Cardiomyocyte apoptosis related with mitochondrial PTP in ischemia-reperfusion injury and the development of new cardiac drug.

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1.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+> uptake by acidification and Ca^<2+> content changes similar to reperfusion after global ischemia were suppressed with both NHE inhibitors. SM-197378 was found to quench directly the active oxygen radical, though SM-198110 had no effect. Number of apoptotic cells after long ischemia by reperfusion was significantly smaller in SM-197378-treated than SM-198110-treated hearts, consist with the level of activity of caspase-3 (Eur.J.Pharmacol.2004).2.5HT_<2A>(Mol.Cell.Biochem.2005), 5HT_<1A> (Eur.J.Pharmacol.2006) antagonist or SSRI (Life Sciense, in preparation) was beneficial effect against ischemia/reperfusion injury with ATP contents, quenching the active oxygen radical an … More d inhibition of mitochondrial Ca^<2+> upteke by acidification or Ca^<2+> content of perfusate. These compounds also depressed apoptotic cell and the level of activity of caspase-3 in related with 5HT.3.Atractyroside (10^<-3> M), which opens mitochondrial permeability transition pore (MPTP) also caused similar increases in mitochondrial Na^+, Ca^<2+> uptake by acidification or Ca^<2+> content change. Cyclosporine A (10^<-4> M), which inhibits MPTP or many drugs (Na-Ca exchange or Na-H inhibitor) 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 (Eur.J.Pharmacol.in preparation). This result may be relate with mitochondrial Na^+ or Ca^<2+> and MPTP against ischemia-reperfusion injury.4.Nicorandil, a K_<ATP>-channel opener (Ther.Res.2005), a green tea cathechin (Eur.J.Pharmacol.In press, Life Science, in preparation), or cyclic dipeptides (in beer or the distilled residue of millet brandy) like the NO donor, was beneficial effect with inhibit MPTP5.Ex-vivo ESR spectrometry could measure directly the generation of reactive oxygen species (ROS) in ischemia-reperfusion injury model of guinea-pig Langendorff heart preparation (J.Pharmacol.Sci.2005)These results suggested that ROS and NO are closely involved to the role of the induction of myocardial cell apoptosis through MPTP in post-ischemic myocardial dysfunction. Less