Ischemic preconditioning does not protect against contractile dysfunction in the presence of residual flow: studies in the isolated, blood-perfused rat heart.

Abstract

We have previously demonstrated that ischemic preconditioning (PC) does not protect when oxygen deprivation is accompanied by a high level of perfusion (hypoxia). Since clinical ischemia can vary from mild to severe, we wished to determine whether PC could protect against injury arising from low-flow ischemia. Functional recovery after 30 minutes of reperfusion was assessed in isolated, blood-perfused rat hearts (n=6 per group) subjected to (A) 30 minutes of zero-flow ischemia, (B) 30 minutes of zero-flow ischemia preceded by 3xPC (PC=5 minutes of ischemia+5 minutes of reperfusion), (C) 90 minutes of low-flow ischemia at 10% of baseline coronary flow (0.31+/-0.02 mL/min per gram wet wt), (D) 90 minutes of low-flow ischemia at 10% of baseline coronary flow (0.29+/-0.02 mL/min per gram wet wt) preceded by 3xPC. PC significantly protected against injury resulting from zero-flow ischemia (developed pressure recovered to 67+/-6% versus 31+/-12% in B and A, respectively; P<.05) but not resulting from low-flow ischemia (recovery of developed pressure was 40+/-8% versus 37+/-7% in C and D, respectively). Protein kinase C (PKC) is widely considered to be involved in the mechanism of PC such that prior activation and translocation of PKC by the PC protocol allows phosphorylation of the end-effector protein early during the subsequent ischemic insult, before loss of adenosine triphosphate occurs. However, because adenosine triphosphate content falls slowly during low-flow ischemia, PKC may be activated and translocated early enough to be active during this insult. If so, inhibition of PKC should decrease functional recovery in the control group. However, functional recovery in control groups was not decreased in the presence of the PKC inhibitor polymyxin B (50+/-6%), suggesting that if activation of PKC occurred during low-flow ischemia, it was not protective. PC does not protect against contractile dysfunction in the rat when a low level (10% of baseline flow) of ischemic perfusion remains during the prolonged insult.