Xiao Xiao-Hui, Allen David G
Department of Physiology and Institute for Biomedical Research, University of Sydney F13, NSW 2006, Australia.
Pflugers Arch. 2003 Dec;447(3):272-9. doi: 10.1007/s00424-003-1183-z. Epub 2003 Oct 8.
The mechanisms of recovery of the isolated rat heart were studied after 30 min of global ischemia. Functional recovery was assessed by the percentage recovery of developed pressure after 30 min reperfusion and by the magnitude of the contracture on reperfusion. After a control ischemia, developed pressure recovered to only 12+/-2% of pre-ischemic control and the reperfusion contracture was very large (81+/-6 mmHg). Activation of the mitochondrial KATP channel with 100 microM diazoxide present throughout ischemia and reperfusion improved recovery of developed pressure to 36+/-3% and reduced the reperfusion contracture (53+/-4 mmHg). Inhibition of the sodium/hydrogen exchanger with 10 microM cariporide caused a larger recovery of developed pressure to 72+/-4% and further reduced the reperfusion contracture (11+/-3 mmHg). The combination of both drugs increased recovery of developed pressure to 96+/-4% and the reperfusion contracture remained small (11+/-5 mmHg). The effectiveness of the timing of exposure to these drugs was explored. When both diazoxide and cariporide were applied 2 min before the end of ischaemia and remained present during reperfusion the recovery of developed pressure was 81+/-4% and the reperfusion contracture was small (12+/-3 mmHg); neither was significantly different to the recovery when both drugs were present throughout ischemia and reperfusion. We conclude that mitochondrial damage, blocked by diazoxide, and the coupled exchanger pathway, blocked by cariporide, are two of the principal damage pathways and functional recovery appears to be complete when both are blocked. The combination of these drugs is also highly effective when given 2 min before the end of ischemia.
在大鼠离体心脏经历30分钟全心缺血后，对其恢复机制进行了研究。通过再灌注30分钟后左心室发展压的恢复百分比以及再灌注时挛缩的程度来评估功能恢复情况。在对照性缺血后，左心室发展压仅恢复至缺血前对照值的12±2%，且再灌注挛缩非常大（81±6 mmHg）。在整个缺血和再灌注过程中使用100 μM二氮嗪激活线粒体ATP敏感性钾通道，可使左心室发展压的恢复提高至36±3%，并减少再灌注挛缩（53±4 mmHg）。使用10 μM卡立泊来德抑制钠/氢交换体，可使左心室发展压有更大程度的恢复，达到72±4%，并进一步减少再灌注挛缩（11±3 mmHg）。两种药物联合使用可使左心室发展压的恢复提高至96±4%，且再灌注挛缩仍然很小（11±5 mmHg）。还探究了这些药物给药时机的有效性。当二氮嗪和卡立泊来德在缺血结束前2分钟应用并在再灌注期间持续存在时，左心室发展压的恢复为81±4%，且再灌注挛缩很小（12±3 mmHg）；这与两种药物在整个缺血和再灌注过程中都存在时的恢复情况相比，均无显著差异。我们得出结论，二氮嗪所阻断的线粒体损伤以及卡立泊来德所阻断的偶联交换体途径是两个主要的损伤途径，当两者都被阻断时，功能恢复似乎是完全的。在缺血结束前2分钟给予这些药物联合使用时也具有高效性。
