通过钾通道阻滞发挥的Ⅲ类抗心律失常作用：多非利特减轻缺氧诱导的机电变化。

Class III antiarrhythmic action by potassium channel blockade: dofetilide attenuates hypoxia induced electromechanical changes.

作者信息

Yang T, Tande P M, Lathrop D A, Refsum H

机构信息

Department of Medical Physiology, University of Tromsø, Norway.

出版信息

Cardiovasc Res. 1992 Nov;26(11):1109-15. doi: 10.1093/cvr/26.11.1109.

DOI:10.1093/cvr/26.11.1109

PMID:1291089

Abstract

OBJECTIVE

The aim was to examine the electromechanical effects of dofetilide, a new class III antiarrhythmic agent, in isolated guinea pig ventricular muscle during hypoxia.

METHODS

Hypoxia was induced by superfusing guinea pig right ventricular papillary, muscles with Tyrode's solution gassed with 95% N2 + 5% CO2 [PO2 = 5.3(SEM 1.3) kPa]. Prior to hypoxia, the preparations were either pretreated for 30 min with 0.1 microM dofetilide (n = 6) or with 100 microM glibenclamide (a blocker of ATP sensitive K+ channels, n = 6), or not pretreated (n = 6). Sixteen additional preparations were exposed to 1 mM nicorandil (an activator of ATP sensitive K+ channels) in the absence (n = 6) and presence of dofetilide (n = 6) or glibenclamide (n = 4). Transmembrane action potentials and developed force were recorded using conventional microelectrode techniques and a force transducer.

RESULTS

During normoxia, dofetilide markedly increased APD90 from 236(SEM 6) ms to 298(7) ms (p < 0.05) and the effective refractory period (ERP) from 248(5) ms to 315(6) ms (p < 0.05). In the drug free group, 60 min hypoxia decreased APD90 by 47(5)% (p < 0.05), ERP by 48(4)% (p < 0.05) and developed force by 71(6)% (p < 0.05) of baseline, respectively. These hypoxia induced effects were significantly attenuated after pretreatment with dofetilide or glibenclamide. Nicorandil decreased APD90 by 45(5)% (p < 0.05), ERP by 44(6)% (p < 0.05), and developed force by 69(10)% (p < 0.05) of baseline, respectively. Pretreatment with dofetilide or glibenclamide also significantly attenuated the nicorandil induced decreases in APD90, ERP, and developed force.

CONCLUSIONS

Dofetilide, like glibenclamide, effectively attenuates hypoxia and nicorandil induced action potential shortening and the associated reduction in contractile force. Thus dofetidile would be expected to retain its antiarrhythmic efficacy during myocardial hypoxia or ischaemia.

摘要

目的

研究新型III类抗心律失常药物多非利特在豚鼠离体心室肌缺氧时的机电效应。

方法

用含95%N₂ + 5%CO₂ [PO₂ = 5.3(标准误1.3)kPa]的台氏液灌注豚鼠右心室乳头肌诱导缺氧。在缺氧前，将标本分别用0.1微摩尔/升多非利特预处理30分钟（n = 6）或用100微摩尔/升格列本脲（ATP敏感性钾通道阻滞剂，n = 6）预处理，或不进行预处理（n = 6）。另外16个标本在不存在（n = 6）和存在多非利特（n = 6）或格列本脲（n = 4）的情况下暴露于1毫摩尔/升尼可地尔（ATP敏感性钾通道激活剂）。使用传统微电极技术和力传感器记录跨膜动作电位和产生的力。

结果

在常氧期间，多非利特使动作电位时程90（APD90）从236(标准误6)毫秒显著增加到298(7)毫秒（p < 0.05），有效不应期（ERP）从248(5)毫秒增加到315(6)毫秒（p < 0.05）。在无药物组中，60分钟缺氧使APD90降低47(5)%（p < 0.05），ERP降低48(4)%（p < 0.05），产生的力降低71(6)%（p < 0.05）。多非利特或格列本脲预处理后，这些缺氧诱导的效应显著减弱。尼可地尔使APD90降低45(5)%（p < 0.05），ERP降低44(6)%（p < 0.05），产生的力降低69(10)%（p < 0.05）。多非利特或格列本脲预处理也显著减弱了尼可地尔诱导的APD90、ERP和产生的力的降低。