Nitric oxide production and endothelium-dependent vasorelaxation ameliorated by N 1-methylnicotinamide in human blood vessels

Teresa B. Domagala, Agata Szeffler, Lawrence W. Dobrucki, Jerzy Dropinski, Stanisław Polanski, Magdalena Leszczynska-Wiloch, Katarzyna Kotula-Horowitz, Jacek Wojciechowski, Leszek Wojnowski, Andrzej Szczeklik, Leszek Kalinowski

Research output: Contribution to journalArticle

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 2 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.

Original languageEnglish (US)
Pages (from-to)825-832
Number of pages8
JournalHypertension
Volume59
Issue number4
DOIs
StatePublished - Apr 2012

Keywords

  • endothelial cells
  • endothelial nitric oxide synthase
  • flow-mediated dilation
  • N -methylnicotinamide
  • nitric oxide
  • oxidized low-density lipoprotein
  • superoxide

ASJC Scopus subject areas

  • Internal Medicine

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  • Cite this

    Domagala, T. B., Szeffler, A., Dobrucki, L. W., Dropinski, J., Polanski, S., Leszczynska-Wiloch, M., Kotula-Horowitz, K., Wojciechowski, J., Wojnowski, L., Szczeklik, A., & Kalinowski, L. (2012). Nitric oxide production and endothelium-dependent vasorelaxation ameliorated by N 1-methylnicotinamide in human blood vessels. Hypertension, 59(4), 825-832. https://doi.org/10.1161/HYPERTENSIONAHA.111.183210