N-Methyl-2-pyridone-5-carboxamide is 1-methylnicotinamide metabolite of low cyclooxygenase-dependent vasodilating activity

ABSTRACT

1-Methylnicotinamide (MNA) is a primary metabolite of nicotinamide recently proven to cause systemic increase in PGI2 plasma levels in an unknown mechanism. Our present study was aimed at verifying whether the increased production of PGI2, a vasodilating prostanoid, in response to MNA, its metabolite N-methyl-2-pyridone-5-carboxamide (Met2PY), and nicotinamide may be reproduced under in vitro conditions. Since prostacyclin is a vasodilating prostanoid, we also performed the functional tests in the ex vivo model of coronary vascular bed perfusion to evaluate the vasoactive properties of those compounds. We did not observe any significant effect of the tested drugs on either PGI2 or PGE2 secretion in our in vitro model. Nicotinamide at the concentrations of 10 and 100 ìmol/l and 100 ìmol/l Met2PY slightly but significantly increased coronary flow in rat heart. These increases, however, remained very low when compared to that induced by the reference compound, bradykinin (100 nmol/l). Perfusion of rat hearts with Met2PY in the presence of 50 ìmol/l indomethacin resulted in decreased coronary flow, which proves that the effect is cyclooxygenase dependent. We conclude that MNA metabolites should be more carefully addressed in reference to pro-prostacyclin activity and that systemic mechanism of MNA-induced PGI2 production needs further clarification (AU)