APPS November 2002 Meeting Abstract 201

David G. Allen, Xiao-Hui Xiao, Department of Physiology and Institute for Biomedical Research, University of Sydney, NSW 2006, Australia.

Early myocardial infarcts in humans are currently treated by reperfusing the ischaemic region of the myocardium. Successful outcome depends on the ability of the myocardium to recover after a period of ischaemia. In this talk I will discuss some of the mechanisms involved in recovery from ischaemia and consider the extent to which the damage can be minimised.

Isolated rat hearts subjected to 30 min of global ischaemia show only limited functional recovery on reperfusion. Two classic studies established that this damage was partly reversible either by ischaemic preconditioning¹ or by inhibition of the cardiac Na⁺/H⁺ exchanger (NHE1)². Ionic measurements show that the intracellular Ca²⁺ rises very high on reperfusion and this is thought to instigate much of the damage by activating proteases and by excessive loading of Ca²⁺ into the mitochondria. The coupled exchanger theory proposes that the accumulation of protons during ischaemia activates NHE1 leading to H⁺ efflux and Na⁺ influx and that subsequently the elevated Na⁺ leads to Ca²⁺ influx on the Na⁺/Ca²⁺ exchanger. The success of NHE1 inhibitors is attributed to inhibiting this deleterious pathway.

Currently preconditioning is thought to result from activation of K_ATP channels in the mitochondria. We have proposed that, in addition, preconditioning inhibits NHE1 during reperfusion³. If the benefits of preconditioning arise from both NHE1 inhibition and K_ATP activation, then it would be predicted that recovery from ischaemia would benefit from pharmacological approaches which target both pathways. The results presented show that regulation of NHE1 activity is central to recovery from ischaemia and we show that endogenous angiotensin has a key role in modulating the activity of NHE1.