The protective effects of cyclic dipeptides in alcoholic beverages were 
investigated in the perfused guinea-pig hearts subjected to ischemia and 
reperfusion. Subsequently, in order to determine the importance of cyclic 
dipeptide structure, the effects of cyclo(L-Leu-L-Tyr) (cLY) were compared with 
those of the newly synthesized non-cyclic dipeptides, L-Leu-L-Tyr (LY) and 
L-Tyr-L-Leu (YL). After reperfusion, pressure recovery (%) in the left ventricle 
reached a peak of over 90% in the presence of cLY (10(-6) M and 10(-5) M) 
(control: 22.9%). The recovery by LY and YL was significantly lower than that by 
cLY, and ATP levels simultaneously monitored using (31)P-NMR were already lower 
during the ischemic end period than those observed with cLY treatment. In 
perfused mitochondrial preparations, cLY significantly inhibited mitochondrial 
Ca(2+) ([Ca(2+)](m)) elevation in a similar way to that of the mitochondrial 
permeability transition pore (MPTP) inhibitor cyclosporin A. In vitro electron 
paramagnetic resonance (EPR) revealed that the active oxygen radicals quenching 
activity of cLY was greater than those of non-cyclic dipeptides. cLY inhibited 
caspase-3-induced apoptosis. The cyclic dipeptide structure inhibits opening of 
the MPTP by preventing [Ca(2+)](m) overload-induced apoptosis related to 
mitochondrial active oxygen radical accumulation in ischemia-reperfusion hearts.