背景/目的： Sacubitril (SAC) 被認為是一種腦啡肽酶 (neprilysin) 的抑制劑，是一種與valsartan (VAL) 合併使用的新型抗高血壓藥物，而 VAL 則是已知的血管加壓素 II 受體的阻滯劑。 然而，目前還不清楚這兩種藥劑可能在多大程度上直接擾亂膜離子電流的振幅和動力學。 在這項研究中，我們試圖確定 SAC 及其相關化合物對腦下垂體細胞和海馬迴神經元的離子電流的影響。 研究方法：以膜片鉗 (patch clamp) 之全細胞(whole-cell) 或細胞貼附 (cell-attach) 的配置下進行記錄。 結果：向腦下垂體細胞株 GH3 添加 SAC會以濃度依賴性的方式降低M型鉀離子電流 (IK(M)) 的電流幅度，其半抑制濃度 (IC50) 值約為 9.8 μM。 在添加 SAC 後， M型鉀離子電流的激活曲線偏移到更為去極化的電位，但電流的門控電荷量 (gating charge) 沒有變化。 該藥物與 metformin或 sitagliptin 合併使用可以協同性抑制M型鉀離子電流，聯合指數 (CI) 小於 1.0，該指數由 Chou-Talalay 圖形進行計算。 濃度達 30 μM 的 SAC 能些微抑制 GH3 細胞中的延遲整流器型鉀離子電流；然而，它的存在對大型電導的鈣離子激活的鉀離子通道的活性改變極小。 而 SAC 也能略微的抑制電壓門控型的鈉離子電流 (INa)，進一步添加 VAL 或 metofluthrin 則可增加電流的幅度，同時降低電流的失活率。 在電流鉗 (current-clamp) 的記錄模式下， SAC 能有效增加自發性動作電位 (APs) 的觸發頻率，隨後添加 flupirtine 則能逆轉其對動作電位頻率加速的效果。 在海馬迴神經元細胞株mHippoE-14的實驗中，也觀察到 SAC 有抑制 M型鉀離子電流幅度的能力。 結論：除去對腦啡肽酶抑制的效果外，由 SAC 所誘導的M型鉀離子電流擾動可能是直接作用的，並且是因其對其他體內神經元、神經內分泌細胞或內分泌細胞之廣泛藥理作用的影響所致。

Background/Aims: Sacubitril (SAC) recognized to be a neprilysin inhibitor is a novel antihypertensive drug used in combination with valsartan (VAL) that is thought to be a blocker of angiotensin II receptors. However, it is largely unclear to what extent these two agents might directly perturb the amplitude and kinetics of membrane ionic currents. In this study, we sought to determine the effects of SAC and its related compounds on ionic currents in pituitary cells and hippocampal neurons. Methods: Patch-clamp recordings were performed under whole-cell, cell-attached or inside-out configuration. Results: Addition of SAC to GH3 cells decreased the amplitude of M-type K+ current (IK(M)) in a concentration-dependent manner with an IC50 value of 9.8 μM. The activation curve of IK(M) after addition of SAC was shifted to depolarized potential with no change in the gating charge of the current. This drug in combination with either metformin or sitagliptin acts synergistically to suppress IK(M) with the combination index less than 1.0, which was calculated from Chou-Talalay plot. SAC at a concentration of 30 μM slightly suppressed delayed-rectifier K+ current in GH3 cells; however, minimal change in the activity of large-conductance Ca2+-activated K+ channels was demonstrated in its presence. SAC slightly suppressed voltage-gated Na+ current (INa) and further addition of VAL or metofluthrin enhanced current amplitude together with decreased rate of current inactivation. Under current-clamp recordings, this compound was effective at increasing firing frequency of spontaneous actions potentials (APs) and subsequent addition of flupirtine reversed its increase of AP frequency. In mHippoE-14 hippocampal neurons, the ability of SAC to inhibit IK(M) amplitude was also observed. Conclusion: Apart from neprilysin inhibition, SAC-induced perturbation of IK(M) is direct and may reasonably be responsible for its widely pharmacological actions on neurons, or neuroendocrine or endocrine cells arising in vivo.

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