Inhibition of sodium-hydrogen exchange reduces infarct size in the isolated rat heart--a protective additive to ischaemic preconditioning.
OBJECTIVE
Inhibition of Na+/H+ exchange with amiloride analogues has been shown to protect the ischaemic and reperfused heart. The aim of this study was to examine if preischaemic or postischaemic treatment with the selective Na+/H+ exchange inhibitor ethyl-isopropyl amiloride (EIPA, 1 microM) influenced infarct size in an isolated rat heart model of regional ischaemia and reperfusion, and if any such protection was additive to the protection afforded by ischaemic preconditioning.


METHODS
Langendorff perfused rat hearts were subjected to 30 or 45 min of regional ischaemia and 120 min of reperfusion. The risk zone was determined by fluorescent particles and infarct size was determined by staining with triphenyltetrazolium chloride.


RESULTS
Treatment with EIPA for 20 min before 30 min regional ischaemia significantly reduced infarct size (in % of the risk zone) compared to untreated controls [3.1 (SEM 1.0)% v 38.1(5.8)%, P < 0.001], a protection similar to that afforded by ischaemic preconditioning [6.1(2.5)%]. Combination of preischaemic EIPA treatment and ischaemic preconditioning also reduced infarct size [5.2(2.0)%, P < 0.01 v control group]. When EIPA was added to the buffer only during the first 30 min of reperfusion, no protection was observed [infarct size = 37.8(5.8)%, NS v control group]. In order to clarify if the protection observed with EIPA treatment was additive to protection by ischaemic preconditioning, another set of experiments was performed. In these experiments regional ischaemia was extended to 45 min. Preischaemic EIPA treatment reduced infarct size also in this model compared to controls [15.3(2.9)% v 64.3(2.9)%, P < 0.001], as did ischaemic preconditioning [23.5(4.2)%, P < 0.001 v controls, NS v EIPA treated hearts]. Combination of ischaemic preconditioning and preischaemic EIPA treatment further reduced infarct size significantly [3.9(0.6)%, P < 0.05 v all other groups with 45 min regional ischaemia].


CONCLUSIONS
Inhibition of Na+/H+ exchange reduces infarct size in the isolated rat heart infarct model if the exchanger is inhibited during the ischaemic period, and this protection is additive to the protection afforded by ischaemic preconditioning.
Bugge
E
E
Department of Medical Physiology, University of Tromsø, Norway.
Ytrehus
K
K
D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride; C039614:ethylisopropylamiloride