BACKGROUND: A new 1,4-benzothiazepine derivative, JTV519, has a strong 
protective effect against Ca(2+) overload-induced myocardial injury. We 
investigated the effect of JTV519 on ischemia/reperfusion injury in isolated rat 
hearts.
METHODS AND RESULTS: At 30 minutes of reperfusion after 30-minute global 
ischemia, the percent recovery of left ventricular developed pressure was 
improved, and the creatine phosphokinase and lactate dehydrogenase leakage was 
reduced in a concentration-dependent manner when JTV519 was administered in the 
coronary perfusate both at 5 minutes before the induction of ischemia and at the 
time of reperfusion. The myocardial protective effect of JTV519 was completely 
blocked by pretreatment of the heart with GF109203X, a specific protein kinase C 
(PKC) inhibitor. In contrast, the effect of JTV519 was not affected by 
alpha(1)-, A(1)-, and B(2)-receptor blockers that couple with PKC in the 
cardiomyocyte. Both immunofluorescence images and immunoblots of JTV519-treated 
left ventricular myocardium and isolated ventricular myocytes demonstrated that 
this agent induced concentration-dependent translocation of the delta-isoform 
but not the other isoforms of PKC to the plasma membrane.
CONCLUSIONS: The mechanism of cardioprotection by JTV519 against 
ischemia/reperfusion injury involves isozyme-specific PKC activation through a 
receptor-independent mechanism. This agent may provide a novel pharmacological 
approach for the treatment of patients with acute coronary diseases via a 
subcellular mechanism mimicking ischemic preconditioning.