Enhancement of ventricular gap-junction coupling by rotigaptide
Enhancement of ventricular gap-junction coupling by rotigaptide
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DOI：
10.1093/cvr/cvn100
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发表时间：
2008-08-01
影响因子：
10.8
通讯作者：
Veenstra, Richard D.
中科院分区：
文献类型：
--
作者：
Lin, Xianming;Zemlin, Christian;Veenstra, Richard D.
目的罗替加肽可能通过改善心肌缝隙连接通讯发挥其抗心肌缺血作用。为了直接研究罗替加肽作用的机制，我们用临床药理剂量的罗替加肽处理培养的新生小鼠心室肌细胞，并直接确定其对缝隙连接电流的影响。方法和结果新生小鼠心室肌细胞酶促分离和培养1-4天。原代培养细胞对进行双全细胞膜片钳程序以直接测量间隙连接电流（Ij）和电压（Vj）。将罗替加肽（0-350 nM）应用过夜或急性灌注到35 mm培养皿中。罗替加肽（35-100 nM）急性和慢性增加静息间隙连接电导（gj），并使稳态最小值（Gmin）正常化5- 20%。更高的浓度产生了递减的反应，这模拟了观察到的药物疗效。失活动力学同样以治疗浓度依赖性方式减慢，而不影响失活或恢复的Vj依赖性。0-100 nM rotigaptide对心室Argj在心脏动作电位传播过程中的作用通过计算机模拟准确地建模，这表明临床有效浓度的rotigaptide可以部分逆转由于减少ingj和失活而导致的传导减慢。以浓度依赖性方式进行状态失活。罗替加肽可能通过改善传导和防止部分非偶联心肌中折返环路的形成而有效治疗折返型心律失常。
AimsRotigaptide is proposed to exert its anti-arrhythmic effects by improving myocardial gap-junction communication. To directly investigate the mechanisms of rotigaptide action, we treated cultured neonatal murine ventricular cardiomyocytes with clinical pharmacological doses of rotigaptide and directly determined its effects on gap-junctional currents.Methods and resultsNeonatal murine ventricular cardiomyocytes were enzymatically isolated and cultured for 1–4 days. Primary culture cell pairs were subjected to dual whole cell patch-clamp procedures to directly measure gap-junctional currents (Ij) and voltage (Vj). Rotigaptide (0–350 nM) was applied overnight or acutely perfused into 35 mm culture dishes. Rotigaptide (35–100 nM) acutely and chronically increased the resting gap-junction conductance (gj), and normalized steady-state minimumgj(Gmin) by 5–20%. Higher concentrations produced a diminishing response, which mimics the observed therapeutic efficacy of the drug. The inactivation kinetics was similarly slowed in a therapeutic concentration-dependent manner without affecting theVjdependence of inactivation or recovery. The effects of 0–100 nM rotigaptide on ventriculargjduring cardiac action potential propagation were accurately modelled by computer simulations which demonstrate that clinically effective concentrations of rotigaptide can partially reverse conduction slowing due to decreases ingjand inactivation.ConclusionThese results demonstrate that therapeutic concentrations of rotigaptide increase the resting gap-junction conductance and reduce the magnitude and kinetics of steady-state inactivation in a concentration-dependent manner. Rotigaptide may be effective in treating re-entrant forms of cardiac arrhythmias by improving conduction and preventing the formation of re-entrant circuits in partially uncoupled myocardium.