Abstract 12564: Nitric Oxide Production and Endothelium-dependent Vasorelaxation Induced by 1-methylnicotinamide in Human Blood Vessels
Background: Until recently N1-methylnicotinamide (MNA+) has been believed to be a biologically inactive product of nicotinamide metabolism in the pyridine nucleotides pathway. Latest observations suggest, however, that MNA+ can exert anti-thrombotic and anti-inflammatory effects through direct action on the endothelium.
Aim: To further investigate the therapeutic endothelial potential of MNA+, we examined both in vivo and in vitro whether this compound might induce vasorelaxation in human blood vessels through an improvement of NO bioactivity and a reduction of oxidative stress mediated by eNOS function.
Methods: We examined the effect of oral MNA+ administration (100 mg/m2 body surface area) or placebo on endothelial function in young, healthy, non-smoking male volunteers (n=8). Endothelium-dependent, flow-mediated dilation (FMD) of brachial artery in response to reactive hyperemia was evaluated non-invasively by high-resolution ultrasound before, 2 and 4 hours after oral administration of MNA+. A three-electrode system was used for concurrent measurements of NO and O2-.
Results: MNA+ treatment of healthy subjects remarkably increased the FMD of brachial artery responses that also positively correlated with MNA+ serum concentrations (r=0.73; P<0.0001). MNA+ increased FMD at the concentration range at which the compound enhanced NO release from cultured human endothelial cells (EA.hy 926 cells) after stimulation with either the receptor-dependent (acetylcholine), or the receptor-independent eNOS agonists (calcium ionophore A23187). MNA+ normalized the agonists-stimulated NO release after the exposure of the cells to oxidized-LDL. The simultaneous detections of NO with superoxide revealed this effect to be also associated with the normalizing [NO]/[O2-] balance in the endothelial cells after the stimulation of eNOS activity by the agonists.
Conclusions: It was demonstrated for the first time that the increased NO bioactivity in the endothelium contributed to the vasorelaxation properties of MNA+ and its potentially therapeutic action targeting eNOS functional state in the endothelium-impaired function disorders like atherosclerosis.
- © 2010 by American Heart Association, Inc.