title: 1-Methylnicotinamide (MNA), a primary metabolite of nicotinamide, exerts anti-thrombotic activity mediated by a cyclooxygenase-2/prostacyclin pathway.
abstract: OBJECTIVE
  1-methylnicotinamide (MNA) has been considered to be an inactive metabolite of nicotinamide. Here we assessed the anti-thrombotic activity of MNA in vivo.
  
  
  METHODS
  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).
  
  
  RESULTS
  MNA (3-100 mg kg(-1)) induced a dose-dependent and sustained thrombolytic response, associated with a rise in 6-keto-PGF(1alpha) 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
  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.
authors.affiliation: Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, Krakow, Poland. s.chlopicki@cyfronet.krakow.pl
authors.forename: S
authors.initials: S
authors.lastname: Chlopicki
authors.forename: J
authors.initials: J
authors.lastname: Swies
authors.forename: A
authors.initials: A
authors.lastname: Mogielnicki
authors.forename: W
authors.initials: W
authors.lastname: Buczko
authors.forename: M
authors.initials: M
authors.lastname: Bartus
authors.forename: M
authors.initials: M
authors.lastname: Lomnicka
authors.forename: J
authors.initials: J
authors.lastname: Adamus
authors.forename: J
authors.initials: J
authors.lastname: Gebicki
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000097:blood / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D066298:In Vitro Techniques; D007783:Lactones / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011453:Prostaglandins / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D013450:Sulfones / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D020246:Venous Thrombosis / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D005343:Fibrinolytic Agents; D007783:Lactones; D011453:Prostaglandins; D013450:Sulfones; C116926:rofecoxib; D009536:Niacinamide; D011464:Epoprostenol; D051546:Cyclooxygenase 2; C024058:N(1)-methylnicotinamide