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      The novel organic mononitrate NDHP attenuates hypertension and endothelial dysfunction in hypertensive rats

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          Abstract

          Rationale

          Development and progression of cardiovascular diseases, including hypertension, are often associated with impaired nitric oxide synthase (NOS) function and nitric oxide (NO) deficiency. Current treatment strategies to restore NO bioavailability with organic nitrates are hampered by undesirable side effects and development of tolerance. In this study, we evaluated NO release capability and cardiovascular effects of the newly synthesized organic nitrate 1, 3-bis (hexyloxy) propan-2-yl nitrate (NDHP).

          Methods

          A combination of in vitro and in vivo approaches was utilized to assess acute effects of NDHP on NO release, vascular reactivity and blood pressure. The therapeutic value of chronic NDHP treatment was assessed in an experimental model of angiotensin II-induced hypertension in combination with NOS inhibition.

          Results

          NDHP mediates NO formation in both cell-free system and small resistance arteries, a process which is catalyzed by xanthine oxidoreductase. NDHP-induced vasorelaxation is endothelium independent and mediated by NO release and modulation of potassium channels. Reduction of blood pressure following acute intravenous infusion of NDHP was more pronounced in hypertensive rats (two-kidney-one-clip model) than in normotensive sham-operated rats. Toxicological tests did not reveal any harmful effects following treatment with high doses of NDHP. Finally, chronic treatment with NDHP significantly attenuated the development of hypertension and endothelial dysfunction in rats with chronic NOS inhibition and angiotensin II infusion.

          Conclusion

          Acute treatment with the novel organic nitrate NDHP increases NO formation, which is associated with vasorelaxation and a significant reduction of blood pressure in hypertensive animals. Chronic NDHP treatment attenuates the progression of hypertension and endothelial dysfunction, suggesting a potential for therapeutic applications in cardiovascular disease.

          Graphical abstract

          Highlights

          • The organic nitrate NDHP mediates NO formation in cell-free system and blood vessels.

          • NDHP-mediated NO release is dependent on functional XOR.

          • NDHP induces endothelium-independent vasorelaxation and significant reduction of blood pressure.

          • NDHP-mediated vasorelaxation involves activation of NO/cGMP/PKG pathway and K + channels (K v and BK Ca).

          • Chronic treatment with NDHP attenuates the development of hypertension and endothelial dysfunction.

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          Most cited references52

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          Oxidative stress and cardiovascular injury: Part I: basic mechanisms and in vivo monitoring of ROS.

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            Strategies to increase nitric oxide signalling in cardiovascular disease.

            Nitric oxide (NO) is a key signalling molecule in the cardiovascular, immune and central nervous systems, and crucial steps in the regulation of NO bioavailability in health and disease are well characterized. Although early approaches to therapeutically modulate NO bioavailability failed in clinical trials, an enhanced understanding of fundamental subcellular signalling has enabled a range of novel therapeutic approaches to be identified. These include the identification of: new pathways for enhancing NO synthase activity; ways to amplify the nitrate-nitrite-NO pathway; novel classes of NO-donating drugs; drugs that limit NO metabolism through effects on reactive oxygen species; and ways to modulate downstream phosphodiesterases and soluble guanylyl cyclases. In this Review, we discuss these latest developments, with a focus on cardiovascular disease.
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              Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle.

              Nitric oxide is the major endothelium-derived relaxing factor (EDRF), and it is thought to relax smooth muscle cells by stimulation of guanylate cyclase, accumulation of its product cyclic GMP, and cGMP-dependent modification of several intracellular processes, including activation of potassium channels through cGMP-dependent protein kinase. Here we present evidence that both exogenous nitric oxide and native EDRF can directly activate single Ca(2+)-dependent K+ channels (K+Ca) in cell-free membrane patches without requiring cGMP. Under conditions when guanylate cyclase was inhibited by methylene blue, considerable relaxation of rabbit aorta to nitric oxide persisted which was blocked by charybdotoxin, a specific inhibitor of K+Ca channels. These studies demonstrate a novel direct action of nitric oxide on K+Ca channels.
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                Author and article information

                Contributors
                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                11 December 2017
                May 2018
                11 December 2017
                : 15
                : 182-191
                Affiliations
                [a ]Biotechnology Center, Federal University of Paraíba, João Pessoa, PB, Brazil
                [b ]Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
                [c ]Department of Chemistry, Federal University of Paraíba, João Pessoa, PB, Brazil
                [d ]Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
                Author notes
                [* ]Corresponding author. Mattias.Carlstrom@ 123456ki.se
                [1]

                Equal contribution.

                Article
                S2213-2317(17)30769-3
                10.1016/j.redox.2017.12.004
                5735329
                29268201
                48766bef-d4e8-4c9b-bb1f-f9c96863d332
                © 2017 Published by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 9 October 2017
                : 30 November 2017
                : 6 December 2017
                Categories
                Research Paper

                nitric oxide,cardiovascular disease,hypertension,organic nitrates,nitrite

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