Takano H, Tang X L, Bolli R
Experimental Research Laboratory, Division of Cardiology, University of Louisville, Louisville, Kentucky 40292, USA.
Am J Physiol Heart Circ Physiol. 2000 Nov;279(5):H2350-9. doi: 10.1152/ajpheart.2000.279.5.H2350.
The role of ATP-sensitive potassium (K(ATP)) channels in the late phase of ischemic preconditioning (PC) remains unclear. Furthermore, it is unknown whether K(ATP) channels serve as end effectors both for late PC against infarction and against stunning. Thus, in phase I of this study, conscious rabbits underwent a 30-min coronary occlusion (O) followed by 72 h of reperfusion (R) with or without ischemic PC (6 4-min O/4-min R cycles) 24 h earlier. Late PC reduced infarct size approximately 46% versus controls. The K(ATP) channel blocker 5-hydroxydecanoic acid (5-HD), given 5 min before the 30-min O, abrogated the infarct-sparing effect of late PC but did not alter infarct size in non-PC rabbits. In phase II, rabbits underwent six 4-min O/4-min R cycles for 3 consecutive days (days 1, 2, and 3). In controls, the total deficit of systolic wall thickening (WTh) after the sixth reperfusion was reduced by 46% on day 2 and 54% on day 3 compared with day 1, indicating a late PC effect against myocardial stunning. Neither 5-HD nor glibenclamide, given on day 2, abrogated late PC. The K(ATP) channel opener diazoxide, given on day 1, attenuated stunning, and this effect was completely blocked by 5-HD. Thus the same dose of 5-HD that blocked the antistunning effect of diazoxide failed to block the antistunning effects of late PC. Furthermore, when diazoxide was administered in PC rabbits on day 2, myocardial stunning was further attenuated, indicating that diazoxide and late PC have additive anti-stunning effects. We conclude that K(ATP) channels play an essential role in late PC against infarction but not in late PC against stunning, revealing an important pathogenetic difference between these two forms of cardioprotection.
ATP敏感性钾（K(ATP)）通道在缺血预处理（PC）后期的作用仍不清楚。此外，K(ATP)通道是否作为晚期PC对抗梗死和对抗心肌顿抑的终效应器也尚不清楚。因此，在本研究的第一阶段，清醒家兔接受30分钟冠状动脉闭塞（O），随后在有或没有提前24小时进行缺血PC（6个4分钟O/4分钟R周期）的情况下进行72小时再灌注（R）。与对照组相比，晚期PC使梗死面积减少了约46%。在30分钟O前5分钟给予K(ATP)通道阻滞剂5-羟基癸酸（5-HD），消除了晚期PC的梗死保护作用，但未改变非PC家兔的梗死面积。在第二阶段，家兔连续3天（第1、2和3天）接受6个4分钟O/4分钟R周期。在对照组中，与第1天相比，第2天第六次再灌注后收缩期壁增厚（WTh）的总缺损减少了46%，第3天减少了54%，表明晚期PC对心肌顿抑有作用。第2天给予5-HD或格列本脲均未消除晚期PC。第1天给予K(ATP)通道开放剂二氮嗪可减轻顿抑，且该作用被5-HD完全阻断。因此，阻断二氮嗪抗顿抑作用的相同剂量的5-HD未能阻断晚期PC的抗顿抑作用。此外，当在第2天给PC家兔施用二氮嗪时，心肌顿抑进一步减轻，表明二氮嗪和晚期PC具有相加的抗顿抑作用。我们得出结论，K(ATP)通道在晚期PC对抗梗死中起重要作用，但在晚期PC对抗顿抑中不起作用，揭示了这两种心脏保护形式之间重要的发病机制差异。
