THE CARDIOPROTECTIVE EFFECTS OF Na+-H+ EXCHANGER INHIBITION AND KATP CHANNEL ACTIVATION ARE ADDITIVE
X-H. Xiao, D.G. Allen, Department of Physiology F13, University of Sydney, NSW 2006, Australia.
Inhibition of the Na+-H+ exchanger1 and the activation of mitochondrial KATP channels2 protect against cardiac ischemia-reperfusion damage. In the present study we examined whether these effects are additive.
Ischemic injury was assessed by measuring the developed pressure (DP) and the reperfusion contracture (RC) on reperfusion in rat hearts after 30 min of global ischemia. A Na+-H+ exchanger inhibitor, HOE 642 (10 µM), or a mitochondrial KATP channel opener, diazoxide (100 µM), were used.
After a control ischemia recovery of DP was poor with a very large contracture (DP 14 ± 3 %; RC 62 ± 10 mmHg; mean + SEM; n = 8). When HOE was applied throughout ischemia and reperfusion a substantial improvement in recovery occurred (DP 77 ± 9 %; RC 13 ± 3 mmHg; n = 11). In order to determine whether the beneficial effects of HOE occurred in ischemia or reperfusion, HOE was also applied during reperfusion but with a 15 s preperfusion 2 min before the end of ischemia to ensure that the exchanger was inhibited from the start of reperfusion. The recovery under these conditions was not significantly different to HOE present throughout ischemia and reperfusion1.
When diazoxide was applied throughout ischemia and reperfusion it cause a moderate improvement in recovery (DP 36 ± 3 %; RC 48 ± 5 mmHg; n = 7). When both HOE and diazoxide were applied throughout ischemia and reperfusion, recovery of DP was signficantly greater than for either alone (DP 95 ± 5 %; RC 11 ± 6 mmHg; n =5). However, when diazoxide and HOE were applied during reperfusion (plus preperfusion as above) no additive effect was observed (DP 73 ± 5 %; RC 15 ± 5 mmHg; n =7).
Thus there was an additive cardioprotective effect of HOE 642 and diazoxide on ischemic-reperfusion damage which only occurred only when they were applied throughout ischemia and reperfusion.
(1) Xiao XH, Allen DG. Cardiovascular Research. 2000;48:244-253.
(2) Liu Y, Sato T, O'Rourke B, Marban E. Circulation. 1998;97:2463-2469.
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