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조미라,박정우,정인상,이규양,유성은,정훈종,윤여표,권석형,신화섭 대한약학회 2005 Archives of Pharmacal Research Vol.28 No.1
We evaluated the antiplatelet effects of two classes of ATP-sensitive potassium hannel openers (KATP openers) on washed human platelets, and the study's emphasis was on the role of mitochondrial KATP in platelet aggregation. Collagen-induced platelet aggregation was inhibited in a dose dependent manner by lemakalim and SKP-450, which are potent cardio-nonselective KATP openers, and also by cardioselective BMS-180448 and BMS-191095 (IC50: 1,130, >1,500, 305.3 and 63.9 µM, respectively), but a significantly greater potency was noted for the cardioselective KATP openers. The latter two KATP openers also inhibited platelet aggregation induced by thrombin, another important blood-borne platelet activator, with similar rank order of potency (IC50: 498.0 and 104.8 µM for BMS-180448 and BMS-191095, respectively). The inhibitory effects of BMS-191095 on collagen-induced platelet aggregation were significantly blocked by a 30-min pretreatment of platelets with lyburide (1 µM) or sodium 5-hydroxydecanoate (5-HD, 100 µM), a nonselective and selective mitochondrial KATP antagonist, respectively, at similar magnitudes; this indicates the role of mitochondrial KATP in the antiplatelet activity of BMS-191095. However, glyburide and 5-HD had no effect when they were added to the platelet cuvette immediately prior to the addition of BMS-191095. These findings indicate that cardioselective mitochondrial KATP openers like BMS-191095 are able to exert cardioprotective effects in cardiac schemia/reperfusion injury via dual mechanisms directed at the inhibition of platelet aggregation and the protection of cardiomyocytes, and both these mechanisms are mediated by mitochondrial KATP.
박은석,강도현,강준철,장용창,이민주,정훈종,이규양,김대은,김보경,신화섭 대한약학회 2017 Archives of Pharmacal Research Vol.40 No.5
Oxidative stress plays a critical role in cardiacinjury during ischemia/reperfusion (I/R). Despite a potentcardioprotective activity of KR-33889, a novel poly (ADPribose)polymerase inhibitor, its underlying mechanismremains unresolved. This study was designed to investigatethe protective effects of KR-33889 against oxidative stressinducedapoptosis in rat cardiomyocytes H9c2 cells andisolated rat hearts. H2O2 caused severe injury to H9c2 cells,mainly due to apoptosis, as revealed by TUNEL assay. However, KR-33889 pretreatment significantly attenuatedH2O2-induced apoptosis of H9c2 cells, which wasaccompanied by decrease in expression of both cleavedcaspase-3 and Bax and increase in Bcl-2 expression and theratio of Bcl-2/Bax. KR-33889 also significantly enhancedthe expression of anti-oxidant enzymes including hemeoxygenase-1, Cu/Zn-superoxide dismutase (SOD), Mn-SOD, and catalase, thereby inhibiting production of intracellularROS. Furthermore, KR-33889 reversed H2O2-induceddecrease in phosphorylation of Akt, GSK-3b, ERK1/2, p38 MAPK, and SAPK/JNK during most H2O2 exposuretime. In globally ischemic rat hearts, KR-33889 inhibitedboth I/R-induced decrease in cardiac contractility andapoptosis by increasing Bcl-2, decreasing both cleavedcaspase-3 and Bax expression, and enhancing expression ofanti-oxidant enzymes. Taken together, these results suggestthat KR-33889 may have therapeutic potential to preventI/R-induced heart injury in ischemic heart diseases mainlyby reducing oxidative stress-mediated myocardialapoptosis.