D'Alonzo A J, Darbenzio R B, Hess T A, Sewter J C, Sleph P G, Grover G J
Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Pharmacology, Princeton, NJ 08543-4000.
Cardiovasc Res. 1994 Jun;28(6):881-7. doi: 10.1093/cvr/28.6.881.
The ATP sensitive potassium channel openers cromakalim (n = 10) and pinacidil (n = 10), and a blocker of this channel, glibenclamide (n = 10), were studied in isolated perfused rat hearts subjected to regional ischaemia at varying concentrations (2 to 8 mM) of external potassium ([K+]o).
Hearts were isolated and perfused on a Langendorff apparatus. Vehicle (0.1% DMSO), cromakalim (10 microM), pinacidil (10 microM), or glibenclamide (10 microM) were given 10 min before ischaemia. The left coronary artery was then occluded for 15 min and reperfused for 5 min.
No agent caused more than a 10% change in heart rate. Both cromakalim and pinacidil increased (30%), and glibenclamide decreased (30%) coronary flow at 4 and 6 mM [K+]o. In the vehicle group, increases in [K+]o produced concentration dependent reductions in arrhythmia scores by decreasing ventricular fibrillation. No concentration dependent effects of [K+]o on ischaemic ventricular tachycardia was observed. Under ischaemic conditions, potassium channel openers and glibenclamide more markedly reduced ischaemic ventricular tachycardia and fibrillation relative to the effects of increased [K+]o.
Ischaemic ventricular fibrillation was inversely related to changes in [K+]o, whereas effects on ventricular tachycardia were all-or-none. Neither potassium channel openers nor glibenclamide elicited significant proarrhythmic activity despite variations in [K+]o. These data suggest that both potassium channel openers and glibenclamide display potential antiarrhythmic activity through their ability to abolish two distinct arrhythmogenic mechanisms during ischaemia. It is also suggested that the underlying mechanisms of ventricular tachycardia and fibrillation are coupled during ischaemia in the rat.
在不同浓度（2至8 mM）的细胞外钾离子（[K+]o）条件下，对离体灌注大鼠心脏进行局部缺血处理，研究ATP敏感性钾通道开放剂克罗卡林（n = 10）和吡那地尔（n = 10）以及该通道阻滞剂格列本脲（n = 10）。
将心脏分离并在Langendorff装置上进行灌注。在缺血前10分钟给予溶媒（0.1%二甲亚砜）、克罗卡林（10 microM）、吡那地尔（10 microM）或格列本脲（10 microM）。然后将左冠状动脉闭塞15分钟并再灌注5分钟。
没有药物导致心率变化超过10%。在4和6 mM [K+]o时，克罗卡林和吡那地尔均使冠脉流量增加（30%），而格列本脲使其降低（30%）。在溶媒组中，[K+]o的增加通过减少心室颤动产生浓度依赖性的心律失常评分降低。未观察到[K+]o对缺血性室性心动过速的浓度依赖性影响。在缺血条件下，相对于[K+]o增加的影响，钾通道开放剂和格列本脲更显著地降低了缺血性室性心动过速和颤动。
缺血性心室颤动与[K+]o的变化呈负相关，而对室性心动过速的影响是全或无的。尽管[K+]o有所变化，但钾通道开放剂和格列本脲均未引发明显的促心律失常活性。这些数据表明，钾通道开放剂和格列本脲均通过其在缺血期间消除两种不同致心律失常机制的能力而显示出潜在的抗心律失常活性。还表明在大鼠缺血期间，室性心动过速和颤动的潜在机制是相互关联的。
