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      Effect of the double bond conjugation on the vascular physiology and nitric oxide production of isomers of eicosapentaenoic and docosahexaenoic acids prepared from shark oil

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          Abstract

          A collection of evidence suggests that conjugation of double bonds of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, omega-3 polyunsaturated fatty acids (n-3 PUFAs), increases their anticarcinogenic activity; however, the effect of such conjugation on vascular tone activity remains unknown. We propose that the mixture of conjugated PUFAs exerts higher vasorelaxation activity than the corresponding mixture of nonconjugated PUFAs. The vascular response to different concentrations of conjugated and nonconjugated isomers of EPA and DHA, among other fatty acids (FAs) naturally present in shark oil, and the role of nitric oxide (NO) as a vasorelaxant agent were investigated. Both conjugated EPA (CEPA) and conjugated DHA (CDHA) were prepared by alkaline isomerization of all PUFAs contained in shark oil. Different concentrations of conjugated and nonconjugated PUFAs were placed in contact with precontracted aortic rings of Wistar rats to assess their effect on vascular tone. All tested samples exerted a vasorelaxant effect. Compared to nonconjugated PUFAs, conjugated isomers exhibited an increase in the dilatation of the aortic rings (P<0.001) in a dose-dependent manner (P<0.001). In addition, nonconjugated PUFAs produced nitric oxide (NO) in a dose-dependent manner, while conjugated PUFAs did not, suggesting that their dilatation mechanism is not totally dependent on NO.

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          n-3 Fatty acids and cardiovascular disease: evidence explained and mechanisms explored.

          Long chain n-3 PUFAs (polyunsaturated fatty acids) are found in fatty fish and in fish oils. Substantial evidence from epidemiological and case-control studies indicates that consumption of fish, fatty fish and long-chain n-3 PUFAs reduces the risk of cardiovascular mortality. Secondary prevention studies using long-chain n-3 PUFAs in patients post-myocardial infarction have shown a reduction in total and cardiovascular mortality, with an especially potent effect on sudden death. Long-chain n-3 PUFAs have been shown to decrease blood triacylglycerol (triglyceride) concentrations, to decrease production of chemoattractants, growth factors, adhesion molecules, inflammatory eicosanoids and inflammatory cytokines, to lower blood pressure, to increase nitric oxide production, endothelial relaxation and vascular compliance, to decrease thrombosis and cardiac arrhythmias and to increase heart rate variability. These mechanisms most likely explain the primary and secondary cardiovascular protection afforded by long-chain n-3 PUFA consumption. A recent study suggests that long-chain n-3 PUFAs might also act to stabilize advanced atherosclerotic plaques, perhaps through their anti-inflammatory effects. As a result of the robust evidence in their favour, a number of recommendations to increase intake of long-chain n-3 PUFAs have been made.
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            Docosahexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans.

            Animal studies suggest that the 2 major omega3 fatty acids found in fish, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may have differential effects on blood pressure (BP) and heart rate (HR). The aim of this study was to determine whether there were significant differences in the effects of purified EPA or DHA on ambulatory BP and HR in humans. In a double-blind, placebo-controlled trial of parallel design, 59 overweight, mildly hyperlipidemic men were randomized to 4 g/d of purified EPA, DHA, or olive oil (placebo) capsules and continued their usual diets for 6 weeks. Fifty-six subjects completed the study. Only DHA reduced 24-hour and daytime (awake) ambulatory BP (P<0.05). Relative to the placebo group, 24-hour BP fell 5.8/3.3 (systolic/diastolic) mm Hg and daytime BP fell 3.5/2.0 mm Hg with DHA. DHA also significantly reduced 24-hour, daytime, and nighttime (asleep) ambulatory HRs (P=0. 001). Relative to the placebo group, DHA reduced 24-hour HR by 3. 5+/-0.8 bpm, daytime HR by 3.7+/-1.2 bpm, and nighttime HR by 2. 8+/-1.2. EPA had no significant effect on ambulatory BP or HR. Supplementation with EPA increased plasma phospholipid EPA from 1. 66+/-0.07% to 9.83+/-0.06% (P<0.0001) but did not change DHA levels. Purified DHA capsules increased plasma phospholipid DHA levels from 4.00+/-0.27% to 10.93+/-0.62% (P<0.0001) and led to a small, nonsignificant increase in EPA (1.52+/-0.12% to 2.26+/-0.16%). Purified DHA but not EPA reduced ambulatory BP and HR in mildly hyperlipidemic men. The results of this study suggest that DHA is the principal omega3 fatty acid in fish and fish oils that is responsible for their BP- and HR-lowering effects in humans. These results have important implications for human nutrition and the food industry.
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              Differential effects of eicosapentaenoic acid and docosahexaenoic acid on vascular reactivity of the forearm microcirculation in hyperlipidemic, overweight men.

              Recent evidence supports differential effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the 2 major omega3 fatty acids of marine origin, on blood pressure in humans and vascular reactivity in adult spontaneously hypertensive rats. We investigated possible differences in the effects of purified EPA or DHA on forearm vascular reactivity in overweight hyperlipidemic men that might contribute to the blood pressure-lowering effects of fish oils. With a double-blind, placebo-controlled trial of parallel design, 59 overweight, mildly hyperlipidemic men were randomized to receive 4 g/d purified EPA, DHA, or olive oil (placebo) capsules while continuing their usual diets for 6 weeks. Forearm blood flow (FBF) was measured with venous occlusion, strain-gauge plethysmography during the sequential intra-arterial administration of acetylcholine (7.5, 15, and 30 microg/min), sodium nitroprusside (1.5, 3, and 10 microg/min), norepinephrine (10, 20, and 40 ng/min), a single-dose infusion of N:(G)-monomethyl-L-arginine (L-NMMA) (1 mg/min), and coinfusion of acetylcholine (7.5, 15, and 30 microg/min) and L-NMMA. Forty of the 56 subjects who completed the study underwent FBF measurements. Plasma phospholipid EPA levels increased significantly (P:<0.0001) after supplementation with EPA, and DHA composition increased with DHA supplementation (P:<0.0001). Relative to placebo, DHA, but not EPA, supplementation significantly improved FBF in response to acetylcholine infusion (P:=0.040) and coinfusion of acetylcholine with L-NMMA (P:=0.040). Infusion of L-NMMA alone showed no group differences. DHA significantly enhanced dilatory responses to sodium nitroprusside (P:<0.0001) and attenuated constrictor responses to norepinephrine (P:=0.017). Relative to placebo, DHA, but not EPA, enhances vasodilator mechanisms and attenuates constrictor responses in the forearm microcirculation. Improvements in endothelium-independent mechanisms appear to be predominant and may contribute to the selective blood pressure-lowering effect observed with DHA compared with EPA in humans.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draft
                Role: Formal analysisRole: InvestigationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysis
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                27 February 2020
                2020
                : 15
                : 2
                : e0229435
                Affiliations
                [1 ] Facultad de Ciencias Quimicas, Universidad Autonoma de San Luis Potosi, San Luis Potosí, San Luis Potosi, Mexico
                [2 ] Centro de Investigacion en Ciencias de la Salud y Biomedicina (CICSaB), Universidad Autonoma de San Luis Potosi, San Luis Potosi, San Luis Potosi, Mexico
                [3 ] Consejo Nacional de Ciencia y Tecnologia, Mexico City, Mexico
                University of Rochester, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-0233-4384
                Article
                PONE-D-19-02815
                10.1371/journal.pone.0229435
                7046235
                32107491
                eafd6976-f70c-4af8-856e-01ffd347f735
                © 2020 Gonzalez et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 1 March 2019
                : 6 February 2020
                Page count
                Figures: 7, Tables: 2, Pages: 20
                Funding
                Funded by: FAI-UASLP
                Award ID: C08-FAI-10-26.62
                Award Recipient :
                Alejandro Rocha-Uribe was supported by the grant by Fondo de Apoyo a la Investigacion de la Universidad Autonoma de San Luis Potosi (C08-FAI-10-26.62). http://www.uaslp.mx/InvestigacionyPosgrado/Paginas/FAI/inicio.aspx.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Lipids
                Oils
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Fish
                Chondrichthyes
                Elasmobranchii
                Sharks
                Biology and Life Sciences
                Biochemistry
                Lipids
                Fatty Acids
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Endothelium
                Medicine and Health Sciences
                Anatomy
                Cardiovascular Anatomy
                Endothelium
                Physical Sciences
                Chemistry
                Chemical Compounds
                Isomers
                Physical Sciences
                Chemistry
                Stereochemistry
                Isomerism
                Isomers
                Physical Sciences
                Chemistry
                Chemical Reactions
                Isomerization
                Physical Sciences
                Chemistry
                Stereochemistry
                Isomerism
                Isomerization
                Medicine and Health Sciences
                Vascular Medicine
                Vasodilation
                Biology and Life Sciences
                Biochemistry
                Neurochemistry
                Neurochemicals
                Nitric Oxide
                Biology and Life Sciences
                Neuroscience
                Neurochemistry
                Neurochemicals
                Nitric Oxide
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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