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 μg mL −1) and arachidonic acid (AA; 100 μM), with IC 50 values of 25 and 46 μM, respectively. Whereas, KR-32560 showed weaker potency against aggregation induced by thrombin (0.05 U mL −1) and U46619 (1 μM), and had no effect on thapsigargin (0.5 μM)- or A23187 (5 μM)-induced platelet aggregation up to 50 μM. KR-32560 inhibited the collagen-induced [ 3H]AA liberation in a concentration-dependent manner. In addition, KR-32560 significantly suppressed TXB 2 formation in AA-exposed platelets, but had no effect on production of PGD 2, indicating an inhibitory effect on TXA 2 synthase. This finding was supported by a TXA 2 synthase assay that KR-32560 inhibited the conversion of PGH 2 into TXB 2 with a similar magnitude to suppression of TXB 2 formation. Furthermore, KR-32560 significantly inhibited the collagen-induced [Ca 2+] 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 Ca 2+ mobilization and AA liberation.
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