Cardiomyocyte apoptosis induced in ischemia-reperfusion Langendorff preparation and the development of new cardiac drug.

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1.Apoptosis in the ischemia-reperfusion Langendorff hearts was not induced by oxygen-deprivation alone, but the deprivation of glucose that induced myocardial cell death mainly by apoptosis in the presence or absence of oxygen. The deprivation of both oxygen and glucose exaggerated the apoptotic lesion morphologically. Glucose deprivation coincided with the decrease in ATPi content and intracellular acidosis in the presence or absence of oxygen (Tong et al., 2001).2.The protective effects of Na^+H^+ exchange (NHE) inhibitors SM-198110 (Cl in structure) and SM-197378 (F in structure) had beneficial effects of LVDP (about 100% vs. drug free heart 39%) from ischemia/reperfusion injury in Langendorff hearts. In perfused fura-2 loaded mitochondria preparation, mitochondrial Ca^<2+> by acidification and Ca changes similar to reperfusion after global ischemia were suppressed with both NHE inhibitors. SM-197378 was found to directly quench the active oxygen radical, though SM-198110 had no eff … More ect. The number of apoptotic cells after long ischemia by reperfusion was significantly smaller in SM-197278-treated than SM-198110-treated hearts, consist with the level of activity of caspase-3 (Hotta et al., 2003).3.5-HT_<1A> or cyclic dipeptides (in beer or the distilled residue of millet brandy) had a beneficial effect against ischemia/reperfusion injury with Alp contents, quenching the active oxygen radical and inhibition of mitochondrial Ca^<2+> by acidification or Ca^<2+> contents of perfusate. These compounds also depressed apoptotic cell and the level of activity of caspase-3 (Huang and Akutagawa et al., 2004).4.Atractyroside (10^<->3 M), which opens mitochondrial permeability transition pores (MPTP) also caused similar increases in mitochondrial Ca^<2+> by acidification or Ca^<2+> content change. Cyclosporine A (10^<-4> M), which inhibits MPTP or many drugs that promote good recovery of the LVDP in the Langendorff ischemia/reperfusion injury model, were also suppressed, but not FK506 (10^<-4> M), which does not inhibit MPTP (Hotta et al., 2004). Less