Manganese / Nitric Oxide in the Immunesystem

percyval577

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Manganese is obviously used by the immunesystem to sensitze itself to/for infections, which the thread is thought to give some literature.
__________​
The following article summarizes some findings which have been made in microglia and astrocytes.

Manganese-induced potentation of in vitro proinflammatory cytokine production by activate microglia cells is associated with persistent activation of p38 MAPK
Crittenden anad Filipov 2008

Introduction (my bold)
Manganese (Mn), while an essential metal, is also a common environmental contaminant. The presence of Mn in alloys, fertilizers, batteries, and fungicides, as well as the re-introduction of the fuel additive methylcyclopentdienyl manganese tricarbonyl (MMT), is of environmental and occupational concern (Aschner, 2000; Frumkin et al., 1997). Occupational exposure to Mn has been linked to a specific neuropathology, manganism, that is characterized by clinical signs and lesions similar to Parkinson’s Disease (PD; Meco et al., 1994). Manganese is thought to exert its effects, at least partially, by disrupting mitochondrial respiration leading to increased oxidative stress (Aschner and Aschner, 1991; Gavin et al., 1999). This is supported by studies demonstrating that Mn-containing compounds, such as the fungicide Maneb and the fuel additive MMT, can inhibit mitochondrial respiration (Auttissier et al., 1977; Zhang et al., 2003).

While Mn is directly toxic to neuronal cells, neurons are not the only CNS cells that are associated with and contribute to Mn neurotoxicity. Astrocytes, for example, accumulate Mn and may produce reactive oxygen species (ROS) and other substances that may be damaging to neurons (Aschner et al., 2000). Importantly, it has been demonstrated that the other CNS resident cells, the microglia, and/or the astrocytes may produce inflammatory mediators that could be involved in the mechanisms of Mn neurotoxicity, especially in cases where an additional inflammatory stimulus is present (Chang and Liu, 1999; Filipov et al., 2005; Spranger et al., 1998).

Microglia have been implicated in PD (humans and animal models) and research utilizing the model PD toxicant MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has shown that activated microglia persist long after exposure to MPTP has ended (McGeer et al., 1988, 2003). Additionally, it has been demonstrated that prior exposure to Mn before challenge with MPTP will result in greater basal ganglia pathology than exposure to Mn or MPTP alone (Takahashi et al., 1989). Therefore, this study suggests that Mn exposure has the potential of interacting with other basal ganglia toxicants, thus causing greater neurotoxicity. However, the likelihood of such exposure (i.e. Mn + MPTP) is remote. On the other hand, a more relevant model, may involve Mn and lipopolysaccharide (LPS). LPS is a common environmental contaminant (Niehaus and Lange, 2003) and model inflammogen due to its ability to stimulate microglia to produce cytokines, nitric oxide (NO), and ROS (Chao et al., 1992; Jeohn et al., 2002; Liu et al., 2002). Importantly, LPS exposure is also associated with basal ganglia toxicity (Niehaus and Lange, 2003) and it has been used as a model for PD in in vitro and in vivo studies (Liu et al., 2002; Castano et al., 1998)

Binding of LPS to CD14 and TLR4 cell surface receptors leads to the activation of intracellular kinases, including the mitogen activated protein kinases (MAPK; Bhat et al., 1998; Jeohn et al., 2002). The MAPK family of proteins is comprised of the extracellular signal-regulated kinases (ERK), stress-activated or c-Jun N-terminal kinases (SAPK/JNK), big MAPK 1 (BMK1), and the p38 MAPK (Koistinaho and Koistinaho, 2002). Of these MAPK, p38 MAPK (p38) and ERK appear to be primarily involved in the production of inflammatory mediators by microglia. In primary microglia and microglial cell lines, LPS has been shown to dose- and time-dependently increase the phosphorylation of ERK and p38, as well as increase the expression of iNOS and TNF-α (Bhat et al., 1998; Lee et al., 1994; Lee et al., 1993). Of note, the p38-dependent increases in NO production require not only the phosphorylation of p38 but increased kinase activity as well (Jeohn et al., 2002). Additionally, by exposing microglia to ERK-and p38-inhibitors prior to exposure to LPS, the LPS-induced increases in NO and TNFα were inhibited (Bhat et al., 1998). Furthermore, LPS-induced, p38-dependent, increases in NO and TNF-α by microglia have been shown to decrease neuronal survivability in neuronalglial co-culture (Jeohn et al., 2002). The fact that this effect can be inhibited by pretreatment with inhibitors of p38 suggests that p38 appears to play a dominant role in the process.

Although inflammatory responses are essential for the maintenance and defense of tissues, uncontrolled or chronic inflammation can be detrimental to tissue homeostasis, especially in sensitive tissues like the nervous system. In fact, abnormally high levels of inflammatory cytokines, such as TNF-α, have been implicated in the etiology of PD (Nagatsu et al., 2000). Within the context of Mn neurotoxicity, Mn enhances the production of inflammatory mediators by microglia. Indeed, exposure to Mn potentiates LPS-induced production of Crittenden and Filipov Page 2 Toxicol In Vitro. Author manuscript; available in PMC 2009 February 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript inflammatory cytokines (TNF-α & IL-6) and NO in vitro (Filipov et al., 2005). Additionally, this effect is NF-kB-dependent as inhibitors of NF-kB were able to prevent the potentiation observed in Mn+LPS exposed cells (Filipov et al., 2005). At present, it is not known whether the potentiation of inflammatory cytokine production by Mn occurs at the level of NF-kB or further upstream in the intracellular signaling cascade. Since potential upstream targets include p38 and ERK and because a p38 inhibitor alone or in combination with an ERK inhibitor prevents the LPS-induced production of inflammatory mediators (Bhat et al., 1998), we conducted preliminary studies examining the effect of MAPK inhibition on cytokine production in Mn-exposed microglial cells activated with LPS (Crittenden and Filipov, 2004). From these studies we determined that inhibition of p38, but not of ERK, eliminated the potentiation of LPS-induced cytokine production in N9 microglial cells.

After we established the role of p38 in the enhancement of LPS-induced proinflammatory cytokine production by Mn, our objectives in this study were to (i) examine in detail the functional activation of p38 by exposure to Mn by itself or in combination with LPS and (ii) evaluate the time-window during the proinflammatory cytokine production process which is dependent upon p38 in Mn+LPS-exposed microglia.
open access
Toxicol In Vitro. 2008 Feb;22(1):18-27. Epub 2007 Jul 21.

 
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percyval577

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This seems to be the only articel so far which is not on microglia or astrocyctes but on a kind of peripheral blood cells.They tested also RNA viruses and probably refused to mention it in the title b/c RNA viruses are difficult to detect.
For ME/CFS Ron Davis mentionend that his patients would be especially low in DNA viruses, RNA viruses still to be tested. With this article one might guess that he will not find any, hypothesis being that the immune system is hypersensitized.

Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses
Wang et al 2018


Introduction (my bold)
Viral infection triggers host antiviral innate immune responses. Cells use different pattern recognition receptors (PRRs) to detect viral infection by sensing viral nucleic acids (Ablasser et al., 2013, Barrat et al., 2016, Chen et al., 2016, Roers et al., 2016). For cytoplasmic DNA sensing, cGAS (cyclic GMP-AMP [cGAMP] synthase) (Sun et al., 2013) recognizes cytosolic double-stranded DNA and produces the second messenger cGAMP (Civril et al., 2013, Gao et al., 2013, Wu et al., 2013) to activate STING (stimulator of IFN genes, also named MITA/ERIS) (Ishikawa and Barber, 2008, Sun et al., 2009, Zhong et al., 2008). Activation of PRRs leads to the activation of transcription factors NF-κB and interferon regulatory factor IRF3 and/or IRF7, and the production of various cytokines including type I-interferons (IFNs). Type I-IFNs induce the expression of hundreds of interferon-stimulated genes (ISGs), which interfere with almost every step of viral replication, resulting in the establishment of a cellular antiviral state.
Transition metals such as iron (Fe), manganese (Mn), copper (Cu), and zinc (Zn) are essential for all forms of life, as 30% of enzymes require a metal cofactor (Hood and Skaar, 2012). Clinical deficiency of either Fe or Zn in the host increases the incidence of infectious disease and mortality (Clark et al., 2016, Stacy et al., 2016). Manganese is one of the most abundant metals in the tissues of mammals, ranging from 0.3 to 2.9 mg/kg wet tissue weight, and is required for a variety of physiological processes including development, reproduction, neuronal function, immune regulation, and antioxidant defenses (Horning et al., 2015, Kwakye et al., 2015). Mn exerts its function by regulating various Mn-dependent enzymes, including oxidoreductases, isomerases, transferases, ligases, lyases, and hydrolases. It is also an essential component of some metalloenzymes such as Mn superoxide dismutase (SOD2), glutamine synthetase (GS), and arginase (Waldron et al., 2009). Although Mn has been implicated in the host-bacteria interface (Corbin et al., 2008, Radin et al., 2016), its function in innate immunity has never been reported.

We identified here a role of Mn2+ in alerting cells to viral infection via sensitizing both cGAS and STING. Mn2+ was liberated from membrane-enclosed organelles and accumulated in the cytosol, and bound to cGAS by increasing both the dsDNA sensitivity and the enzymatic activity of cGAS. Mn2+ also promoted STING’s activity through the enhanced cGAMP-STING binding affinity. The liberated cytosolic Mn2+ thus lowered the detection limit of host cells to dsDNA and virus by several orders of magnitude. Consequently, Mn-deficient mice produced decreased amounts of cytokines and were more vulnerable to DNA viruses as Sting-deficient (Tmem173−/−) mice did. Mn-deficient Tmem173−/− mice displayed no further increased susceptibility to virus compared with Mn-sufficient Tmem173−/− mice. Reconstitution of cellular Mn in Mn-deficient cells effectively restored their responses to DNA viruses. In addition, Mn2+ itself was a potent innate immune stimulator, inducing a type I-IFN response and cytokine production in the absence of any infection. Our results thus demonstrated that Mn is critically involved and required for the host defense against virus.
from the Discussion (my bold)
Manganese is an essential constituent of many metalloenzymes and serves as an enzyme activator. The normal concentrations of Mn range from 0.072 μM to 0.27 μM in human blood (Aschner and Aschner, 200) and from 20 μM to 53 μM in human brain (Bowman and Aschner, 2014). We observed that THP1 cells, a cell line derived from peripheral blood, started to gain antiviral activity when the medium Mn2+ level reached 2 μM. Thus, the concentrations of Mn2+ required to activate innate immunity appeared to be within the physiological range. We further demonstrated that the cytosolic Mn levels increased 60 times to 5.8–6.8 μM after virus infection. Critically, Mn2+ supported cGAS to produce cGAMP with low levels of dsDNA while Mg2+ didn’t at all. The elevated cytosolic Mn2+ thus significantly lowered the detection limit of cells to cytosolic dsDNA or DNA viruses. Accordingly, Mn-deficient mice were highly susceptible to DNA virus as Tmem173−/− mice did. Accumulation of extracellular soluble Mn was also observed. It is conceivable that the extracellular Mn was released by virus-infected cells, both alive and pyroptotic. In fact, the increased Mn contents in bronchoalveolar lavage fluid, white blood cells, and alveolar macrophages in virus-infected mice confirmed the physiological relevance of the Mn extracellular release, suggesting that Mn alerts host both locally at the site of infection and systemically through the circulation. Interestingly, Burleson’s group reported that a single intraperitoneal injection of 10, 20, or 40 μg MnCl2/g body weight caused significantly enhanced NK activity, probably mediated by the production of type I-IFNs (Smialowicz et al., 1988). Although the amount of Mn used in that work was 10 times higher than what we used (10–40 μg versus 1–2 μg MnCl2/g body weight), we believe that it was most likely through the cGAS-STING activation.
Mn2+ is very similar to Mg2+ in terms of the chemical properties. Previous work showed that Mn2+ is able to replace Mg2+ in vitro in almost half of Mg2+-dependent enzymes, in which the catalytic activity of the enzymes are often maintained (Wedler, 1993). In this study, however, we found that Mn2+ not only replaces Mg2+ in cGAS activation, but also enhances its enzymatic activity and ligand sensitivity. Similar results have been reported in the insulin receptor associated protein kinase, the kinase activity of which was activated substantially by Mn2+, but not by Mg2+ (Suzuki et al., 1987, Wente et al., 1990). It is possible that cGAS binds Mn-ATP much tighter than Mg-ATP, thereby activating cGAS. Alternatively, Mn2+ may induce an activating conformational change of cGAS protein. The crystal structure of cGAS with Mg2+ or Mn2+, probably in the presence of ATP/GTP, will provide insight into the detailed mechanism. Nevertheless, we found that in contrast to Mg2+, cGAS incubated with Mn2+ is inclined to precipitate, suggesting that Mn2+ may induce cGAS protein into a compact conformation which is easier to be activated. Unfortunately, this feature disallowed us to test the interaction of cGAS with ATP, GTP, or dsDNA in the presence of Mn2+. In addition, Mn2+ promoted STING activation through the enhanced cGAMP-STING affinity. This result agreed with previous work showing that Mn2+ promotes the dimerization of c-di-GMP and 3′3’-cGAMP (Roembke et al., 2014, Stelitano et al., 2013). Mn is the only essential metal of which the transportation and the subcellular distribution in organelles are not defined (Horning et al., 2015, Kwakye et al., 2015). We found that upon DNA virus infection, Mn2+ is liberated from mitochondria and/or Golgi apparatus, the major intracellular reservoirs for Mn2+ storage. In addition, free Mn2+ may also be released from Mn-binding proteins such as metallothioneins and calprotectin, an Mn2+-sequestering protein constituting about 40% of the total cytoplasmic protein in neutrophils (Brophy and Nolan, 2015), and/or albumin, the major Mn2+-binding protein in plasma (Foradori et al., 1967, Rabin et al., 1993). The released Mn2+ from organelles and Mn2+-binding proteins altogether leads to the elevated cytosolic Mn2+ and the activation of cGAS-STING pathway. However, excessive exposure or accumulation of Mn is harmful to the central nervous system due to its preferential Mn uptake by the brains and spinal cords. It is reported that Manganism occurs in response to acute Mn exposures, while Parkinsonism may result from long-term exposure to low levels of Mn (Martinez-Finley et al., 2013). In fact, the cellular toxicity of Mn (mainly exerted by Mn2+) has long been recognized and attributed to multiple mechanisms, nevertheless the molecular basis is still inconclusive, or even contradictory in some cases (Horning et al., 2015). In particular, elevated type I-IFNs were implicated in the development of Parkinson’s disease. In some extreme cases, type I-IFN treatment caused severe Parkinsonism that was resolved after interferon withdrawal (Mizoi et al., 1997, Sarasombath et al., 2002). We showed that Mn2+ accumulation causes prominent innate immune activation, leading to the production and secretion of cytokines. Such pathological immune activation in the central nervous system will certainly contribute to the cellular and tissue damage, culminating in Manganism and Parkinsonism. These findings therefore may provide new insights into the molecular basis underlying the development of Manganism, in which Mn-caused toxicity has long been recognized. New therapeutic attempts should focus to prevent this detrimental immune activation in the central nervous system.
In the first chapter of the Results they describe how they discovered the Mn-dependency (my bold)
During our daily experiments, we noticed repeatedly that cellular antiviral activity differed dramatically among distinct cell states under different culture conditions. We reasoned that some components in culture medium may influence such activity in cells. To search for potential factors involved, we focused on the basic components in the culture medium, including serum, carbohydrates, amino acids, vitamins, trace elements, fatty acids, and some metabolites and salts critical for cell growth. A human leukemia monocytic cell line, THP1, was pretreated with different amounts of each component for 24 hr before cells were infected with GFP-tagged vesicular stomatitis virus (VSV-GFP). After another 18 hr, cells were analyzed for viral infection by flow cytometry. The mean fluorescence intensity (MFI) of viral-GFP was used as an indicator of viral propagation (Figures S1A–S1E, concentrations of metabolite composition are listed in the Table S4). We found that Vitamin D3, a prehormone that is implicated in regulating the synthesis of hundreds of enzymes, restricted the propagation of viruses in a dose-dependent manner as indicated by the significantly reduced MFI of viral-GFP (Figure 1A, indicated by ∗), which agreed with previous reports showing that vitamin D3 is an antiviral agent against hepatitis C virus (HCV) in human hepatocytes (Abu-Mouch et al., 2011, Gal-Tanamy et al., 2011). We also found that lower concentrations of fetal bovine serum (FBS) in culture medium made otherwise unresponsive tumor cells sensitive to cytosolic dsDNA and DNA viruses and that higher FBS concentrations abrogated such sensitivity in sensitive cells (Fang et al., 2017b, Wang et al., 2017). However, we found that MnCl2-treated cells were almost completely resistant to VSV infection (Figure 1B, indicated by ∗). To confirm this result and to exclude viral type specificity, MnCl2-treated THP1 cells were infected with distinct types of GFP-expressing viruses, either DNA viruses (Herpes simplex virus 1 [HSV-1] or RNA viruses (Newcastle disease [NDV] and VSV). We found that MnCl2-pretreated cells acquired resistance to all tested viruses (Figure 1C). We next tested this virus-resistant effect by adding different concentrations of Mn and observed that THP1 cells started to gain antiviral activity when the Mn2+ level in medium reached 2 μM (Figure 1D), in which the propagation of HSV-1 and VSV was suppressed. Whereas 5 μM (for VSV) or 20 μM (for HSV-1 and NDV) of MnCl2 inhibited virus infection, 50 μM of MnCl2 essentially rendered cells complete protection from all the viruses (Figures 1D and 1E). The cytosolic Mn concentration, measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) after MnCl2 treatment, accumulated approximately to a concentration 10 times higher than that in the medium within 6–18 hr (Figure S1F). These data indicated that the elevated cytosolic manganese functions to inhibit viral infection. ...
open access
Immunity. 2018 Apr 17;48(4):675-687.e7. doi: 10.1016/j.immuni.2018.03.017. Epub 2018 Apr 10.
 
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percyval577

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Protein kinase RNA-activated (PKR) has been shown to be abnormally activated in mecfs:

Unravelling intracellular immune dysfunction in chronic fatique syndrome: Interactions between protein kinase R activity , RNase L cleavage and elastase activity , and their clinical relevance
Meeus et al 2008

Confirmed by Sweetman et al 2018 [38]. which is referred to here:

Current Research Provides Insight into the Biological Basis and Diagnostic Potential for [ME/CFS]
Sweetman et al 2019

page 6
With the same study group, we have investigated the abnormal activation of protein kinase RNA-activated (PKR) as a potential biomarker for ME/CFS. This kinase has been described as a ‘universal immunological abnormality’ in ME/CFS [52]. ME/CFS often follows an acute viral infection, suggesting that the key role PKR plays in the innate immune response to infection may be significant in ME/CFS symptomology. The efficacy of PKR as a diagnostic biomarker for ME/CFS results from the fact that PKR is phosphorylated when activated. Healthy controls had undetectable phosphorylated PKR in protein extracts of PBMC cells using an in-house affinity purified antibody (two stage purification-positive and negative affinity steps). Phosphorylated PKR (pPKR) was in contrast detected in the protein cell extracts of ME/CFS patients.


Effect of Mn on PKR mentioned here: https://www.uniprot.org/uniprot/P19525
They give also a very interesting review on its function.

Activity Regulation [my paragraphs and bold]
Initially produced in an inactive form and is activated by binding to viral dsRNA, which causes dimerization and autophosphorylation in the activation loop and stimulation of function. ISGylation can activate it in the absence of viral infection.

Can also be activated by heparin, proinflammatory stimuli, growth factors, cytokines, oxidative stress and the cellular protein PRKRA. Activity is markedly stimulated by manganese ions.

Activation is blocked by the viral components HIV-1 Tat protein and large amounts of HIV-1 trans-activation response (TAR) RNA element as well as by the cellular proteins TARBP2, DUS2L, NPM1, NCK1 and ADAR. Down-regulated by Toscana virus (TOS) and Rift valley fever virus (RVFV) NSS which promote its proteasomal degradation. Inhibited by vaccinia virus protein E3, probably via dsRNA sequestering
5 publications​


Function [my paragraphs]
IFN-induced dsRNA-dependent serine/threonine-protein kinase which plays a key role in the innate immune response to viral infection and is also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation. Exerts its antiviral activity on a wide range of DNA and RNA viruses including hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV) and herpes simplex virus 1 (HHV-1).

Inhibits viral replication via phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (EIF2S1), this phosphorylation impairs the recycling of EIF2S1 between successive rounds of initiation leading to inhibition of translation which eventually results in shutdown of cellular and viral protein synthesis. Also phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its ubiquitination and proteosomal degradation.

Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding proinflammatory cytokines and IFNs. Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6.

Can act as both a positive and negative regulator of the insulin signaling pathway (ISP). Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at 'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2 (IRS2). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes. Can trigger apoptosis via FADD-mediated activation of CASP8. Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin
24 publications​
 

Wishful

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I can't follow all that in detail, but since I believe that IFN-g, insulin, and possibly RNA transcription are involved in my ME, that line of research looks promising to me.
 

percyval577

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I don´t want to make a new thread, so I put this here, as it may be related in some way to the immune system. It may be not very important though.

The Effect of Dietry Manganese on Arterial Functional Properties
Kalea 2005


Dietary manganese affects the structure and integrity of blood vessels, as well as vessel predisposition to endothelial dysfunction and cardiovascular disease. In this thesis, we studied the role of manganese on the functional properties of rat aorta as defined by the endothelial and vascular smooth muscle cell pathways for adrenergic-mediated vasoconstriction and cholinergic-mediated vasodilation.

Weanling Sprague-Dawley rats were fed a manganese deficient (MnD), adequate (MnA-control group) or supplemented (MnS) diet (<1, 10-15 and 45-50ppm Mn respectively). After 14 weeks on the diet the aorta was excised and four aortic rings of three mm length were prepared from each animal. Alterations in vasoconstriction among diet groups were detected by dose-response curves to the ^-adrenergic agonist LPhenylephrine in endothelium-intact and endothelium-disrupted rings. Alterations in endothelium-dependent vasodilation among diet groups were determined by doseresponse curves to Acetylcholine.

We studied the mechanism by which dietary manganese affects two different endothelium-dependent vasodilation pathways: the Larginine/ nitric oxide (NO) and the cyclooxygenase (COX) pathways. Inhibition of the enzymes for NO synthesis (NOS) with L-NMMA, and of prostanoids (COX I and II) with Mefenamic acid, determination of NOS expression, and in vitro addition of L-Arginine (substrate for NO formation) to vessel rings revealed the effect of manganese on the regulation of endothelium-mediated vasodilation and vasoconstriction. Dose-response curves to sodium nitroprusside provided data for the dietary effect on endotheliumindependent vasodilation.

Supplementary dietary manganese increased adrenoreceptor-mediated vascular smooth muscle contraction, which was significantly reduced in the presence of functional endothelium. Absence of dietary manganese increased endothelial cell sensitivity to the (Xi-adrenergic vasoconstrictor agent.

Manganese had a small effect on the cGMP-pathway for dilation of vascular smooth muscle but affected vasodilation primarily through an endothelium-mediated pathway, probably by preserving NO bioavailability. Inhibition of vasodilation in Mn deficiency appears to occur through an endothelium-derived vasoconstrictor, possibly thromboxane with a concomitant decrease in the synthesis of endothelium-mediated vasodilator prostanoids.

Our results demonstrate that dietary manganese influences the contractile machinery of vascular smooth muscle cells and regulates the bioactivity of endothelium-mediated vasodilators to affect agonist-induced signaling pathways that participate in the regulation of vasomotor tone. This suggests possibilities for dietary intervention in blood pressure regulation.