Effects of MN-9202 on platelet aggregation, 5-HT release, TXB2 synthesis, and calcium mobilization in rabbit platelets in vitro.
OBJECTIVE
To study the effects of MN-9202, a new effective Ca2+ channel blocker, on platelet aggregation, 5-HT and TXB2 release, and calcium transport induced by platelet activators.


METHODS
The mobilization of cytosolic-free calcium induced by thrombin in washed platelets was observed by Ca(2+)-sensitive fluorescent indicator, Fura-2 AM and time scan measurement. Aggregation induced by ADP and thrombin in rabbits citrate platelet-rich plasma (PRP) was measured by aggregometer. 5-HT and TXB2 were assayed by HPLC/ECD and RIA, respectively.


RESULTS
MN-9202 inhibited platelet aggregation induced by ADP and thrombin in a concentration-dependent manner. MN-9202 1 mumol.L-1 inhibited release of 5-HT in PRP induced by collagen at 15 mg.L-1 (113 +/- 15 vs 178 +/- 18, P < 0.05), however, MN-9202 did not have effect on 5-HT secreted by high dose of collagen. MN-9202 0.1 and 1 mumol.L-1 blocked extracellular calcium influx and sarcoplasmic calcium release, and the suppression on extracellular calcium influx was more obvious. Furthermore, treatment with MN-9202 0.01, 0.1, and 1 mumol.L-1 markedly decreased ADP-induced TXB2 (pg/10(8) platelet) release from PRP (906 +/- 200, 881 +/- 131, and 793 +/- 169 vs 1264 +/- 202, P < 0.01).


CONCLUSIONS
MN-9202 acts as an effective Ca2+ antagonist and blocks platelet activation by inhibiting platelet Ca2+ influx and arachidonic acid metabolism.
Wang
L L
LL
Department of Pharmacology, Fourth Military Medical University, Xi'an 710032, China. wh@mic.bmi.ac.cn
Mei
Q B
QB
Zhao
D H
DH
Guo
Z A
ZA
D000818:Animals; D001693:Biological Transport, Active; D001792:Blood Platelets / Q000378:metabolism; D002118:Calcium / Q000097:blood*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology*; D008297:Male; D009578:Nitrobenzenes / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D011817:Rabbits; D012701:Serotonin / Q000097:blood*; D013929:Thromboxane B2 / Q000096:biosynthesis*
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D009578:Nitrobenzenes; C429364:methylpentyl-1,4-dihydro-2,6-dimehtyl-4-(3-nitrophenyl)-3,5-pydridinedicarboxylate; D012701:Serotonin; D013929:Thromboxane B2; D002118:Calcium