Cardiovascular characterization of the novel organic mononitrate NDIBP in rats.

Autor: Cavalcanti ALM; Biotechnology Center, Federal University of Paraíba, Cidade Universitária, 58051970, João Pessoa, PB, Brazil., Rocha PKL; Biotechnology Center, Federal University of Paraíba, Cidade Universitária, 58051970, João Pessoa, PB, Brazil., Zhuge Z; Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden., Paulo LL; Biotechnology Center, Federal University of Paraíba, Cidade Universitária, 58051970, João Pessoa, PB, Brazil., Mendes-Júnior LDG; Biotechnology Center, Federal University of Paraíba, Cidade Universitária, 58051970, João Pessoa, PB, Brazil., Brandão MCR; Department of Chemistry, Federal University of Paraíba, Cidade Universitária, 58059900, João Pessoa, PB, Brazil., Athayde-Filho PF; Department of Chemistry, Federal University of Paraíba, Cidade Universitária, 58059900, João Pessoa, PB, Brazil., Lundberg JO; Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden., Weitzberg E; Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden., Carlström M; Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden., Braga VA; Biotechnology Center, Federal University of Paraíba, Cidade Universitária, 58051970, João Pessoa, PB, Brazil. Electronic address: valdir@cbiotec.ufpb.br., Montenegro MF; Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden.
Jazyk: angličtina
Zdroj: Nitric oxide : biology and chemistry [Nitric Oxide] 2022 Feb 01; Vol. 119, pp. 50-60. Date of Electronic Publication: 2021 Dec 24.
DOI: 10.1016/j.niox.2021.12.007
Abstrakt: Organic nitrates are widely used to restore endogenous nitric oxide (NO) levels reduced by endothelial nitric oxide synthase dysfunction. However, these drugs are associated with undesirable side effects, including tolerance. This study aims to investigate the cardiovascular effects of the new organic nitrate 1,3-diisobutoxypropan-2-yl nitrate (NDIBP). Specifically, we assessed its effects on blood pressure, vascular reactivity, acute toxicity, and the ability to induce tolerance. In vitro and ex vivo techniques showed that NDIBP released NO both in a cell-free system and in isolated mesenteric arteries preparations through a process catalyzed by xanthine oxidoreductase. NDIBP also evoked endothelium-independent vasorelaxation, which was significantly attenuated by 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl 3-oxide (PTIO, 300 μM), a nitric oxide scavenger; 1-H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 μM), a soluble guanylyl cyclase inhibitor; tetraethylammonium (TEA, 3 mM), a potassium channel blocker; febuxostat (500 nM), a xanthine oxidase inhibitor; and proadifen (10 μM), an inhibitor of cytochrome P450 enzyme. Furthermore, this organic nitrate did not induce tolerance in isolated vessels and presented low toxicity following acute oral administration. In vivo changes on cardiovascular parameters were assessed using normotensive and renovascular hypertensive rats. NDIBP evoked a reduction of blood pressure that was significantly higher in hypertensive animals. Our results suggest that NDIBP acts as a NO donor, inducing blood pressure reduction without having the undesirable effects of tolerance. Those effects seem to be mediated by activation of NO-sGC-cGMP pathway and positive modulation of K + channels in vascular smooth muscle.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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