康普瑞丁磷酸二钠对豚鼠心室肌细胞动作电位和hERG通道电流的影响
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摘要
目的研究康普瑞汀磷酸二钠(CA4P)对豚鼠心室肌细胞动作电位间期(APD)和人类ether-a-go-go相关基因(hERG)编码的K~+离子通道的影响,探讨CA4P对心脏毒性作用的体外细胞学机制。方法使用全细胞膜片钳技术记录CA4P10、100μmol/L作用下豚鼠心肌细胞的动作电位,并记录CA4P 3、10、30、100、300μmol/L下对HEK293细胞hERG通道尾电流的抑制率及CA4P 30μmol/L在10、20、30、40、50 mV时对h ERG电流的抑制率。结果 CA4P 10、100μmol/L显著延长动作电位复极50%时程(ADP_(50))和动作电位复极90%时程(ADP_(90))。CA4P可浓度相关性和电压相关性抑制hERG尾电流幅度,半数抑制浓度(IC_(50))为54.9μmol/L,安全边缘范围为30.5～2.8。结论 CA4P可延长动作电位间期及抑制hERG通道电流。
Objective To investigate the effects of combretastatin A4 phosphate(CA4P) on action potential duration(APD) and human-ether-a-go-go-related gene(hERG) K~+ channel of ventricle muscle cell in cavy, and to explore in vitro celluar mechanism of CA4P in cardiotoxicity effects. Methods APD of ventricle muscle cell in cavy under the action of CA4P 10 and 100 μmol/L were recorded by the whole cell patch clamp technique. The inhibition ratio of hERG channel tail current under the action of CA4P 3, 10,30, 100, and 300 μmol/L and the inhibition ratio of hERG channel tail current under the action of CA4P 30 μmol/L in 10, 20, 30, 40, and50 mV were recorded. Results CA4P 10 and 100 μmol/L significantly prolonged the action potential duration at 50% of repolarization(ADP_(50)) and the action potential duration at 90% of repolarization(ADP_(90)). CA4P induced a concentration-and voltage-dependent inhibition of the current amplitude in the hERG tail current. The half-maximal inhibitory concentration(IC_(50)) was 54.9 μmol/L. The safety margin ratio was 30.5 — 2.8. Conclusion CA4P can prolong APD and inhibit hERG channel current.
Objective To investigate the effects of combretastatin A4 phosphate(CA4P) on action potential duration(APD) and human-ether-a-go-go-related gene(hERG) K~+ channel of ventricle muscle cell in cavy, and to explore in vitro celluar mechanism of CA4P in cardiotoxicity effects. Methods APD of ventricle muscle cell in cavy under the action of CA4P 10 and 100 μmol/L were recorded by the whole cell patch clamp technique. The inhibition ratio of hERG channel tail current under the action of CA4P 3, 10,30, 100, and 300 μmol/L and the inhibition ratio of hERG channel tail current under the action of CA4P 30 μmol/L in 10, 20, 30, 40, and50 mV were recorded. Results CA4P 10 and 100 μmol/L significantly prolonged the action potential duration at 50% of repolarization(ADP_(50)) and the action potential duration at 90% of repolarization(ADP_(90)). CA4P induced a concentration-and voltage-dependent inhibition of the current amplitude in the hERG tail current. The half-maximal inhibitory concentration(IC_(50)) was 54.9 μmol/L. The safety margin ratio was 30.5 — 2.8. Conclusion CA4P can prolong APD and inhibit hERG channel current.
引文
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[2]Liang W,Ni Y,Chen F.Tumor resistance to vascular disrupting agents:mechanisms,imaging,and solutions[J].Oncotarget,2016,7(13):15444-15459.
[3]Mohammed A A,El-Shentenawy A.Advanced thyroid cancers:new era of treatment[J].Med Oncol,2014,31(7):49.
[4]Jaroch K,Karolak M,Górski P,et al.Combretastatins:in vitro,structure-activity relationship,mode of action and current clinical status[J].Pharmacol Rep,2016,68(6):1266-1275.
[5]Chase D M,Chaplin D J,Monk B J.The development and use of vascular targeted therapy in ovarian cancer[J].Gynecol Oncol,2017,145(2):393-406.
[6]De Ponti F,Poluzzi E,Cavalli A,et al.Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes:an overview[J].Drug Saf,2002,25(4):263-286.
[7]Kraushaar U,Meyer T,Hess D,et al.Cardiac safety pharmacology:from human ether-a-gogo related gene channel block towards induced pluripotent stem cell based disease models[J].Expert Opin Drug Saf,2012,11(2):285-298.
[8]Walsh K B.Targeting cardiac potassium channels for state-of-the-art drug discovery[J].Expert Opin Drug Discov,2015,10(2):157-169.
[9]Rustin G J,Shreeves G,Nathan P D,et al.A Phase Ib trial of CA4P(combretastatin A-4 phosphate),carboplatin,and paclitaxel in patients with advanced cancer[J].Br JCancer,2010,102(9):1355-1360.
[10]Dowlati A,Robertson K,Cooney M,et al.A phase Ipharmacokinetic and translational study of the novel vascular targeting agent combretastatin a-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer[J].Cancer Res,2002,62(12):3408-3416.
[11]Redfern W S,Carlsson L,Davis A S,et al.Relationships between preclinical cardiac electrophysiology,clinical QTinterval prolongation and torsade de pointes for a broad range of drugs:evidence for a provisional safety margin in drug development[J].Cardiovasc Res,2003,58(1):32-45.
[12]He X,Li S,Huang H,et al.A pharmacokinetic and safety study of single dose intravenous combretastatin A4phosphate in Chinese patients with refractory solid tumours[J].Br J Clin Pharmacol,2011,71(6):860-870.
[13]Hazell L,Raschi E,De Ponti F,et al.Evidence for the hERG liability of antihistamines,antipsychotics,and anti-infective agents:a systematic literature review from the ARITMO project[J].J Clin Pharmacol,2017,57(5):558-572.
[14]Pratt C M,Ruberg S,Morganroth J,et al.Dose-response relation between terfenadine(Seldane)and the QTc interval on the scalar electrocardiogram:distinguishing a drug effect from spontaneous variability[J].Am Heart J,1996,131(3):472-480.
[15]Wisniowska B,Tylutki Z,Wyszogrodzka G,et al.Drug-drug interactions and QT prolongation as a commonly assessed cardiac effect-comprehensive overview of clinical trials[J].BMC Pharmacol Toxicol,2016,17:12.