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      Induction of resistance vessel dilation by ginger root juice, possibly through extracellular signal-regulated kinase 1/2 and endothelial nitric oxide synthase activation in endothelial cells


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          Objective: To investigate the effects of ginger root juice on contractibility of resistance blood vessels from mice and on activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and endothelial nitric oxide synthase (eNOS) in human endothelial cells.

          Methods: Juice was prepared from semi-dry ginger roots. Mesenteric artery rings were dissected from healthy adult C57BL/J6 mice. Primary human umbilical vein endothelial cells (HUVECs) were isolated from umbilical cords of normal full-term babies. The contractibility of the dissected vessel rings in the presence or absence of ginger root juice at 0.1% (v/v) after potassium (100 mM KCL) stimulation was measured by wire myography. The phosphorylation levels of ERK1/2 and eNOS in the presence of ginger root juice in the culture medium at 0, 0.025%, 0.05%, 0.1%, and 0.2% (v/v) in HUVECs were assessed by western blotting analysis.

          Results: An immediate sharp increase in the contractile activity was observed in mesenteric artery rings in response to KCL stimulation. Ginger root juice effectively attenuated the KCL-mediated vessel contraction. Moreover, ginger root juice significantly increased phosphorylation of ERK1/2 and eNOS in a dose-dependent manner.

          Conclusions: Ginger root juice is capable of relaxing resistance blood vessels. Activation of ERK1/2 and eNOS through phosphorylation in endothelial cells may be a mechanism underlying the vasodilator activity of ginger root.

          Most cited references29

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          Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression.

          The ability of the endothelium to produce nitric oxide is essential to maintenance of vascular homeostasis; disturbance of this ability is a major contributor to the pathogenesis of vascular disease. In vivo studies have demonstrated that expression of endothelial nitric oxide synthase (eNOS) is vital to endothelial function and have led to the understanding that eNOS expression is subject to modest but significant degrees of regulation. Subsequently, numerous physiological and pathophysiological stimuli have been identified that modulate eNOS expression via mechanisms that alter steady-state eNOS mRNA levels. These mechanisms involve changes in the rate of eNOS gene transcription (transcriptional regulation) and alteration of eNOS mRNA processing and stability (posttranscriptional regulation). In cultured endothelial cells, shear stress, transforming growth factor-beta1, lysophosphatidylcholine, cell growth, oxidized linoleic acid, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, and hydrogen peroxide have been shown to increase eNOS expression. In contrast, tumor necrosis factor-alpha, hypoxia, lipopolysaccaride, thrombin, and oxidized LDL can decrease eNOS mRNA levels. For many of these stimuli, both transcriptional and posttranscriptional mechanisms contribute to regulation of eNOS expression. Recent studies have begun to further define signaling pathways responsible for changes in eNOS expression and have characterized cis- and trans-acting regulatory elements. In addition, a role has been identified for epigenetic control of eNOS mRNA levels. This review will discuss transcriptional and posttranscriptional regulation of eNOS with emphasis on the molecular mechanisms that have been identified for these processes.
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            Mesenteric artery contraction and relaxation studies using automated wire myography.

            Proximal resistance vessels, such as the mesenteric arteries, contribute substantially to the peripheral resistance. These small vessels of between 100-400 μm in diameter function primarily in directing blood flow to various organs according to the overall requirements of the body. The rat mesenteric artery has a diameter greater than 100 μm. The myography technique, first described by Mulvay and Halpern(1), was based on the method proposed by Bevan and Osher(2). The technique provides information about small vessels under isometric conditions, where substantial shortening of the muscle preparation is prevented. Since force production and sensitivity of vessels to different agonists is dependent on the extent of stretch, according to active tension-length relation, it is essential to conduct contraction studies under isometric conditions to prevent compliance of the mounting wires. Stainless steel wires are preferred to tungsten wires because of oxidation of the latter, which affects recorded responses(3).The technique allows for the comparison of agonist-induced contractions of mounted vessels to obtain evidence for normal function of vascular smooth muscle cell receptors. We have shown in several studies that isolated mesenteric arteries that are contracted with phenylyephrine relax upon addition of cumulative concentrations of extracellular calcium (Ca(2+)(e;)). The findings led us to conclude that perivascular sensory nerves, which express the G protein-coupled Ca(2+)-sensing receptor (CaR), mediate this vasorelaxation response. Using an automated wire myography method, we show here that mesenteric arteries from Wistar, Dahl salt-sensitive(DS) and Dahl salt-resistant (DR) rats respond differently to Ca(2+)(e;). Tissues from Wistar rats showed higher Ca(2+)-sensitivity compared to those from DR and DS. Reduced CaR expression in mesenteric arteries from DS rats correlates with reduced Ca(2+)(e;)-induced relaxation of isolated, pre-contracted arteries. The data suggest that the CaR is required for relaxation of mesenteric arteries under increased adrenergic tone, as occurs in hypertension, and indicate an inherent defect in the CaR signaling pathway in Dahl animals, which is much more severe in DS. The method is useful in determining vascular reactivity ex vivo in mesenteric resistance arteries and similar small blood vessels and comparisons between different agonists and/or antagonists can be easily and consistently assessed side-by-side(6,7,8).
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              Cicletanine stimulates eNOS phosphorylation and NO production via Akt and MAP kinase/Erk signaling in sinusoidal endothelial cells.

              The function of the endothelial isoform of nitric oxide synthase (eNOS) and production of nitric oxide (NO) is altered in a number of disease states. Pharmacological approaches to enhancing NO synthesis and thus perhaps endothelial function could have substantial benefits in patients. We analyzed the effect of cicletanine, a synthetic pyridine with potent vasodilatory characteristics, on eNOS function and NO production in normal (liver) and injured rat sinusoidal endothelial cells, and we studied the effect of cicletanine-induced NO on stellate cell contraction and portal pressure in an in vivo model of liver injury. Sinusoidal endothelial cells were isolated from normal and injured rat livers. After exposure to cicletanine, eNOS phosphorylation, NO synthesis, and the signaling pathway regulating eNOS activation were measured. Cicletanine led to an increase in eNOS (Ser¹¹⁷⁷) phosphorylation, cytochrome c reductase activity, L-arginine conversion to L-citrulline, as well as NO production. The mechanism of the effect of cicletanine appeared to be via the protein kinase B (Akt) and MAP kinase/Erk signaling pathways. Additionally, cicletanine improved NO synthesis in injured sinusoidal endothelial cells. NO production induced by cicletanine in sinusoidal endothelial cells increased protein kinase G (PKG) activity as well as relaxation of stellate cells. Finally, administration of cicletanine to mice with portal hypertension induced by bile duct ligation led to reduction of portal pressure. The data indicate that cicletanine might improve eNOS activity in injured sinusoidal endothelial cells and likely activates hepatic stellate cell NO/PKG signaling. It raises the possibility that cicletanine could improve intrahepatic vascular function in portal hypertensive patients.

                Author and article information

                Family Medicine and Community Health
                Family Medicine and Community Health & American Chinese Medical Education Association (USA )
                September 2013
                September 2014
                : 1
                : 3
                : 12-18
                [1] 1Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI, USA
                Author notes
                CORRESPONDING AUTHOR: Dinesh M. Shah, Professor and Director, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Wisconsin Medical School, 1010 Mound St, Madison, WI 53715, E-mail: dmshah@ 123456wisc.edu , Tel.: +1-608-417-6099
                Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
                Copyright © 2013 Family Medicine and Community Health

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 Unported License (CC BY-NC 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See https://creativecommons.org/licenses/by-nc/4.0/.

                : 16 September 2013
                : 25 November 2013
                Original Research

                General medicine,Medicine,Geriatric medicine,Occupational & Environmental medicine,Internal medicine,Health & Social care
                Vasodilation,Ginger,Resistance blood vessels,ERK1/2,eNOS,Phosphorylation,Myography,Endothelial cell


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