6-[4-(1-Cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2-(1H)quinolinone(cilostazol), a phosphodiesterase type 3 inhibitor, reduces infarct size via activation of mitochondrial Ca2+-Activated K+ channels in rabbit hearts

[摘要]：

6-[4-(1-Cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2-(1H)quinolinone (cilostazol), a phosphodiesterase type 3 (PDE III) inhibitor, activates cAMP-dependent protein kinase A (PKA). The cAMP/PKA pathway potentiates the opening of mitochondrial Ca2+-activated K+ (mitoK(Ca)) channels and confers cardioprotection. Although cilostazol has been reported to directly activate sarcolemmal large-conductance Ca2+-activated K+ channels, it remains unclear whether cilostazol modulates the opening of mitoK(Ca) channels. Therefore, we tested the possibility that cilostazol opens mitoK(Ca) channels and protects hearts against ischemia/reperfusion injury. Flavoprotein fluorescence in rabbit ventricular myocytes was measured to assay mitoK(Ca) channel activity. Infarct size in the isolated perfused rabbit hearts subjected to 30-min global ischemia and 120-min reperfusion was determined by triphenyltetrazolium chloride staining. Cilostazol (1, 3, 10, and 30 mu M) oxidized flavoprotein in a concentration-dependent manner. The oxidative effect of cilostazol (10 mu M) was antagonized by the mitoK(Ca) channel blocker paxilline (2 mu M). Activation of PKA by 8-bromoadenosine 3'5'-cyclic monophosphate (0.5 mM) potentiated the cilostazol-induced flavoprotein oxidation. Treatment with cilostazol (10 mu M) for 10 min before ischemia significantly reduced the infarct size from 67.2 +/- 1.3 (control) to 33.6 +/- 5.3% (p < 0.05). This infarct size-limiting effect of cilostazol was abolished by paxilline (60.3 +/- 4.9%) but not by the PKA inhibitor (9S, 10S, 12R)2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9, 12epoxy-1H-diindolo[1,2,3-fg:3', 2', 1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid hexyl ester (KT5720) (200 nM, 40.5 +/- 3.5%). On the other hand, another PDE III inhibitor, milrinone (10 mu M), neither oxidized flavoprotein nor reduced infarct size. Our results suggest that cilostazol exerts a cardio-protective effect via direct activation of mitoK(Ca) channels.

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