一氧化氮和线粒体ATP敏感性钾通道介导血管紧张素转换酶抑制剂加强阈下预处理的作用

实验采用离体大鼠心脏Langendorff灌流模型,观察含巯基（卡托普利）和不含巯基（培哚普利拉）的两种血管紧张素转换酶抑制剂（angiotensin-converting enzyme inhibitors,ACEI）对抗心肌缺血的作用,并探讨一氧化氮（nitric oxide,NO）和线粒体ATP敏感性钾通道（mimchondrial ATP-sensitive potassium channel,mitoKATP channel）是否参与ACEI的心肌保护作用。结果表明：（1）给予大鼠心脏2min全心停灌和10min复灌作为闽下缺血预处理（subthreshold preconditioning,sPC）、卡托普利或培哚普利拉单独使用,均不能改善长时间缺血复灌（缺血30min＋复灌120min）引起的心肌损伤。（2）当两种ACEI分别和sPC联合使用时,与sPC组相比,缺血心脏在长时间缺血后的复灌期问左室舒张末压（left ventricular end-diastolic pressure,LVEDP）明显降低,左宦发展压（left ventricular developed pressure,LVDP）和冠脉流量明显增高,乳酸脱氢酶（lactate dehydrogenase,LDH）的释放量和心肌梗死面积明显低于sPC组。（3）利用NOS抑制剂L-NAME和mitoKATP通道的抑制剂5-HD灌流10min后,可明显抑制卡托普利／培哚普利拉和sPC联合使用引起的LVEDP降低,并使LVDP和冠脉流量降低,LDH的释放量和心肌梗死面积明显增高（P〈0．05）。（4）sPC、卡托普利或培哚普利拉单独使用,心脏NO的产生增加。ACEI和sPC联合使用,与三者单独使用相比NO的浓度亦明显增高（P〈0．05）。结果提示：含与不含巯基的ACEI与闽下缺血预处理联合使用均可使大鼠心脏功能明显改善,其心肌保护作用的机制可能通过NO途径,并和mitoKATP通道的激活有关。

Angiotensin-converting enzyme inhibitors potentiate subthreshold preconditioning through NO and mitoK(ATP) channel.

The aim of the present study was to determine whether angiotensin-converting enzyme inhibitors (ACEI) could contribute to the protective effects of preconditioning, and to explore its underlying mechanism. The Langendorff model of isolated rat heart was used. Cardiac contractility and lactate dehydrogenase (LDH) in the coronary effluent were measured, and infarct area of hearts after 30 min of ischemia followed by 120 min of reperfusion was analyzed. We found that: (1) The subthreshold preconditioning (2 min of ischemia and 10 min of reperfusion), captopril (an ACEI with sulfhydryl groups) or perindoprilate (an ACEI without sulfhydryl groups) alone did not protect the hearts from being injured by 30 min of ischemia and 120 min of reperfusion. (2) However, the combination of captopril or perindoprilate with subthreshold preconditioning could decrease left ventricular end-diastolic pressure (LVEDP), increase left ventricular developed pressure (LVDP) and coronary flow compared with the subthreshold preconditioned group. The combination treatments also inhibited the release of LDH from ischemia/reperfusion hearts, and reduced the infarct area in ischemic heart after 2 h of reperfusion (P<0.05). (3) By using NOS inhibitor L-NAME (100 mumol/L) before combined administration of ACEI with subthreshold preconditioning, the protection effect triggered by the combination treatment was significantly reduced. Pretreatment of the hearts with mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel inhibitor 5-HD (100 mumol/L) also abolished the protection effect (P<0.05). (4) Subthreshold preconditioning, captopril or perindoprilate alone could enhance the NO content in coronary effluent (P<0.05), but the combination of captopril or perindoprilate with subthreshold preconditioning could further augment the NO content compared with the subthreshold preconditioned group (P<0.05). The results indicate that ACEIs with or without sulfhydryl groups may potentiate the subthreshold preconditioning to trigger cardiac protection effect against the ischemia/reperfusion injury. This protection effect in the heart is possibly mediated by the generation of NO and the activation of mitoK(ATP) channel.