In:
British Journal of Pharmacology, Wiley, Vol. 162, No. 8 ( 2011-04), p. 1871-1883
Abstract:
1,4‐Naphthoquinones exhibit antiplatelet activity both in vivo and in vitro . In the present study, we investigated the antiplatelet effect of a novel naphthoquinone derivative NP‐313, 2‐acetylamino‐3‐chloro‐1,4‐naphthoquinone and its mechanism of action. EXPERIMENTAL APPROACH We measured platelet aggregation, Ca 2+ mobilization, thromboxane B2 formation and P‐selectin expression and examined several enzymatic activities. Furthermore, we used the irradiated mesenteric venules in fluorescein sodium–treated mice to monitor the antithrombotic effect of NP‐313 in vivo . KEY RESULTS NP‐313 concentration‐dependently inhibited human platelet aggregation induced by collagen, arachidonic acid, thapsigargin, thrombin and A23187. NP‐313 also inhibited P‐selectin expression, thromboxane B 2 formation and [Ca 2+ ] i elevation in platelets stimulated by thrombin and collagen. NP‐313 at 10 µM inhibited cyclooxygenase, thromboxane A 2 synthase, and protein kinase Cα, whereas it did not affect phospholipase A 2 or phospholipase C activity. In the presence of indomethacin and an adenosine 5‐diphosphate scavenger, NP‐313 concentration‐dependently inhibited thrombin‐ and A23187‐induced [Ca 2+ ] i increase through its inhibitory effects on Ca 2+ influx, rather than blocking Ca 2+ release from intracellular stores. NP‐313 also inhibited thapsigargin‐mediated Ca 2+ influx through store‐operated calcium channel but had no effect on Ca 2+ influx through store‐independent calcium channel evoked by the diacylglycerol analogue 1‐oleoyl‐2‐acetyl‐sn‐glycerol. Nevertheless, it had little effect on cyclic AMP and cyclic GMP levels. Also, intravenously administered NP‐313 dose‐dependently inhibited the thrombus occlusion of the irradiated mesenteric vessels of fluorescein‐pretreated mice. CONCLUSIONS AND IMPLICATIONS Taken together, these results indicate that NP‐313 exerts its antithrombotic activity through dual inhibition of thromboxane A 2 synthesis and Ca 2+ influx through SOCC.
Type of Medium:
Online Resource
ISSN:
0007-1188
,
1476-5381
DOI:
10.1111/bph.2011.162.issue-8
DOI:
10.1111/j.1476-5381.2011.01200.x
Language:
English
Publisher:
Wiley
Publication Date:
2011
detail.hit.zdb_id:
80081-8
detail.hit.zdb_id:
2029728-2
SSG:
15,3
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