Interaction of heavy metal toxicants with brain constitutive nitric oxide synthase

Mittal, Chandra K.; Harrell, William B.; Mehta, Chander S.

doi:10.1007/978-1-4615-2015-3_29

Cited by 24 publications

(19 citation statements)

References 10 publications

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“…15 These observations were confirmed by results of the present study, which demonstrated significant inhibition of NOS activity at lead acetate concentrations Ն10 g/dL. It should be noted that according to our previous studies, plasma lead concentration in this model is 10 g/dL and, as such, is sufficient to partially inhibit NOS activity in vivo.…”

Section: Discussionsupporting

confidence: 91%

Nitric Oxide Synthase Expression in the Course of Lead-Induced Hypertension

Vaziri

Ding

1999

Hypertension

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Abstract-We recently showed elevated reactive oxygen species (ROS), reduced urinary excretion of NO metabolites (NOx), and increased NO sequestration as nitrotyrosine in various tissues in rats with lead-induced hypertension. This study was designed to discern whether the reduction in urinary NOx in lead-induced hypertension is, in part, due to depressed NO synthase (NOS) expression. Male Sprague-Dawley rats were randomly assigned to a lead-treated group (given lead acetate, 100 ppm, in drinking water and regular rat chow), a group given lead and vitamin E-fortified chow, or a normal control group given either regular food and water or vitamin E-fortified food for 12 weeks. Tail blood pressure, urinary NOx excretion, plasma malondialdehyde (MDA), and endothelial and inducible NOS (eNOS and iNOS) isotypes in the aorta and kidney were measured. The lead-treated group exhibited a rise in blood pressure and plasma MDA concentration, a fall in urinary NOx excretion, and a paradoxical rise in vascular and renal tissue eNOS and iNOS expression. Vitamin E supplementation ameliorated hypertension, lowered plasma MDA concentration, and raised urinary NOx excretion while significantly lowering vascular, but not renal, tissue eNOS and iNOS expression. Vitamin E supplementation had no effect on either blood pressure, plasma MDA, or NOS expression in the control group. The study also revealed significant inhibition of NOS enzymatic activity by lead in cell-free preparations. In conclusion, lead-induced hypertension in this model was associated with a compensatory upregulation of renal and vascular eNOS and iNOS expression. This is, in part, due to ROS-mediated NO inactivation, lead-associated inhibition of NOS activity, and perhaps stimulatory actions of increased shear stress associated with hypertension. (Hypertension. 1999;34:558-562.)Key Words: lead Ⅲ hypertension, lead-induced Ⅲ free radicals Ⅲ nitric oxide Ⅲ vitamins Ⅲ antioxidants Ⅲ lipids P rolonged exposure to low levels of lead causes systemic hypertension in humans and laboratory animals. [1][2][3][4][5] In a series of recent studies, we showed that elevation of blood pressure in rats with lead-induced hypertension is accompanied by a marked increase in plasma and tissue lipid peroxidation product, an increase in malondialdehyde (MDA), and a substantial reduction in urinary excretion of stable NO metabolites (NOx). 4 -6 On the basis of these findings, we hypothesized that lead-induced hypertension in this model may be due, in part, to enhanced NO inactivation by reactive oxygen species (ROS). In support of this proposition, we demonstrated marked amelioration of hypertension together with normalization of plasma MDA concentration and urinary NOx excretion with a variety of antioxidants, including des-methyltirilazad, 4 dimercaptosuccinic acid, 6 and vitamin E, 7 with this model.The reduction in urinary NOx excretion, which is consistently found in this model, 4,6 may be due to either diminished NO production and/or enhanced NO sequestration. With respect to the la...

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Section: Discussionsupporting

confidence: 91%

Nitric Oxide Synthase Expression in the Course of Lead-Induced Hypertension

Vaziri

Ding

1999

Hypertension

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“…It is well established that chronic lead exposure induces the production or release of endothelin, a powerful vasoconstrictor (19), inhibits the production or release of a hyperpolarizing factor (26) and reduces the release or production of NO (21,27). The combination of these lead-induced effects might increase vascular tonus and consequently blood pressure.…”

Section: Discussionmentioning

confidence: 99%

Acute lead-induced vasoconstriction in the vascular beds of isolated perfused rat tails is endothelium-dependent

Silveira

Lizardo

Souza

et al. 2010

Braz J Med Biol Res

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Chronic lead exposure induces hypertension in humans and animals, affecting endothelial function. However, studies concerning acute cardiovascular effects are lacking. We investigated the effects of acute administration of a high concentration of lead acetate (100 µΜ) on the pressor response to phenylephrine (PHE) in the tail vascular bed of male Wistar rats. Animals were anesthetized with sodium pentobarbital and heparinized. The tail artery was dissected and cannulated for drug infusion and mean perfusion pressure measurements. Endothelium and vascular smooth muscle relaxation were tested with acetylcholine (5 µg/100 µL) and sodium nitroprusside (0.1 µg/100 µL), respectively, in arteries precontracted with 0.1 µM PHE. Concentrationresponse curves to PHE (0.001-300 µg/100 µL) were constructed before and after perfusion for 1 h with 100 µΜ lead acetate. In the presence of endothelium (E + ), lead acetate increased maximal response (E max ) (control: 364.4 ± 36, Pb 2+ : 480.0 ± 27 mmHg; P < 0.05) and the sensitivity (pD 2 ; control: 1.98 ± 0.07, 2.38 ± 0.14 log mM) to PHE. In the absence of endothelium (E -) lead had no effect but increased baseline perfusion pressure (E + : 79.5 ± 2.4, E -: 118 ± 2.2 mmHg; P < 0.05). To investigate the underlying mechanisms, this protocol was repeated after treatment with 100 µM L-NAME, 10 µM indomethacin and 1 µM tempol in the presence of lead. Lead actions on E max and pD 2 were abolished in the presence of indomethacin, and partially abolished with L-NAME and tempol. Results suggest that acute lead administration affects the endothelium, releasing cyclooxygenasederived vasoconstrictors and involving reactive oxygen species.

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“…Earlier studies in mammals showed that Cd inhibits activity of Ca 2+ -dependent constitutive NOS, likely due to the competitive displacement of Ca 2+ from calmodulin (Mittal et al, 1995;Weaver et al, 2002;Weaver et al, 2004). Such direct inhibition by Cd may explain the observed decline in NOS activity in oyster cells incubated for a short time (24h) at high concentrations of ).…”

Section: Nos Activity and No Metabolism During Environmental Stressmentioning

confidence: 92%

Effects of cadmium exposure and intermittent anoxia on nitric oxide metabolism in eastern oysters,Crassostrea virginica

Ivanina

Eilers

Kurochkin

et al. 2010

Journal of Experimental Biology

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SUMMARY Nitric oxide (NO) is an intracellular signaling molecule synthesized by a group of enzymes called nitric oxide synthases (NOS)and involved in regulation of many cellular functions including mitochondrial metabolism and bioenergetics. In invertebrates, the involvement of NO in bioenergetics and metabolic responses to environmental stress is poorly understood. We determined sensitivity of mitochondrial and cellular respiration to NO and the effects of cadmium (Cd) and intermittent anoxia on NO metabolism in eastern oysters, Crassostrea virginica. NOS activity was strongly suppressed by exposure to 50gl -1 Cd for 30days (4.76 vs 1.19pmol NO min -1 mg -1 protein in control and Cd-exposed oysters, respectively) and further decreased during anoxic exposure in Cd-exposed oysters but not in their control counterparts. Nitrate/nitrite content (indicative of NO levels) decreased during anoxic exposure to less than 10% of the normoxic values and recovered within 1h of re-oxygenation in control oysters. In Cd-exposed oysters, the recovery of the normoxic NO levels lagged behind, reflecting their lower NOS activity. Oyster mitochondrial respiration was inhibited by exogenous NO, with sensitivity on a par with that of mammalian mitochondria, and ADP-stimulated mitochondrial respiration was significantly more sensitive to NO than resting respiration. In isolated gill cells, manipulations of endogenous NOS activity either with a specific NOS inhibitor (aminoguanidine) or a NOS substrate (L-arginine) had no effect on respiration, likely due to the fact that mitochondria in the resting state are relatively NO insensitive. Likewise, Cdinduced stimulation of cellular respiration did not correlate with decreased NOS activity in isolated gill cells. High sensitivity of phosphorylating (ADP-stimulated) oyster mitochondria to NO suggests that regulation of bioenergetics is an evolutionarily conserved function of NO and that NO-dependent regulation of metabolism may be most prominent under the conditions of high metabolic flux when the ADP-to-ATP ratio is high. Supplementary material available online at

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Interaction of heavy metal toxicants with brain constitutive nitric oxide synthase

Cited by 24 publications

References 10 publications

Nitric Oxide Synthase Expression in the Course of Lead-Induced Hypertension

Nitric Oxide Synthase Expression in the Course of Lead-Induced Hypertension

Acute lead-induced vasoconstriction in the vascular beds of isolated perfused rat tails is endothelium-dependent

Effects of cadmium exposure and intermittent anoxia on nitric oxide metabolism in eastern oysters,Crassostrea virginica

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