BMS-191095, a cardioselective mitochondrial K(ATP) opener, inhibits human platelet aggregation by opening mitochondrial K(ATP) channels.
We evaluated the antiplatelet effects of two classes of ATP-sensitive potassium channel openers (K(ATP) openers) on washed human platelets, and the study's emphasis was on the role of mitochondrial K(ATP) in platelet aggregation. Collagen-induced platelet aggregation was inhibited in a dose dependent manner by lemakalim and SKP-450, which are potent cardio-nonselective K(ATP) openers, and also by cardioselective BMS-180448 and BMS-191095 (IC50: 1,130, >1,500, 305.3 and 63.9 microM, respectively), but a significantly greater potency was noted for the cardioselective K(ATP) openers. The latter two K(ATP) 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 microM 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 glyburide (1 microM) or sodium 5-hydroxydecanoate (5-HD, 100 microM), a nonselective and selective mitochondrial K(ATP) antagonist, respectively, at similar magnitudes; this indicates the role of mitochondrial K(ATP) 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 K(ATP) openers like BMS-191095 are able to exert cardioprotective effects in cardiac ischemia/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 K(ATP).
Cho
Mi-Ra
MR
College of Pharmacy, Chungbuk National University, Cheongju 361-763, Korea.
Park
Jung-Woo
JW
Jung
In-Sang
IS
Yi
Kyu-Yang
KY
Yoo
Sung-Eun
SE
Chung
Hun-Jong
HJ
Yun
Yeo-Pyo
YP
Kwon
Suk-Hyung
SH
Shin
Hwa-Sup
HS
D000255:Adenosine Triphosphate / Q000502:physiology; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015221:Potassium Channels / Q000502:physiology*
C428117:BMS 191095; D001578:Benzopyrans; D002317:Cardiovascular Agents; D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D015221:Potassium Channels; D000255:Adenosine Triphosphate