCC9) subunits. However, the evidence is strong that SUR1 (sulfonylurea receptor type 1, ABCC8) subunits are also expressed in the heart and that they play a significant functional role in the atria. To examine this further, we have assessed the effects of isotype-specific potassium channel-opening drugs, diazoxide (specific to SUR1>SUR2A) and pinacidil (SUR2A>SUR1), in intact hearts from wild type mice (WT, n=6), SUR1−/− (n=6), and Kir6.2−/− mice (n=5). Action potential durations (APDs) in both atria and ventricles were estimated by optical mapping of the posterior surface of Langendorff-perfused hearts. To confirm the atrial effect of both openers, isolated atrial preparations were mapped in both WT (n=4) and SUR1−/− (n=3) mice. The glass microelectrode technique was also used to validate optical action potentials. In WT hearts, diazoxide (300 µM) decreased APD in atria (from 33.8±1.9 ms to 24.2±1.1 ms, p<0.001) but was without effect in ventricles (APD 60.0±7.6 ms vs 60.8±7.5 ms, respectively, NS), consistent with an atrial-specific role for SUR1. The absence of SUR1 resulted in loss of efficacy of diazoxide in SUR1−/− atria (APD 36.8±1.9 ms vs 36.8±2.8 ms, respectively, NS). In contrast, pinacidil (300 µM) significantly decreased ventricular APD in both WT and SUR1−/− hearts (from 60.0±7.6 ms to 29.8±3.5 ms in WT, p<0.001; and from 63.5±2.1 ms to 24.8±3.8 ms in SUR1−/−, p<0.001), but did not decrease atrial APD in either WT or SUR1−/− hearts. Glibenclamide (10µM) reversed the effect of pinacidil in ventricles and restored APD to control values. The absence of Kir6.2 subunits in Kir6.2−/− hearts resulted in loss of efficacy of both openers (APD 47.2±2.2 ms vs 47.6±2.1 ms and 50.8±2.4 ms, and 90.6±5.7 ms vs 93.2±6.5 ms and 117.3±6.4 ms, for atria and ventricle in control versus diazoxide and pinacidil, respectively). Collectively, these results indicate that in the same mouse heart, significant differential KATP pharmacology in atria and ventricles, resulting from SUR1 predominance in forming the atrial channel, leads to differential effects of potassium channel openers on APD in the two chambers.
登录
查看更多内容
影响因子：
20.1
作者：
Baron, A;van Bever, L;Baertschi, AJ
通讯作者：
Baertschi, AJ
影响因子：
5.5
作者：
Fedorov, Vadim V.;Lozinsky, Ilya T.;Efimov, Igor R.
通讯作者：
Efimov, Igor R.
影响因子：
4.8
作者：
Crawford, RM;Ranki, HJ;Jovanovic, A
通讯作者：
Jovanovic, A
影响因子：
--
作者：
Morrissey, Alison;Rosner, Erika;Coetzee, William A
通讯作者：
Coetzee, William A
影响因子：
5.5
作者：
Fukuzaki, Koichi;Sato, Toshiaki;Nakaya, Haruaki
通讯作者：
Nakaya, Haruaki