Na+/H+ exchanger inhibitor HOE-642 improves cardioplegic myocardial preservation under both normothermic and hypothermic conditions.
BACKGROUND
The sarcolemmal Na+/H+ exchanger has been implicated in the pathogenesis of myocardial injury during ischemia/reperfusion. We determined the cardioprotective efficacy of the Na+/H+ exchanger inhibitor HOE-642 (HOE) as an alternative, adjunct, or additive to cardioplegia (CP).


RESULTS
In isolated working rat hearts (n=6 per group) subjected to 25 minutes of ischemia at 37 degrees C, the postischemic recovery of aortic flow (AF) was 5+/-3% in controls; this was improved to 18+/-4% by the preischemic infusion of 1 micromol/L HOE (P<.05 versus control) and to 53+/-7% by CP (P<.05 versus control and HOE). In hearts subjected to CP and 35 minutes of ischemia at 37 degrees C, AF recovered to 9+/-3% with CP alone; this was improved to 18+/-3% by the adjunctive administration of HOE during early reperfusion (CP+repHOE, P<.05 versus CP) and to 27+/-4% by the use of HOE as an additive to CP (CP+HOE, P<.05 versus CP and CP+repHOE). With 120 minutes of ischemia at 28 degrees C, AF recoveries were 16+/-3% in CP, 32+/-3% in CP+repHOE (P<.05 versus CP) and to 50+/-4% in CP+HOE (P<.05 versus CP and CP+repHOE). With 300 minutes of ischemia at 7.5 degrees C, the corresponding values were 30+/-4% 45+/-5% (P<.05 versus CP), and 63+/-5% (P<.05 versus CP and CP+repHOE). Improved recovery of pump function was often accompanied by a reduction in creatine kinase leakage during reperfusion.


CONCLUSIONS
(i) HOE alone affords significant protection at normothermia but is not a superior alternative to CP, and (ii) the use of HOE as an adjunct or additive to CP provides significant benefit at normothermia, moderate hypothermia, and severe hypothermia.
Shipolini
A R
AR
Department of Cardiovascular Research, The Rayne Institute, St Thomas' Hospital, London, UK.
Galiñanes
M
M
Edmondson
S J
SJ
Hearse
D J
DJ
Avkiran
M
M
D000818:Animals; D006146:Guanidines / Q000494:pharmacology*; D006324:Heart Arrest, Induced; D007036:Hypothermia, Induced; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology*
D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide