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CARDIOVASCULAR

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

Departments of Pharmacology (M.F., H.Ni., T.S., H.Na.) and General Surgery (H.Ni., M.M.), Chiba University Graduate School of Medicine, Chiba, Japan

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 µM) oxidized flavoprotein in a concentration-dependent manner. The oxidative effect of cilostazol (10 µM) was antagonized by the mitoK_Ca channel blocker paxilline (2 µM). Activation of PKA by 8-bromoadenosine 3'5'-cyclic monophosphate (0.5 mM) potentiated the cilostazol-induced flavoprotein oxidation. Treatment with cilostazol (10 µM) 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-9,12-epoxy-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 µM), neither oxidized flavoprotein nor reduced infarct size. Our results suggest that cilostazol exerts a cardioprotective effect via direct activation of mitoK_Ca channels.

Address correspondence to: Dr. Haruaki Nakaya, Department of Pharmacology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail: nakaya{at}faculty.chiba-u.jp