Bernardino-Paula R, Carvalho-Galvão A, Cavalcanti ALM, Rocha PKL, Carvalho LRRA, Brandão MCR, Athayde-Filho PF, Diniz TF, Lemos VS, França-Silva MS, Montenegro MF, Weitzberg E, Lundberg JO, Carlström M, and Braga VA
Introduction: Cardiovascular diseases are coupled to decreased nitric oxide (NO) bioavailability, and there is a constant search for novel and better NO-donors. Here we synthesized and characterized the cardiovascular effects of the new organic nitrate 2-nitrate-1,3-dioctanoxypropan (NDOP)., Methods: A combination of in vitro and in vivo experiments was performed in C57BL/6 mice and Wistar rats. Thus, the ability of NDOP in donating NO in a cell-free system and in vascular smooth muscles cells (VSMC) and its ability to induce vasorelaxation in aortic rings from mice were evaluated. In addition, changes in blood pressure and heart rate to different doses of NDOP were evaluated in conscious rats. Finally, acute pre-clinical toxicity to oral administration of NDOP was assessed in mice., Results: In cell-free system, NDOP increased NO levels, which was dependent on xanthine oxidoreductase (XOR). NDOP also increased NO levels in VSMC, which was not influenced by endothelial NO synthase. Furthermore, incubation with the XOR inhibitor febuxostat blunted the vasorelaxation in aortic ring preparations. In conscious rats, NDOP elicited dose-dependent reduction in blood pressure accompanied with increased heart rate. In vessel preparations, NDOP (10 -8 -10 -3 mol/L) induced endothelium-independent vasorelaxation, which was inhibited by the NO scavengers 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide and hydroxocobalamin or by inhibition of soluble guanylyl cyclase using H- [1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one. To investigate if NDOP acts through potassium channels, selective blockers were used. Inhibition of BK Ca , K v or K ATP subtypes of potassium channels had no effect, but inhibition of inward-rectifier potassium channels (K IR ) significantly reduced NDOP-mediated vasorelaxation. Lastly, NDOP showed low toxicity (LD 50 ~5000 mg/kg)., Conclusion: Bioactivation of NDOP involves functional XOR, and this new organic nitrate elicits vasorelaxation via NO-cGMP-PKG signaling and activation of K IR channels. Future studies should further characterize the underlying mechanism and evaluate the therapeutic benefits of chronic NDOP treatment in relevant cardiovascular disease models., (Copyright © 2020 Elsevier Inc. All rights reserved.)