1-methylnicotinamide (MNA), a primary metabolite of nicotinamide, exerts anti-thrombotic activity mediated by a cyclooxygenase-2/prostacyclin pathway
1-methylnicotinamide (MNA), a primary metabolite of nicotinamide, exerts anti-thrombotic activity mediated by a cyclooxygenase-2/prostacyclin pathway
复制标题
DOI：
10.1038/sj.bjp.0707383
复制
发表时间：
2007-09-01
影响因子：
7.3
通讯作者：
Gebicki, J.
中科院分区：
文献类型：
--
作者：
Chlopicki, S.;Swies, J.;Gebicki, J.
背景和目的：1-甲基烟酰胺(MNA)一直被认为是烟酰胺的非活性代谢物。实验方法：在体外血栓形成的正常血压大鼠(血栓形成)、动脉血栓形成的肾血管性高血压大鼠(动脉血栓形成)和静脉血栓形成的大鼠(静脉血栓形成)上研究MNA的抗血栓作用。关键结果：MNA(3-100 mg kg(-1))诱导了剂量依赖的持续溶栓反应，并与血液中6-keto-PGF(1α)升高有关。与MNA结构相关的各种化合物要么是无效的，要么是较弱的溶栓剂。罗非昔布(0.01~1 mg·kg~(-1))可剂量依赖性地抑制MNA的溶栓作用，吲哚美辛(5 mg·kg~(-1))可阻断其作用，而L(5 mg·kg~(-1))则无此作用。MNA(3-30 mg kg(-1))也可减少动脉血栓形成，这种作用可被消炎痛(2.5 mg kg(-1))和罗非昔布(1 mg kg(-1))所阻断。然而，MNA并不影响静脉血栓形成。在体外，MNA没有改变血小板聚集或诱导血管扩张。结论和意义：MNA在体内显示出比密切相关化合物更强的抗血栓活性。MNA通过环氧合酶-2和前列环素抑制血小板依赖性血栓形成。我们的发现表明，肝脏中由烟酰胺N-甲基转移酶产生的内源性MNA可能是前列环素产生的内源性激活剂，从而可能调节心血管系统的血栓形成和炎症过程。
Background and purpose: 1-methylnicotinamide ( MNA) has been considered to be an inactive metabolite of nicotinamide. Here we assessed the anti-thrombotic activity of MNA in vivo.Experimental approach: Antithrombotic action of MNA was studied in normotensive rats with extracorporeal thrombus formation ( thrombolysis), in renovascular hypertensive rats with intraarterial thrombus formation ( arterial thrombosis) and in a venous thrombosis model in rats ( venous thrombosis).Key results: MNA ( 3-100 mg kg(-1)) induced a dose-dependent and sustained thrombolytic response, associated with a rise in 6-keto-PGF(1 alpha) in blood. Various compounds structurally related to MNA were either inactive or weaker thrombolytics. Rofecoxib ( 0.01-1 mg kg(-1)), dose-dependently inhibited the thrombolytic response of MNA, indomethacin ( 5 mg kg(-1)) abolished it, while L-NAME ( 5 mg kg(-1)) were without effect. MNA ( 3-30 mg kg(-1)) also reduced arterial thrombosis and this effect was abrogated by indomethacin ( 2.5 mg kg(-1)) as well as by rofecoxib ( 1mg kg(-1)). MNA, however, did not affect venous thrombosis. In vitro MNA did not modify platelet aggregation nor induce vasodilation.Conclusions and implications: MNA displayed a profile of anti-thrombotic activity in vivo that surpasses that of closely related compounds. MNA inhibited platelet-dependent thrombosis by a mechanism involving cyclooxygenase-2 and prostacyclin. Our findings suggest that endogenous MNA, produced in the liver by nicotinamide N-methyltransferase, could be an endogenous activator of prostacyclin production and thus may regulate thrombotic as well as inflammatory processes in the cardiovascular system.