Remme C A, Schumacher C A, de Jong J W, Fiolet J W, de Groot J R, Coronel R, Wilde A A
Experimental and Molecular Cardiology Group, Academic Medical Center, University of Amsterdam, The Netherlands.
J Cardiovasc Pharmacol. 2001 Sep;38(3):406-16. doi: 10.1097/00005344-200109000-00009.
Cardioprotection by K(ATP) channel openers during ischemia is well documented although ill understood. Proarrhythmic effects may be an important drawback. K(ATP) channel modulation influences neurotransmitter release during ischemia in brain synaptosomes. Therefore, we studied the effects of K(ATP) channel modulation on myocardial noradrenaline release and arrhythmias in ischemic rabbit hearts. Isolated rabbit hearts were perfused according to Langendorff and stimulated. Local electrograms were recorded and K+-selective electrodes were inserted in the left ventricular free wall. Cromakalim (3 microM) or glibenclamide (3 microM) was added 20 min prior to induction of global ischemia. After 15, 20, or 30 min of ischemia, hearts were reperfused and noradrenaline content of the first 100 ml of reperfusate was measured. Cromakalim (n = 16) prevented the second rise of extracellular [K(+)] in accordance with its cardioprotective effect. Cromakalim significantly reduced noradrenaline release after 15 min (mean, 169 +/- SEM 97 pmol/gr dry weight vs. control 941 +/- 278; p < 0.05) and 20 min of ischemia (230 +/- 125 pmol/gr dry wt vs. control 1,460 +/- 433; p < 0.05), but after 30 min of ischemia, the difference in noradrenaline release was no longer significant (cromakalim 2,703 +/- 1,195 pmol/gr dry wt vs. control 5,413 +/- 1,310; p = 0.08). Ventricular fibrillation or ventricular tachycardia occurred in 10 of 13 control hearts (77%) (n = 19), in six of 10 glibenclamide-treated hearts (60%) (n = 15), and in six of 14 cromakalim-treated hearts (43%) (p = NS). Cromakalim significantly accelerated onset of ventricular tachycardia or fibrillation (mean +/- SEM onset after 12.5 +/- 1.6 min ischemia vs. control 16.2 +/- 0.7 min; p < 0.05). Noradrenaline release occurred only in cromakalim-treated hearts with early-onset arrhythmias whereas no noradrenaline release was observed in cromakalim-treated hearts without ventricular tachycardia or fibrillation. Our results show that activation of the K(ATP) channel by cromakalim during ischemia reduces myocardial noradrenaline release and postpones the onset of irreversible damage, contributing to the cardioprotective potential of K(ATP) openers during myocardial ischemia.
尽管对其了解尚浅，但K(ATP)通道开放剂在缺血期间的心脏保护作用已有充分记录。促心律失常作用可能是一个重要缺点。K(ATP)通道调节会影响脑突触体在缺血期间的神经递质释放。因此，我们研究了K(ATP)通道调节对缺血兔心脏心肌去甲肾上腺素释放和心律失常的影响。将离体兔心脏按照Langendorff法进行灌注并刺激。记录局部心电图，并将K+选择性电极插入左心室游离壁。在诱导全心缺血前20分钟加入克罗卡林（3 microM）或格列本脲（3 microM）。缺血15、20或30分钟后，心脏进行再灌注，并测量最初100 ml再灌注液中的去甲肾上腺素含量。克罗卡林（n = 16）根据其心脏保护作用防止细胞外[K+]的第二次升高。克罗卡林在缺血15分钟（平均值，169 +/- SEM 97 pmol/克干重，对照组为941 +/- 278；p < 0.05）和20分钟（230 +/- 125 pmol/克干重，对照组为1,460 +/- 433；p < 0.05）后显著降低去甲肾上腺素释放，但在缺血30分钟后，去甲肾上腺素释放的差异不再显著（克罗卡林为2,703 +/- 1,195 pmol/克干重，对照组为5,413 +/- 1,310；p = 0.08）。13个对照组心脏中有10个（77%）（n = 19）发生心室颤动或室性心动过速，10个格列本脲治疗组心脏中有6个（60%）（n = 15）发生，14个克罗卡林治疗组心脏中有6个（43%）发生（p = 无显著性差异）。克罗卡林显著加速室性心动过速或颤动的发作（平均 +/- SEM发作时间在缺血12.5 +/- 1.6分钟后，对照组为16.2 +/- 0.7分钟；p < 0.05）。去甲肾上腺素释放仅发生在早期发作心律失常的克罗卡林治疗组心脏中，而在无室性心动过速或颤动的克罗卡林治疗组心脏中未观察到去甲肾上腺素释放。我们的结果表明，缺血期间克罗卡林激活K(ATP)通道可减少心肌去甲肾上腺素释放并推迟不可逆损伤的发作，这有助于K(ATP)开放剂在心肌缺血期间的心脏保护潜力。
