Skibsbye Lasse, Wang Xiaodong, Axelsen Lene Nygaard, Bomholtz Sofia Hammami, Nielsen Morten Schak, Grunnet Morten, Bentzen Bo Hjorth, Jespersen Thomas
*Danish National Research Foundation Centre for Cardiac Arrhythmia and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; †Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; and ‡Acesion Pharma, Copenhagen, Denmark.
J Cardiovasc Pharmacol. 2015 Aug;66(2):165-76. doi: 10.1097/FJC.0000000000000259.
SK channels have functional importance in the cardiac atrium of many species, including humans. Pharmacological blockage of SK channels has been reported to be antiarrhythmic in animal models of atrial fibrillation; however, the exact antiarrhythmic mechanism of SK channel inhibition remains unclear.
We speculated that together with a direct inhibition of repolarizing SK current, the previously observed depolarization of the atrial resting membrane potential (RMP) after SK channel inhibition reduces sodium channel availability, thereby prolonging the effective refractory period and slowing the conduction velocity (CV). We therefore aimed at elucidating these properties of SK channel inhibition and the underlying antiarrhythmic mechanisms using microelectrode action potential (AP) recordings and CV measurements in isolated rat atrium. Automated patch clamping and two-electrode voltage clamp were used to access INa and IK,ACh, respectively.
The SK channel inhibitor N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) exhibited antiarrhythmic effects. ICA prevented electrically induced runs of atrial fibrillation in the isolated right atrium and induced atrial postrepolarization refractoriness and depolarized RMP. Moreover, ICA (1-10 μM) was found to slow CV; however, because of a marked prolongation of effective refractory period, the calculated wavelength was increased. Furthermore, at increased pacing frequencies, SK channel inhibition by ICA (10-30 μM) demonstrated prominent depression of other sodium channel-dependent parameters. ICA did not inhibit IK,ACh, but at concentrations above 10 μM, ICA use dependently inhibited INa.
SK channel inhibition modulates multiple parameters of AP. It prolongs the AP duration and shifts the RMP towards more depolarized potentials through direct ISK block. This indirectly leads to sodium channel inhibition through accumulation of state dependently inactivated channels, which ultimately slows conduction and decreases excitability. However, a contribution from a direct sodium channel inhibition cannot be ruled. We here propose that the primary antiarrhythmic mechanism of SK channel inhibition is through direct potassium channel block and through indirect sodium channel inhibition.
SK通道在包括人类在内的许多物种的心房中具有重要功能。据报道，在心房颤动动物模型中，SK通道的药理学阻断具有抗心律失常作用；然而，SK通道抑制的确切抗心律失常机制仍不清楚。
我们推测，除了直接抑制复极化SK电流外，先前观察到的SK通道抑制后心房静息膜电位（RMP）的去极化会降低钠通道的可用性，从而延长有效不应期并减慢传导速度（CV）。因此，我们旨在使用微电极动作电位（AP）记录和分离大鼠心房中的CV测量来阐明SK通道抑制的这些特性及其潜在的抗心律失常机制。分别使用自动膜片钳和双电极电压钳来记录INa和IK,ACh。
SK通道抑制剂N-(吡啶-2-基)-4-(吡啶-2-基)噻唑-2-胺（ICA）表现出抗心律失常作用。ICA可预防离体右心房中电诱导的房颤发作，并诱导心房复极化后不应期和RMP去极化。此外，发现ICA（1-10μM）可减慢CV；然而，由于有效不应期显著延长，计算出的波长增加。此外，在起搏频率增加时，ICA（10-30μM）对SK通道的抑制表现出对其他钠通道依赖性参数的显著抑制。ICA不抑制IK,ACh，但在浓度高于10μM时，ICA会使用依赖性地抑制INa。
SK通道抑制可调节AP的多个参数。它通过直接阻断ISK延长AP持续时间并使RMP向更去极化的电位移动。这通过状态依赖性失活通道的积累间接导致钠通道抑制，最终减慢传导并降低兴奋性。然而，不能排除直接钠通道抑制的作用。我们在此提出，SK通道抑制的主要抗心律失常机制是通过直接阻断钾通道和间接抑制钠通道。
