title: Anti-platelet activity of KR-32560, a novel sodium/hydrogen exchanger-1 inhibitor.
abstract: We investigated the anti-platelet effect of a newly synthesized guanidine derivative KR-32560, a sodium/hydrogen exchanger-1 (NHE-1) inhibitor, together with the elucidation of the possible mode of action. KR-32560 concentration dependently inhibited the aggregation of washed rabbit platelets induced by collagen (10 microg mL(-1)) and arachidonic acid (AA; 100 microM), with IC50 values of 25 and 46 microM, respectively. Whereas, KR-32560 showed weaker potency against aggregation induced by thrombin (0.05 UmL(-1)) and U46619 (1 microM), and had no effect on thapsigargin (0.5 microM)- or A23187 (5 microM)-induced platelet aggregation up to 50 microM. KR-32560 inhibited the collagen-induced [3H]AA liberation in a concentration-dependent manner. In addition, KR-32560 significantly suppressed TXB2 formation in AA-exposed platelets, but had no effect on production of PGD2, indicating an inhibitory effect on TXA2 synthase. This finding was supported by a TXA2 synthase assay that KR-32560 inhibited the conversion of PGH2 into TXB2 with a similar magnitude to suppression of TXB2 formation. Furthermore, KR-32560 significantly inhibited the collagen-induced [Ca2+]i mobilization and serotonin secretion. Taken together, these observations suggest that the anti-platelet activity of KR-32560 may be mediated by the inhibition of cytoplasmic Ca2+ mobilization and AA liberation.
authors.affiliation: College of Pharmacy, Chungbuk National University, 12 Gaesin-Dong, Heungduk-Gu, Cheongju 361-763, Korea.
authors.forename: Kyung-Sup
authors.initials: KS
authors.lastname: Lee
authors.forename: Yong-Ri
authors.initials: YR
authors.lastname: Jin
authors.forename: Jung-Jin
authors.initials: JJ
authors.lastname: Lee
authors.forename: Yong
authors.initials: Y
authors.lastname: Lim
authors.forename: Dong-Ju
authors.initials: DJ
authors.lastname: Son
authors.forename: Chong-Kil
authors.initials: CK
authors.lastname: Lee
authors.forename: Kyu-Yang
authors.initials: KY
authors.lastname: Yi
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Yoo
authors.forename: Hwa-Sup
authors.initials: HS
authors.lastname: Shin
authors.forename: Yeo-Pyo
authors.initials: YP
authors.lastname: Yun
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D002118:Calcium / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D012701:Serotonin / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D006146:Guanidines; C510993:KR-32560; D010975:Platelet Aggregation Inhibitors; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D016718:Arachidonic Acid; D012701:Serotonin; D013929:Thromboxane B2; D003094:Collagen; D013930:Thromboxane-A Synthase; D002118:Calcium