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CADMIUM, ARGININE, NITRIC OXIDE STORY

If you've stumbled onto this page, it may not make a lot of sense. It doesn't to me yet. However, I have a feeling that there is something in the connections between cadmium (and maybe bismuth), arginine, and nitric oxide. Cadmium seems to be a very critical metal in thyroid function and dysfunction. Nitric oxide is the gas which causes migraines and is also the gas which causes male erections (hyper sex drive). There are a lot of pieces to put together and I'm in the process of accumulating studies at this point.

In the first study IBD is a condition which is associated with hyperT.

Gut 2000 Dec;47(6):771-8

Inhibition of inducible nitric oxide synthase in the human intestinal epithelial cell line, DLD-1, by the inducers of heme oxygenase 1, bismuth salts, heme, and nitric oxide donors.

Cavicchi M, Gibbs L, Whittle BJ

William Harvey Research Institute, St Bartholomew's and the Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK.

[Medline record in process]

BACKGROUND: The inducible isoform of nitric oxide synthase (iNOS) may be involved in the mucosal injury associated with inflammatory bowel disease (IBD). In contrast with iNOS, the inducible heme oxygenase 1 (HO-1) is considered to act as a protective antioxidant system. AIMS: To evaluate the effects of the known HO-1 inducers, cadmium and bismuth salts, heme, and nitric oxide (NO) donors, on iNOS activity, and expression in the human intestinal epithelial cell line DLD-1. METHODS: iNOS activity was assessed by the Griess reaction and the radiochemical L-arginine conversion assay. iNOS mRNA and iNOS protein expression were determined by northern and western blotting, respectively. RESULTS: Cytokine exposure led to induction of iNOS activity, iNOS mRNA, and iNOS protein expression. Preincubation of DLD-1 cells with heme (1-50 &mgr;M) inhibited cytokine induced iNOS activity in a concentration dependent manner. This inhibitory effect was abolished by the HO-1 specific inhibitor tin protoporphyrin. Preincubation with NO donors sodium nitroprusside (SNP 1-1000 &mgr;M) or S-nitroso-acetyl-penicillamine (SNAP 1-1000 &mgr;M), or with the heavy metals cadmium chloride (10-40 &mgr;M), bismuth citrate, or ranitidine bismuth citrate (10-3000 &mgr;M) inhibited iNOS activity in a concentration dependent manner. Moreover, SNP and heme abolished cytokine induced iNOS protein as well as iNOS mRNA expression, whereas cadmium chloride did not modify iNOS protein expression. CONCLUSIONS: Heme, the heavy metals cadmium and bismuth, as well as NO donors, are potent inhibitors of cytokine induced iNOS activity. Heme and NO donors act at the transcriptional level inhibiting iNOS mRNA expression. Such findings suggest the potential for interplay between the iNOS and HO-1 systems, which may modulate the progress of IBD.

In the following study it is found that cadmium reduces nitric oxide (NO) formation by inhibiting the enzyme NO synthase. NO decreases blood pressure so the effect of cadmium in decreasing NO is to cause high blood pressure.

I am thinking now that there is an excess of nitric oxide in hyperT. If this is true does that mean there may be a deficiency of cadmium in  hyperT? That would be strange.

 

Br J Pharmacol 1998 Jan;123(1):129-35

Role of nitric oxide synthase inhibition in the acute hypertensive response to intracerebroventricular cadmium.

Demontis MP, Varoni MV, Volpe AR, Emanueli C, Madeddu P

Clinica Farmacologia, University of Sassari, Italy.

1. In the rat, intracerebroventricular (i.c.v.) injection of cadmium, a pollutant with long biological half-life, causes a sustained increase in blood pressure at doses that are ineffective by peripheral route. Since cadmium inhibits calcium-calmodulin constitutive nitric oxide (NO) synthase in cytosolic preparations of rat brain, this mechanism may be responsible for the acute pressor action of this heavy metal. 2. To test this possibility, we evaluated the effect of i.c.v. injection of 88 nmol cadmium in normotensive unanaesthetized Wistar rats, which were i.c.v. pre-treated with: (1) saline (control), (2) L-arginine (L-Arg), to increase the availability of substrate for NO biosynthesis, (3) D-arginine (D-Arg), (4) 3-[4-morpholinyl]-sydnonimine-hydrochloride (SIN-1), an NO donor, or (5) CaCl2, a cofactor of brain calcium-calmodulin-dependent cNOS(I). In additional experiments, the levels of L-citrulline (the stable equimolar product derived from enzymatic cleavage of L-Arg by NO synthase) were determined in the brain of vehicle- or cadmium-treated rats. 3. The pressor response to cadmium reached its nadir at 5 min (43+/-4 mmHg) and lasted over 20 min in controls. L-Citrulline/protein content was reduced from 35 up to 50% in the cerebral cortex, pons, hippocampus, striatus, hypothalamus (P<0.01) of cadmium-treated rats compared with controls. Central injection of N(G) nitro-L-arginine-methylester (L-NAME) also reduced the levels of L-citrulline in the brain. 4. Both the magnitude and duration of the response were attenuated by 1.21 and 2.42 micromol SIN-1 (32+/-3 and 15+/-4 mmHg, P<0.05), or 1 micromol CaCl2 (6+/-4 mmHg, P<0.05). Selectivity of action exerted by SIN-1 was confirmed by the use of another NO donor, S-nitroso-N-acetyl-penicillamine (SNAP). Both L-Arg and D-Arg caused a mild but significant attenuation in the main phase of the pressor response evoked by cadmium. However, only L-Arg reduced the magnitude of the delayed, pressor response. Despite their similarity in ability to attenuate the cadmium-induced pressure effect, L-Arg and its isomer exerted differential biochemical changes in brain L-citrulline, as L-Arg normalized cadmium-induced reduction in L-citrulline levels, whereas i.c.v. D-Arg did not. 5. We conclude that the pressor effect of i.c.v. cadmium is due, at least in part, to reduced NO formation, consequent to inhibition of brain NO synthase. Accumulation of cadmium in the central nervous system could interfere with central mechanisms (including NO synthase) implicated in the regulation of cardiovascular function.

 

Toxicol Appl Pharmacol 1996 Dec;141(2):540-7

Metal-induced modulation of nitric oxide production in vitro by murine macrophages: lead, nickel, and cobalt utilize different mechanisms.

Tian L, Lawrence DA

Wadsworth Center, Albany, New York 12201-0509, USA.

Macrophages (M phi) can be induced to produce nitric oxide (NO), which has been suggested to be important for macrophages to exercise various functions. We have previously reported that an environmental toxicant, lead (Pb), can significantly inhibit NO production by murine splenic M phis. Herein, eight additional metal ions, gold (Au), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), mercury (Hg), nickel (Ni), and zinc (Zn), were assessed. In addition to Pb, Hg and Cd significantly suppressed NO production by cytokine (interferon-gamma and tumor necrosis factor-alpha)-stimulated murine M phis. Au and Cu also were inhibitory, but less than Pb, Hg, and Cd. In contrast, Cr and Zn were not modulatory, and Ni and Co significantly enhanced NO production by cytokine-stimulated M phis. The enhancement by Ni and Co was inhibited by the arginine analog N-monomethylarginine. The metals showed different activating/inhibiting profiles when added to a cell-free (activated M phi lysate) NO-producing-system in which inducible NO synthase (iNOS) is already expressed. Cr, Cu, Pb, and Zn moderately suppressed iNOS, which suggests that they may directly modify enzyme or cofactor activity. Cd, Hg, Mg, Ni, or Co did not produce any significant effect on NO production by the cell-free system. Inhibition of NO production by Pb-exposed M phis was not due to decreased expression of iNOS nor limited to its modest direct inhibition of iNOS; thus, other mechanism(s) must be accountable for the efficient Pb-induced inhibition of NO production by M phi. Ni or Co did induce a substantial increase of iNOS protein. Overall, these observations provide additional insight into the means by which metals via inhibition or enhancement of NO production may be pathogenic, by suppression of defense mechanisms or induction of hypersensitivity, respectively.

 

Mol Cell Biochem 1995 Aug-Sep;149-150:263-5

Interaction of heavy metal toxicants with brain constitutive nitric oxide synthase.

Mittal CK, Harrell WB, Mehta CS

Division of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston 77004, USA.

This study was designed to evaluate the in vitro effects of transition heavy metal cations on activity of constitutive isoform of nitric oxide synthase (cNOS) in rat brain. NOS activity was determined in the cytosolic fractions of rat cerebral hemispheres by conversion of 3H-L-arginine to 3H-L-citrulline. Different concentrations of mercury (Hg2+), nickel (Ni2+), manganese (Mn2+), zinc (Zn2+), cadmium (Cd2+), lead (Pd2+) and calcium (Ca2+) were tested on NOS activity. While all the cations caused inhibition, there were differences in the apparent inhibition constants (Ki) among the cations. With the exception of calcium ion no other cation required preincubation with the enzyme preparation. These results indicate that while calcium ion modulate cNOS activity at regulatory site(s), inhibitory influence of toxic heavy metal cations may be exerted on the catalytic site(s) either by direct binding to it or by interfering with the electron transfer during catalysis.

 

Biol Trace Elem Res 2000 Nov;77(2):97-106

Tissue and blood levels of zinc, copper, and magnesium in nitric oxide synthase blockade-induced hypertension.

Senturk UK, Kaputlu 1, Gunduz F, Kuru O, Gokalp O

Department of Physiology, Akdeniz University Faculty of Medicine, Antalya, Turkey.

[Medline record in process]

The aim of this study was to determine the levels of tissue and blood zinc (Zn), copper (Cu), magnesium (Mg) in nitric oxide (NO) synthase blockade-induced hypertension. A group of albino rats received a NO synthase inhibitor, N(G)-nitro-L-arginine-methyl ester (L-NAME, 60 mg/kg/d) in their drinking water for 21 d. L-NAME intake caused a progressive rise in this group's resting mean arterial blood pressure compared to a control group (p < 0.01). There were no differences between the groups with regard to tissue and blood levels of Zn or Cu; however, Mg concentrations were significantly lower in the hypertensive rats' erythrocytes (20.2% reduction from control levels), cerebral cortex (17.0%), heart (9.1%), renal cortex (12%), renal medulla (16.7%), and in the tissues of the caval vein (23.7%), mesenteric artery (29.8%), renal artery (18.4%), and renal vein (22.1%). There were no significant Mg concentration changes in the hypertensive group's plasma, cerebellum, liver, duodenum, or aortal tissue. These findings suggest that Mg depletion may play a role in the blood pressure rise that occurs in the model of chronic NO synthase inhibition-induced hypertension.

 

J Biol Chem 2000 Jul 14;275(28):21241-6

Inhibitory effects of nitric oxide and nitrosative stress on dopamine-beta-hydroxylase.

Zhou X, Espey MG, Chen JX, Hofseth LJ, Miranda KM, Hussain SP, Wink DA, Harris CC

Laboratory of Human Carcinogenesis, Radiation Biology Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.

Dopamine-beta-hydroxylase (DbetaH) is a copper-containing enzyme that uses molecular oxygen and ascorbate to catalyze the addition of a hydroxyl group on the beta-carbon of dopamine to form norepinephrine. While norepinephrine causes vasoconstriction following reflex sympathetic stimulation, nitric oxide (NO) formation results in vasodilatation via a guanylyl cyclase-dependent mechanism. In this report, we investigated the relationship between NO and DbetaH enzymatic activity. In the initial in vitro experiments, the activity of purified DbetaH was inhibited by the NO donor, diethylamine/NO (DEA/NO), with an IC(50) of 1 mm. The inclusion of either azide or GSH partially restored DbetaH activity, suggesting the involvement of the reactive nitrogen oxide species, N(2)O(3). Treatment of human neuroblastoma cells (SK-N-MC) with diethylamine/NO decreased cellular DbetaH activity without affecting their growth rate and was augmented by the depletion of intracellular GSH. Co-culture of the SK-N-MC cells with interferon-gamma and lipopolysaccharide-activated macrophages, which release NO, also reduced the DbetaH activity in the neuroblastoma cells. Our results are consistent with the hypothesis that nitrosative stress, mediated by N(2)O(3), can result in the inhibition of norepinephrine biosynthesis and may contribute to the regulation of neurotransmission and vasodilatation.

 

Endothelium 2000;7(2):83-92

Endothelial cell calcium mobilization to acetylcholine is attenuated in copper-deficient rats.

Schuschke DA, Falcone JC, Saari JT, Fleming JT, Percival SS, Young SA, Pass JM, Miller FN

Center for Applied Microcirculatory Research, University of Louisville School of Medicine, KY 40292, USA. DASCHU01@GWISE.LOUISVILLE.EDU

Dietary copper deficiency significantly attenuates nitric oxide (NO)-mediated vascular smooth muscle relaxation and vasodilation. There is evidence for both increased inactivation of the NO radical by superoxide anion, and oxidative damage to the endothelium where NO is produced. The current study was designed to examine the NO synthetic pathway in the endothelium during copper deficiency. Male weanling rats were fed a copper-adequate (CuA, 6.4 mg Cu/kg diet) or copper-deficient (CuD, 0.4 mg Cu/kg diet) diet for four weeks. Cremasteric arterioles (approximately 100 microm diameter) were isolated and used for the experiments. Western blot analysis of the arteriole endothelial nitric oxide synthase (eNOS) concentration did not show a difference between dietary groups. Acetylcholine (Ach)-induced vasodilation was significantly reduced in the CuD group both before and after pretreatment with the eNOS substrate L-arginine. Endothelial intracellular calcium ([Ca2+]i) stimulated by 10(-6) M Ach was significantly inhibited in the arterioles from CuD rats. Coincident with the inhibition of [Ca2+]i and vasodilation was a depression of vascular Cu/Zn-SOD activity and an increase in plasma peroxynitrite activity. These data suggest that endothelial Ca2+ signaling and agonist-stimulated NO-mediated vascular dilation are likely reduced by increased oxidative damage in copper-deficient rats.

 

J Protein Chem 2000 Jan;19(1):51-7

Arginine and ornithine oxidation catalyzed by lentil seedling copper-amine oxidase.

Medda R, Padiglia A, Lorrai A, Finazzi Agro A, Floris G

Department of Sciences Applied to Biosystems, University of Cagliari, Italy.

[Medline record in process]

The oxidation of L-ornithine and L-arginine catalyzed by lentil (Lens esculenta) seedling copper-amine oxidase has been investigated by polarographic techniques, optical spectroscopy, and capillary electrophoresis. Both L-ornithine and L-arginine were found to be poor substrates for lentil amine oxidase. L-Ornithine was oxidized to glutamate-5-semialdehyde and ammonia, in similar manner as usual substrates. Glutamate-5-semialdehyde spontaneously cyclizes to delta1-pyrroline-5-carboxylic acid. Arginine is oxidized by an unusual mechanism yielding glutamate-5-semialdehyde, ammonia, and urea as reaction products.