1-Methylnicotinamide (MNA), a primary metabolite of nicotinamide, exerts anti-thrombotic activity mediated by a cyclooxygenase-2/prostacyclin pathway

Authors


Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, Grzegorzecka 16, Krakow, 31-531 Poland. E-mail: s.chlopicki@cyfronet.krakow.pl

Institute of Applied Radiation Chemistry, Technical University of Lodz, Zeromskiego 116, Lodz, 90-924 Poland. E-mail: jgebicki@p.lodz.pl

Abstract

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-PGF1α 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 (1 mg 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.

British Journal of Pharmacology (2007) 152, 230–239; doi:10.1038/sj.bjp.0707383

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