The cardioprotective effects of Na+/H+ exchange inhibition and mitochondrial KATP channel activation are additive in the isolated rat heart

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 K-ATP channel with 100 muM 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 muM 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.