Since the
Na(+)-H(+) exchanger (NHE) is not the only pathway of Na(+) influx into cardiomyocytes during
ischemia/reperfusion, we hypothesized that blockade of
Na(+)-Ca(2+) exchanger (NCX) may be a more efficient strategy than is NHE inhibition for protecting the myocardium from
infarction. To test this hypothesis, we compared
KB-R7943 (
KBR), a novel selective NCX blocker, with
cariporide, a selective NHE blocker, with regard to their protective effects against
infarction. In isolated rabbit hearts,
infarction was induced by 30-min global
ischemia/2-h reperfusion, and
infarct size was determined by tetrazolium staining and expressed as a percentage of area at risk (%IS/AR). Hearts received no drugs, or were infused with
cariporide (1 microM) for 10 min or
KBR (0.3 or 10 microM) for 5 min before
ischemia or after the onset of reperfusion.
Protein level of NCX was assessed by Western blotting.
Cariporide infusion before
ischemia significantly reduced %IS/AR from 63.9 +/- 2.9% to 20.2 +/- 3.0%, but its infusion upon reperfusion failed to achieve a significant protection (%IS/AR = 53.8 +/- 4.6%). In contrast,
KBR infusion similarly reduced
infarct size both when infused before
ischemia (%IS/AR = 33.3 +/- 6.3% and 21.9 +/- 4.7% by 0.3 and 10 microM
KBR, respectively) and when infused for only 5 min after reperfusion (%IS/AR = 35.3 +/- 7.1% and 31.5 +/- 2.1% by 0.3 and 10 microM
KBR, respectively).
Protein levels of NCX after 30-min
ischemia and 30-min
ischemia/30-min reperfusion were similar to baseline values in both untreated controls and hearts treated with 0.3 microM
KBR upon reperfusion. These results suggest that lethal
reperfusion injury is more efficiently suppressed by blockade of the NCX than by blockade of the NHE.