Lochner A, Genade S, Hattingh S, Marais E, Huisamen B, Moolman J A
MRC Diabetes Research Group, Tygerberg, Republic of South Africa.
Cardiovasc Drugs Ther. 2003 May;17(3):217-30. doi: 10.1023/a:1026116022552.
To further evaluate the significance of p38 MAPK as trigger or mediator in ischaemic preconditioning, anisomycin and SB 203580 were used to manipulate its activation status. Special attention was given to the concentration of the drugs and protocols used. The isolated perfused rat heart, subjected to either 25 min global ischaemia or 35 min regional ischaemia, was used as experimental model. This was preceded by anisomycin (2 or 5 muM: 3 x 5 min; 5 muM: 5 min or 10 min; 5 muM: 10 min + 10 min washout or 20 muM: 20 min) or SB 203580 (2 muM: 3 x 5 min; before and during 3 x 5 min or 1 x 5 min ischaemic preconditioning; 10 min). Endpoints were functional recovery during reperfusion and infarct size.Anisomycin, regardless of the protocol, reduced infarct size, but did not improve functional recovery. In a number of experiments activation of JNK by anisomycin was blocked by SP 600125 (10 muM). SP 600125 had no effect on the anisomycin-induced reduction in infarct size. SB 203580 when administered for 10 min before sustained ischaemia, improved functional recovery and reduced infarct size. SB 203580 could not abolish the beneficial effects of a multi-cycle preconditioning protocol, but it significantly reduced the outcome of 1 x 5 min preconditioning. In all hearts improved functional recovery and reduction in infarct size were associated with attenuation of p38 MAPK activation during sustained ischaemia-reperfusion. The results indicate that activation of p38 MAPK acts as a trigger of preconditioning, while attenuation of its activation is a prerequisite for improved recovery and a reduction in infarct size.
为了进一步评估p38丝裂原活化蛋白激酶（p38 MAPK）作为缺血预处理的触发因素或介导因子的重要性，使用茴香霉素和SB 203580来调控其激活状态。特别关注了所使用药物的浓度和方案。将经历25分钟全心缺血或35分钟局部缺血的离体灌注大鼠心脏用作实验模型。在此之前给予茴香霉素（2或5 μM：3×5分钟；5 μM：5分钟或10分钟；5 μM：10分钟+10分钟洗脱或20 μM：20分钟）或SB 203580（2 μM：3×5分钟；在3×5分钟或1×5分钟缺血预处理之前及期间；10分钟）。观察指标为再灌注期间的功能恢复和梗死面积。无论采用何种方案，茴香霉素均可减小梗死面积，但未改善功能恢复。在一些实验中，茴香霉素对JNK的激活被SP 600125（10 μM）阻断。SP 600125对茴香霉素诱导的梗死面积减小无影响。在持续性缺血前给予SB 203580 10分钟，可改善功能恢复并减小梗死面积。SB 203580不能消除多周期预处理方案的有益作用，但它显著降低了1×5分钟预处理的效果。在所有心脏中，功能恢复的改善和梗死面积的减小与持续性缺血-再灌注期间p38 MAPK激活的减弱相关。结果表明，p38 MAPK的激活作为预处理的触发因素，而其激活的减弱是改善恢复和减小梗死面积的先决条件。
