The cardioprotective effect of
caldaret, a novel intracellular Ca(2+) handling modulator that acts through reverse-mode
Na(+)/Ca(2+) exchanger inhibition and potential sarcoplasmic reticulum (SR) Ca(2+) uptake enhancement, against
reperfusion injury was investigated. We employed a canine model of
myocardial infarction induced by 90-min occlusion of left circumflex (LCX) coronary artery followed by 4 h of reperfusion. Intravenously infused
caldaret (3 or 30 microg/kg per hour) for 30 min at LCX-reperfusion markedly reduced
infarct size (by 51.3% or 71.9%, respectively). This cardioprotection was accompanied by an acceleration of left ventricular (LV) contraction and relaxation during reperfusion, but not by an increase in ischemic regional transmural myocardial blood flow (TMBF) or endocardial/epicardial blood flow ratio (Endo/Epi ratio) or a reduction in double-product throughout the protocol.
Diltiazem (2000 microg/kg per hour) also reduced
infarct size (by 36.1%), but unlike
caldaret, was accompanied by the significant increase in Endo/Epi ratio in the ischemic region and decrease in double-product. There were significant inverse relationships between
infarct size and ischemic regional TMBF in all groups.
Caldaret, but not
diltiazem shifted the regression line downward with a flatter slope. These results suggest that the amelioration of intracellular Ca(2+) handling dysfunction achieved by
caldaret leads to cardioprotective effects against
reperfusion injury following prolonged
ischemia.