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 À1 ) induced a dose-dependent and sustained thrombolytic response, associated with a rise in 6-keto-PGF 1a in blood. Various compounds structurally related to MNA were either inactive or weaker thrombolytics. Rofecoxib (0.01-1 mg kg À1 ), dose-dependently inhibited the thrombolytic response of MNA, indomethacin (5 mg kg À1 ) abolished it, while L-NAME (5 mg kg À1 ) were without effect. MNA (3-30 mg kg À1 ) also reduced arterial thrombosis and this effect was abrogated by indomethacin (2.5 mg kg À1 ) as well as by rofecoxib (1 mg kg À1 ). 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.
Two in vitro and one in vivo assay were performed to study the endothelial pleiotropic actions of “tissue type” angiotensin converting enzyme inhibitors (ACE‐Is) such as perindopril and quinapril, their active forms, that is, quinaprilat and peridoprilat, or of statins belonging to natural (lovastatin), semisynthetic (simvastatin), and synthetic enantiomeric (atorvastatin, cerivastatin) classes. Cytoplasmic [Ca2+]i levels in cultured bovine aortic endothelial cells and endothelium‐dependent nitric oxide‐mediated coronary vasodilatation in the Langendorff preparation of guinea pig heart constituted our in vitro assays. The in vivo assay consisted of study of PGI2‐mediated thrombolytic response in arterial blood of rats after intravenous administration of drugs. In this last assay, perindopril and quinapril proved to be, by two orders of magnitude, more potent PGI2‐dependent thrombolytics than the most potent statin (atorvastatin). However, in both in vitro assays we found a higher endothelial efficacy of statins as compared to ACE‐Is. In particular, those statins that contain the lactone ring in their molecules (lovastatin, simvastatin) were the most potent coronary vasodilators. In summary, the in vivo profile of action of ACE‐Is and statins contrasted with their reversed order of potency in vitro. We hypothesize that the endocrine‐like function of the pulmonary circulation [28‐31] may be responsible for the in vivo bradykinin‐triggered, PGI2‐mediated thrombolysis by ACE‐Is, whereas the pleiotropic action of statins, possibly involving inhibition of prenylation [14‐19], is diffused throughout many vascular beds.
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