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.

journal_name

Pharmacol Res

journal_title

Pharmacological research

authors

Lee KS,Jin YR,Lee JJ,Lim Y,Son DJ,Lee CK,Yi KY,Yoo SE,Shin HS,Yun YP

doi

10.1016/j.phrs.2005.12.003

keywords:

subject

Has Abstract

pub_date

2006-03-01 00:00:00

pages

265-70

issue

3

eissn

1043-6618

issn

1096-1186

pii

S1043-6618(05)00221-5

journal_volume

53

pub_type

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