CAN ISCHEMIC PRECONDITIONING PROTECT AGAINST HYPOXIA-INDUCED DAMAGE -STUDIES OF CONTRACTILE FUNCTION IN ISOLATED-PERFUSED RAT HEARTS

Ischemic preconditioning in the rat significantly improves functional recovery following global ischemia by undefined mechanisms. It has bee n suggested that preconditioning protects by altering the tissue metab olic milieu during ischemia, either by increasing ischemic tissue accu mulation of a beneficial substance (e.g. adenosine), or inhibiting tis sue accumulation of a malefic component (e.g. protons). If this is the case, we hypothesized that no protection should be afforded by precon ditioning against a prolonged period of hypoxia, since the continued c oronary flow would prevent the accumulation of any metabolic products in the myocardium. To test this hypothesis, isolated buffer-perfused r at hearts were preconditioned by 5 min of ischemia + 5 min of reperfus ion and then subjected to 30 min of ischemia, or 25 min of substrate-f ree hypoxia, or 60 or 90 min of hypoxia with substrate. Function was r e-assessed after reperfusion/reoxygenation for a further 30 min and co mpared to non-preconditioned controls. Ischemic preconditioning improv ed functional recovery following 30 min of global ischemia (% recovery of developed pressure (LVDP) in control v preconditioned hearts was 3 1 +/- 4 v 66 +/- 6%; P<0.05). Importantly, this protection was achieve d almost entirely via a better preservation of diastolic function (end diastolic pressure = 78 +/- 3 mmHg in control and 40 +/- 5 mmHg in pr econditioned hearts following 30 min of reperfusion; P<0.05). However, no preconditioning-induced protection was observed following either s ubstrate-free hypoxia or hypoxia with substrate (% recovery of LVDP in control v preconditioned hearts was 31 +/- 4 v 34 +/- 4% after 25 min of substrate-free hypoxia, 48 +/- 3 v 53 +/- 6% after 60 min of hypox ia + substrate and 25 +/- 5 v 30 +/- 6% after 90 min of hypoxia + subs trate respectively). Furthermore, no protection by preconditioning aga inst hypoxia-induced diastolic dysfunction was observed. We conclude t hat preconditioning protects against ischemic injury, but not hypoxic injury. Although hypoxia-induced injury may differ from that induced b y ischemia, the results are consistent with the hypothesis that the co ntinued presence of flow with hypoxia abolishes the protective effect of preconditioning. Furthermore, the results support the concept that preconditioning of the ischemic myocardium requires the accumulation o f a factor in the ischemic myocardium, either to exert the preconditio ning protective effect, or as a factor of injury against which precond itioning affords protection.