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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic exposure to low levels of lead causes hypertension (HTN) in humans and animals. We have previously shown that increased reactive oxygen species (ROS) leads to enhanced NO inactivation, depressed NO bioavailability, and compensatory upregulation of NO synthases (NOSs) in rats with lead-induced HTN. We have further demonstrated increased ROS generation with lead exposure in cultured endothelial cells. In the present study, we tested the effect of lead (medium containing lead acetate, 1 ppm) alone and with either the superoxide dismutase-mimetic agent tempol or a potent antioxidant lazaroid compound (both at 10(-8) and 10(-7) mol/L) on endothelial NOS expression and NO production in cultured human coronary endothelial cells. Lead-treated cells showed a significant upregulation of endothelial NOS (eNOS) protein abundance (P:<0.002) and a significant increase in the production of NO metabolites (NO(2)(-) +NO(3)(-)=NOx, P:<0.01). Cotreatment with either tempol or lazaroid abrogated the lead-induced upregulation of eNOS protein and NO(x) production. In contrast, tempol and lazaroid had no effect on either eNOS protein expression or NO(x) production in the control cells. Thus, lead exposure upregulated eNOS expression in vitro, simulating the results of our previous in vivo studies. This phenomenon points to a direct as opposed to an indirect (eg, HTN-mediated) effect of lead on NO metabolism. The reversal of lead effect by lazaroid and the cell-permeable superoxide dismutase-mimetic agent tempol suggests that lead exposure increases generation and/or reduces dismutation of superoxide, which in turn promotes oxidative stress, enhances NO inactivation, and elicits a compensatory upregulation of eNOS whose expression is negatively regulated by NO.
Hypertension 2001 Feb
PMID:Effect of lead on nitric oxide synthase expression in coronary endothelial cells: role of superoxide. 1123 Feb 75

Lead-induced hypertension has previously been shown to be closely associated with an increase in reactive oxygen species in low lead (100 ppm)-treated rats. The present study has attempted to define the specific moiety involved by noting the blood pressure (BP), reactive oxygen species (MDA-TBA), hydroxyl radical, and nitrotyrosine responses to infusion of the reactive oxygen species scavenger dimethylthiourea. Dimethylthiourea, a reputed scavenger of hydroxyl radical, normalized BP and MDA-TBA in the lead-treated rats but had no effect in normal control animals. MDA-TBA, hydroxyl radical, and nitrotyrosine, the tissue end product of peroxynitrite, were reduced to or toward normal by dimethylthiourea. The results, therefore, are consistent with the suggestion that either hydroxyl radical or peroxynitrite may be the reactive species affected by lead.
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PMID:Lead-induced hypertension. III. Increased hydroxyl radical production. 1124 9

Lead is associated with elevated blood pressure, although the mechanism of action is unknown. Genetic differences in sodium-potassium adenosine triphosphatase (Na(+)-K(+)ATPase) could explain some of the variation in the strength of the blood pressure-blood lead relation that has been observed in previous studies. In 1996-1997, the authors studied the association of blood pressure, hypertension prevalence, and polymorphisms in the gene for the alpha 2 subunit of Na(+)-K(+)ATPase (ATP1A2) among 220 former organolead manufacturing workers from New Jersey. Subjects were genotyped for a restriction fragment length polymorphism (RFLP) on the ATP1A2 gene. The association between blood lead and blood pressure was stronger among persons who were homozygous for the variant allele. Genotype was also associated with hypertension (adjusted odds ratio = 7.7; 95% confidence interval: 1.9, 31.4). Finally, the variant allele was 1.8 times more common among African Americans than among Caucasians. The RFLP may indicate susceptibility to the effect of lead on blood pressure. Moreover, the alpha 2 gene (or a closely linked gene) may contribute to the pathophysiology of hypertension. However, because the number of subjects (especially African Americans) with the susceptible genotype in this study was small, these observations should be considered preliminary.
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PMID:Relation of alleles of the sodium-potassium adenosine triphosphatase alpha 2 gene with blood pressure and lead exposure. 1125 61

Evidence suggests that lead and selected genes known to modify the toxicokinetics of lead--namely, those for the vitamin D receptor (VDR) and delta-aminolevulinic acid dehydratase (ALAD)--may independently influence blood pressure and hypertension risk. We report the relations among ALAD and VDR genotypes, three lead dose measures, and blood pressure and hypertension status in 798 Korean lead workers and 135 controls without occupational exposure to lead. Lead dose was assessed by blood lead, tibia lead measured by X-ray fluorescence, and dimercaptosuccinic acid (DMSA)-chelatable lead. Among lead workers, 9.9% (n = 79) were heterozygous for the ALAD(2) allele, and there were no ALAD(2) homozygotes; 11.2% (n = 89) had at least one copy of the VDR B allele, and 0.5% (n = 4) had the BB genotype. In linear regression models to control for covariates, VDR genotype (BB and Bb vs. bb), blood lead, tibia lead, and DMSA-chelatable lead were all positive predictors of systolic blood pressure. On average, lead workers with the VDR B allele, mainly heterozygotes, had systolic blood pressures that were 2.7-3.7 mm Hg higher than did workers with the bb genotype. VDR genotype was also associated with diastolic blood pressure; on average, lead workers with the VDR B allele had diastolic blood pressures that were 1.9-2.5 mm Hg higher than did lead workers with the VDR bb genotype (p = 0.04). VDR genotype modified the relation of age with systolic blood pressure; compared to lead workers with the VDR bb genotype, workers with the VDR B allele had larger elevations in blood pressure with increasing age. Lead workers with the VDR B allele also had a higher prevalence of hypertension compared to lead workers with the bb genotype [adjusted odds ratio (95% confidence interval) = 2.1 (1.0, 4.4), p = 0.05]. None of the lead biomarkers was associated with diastolic blood pressure, and tibia lead was the only lead dose measure that was a significant predictor of hypertension status. In contrast to VDR, ALAD genotype was not associated with the blood pressure measures and did not modify associations of the lead dose measures with any of the blood pressure measures. To our knowledge, these are the first data to suggest that the common genetic polymorphism in the VDR is associated with blood pressure and hypertension risk. We speculate that the BsmI polymorphism may be in linkage disequilibrium with another functional variant at the VDR locus or with a nearby gene.
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PMID:Associations of blood pressure and hypertension with lead dose measures and polymorphisms in the vitamin D receptor and delta-aminolevulinic acid dehydratase genes. 1133 87

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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PMID:Compensatory up-regulation of nitric-oxide synthase isoforms in lead-induced hypertension; reversal by a superoxide dismutase-mimetic drug. 1145 31

Lead (Pb)-induced hypertension is characterized by an increase in reactive oxygen species (ROS) and a decrease in nitric oxide (NO). In the present study we evaluated the effect of L-arginine (NO precursor), dimercaptosuccinic acid (DMSA, a chelating agent and ROS scavenger), and the association of L-arginine/DMSA on tissue Pb mobilization and blood pressure levels in plumbism. Tissue Pb levels and blood pressure evolution were evaluated in rats exposed to: 1) Pb (750 ppm, in drinking water, for 70 days), 2) Pb plus water for 30 more days, 3) Pb plus DMSA (50 mg kg(-1) day(-1), p.o.), L-arginine (0.6%, in drinking water), and the combination of L-arginine/DMSA for 30 more days, and 4) their respective matching controls. Pb exposure increased Pb levels in the blood, liver, femur, kidney and aorta. Pb levels in tissues decreased after cessation of Pb administration, except in the aorta. These levels did not reach those observed in nonintoxicated rats. All treatments mobilized Pb from the kidney, femur and liver. Pb mobilization from the aorta was only effective with the L-arginine/DMSA treatment. Blood Pb concentrations in Pb-treated groups were not different from those of the Pb/water group. Pb increased blood pressure starting from the 5th week. L-arginine and DMSA treatments (4th week) and the combination of L-arginine/DMSA (3rd and 4th weeks) decreased blood pressure levels of intoxicated rats. These levels did not reach those of nonintoxicated rats. Treatment with L-arginine/DMSA was more effective than the isolated treatments in mobilizing Pb from tissues and in reducing the blood pressure of intoxicated rats.
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PMID:Effect of L-arginine, dimercaptosuccinic acid (DMSA) and the association of L-arginine and DMSA on tissue lead mobilization and blood pressure level in plumbism. 1159 11

Lead exposure elicited an increase in blood pressure and was considered to be a cardiovascular risk factor. The involvements of sympathetic nervous system and circulating catecholamines have been implicated in lead-induced hypertension. This study examined the effects of PbCl(2) on sympathetic preganglionic neurons (SPNs) in vitro and in vivo. In vitro electrophysiological study showed that superfusion of a low concentration (5 microM) of PbCl(2), which had no effects on membrane potential and spontaneous discharge rate, enhanced excitatory postsynaptic potentials (EPSPs) in some of the SPNs examined but inhibited inhibitory postsynaptic potentials (IPSPs) in other SPNs tested. A higher concentration (50 microM) of PbCl(2) inhibited both EPSPs and IPSPs in all SPNs examined. In vivo study showed that intrathecal injection of PbCl(2) (10 and 100 nmol) via an implanted cannula to the T7-T9 segments of urethane-anesthetized rats increased both the heart rate and mean arterial pressure. The pressor and tachycardic responses of intrathecal PbCl(2) (100 nmol) were attenuated by pretreatment with intravenous administration of hexamethonium (10 mg/kg) or intrathecal AP-5 (DL-2-amino-5-phosphonovaleric acid, 100 nmol), but were not significantly antagonized by prior intrathecal administration of CNQX (6-cyano-7-nitroquinoxaline-2,3-dione, 100 nmol). Taken together, these results demonstrated that lead may exert a stimulatory effect on SPNs, which may result from the enhancement of EPSPs and inhibition of IPSPs by low concentrations of lead.
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PMID:Excitatory action of lead on rat sympathetic preganglionic neurons in vitro and in vivo. 1208 63

Lead is a ubiquitous toxin, known to have adverse effects on the body even at low levels of exposure. In this review we explore whether low lead may be the principal or a major contributory cause of essential hypertension, and whether removal of lead from the environment may eventually reduce both the overall incidence of hypertension and the increased incidence with aging.
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PMID:Is lead exposure the principal cause of essential hypertension? 1220 46

Lead (Pb(2+)) has been implicated in the development of hypertension and atherosclerosis. The proliferation of vascular smooth muscle cells (VSMC) is a central feature of both conditions and there is evidence that Pb(2+) potentiates serum-dependent cell growth. The aim of this work was to examine the role of phospholipase A(2) in mitogen-dependent VSMC proliferation and determine if Pb(2+) interacts with this system in order to potentiate mitotic events. It was observed that cell proliferation induced by angiotensin II, or fetal bovine serum, required the activation of a Ca(2+)-dependent cytosolic phospholipase A(2) and the subsequent release of unesterified arachidonic acid. This path was affected by Pb(2+) as the metal increased the amount of arachidonic acid accumulation induced by either mitogen. In addition, Pb(2+) potentiated mitogen-induced DNA synthesis when present at lower doses (0.02 or 0.2 mg%), but had no effect on DNA synthesis, or cell numbers, in unstimulated cells. However, a high dose (2 mg%) of Pb(2+) attenuated the DNA synthesis stimulated by angiotensin II, or serum, but induced the accumulation of unesterified arachidonic acid in unstimulated cells. A biphasic effect of Pb(2+) on cell numbers and viability was also observed as 0.02 or 0.2 mg% Pb(2+) did not affect cell numbers or trypan blue exclusion in unstimulated cells, while 2 mg% Pb(2+) reduced cell numbers and viability. It appeared, therefore, that the lower concentrations of Pb(2+) increased arachidonic acid release and DNA synthesis only in stimulated VSMC, perhaps due to further activation of a Ca(2+)-dependent processes. In contrast, the high dose of Pb(2+) reduced DNA synthesis in stimulated cells and reduced cell numbers and viability in unstimulated cells, which may relate to the noted increase in unesterified arachidonic acid.
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PMID:Lead-dependent effects on arachidonic acid accumulation and the proliferation of vascular smooth muscle. 1243 66

Chronic exposure to inorganic lead (Pb2+) has been shown to facilitate peripheral vasoconstriction causing hypertension. Effect of lead on cerebral vascular function has not been reported. We have suggested in isolated porcine cerebral arteries that alpha 7-nicotinic acetylcholine receptors (alpha 7-nAChRs) on perivascular sympathetic nerves mediate calcium influx in these neurons, resulting in release of norepinephrine. The released norepinephrine then acts on presynaptic beta2-adrenoceptors located on the neighboring nitrergic nerve terminals, causing nitric oxide (NO) release and vasodilation. Because Pb2+ has been shown to inhibit alpha 7-nAChR-mediated responses in the central nervous system, effects of Pb2+ on alpha 7-nAChR-mediated nitrergic neurogenic dilation in isolated porcine basilar arteries and calcium influx in cultured superior cervical ganglion (SCG) cells of the pig were examined using in vitro tissue bath and confocal microscopic techniques. The results indicated that Pb2+ (but not Cd2+, Zn2+, or Al3+) in a concentration-dependent manner blocked relaxation of endothelium-denuded basilar arterial rings induced by nicotine (100 microM) and choline (1 mM) without affecting relaxation induced by sodium nitroprusside or isoproterenol. Furthermore, significant calcium influx in cultured SCG cells induced by choline and nicotine was attenuated specifically by Pb2+ with IC50 values comparable with those from tissue bath study. These results provide evidence supporting that lead is a likely antagonist for alpha 7-nAChRs that are found on postganglionic sympathetic adrenergic nerve terminals of SCG origin. Furthermore, these results indicate that lead can attenuate dilation of cerebral arteries by blocking sympathetic nerve-mediated release of NO from the perivascular nitrergic nerves.
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PMID:Pb2+ inhibition of sympathetic alpha 7-nicotinic acetylcholine receptor-mediated nitrergic neurogenic dilation in porcine basilar arteries. 1262 57


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