Koumi S, Arentzen C E, Backer C L, Wasserstrom J A
Department of Medicine (Reingold ECG Center), Northwestern University School of Medicine, Chicago, IL 60611.
Circulation. 1994 Nov;90(5):2213-24. doi: 10.1161/01.cir.90.5.2213.
A variety of previous studies have demonstrated reduced diastolic potential and electrical activity in atrial specimens from patients with heart disease. Although K+ channels play a major role in determining resting membrane potential and repolarization of the action potential, little is known about the effects of preexisting heart disease on human atrial K+ channel activity.
We characterized the inwardly rectifying K+ channel (IKI) and the muscarinic K+ channel [IK(ACh)] in atrial myocytes isolated from patients with heart failure (HF) and compared electrophysiological characteristics with those from donors (control) by the patch-clamp technique. Resting membrane potentials of isolated atrial myocytes from HF were more depolarized (-51.1 +/- 9.7 mV, mean +/- SD, n = 30 patients) than those from donors (-73.0 +/- 7.2 mV, n = 4 patients, P < .001). The action potential duration in HF was longer than that in donors. Although acetylcholine (ACh) shortened the action potential, reduced the overshoot, and hyperpolarized the atrial cell membrane in HF, these effects were attenuated compared with those observed in donors. The whole-cell membrane current slope conductance in HF was small, the reversal potential was more positive, and the sensitivity to ACh was less compared with donors. In single-channel recordings from cell-attached patches, IK1 channel conductance and gating characteristics were the same in HF and donor atria. When ACh was included in the pipette solution, IK(ACh) was activated in both groups. Single-channel slope conductance of IK(ACh) averaged 42 +/- 3 pS (n = 28) in HF and 44 +/- 2 pS (n = 4) in donors, and mean open lifetime was 1.3 +/- 0.3 milliseconds (n = 24) in HF and 1.5 +/- 0.4 milliseconds (n = 4) in donors. These values were virtually identical in the two groups (not significantly different, NS), although both single IK1 and IK(ACh) channel densities were less in HF. Channel open probability of IK(ACh) was also less in HF (4.0 +/- 1.2%, n = 24) than in donors (6.8 +/- 1.1%, n = 3, P < .01). The concentration of ACh at half-maximal activation was 0.11 mumol/L in HF and 0.03 mumol/L in donors. In excised inside-out patches, IK(ACh) from HF required higher concentrations of GTP and GTP gamma S to activate the channel compared with donors. These results suggest a reduced IK(ACh) channel sensitivity to M2 cholinergic receptor-linked G protein (Gi) in HF compared with donors.
Atrial myocytes isolated from failing human hearts exhibited a lower resting membrane potential and reduced sensitivity to ACh compared with donor atria. Whole-cell and single-channel measurements suggest that these alterations are caused by reduced IK1 and IK(ACh) channel density and reduced IK(ACh) channel sensitivity to Gi-mediated channel activation in HF.
此前的多项研究表明，心脏病患者心房标本的舒张期电位和电活动降低。虽然钾离子通道在决定静息膜电位和动作电位复极化过程中起主要作用，但关于既存心脏病对人房钾离子通道活性的影响却知之甚少。
我们对从心力衰竭（HF）患者分离出的心房肌细胞中的内向整流钾离子通道（IKI）和毒蕈碱钾离子通道[IK(ACh)]进行了特性分析，并通过膜片钳技术将其电生理特性与供体（对照）的进行比较。HF患者分离出的孤立心房肌细胞的静息膜电位比供体的更去极化（-51.1±9.7mV，平均值±标准差，n = 30例患者）（-73.0±7.2mV，n = 4例供体，P <.001）。HF患者的动作电位时程比供体的更长。虽然乙酰胆碱（ACh）缩短了HF患者的动作电位，降低了超射，并使心房细胞膜超极化，但与供体相比，这些作用减弱。与供体相比，HF患者的全细胞膜电流斜率电导较小，反转电位更正，对ACh的敏感性较低。在细胞贴附膜片的单通道记录中，HF和供体心房的IK1通道电导和门控特性相同。当移液管溶液中加入ACh时，两组均激活IK(ACh)。HF患者IK(ACh)的单通道斜率电导平均为42±3pS（n = 28），供体为44±2pS（n = 4），HF患者的平均开放寿命为1.3±0.3毫秒（n = 24），供体为1.5±0.4毫秒（n = 4）。两组的这些值实际上相同（无显著差异，NS），尽管HF患者单个IK1和IK(ACh)通道密度均较低。HF患者IK(ACh)的通道开放概率也低于供体（4.0±1.2%，n = 24）（6.8±1.1%，n = 3，P <.01）。HF患者半数最大激活时ACh的浓度为0.11μmol/L，供体为0.03μmol/L。在切除的内向外膜片中，与供体相比，HF患者的IK(ACh)需要更高浓度的GTP和GTPγS来激活通道。这些结果表明，与供体相比，HF患者IK(ACh)通道对M2胆碱能受体相关G蛋白（Gi）的敏感性降低。
与供体心房相比，从衰竭人心脏分离出的心房肌细胞表现出较低的静息膜电位和对ACh的敏感性降低。全细胞和单通道测量表明，这些改变是由HF患者IK1和IK(ACh)通道密度降低以及IK(ACh)通道对Gi介导的通道激活的敏感性降低引起的。
