BMS-191095, a Cardioselective Mitochondrial KATP Opener, Inhibits Human Platelet Aggregation by Opening Mitochondrial KATP Channels

다국어 초록 (Multilingual Abstract)

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.

참고문헌 (Reference)

1 "a mitochondrial KATP opener withno peripheral vasodilator or cardiac action potential shorteningactivity" 297 : 1184-1192, 2001

2 "Voltage-gated calcium and potassium currents inmegakaryocytes dissociated from guinea-pig bone marrow" 187-2061990

3 "The role of endothelium-derived nitricoxide in relaxations to levcromakalim in the rat aorta" 81 : 362-366, 1999

4 "The mitochondrial KATP channel as areceptor for potassium channel openers" 271 : 8796-8799, 1996

5 "The efflux of 86Rb and [3H]5-HTfrom human platelets during continuous perfusion" 421-428, 1991

6 "Suppression of the voltage-gated K+current of human megakaryocytes by thrombin and prostacyclin" 1355 : 331-342, 1997

7 "Suppression of the delayed rectifier type of voltage gated K+outward current in megakaryocytes from patients withmyelogenous leukemias" 86 : 1043-1055, 1995

8 "Reperfusion after acute coronary occlusion in dogs impairsendothelium-dependent relaxation to acetylcholine andaugments contractile reactivity in vitro" 265-274, 1987

9 "Recent advances in potassiumchannel modulation" 49 : 93-121, 1997

10 "Preconditioning prevents chronic reperfusioninducedcoronary endothelial dysfunction in rats" 271 : -849, 1996

11 "Potassium channels and preconditioning of isolated rabbit cardiomyocytes Effects of glyburide and pinacidil" 27 : 1765-1774, 1995

12 "Pharmacologicalevidence of calcium-activated and voltage-gatedpotassium channels in human platelets" 93 : 249-255, 1997

13 "Pharmacological characterization of vasorelaxant effects ofBMS-180448" 92 : 218-227, 2003

14 "Pharmacologic profile of theselective mitochondrial-KATP opener BMS-191095 for treatmentof acute myocardial ischemia" 20 : 121-136, 2002

15 "MitochondrialATP-sensitive potassium channel plays a dominantrole in ischemic preconditioning of the rabbit heart" 33 : 57-63, 2001

16 "Mitochondrial ATPsensitivepotassium channel activation protects cerebellargranule neurons from apoptosis induced by oxidative stress" 34 : 1796-1802, 2003

17 "Long-termimpairment of endothelium-dependent relaxations to aggregatingplatelets after reperfusion injury in canine coronaryarteries" 1921-19271990

18 "Ischaemic preconditioning limits infarct size in the ratheart" 983-987, 1992

19 "In vivo characterization of themitochondrial selective K" 303 : 4 132-140, 2002

20 "Identification of 4-" -substituted benzopyran derivativeswith high selectivity 40 : 24-34, 1997

21 "Human thrombocytes are able toinduce a myocardial dysfunction in the ischemic andreperfused guinea pig heart mediated by free radicals-role ofthe GPIIb/IIIa-blocker tirofiban" 71 : 2319-2329, 2002

22 "Hemodynamicand cardiac effects of BMS-180448" 52 : 101-112, 1996

23 "Glyburide-reversible cardioprotective effectof BMS-180448 is independent of action potential shortening" 30 : 731-738, 1995

24 "Endothelial protective effects of preconditioning" 55 : 466-473, 2002

25 "Effects of endothelium/leukocytes/platelet interaction on myocardial ischemia--reperfusion injury" 89 : 9-95, 2000

26 "Differential action of KR-31378" 54 : 182-190, 2001

27 "Coronary vascular reactivity after acute myocardialischemia" 576-578, 1982

28 "Clinical experience andpotential uses in cardiology" 1 : 361-370, 1999

29 "Cardiovascularpharmacology of SKP-450" 56 : 111-124, 1998b

30 "Cardioprotective effects of ischaemicpreconditioning are not mediated by prostanoids" 226-231, 1992

31 "Cardioprotective effects of KR-30450 and its major metabolite KR-30818 on isolated rathearts" 76 : 65-73, 1998

32 "Antihypertensiveeffects of the novel potassium channel activator SKP-450 and its major metabolites in rats" 48 : 969-978, 1998a

33 "Abnormal function of potassiumchannels in platelets of patients with Alzheimer's disease" 352 : 1590-1593, 1998

34 "A thrombocyte-inducedmyocardial dysfunction in the ischemic and reperfusedguinea pig heart is mediated by reactive oxygen species" 29 : 1244-1251, 2000

35 "A patch-clamp study of mammalian platelets andtheir voltage-gated potassium current" 467-485, 1987