Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 152, Issue 2, Pages 230-239Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjp.0707383
Keywords
1-methylnicotinamide; thrombolysis; thrombosis; PGI(2); COX-2; platelets
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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.
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