Nitric Oxide Production and Endothelium-Dependent Vasorelaxation Ameliorated by N-Methylnicotinamide in Human Blood Vessels

Abstract

N-methylnicotinamide (MNA ) has until recently been thought to be a biologically inactive product of nicotinamide metabolism in the pyridine nucleotides pathway. However, the latest observations imply that MNA may exert antithrombotic and anti-inflammatory effects through direct action on the endothelium. We examined both in vivo and in vitro whether the compound might induce vasorelaxation in human blood vessels through the improvement of nitric oxide (NO) bioavailability and a reduction of oxidative stress mediated by endothelial NO synthase (eNOS) function. MNA treatment (100 mg/m orally) in healthy normocholesterolemic and hypercholesterolemic subjects increased the L-arginine (L-NMMA)-inhibitable flow-mediated dilation (FMD) of brachial artery responses that also positively correlated with MNA plasma concentrations (r 0.73 for normocholesterolemics and r 0.78 for hypercholesterolemics; P 0.0001). MNA increased FMD at the same concentration range at which it enhanced NO release from cultured human endothelial cells after stimulation with either the receptor-dependent (acetylcholine) or the receptor-independent endothelial NO synthase agonists (calcium ionophore A23187). MNA restored the endothelial NO synthase agonist-stimulated NO release after the exposure of the cells to oxidized low-density lipoprotein. This effect was also associated with the normalization of the [NO]/[superoxide] balance in the endothelial cells. Taken together, the increased NO bioavailability in the endothelium contributes to the vasorelaxating properties of MNA . Targeting eNOS with MNA might be therapeutically relevant for functional disorders of the endothelium, such as hypercholesterolemia and atherosclerosis. (Hypertension. 2012;59:825-832.) ● Online Data Supplement

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Cite this paper

@inproceedings{Domagala2012NitricOP, title={Nitric Oxide Production and Endothelium-Dependent Vasorelaxation Ameliorated by N-Methylnicotinamide in Human Blood Vessels}, author={Teresa B. Domagala and Agata Szeffler and Lawrence W. Dobrucki and Jerzy Dropiński and Stanisław Polański and Magdalena Leszczynska-Wiloch and Katarzyna Kotula-Horowitz and Jacek Wojciechowski and Leszek Wojnowski and Andrzej Szczeklik and Leszek Kalinowski}, year={2012} }