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

Fukasawa, Mika; Nishida, Hitoshi; Sato, Toshiaki; Miyazaki, Masaru; Nakaya, Haruaki

doi:10.1124/jpet.108.136218

Cited by 27 publications

(17 citation statements)

References 20 publications

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“…The results presented here with PDE3B −/− mice strongly suggest that PDE3B is the isoform responsible for the cardioprotective effects against I/R injury associated with the pharmacological inhibition of PDE3 (6)(7)(8)(9). These studies also indicate, for the first time to our knowledge, distinct subcellular locations of PDE3A and PDE3B in cardiomyocytes, with PDE3A distributed with SERCA2 on SR membranes and PDE3B colocalizing with caveolin-3 along the Z-line and on or near T-tubule membranes, close to mitochondria (Fig.…”

Section: Studies With Pde3amentioning

confidence: 52%

“…Taken together, these results (Figs. 1 and 2) strongly suggest that inhibition of PDE3B, but not of PDE3A, is responsible for the reported cardioprotective effects of PDE3 inhibitors in earlier I/R studies (6)(7)(8)(9).…”

Section: Resultsmentioning

confidence: 84%

“…The PDE3 inhibitor cilostazol (6)(7)(8)(9) and the PDE5 inhibitor sildenafil (10,11) have been reported to protect hearts against ischemia/ reperfusion (I/R) injury in various species. Fukasawa et al (8) have suggested that cilostazol exerts its cardioprotective effect by activating mitochondrial Ca 2+ -activated K + (mitoK Ca ) channels, whose opening protects hearts against infarction (12). Furthermore, studies have shown that the opening of mitoK Ca channels is potentiated by cAMP-dependent PKA signaling (13), whereas PKC potentiates mitochondrial ATP-sensitive K + (mitoK ATP ) channel activation (14).…”

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confidence: 99%

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Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury

Chung

Lagranha

Chen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Although inhibition of cyclic nucleotide phosphodiesterase type 3 (PDE3) has been reported to protect rodent heart against ischemia/ reperfusion (I/R) injury, neither the specific PDE3 isoform involved nor the underlying mechanisms have been identified. Targeted disruption of PDE3 subfamily B (PDE3B), but not of PDE3 subfamily A (PDE3A), protected mouse heart from I/R injury in vivo and in vitro, with reduced infarct size and improved cardiac function. The cardioprotective effect in PDE3B −/− heart was reversed by blocking cAMP-dependent PKA and by paxilline, an inhibitor of mitochondrial calcium-activated K channels, the opening of which is potentiated by cAMP/PKA signaling. Compared with WT mitochondria, PDE3B−/− mitochondria were enriched in antiapoptotic Bcl-2, produced less reactive oxygen species, and more frequently contacted transverse tubules where PDE3B was localized with caveolin-3. Moreover, a PDE3B −/− mitochondrial fraction containing connexin-43 and caveolin-3 was more resistant to Ca 2+ -induced opening of the mitochondrial permeability transition pore. Proteomics analyses indicated that PDE3B−/− heart mitochondria fractions were enriched in buoyant ischemia-induced caveolin-3-enriched fractions (ICEFs) containing cardioprotective proteins. Accumulation of proteins into ICEFs was PKA dependent and was achieved by ischemic preconditioning or treatment of WT heart with the PDE3 inhibitor cilostamide. Taken together, these findings indicate that PDE3B deletion confers cardioprotective effects because of cAMP/PKA-induced preconditioning, which is associated with the accumulation of proteins with cardioprotective function in ICEFs. To our knowledge, our study is the first to define a role for PDE3B in cardioprotection against I/R injury and suggests PDE3B as a target for cardiovascular therapies. PDE3B−/− mice | protein kinase A | ischemia/reperfusion injury | signalosome | membrane repair

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Section: Studies With Pde3amentioning

confidence: 52%

Section: Resultsmentioning

confidence: 84%

mentioning

confidence: 99%

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Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury

Chung

Lagranha

Chen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, other studies have observed that cilostazol has a protective effect against ischemic injury in animal models, when observed in other organs 25,26 .…”

Section: Resultsmentioning

confidence: 99%

Effects of ischemic preconditioning and cilostazol on muscle ischemia-reperfusion injury in rats

et al. 2014

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PURPOSE:To evaluate effects of ischemic preconditioning and Cilostazol on muscle ischemia-reperfusion injury. METHODS:Male Wistar rats were submitted to muscle ischemic and reperfusion injury (4h of the left common iliac artery occlusion followed by 1h of reperfusion). Five experimental groups were constituted: Control group (n=4); Ischemia-Reperfusion (IR, n=5); Ischemic preconditioning group (IP, n=6); Ischemia-Reperfusion group treated with cilostazol (IRCi, n=6) and Ischemic preconditioning group treated with cilostazol (IPCi, n=6). At the end, left gracile muscle was removed and embedded in paraffin. Histopathology, neutrophil infiltration, myocyte necrosis and edema were analyzed. RESULTS:When compared with the control group, IR group showed increased neutrophil infiltration, severe necrosis and edema. There was significant difference between myocytes necrosis of IR group and IP group. There was no difference between the histopathological changes between IP, IRCi and IPCi groups. CONCLUSIONS:The model of IR caused severe muscle injury in the rat hind limb and ischemic preconditioning has a protective effect, reducing myocyte necrosis, however, treatment with cilostazol and also the association between cilostazol and preconditioning has no protective effect on the skeletal muscle subjected to ischemia and reperfusion injury.

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“…Experimental studies have demonstrated that cilostazol obtained a protective effect against ischemic injury in animal models when used in another organs than skeletal muscle and kidneys 11,12 .…”

Section: Biochemical Study Of the Effects Of Cilostazol In Rats Subjementioning

confidence: 99%

Biochemical study of the effects of cilostazol in rats subjected to acute ischemia and reperfusion of hind limbs

Júnior¹,

Neto²,

Júnior³

et al. 2013

Acta Cir. Bras.

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PURPOSE:To investigate whether cilostazol has a protective effect on acute ischemia and reperfusion of hind limbs of rats through study of biochemical variables in blood and urine. METHODS:Forty six animals were randomized and divided into two groups. Group I received a solution of cilostazol (10 mg/Kg) and group II received saline solution 0.9% (SS) by orogastric tube after ligature of the abdominal aorta. After four hours of ischemia the animals were divided into four subgroups: group IA (Cilostazol): two hours of reperfusion. Group IIA (SS): two hours of reperfusion.Group IB (Cilostazol): six hours of reperfusion. Group IIB (SS) six hours of reperfusion. After the reperfusion period, was held to collect urine and blood for biochemical measurements. The biochemical parameters studied were: urea, creatinine, sodium, potassium and myoglobin in blood and urea, creatinine, myoglobin in urine. RESULTS:There was no statistically significant difference between groups. CONCLUSION:Cilostazol had no protective effect on ischemic acute reperfusion of hind limbs of rats in this model.

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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

Cited by 27 publications

References 20 publications

Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury

Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury

Effects of ischemic preconditioning and cilostazol on muscle ischemia-reperfusion injury in rats

Biochemical study of the effects of cilostazol in rats subjected to acute ischemia and reperfusion of hind limbs

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