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.