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  • Title: Compensatory up-regulation of nitric-oxide synthase isoforms in lead-induced hypertension; reversal by a superoxide dismutase-mimetic drug.
    Author: Vaziri ND, Ding Y, Ni Z.
    Journal: J Pharmacol Exp Ther; 2001 Aug; 298(2):679-85. PubMed ID: 11454931.
    Abstract:
    Chronic exposure to low levels of lead causes hypertension (HTN) that is, in part, due to increased inactivation of nitric oxide (NO) by reactive oxygen species (ROS). The latter results in functional NO deficiency and compensatory up-regulation of NO synthase (NOS). We have previously shown evidence for increased hydroxyl radical (*OH) activity in rats with lead-induced HTN. Since in the biological systems *OH is primarily derived from superoxide (O2*) we hypothesize that lead-induced oxidative stress and HTN must be due to increased O2* production and as such could be ameliorated by administration of a cell-permeable O2* scavenger. We, therefore, studied the effects of the superoxide dismutase (SOD)-mimetic drug tempol (15 mmol/kg/day i.p. x 2 weeks) and placebo in lead-exposed (given lead acetate, 100 ppm in the drinking water for 12 weeks) and normal control rats. Lead exposure resulted in a marked elevation of blood pressure, a significant reduction in urinary NO metabolites (NO(chi)) excretion, and up-regulations of endothelial and inducible NOS abundance in the kidney, aorta, and heart and of neuronal NOS in the cerebral cortex and brain stem. Administration of tempol ameliorated HTN, increased urinary NO(chi) excretion, and reversed the compensatory up-regulation of NOS isoforms in rats with lead-induced HTN. These abnormalities recurred within 2 wk after discontinuation of tempol. In contrast to the lead-exposed rats, the normal control rats showed no change in either blood pressure, urinary NO(chi) excretion, or tissue NOS expression in response to either administration or discontinuation of tempol. Thus, the study supports the presence of increased O2* activity and its role in the pathogenesis of HTN and altered NO metabolism in lead-exposed animals.
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