Galiñanes M, Shattock M J, Hearse D J
Rayne Institute, St Thomas' Hospital, London, United Kingdom.
Cardiovasc Res. 1992 Nov;26(11):1063-8. doi: 10.1093/cvr/26.11.1063.
The opening of potassium (K+) channels during regional ischaemia may, by inducing rapid contractile arrest, be an intrinsic energy sparing mechanism. Thus K+ channel openers (for example, lemakalim) exert significant anti-ischaemic effects, whereas glibenclamide exacerbates ischaemic contracture and limits postischaemic functional recovery. The aim of the study was to investigate the ability of these compounds to influence ischaemic injury when used either alone or in combination with rapid arrest induced by a high K+ cardioplegic solution.
Contractile function of isolated Langendorff perfused rat hearts was assessed using an intraventricular balloon. Hearts were subjected to normothermic global ischaemia (20 min) or cardioplegic arrest (35 min) with and without glibenclamide or lemakalim. Lemakalim (10 mumol.litre-1) or glibenclamide (10 mumol.litre-1) was given, in the presence or absence of cardioplegia, for 2 min immediately prior to the onset of ischaemia. The rate of ischaemia induced contractile failure, the severity of ischaemic contracture, and the degree of postischaemic functional recovery were all measured.
In the absence of cardioplegia, the time to contractile arrest in control hearts was 133 (SEM 4) s. This was increased by glibenclamide, to 145(6) s, and decreased by lemakalim, to 112(6) s. The time to onset of ischaemic contracture [8(1) min] was accelerated by glibenclamide [4(1) min] and delayed by lemakalim [14(1) min]. Lemakalim significantly improved the recovery of left ventricular developed pressure from 49(7)% in control hearts to 65(3)%, and left ventricular end diastolic pressure from 41(3) to 21(4) mm Hg. Hearts pretreated with glibenclamide showed similar recoveries to control hearts. During reperfusion, lemakalim exerted a transient vasodilator effect whereas glibenclamide caused a transient vasoconstriction. When either glibenclamide or lemakalim was added to a high K+ cardioplegic solution and hearts rendered ischaemic for 35 min, the ability of both compounds to influence ischaemic contracture and postischaemic functional recovery was lost. In additional studies the effect of lemakalim on the relative times to ischaemia induced mechanical failure and electrical arrest was assessed. In control hearts the time to contractile failure was 128(5) s and the time to electrical arrest was 241(30) s, while in the lemakalim treated hearts the values were 103(2) s and 509(161) s, respectively. In the lemakalim group all the hearts showed sustained ventricular arrhythmias; in the control group there were no arrhythmias.
Lemakalim can exert a significant anti-ischaemic effect when given alone. This effect is lost when it is used in combination with high K+ cardioplegia. The anti-ischaemic properties of lemakalim may thus be limited to its ability to accelerate contractile arrest.
局部缺血期间钾（K+）通道的开放可能通过诱导快速收缩停止而成为一种内在的能量节约机制。因此，K+通道开放剂（如雷马卡林）具有显著的抗缺血作用，而格列本脲会加重缺血性挛缩并限制缺血后功能恢复。本研究的目的是探讨这些化合物单独使用或与高钾心脏停搏液诱导的快速停搏联合使用时影响缺血性损伤的能力。
使用心室内球囊评估离体Langendorff灌注大鼠心脏的收缩功能。心脏在有或无格列本脲或雷马卡林的情况下接受常温全心缺血（20分钟）或心脏停搏（35分钟）。在缺血开始前2分钟，在有或无心脏停搏的情况下给予雷马卡林（10 μmol·L-¹）或格列本脲（10 μmol·L-¹）2分钟。测量缺血诱导的收缩功能衰竭的速率、缺血性挛缩的严重程度以及缺血后功能恢复的程度。
在无心脏停搏的情况下，对照心脏收缩停止的时间为133（标准误4）秒。格列本脲使其增加到145（6）秒，雷马卡林使其减少到112（6）秒。缺血性挛缩开始的时间[8（1）分钟]被格列本脲加速至[4（1）分钟]，被雷马卡林延迟至[14（1）分钟]。雷马卡林显著改善左心室发育压力的恢复，从对照心脏的49（7）%提高到65（3）%，左心室舒张末期压力从41（3）降至21（4）毫米汞柱。用格列本脲预处理的心脏显示出与对照心脏相似的恢复情况。在再灌注期间，雷马卡林发挥短暂的血管舒张作用，而格列本脲引起短暂的血管收缩。当将格列本脲或雷马卡林添加到高钾心脏停搏液中并使心脏缺血35分钟时，两种化合物影响缺血性挛缩和缺血后功能恢复的能力丧失。在额外的研究中，评估了雷马卡林对缺血诱导的机械性衰竭和电停搏相对时间的影响。在对照心脏中，收缩功能衰竭的时间为128（5）秒，电停搏的时间为241（30）秒，而在雷马卡林处理的心脏中，相应的值分别为103（2）秒和509（161）秒。在雷马卡林组中，所有心脏均出现持续性室性心律失常；在对照组中无心律失常。
雷马卡林单独使用时可发挥显著的抗缺血作用。当与高钾心脏停搏联合使用时，这种作用丧失。因此，雷马卡林的抗缺血特性可能仅限于其加速收缩停止的能力。
