Lead-induced Hypertension Research Articles

Altered nitric oxide metabolism and increased oxygen free radical activity in lead-induced hypertension: Effect of lazaroid therapy

Chronic exposure to low levels of lead results in sustained hypertension (HTN) in humans and experimental animals. The mechanism of lead-induced HTN remains unclear. We investigated the possible role of reactive oxygen species (ROS) and their impact on nitric oxide (NO) metabolism in lead-induced HTN. Male Sprague-Dawley rats were treated with lead (100 ppm in drinking water) for twelve weeks. They were then treated with either the potent antioxidant, lazaroid (des-methyl-tirilazad, 5 mg/kg i.p., twice daily) (Pb-Lz group) or placebo (Pb group) for two weeks and monitored for an additional two weeks. A group of normal animals served as controls (N = 6 in each group). Lead administration resulted in marked HTN together with a significant rise in plasma concentration of lipid peroxidation product, malondialdehyde (MDA, reflecting increased ROS generation) and a twofold reduction in urinary excretion of NO metabolites, that is, total nitrates and nitrites (NOx). Lazaroid therapy led to prompt normalization of blood pressure, plasma MDA and urinary NOx. In contrast, blood pressure and plasma MDA remained elevated, and recovery of urinary NOx excretion was slow with placebo therapy. No significant difference was found in creatinine clearance between the study groups during the observation period. Thus, chronic lead exposure resulted in marked HTN coupled with increased ROS production and decreased urinary NOx excretion. Administration of the potent antioxidant, lazaroid, abrogated HTN and reversed the abnormalities of plasma MDA and urinary NOx excretion, thus supporting the role of ROS in lead-induced HTN in this model.

Lead-induced hypertension is not associated with altered vascular reactivity in vitro.

In confirmation of a previous study (Am J Hypertens 1993;6:723), mean arterial blood pressure (MBP), as determined by tail cuff plethysmography, was found to be significantly elevated in Sprague-Dawley rats after 3 months of feeding 0.48 mmol/L (100 ppm) lead acetate/day (144 +/- 3.3 [SEM], in lead-treated [L] v 107 +/- 3.3 mm Hg in controls [C], P < .001). Thoracic aorta was excised from L and C animals (n = 6). Segments were suspended in tissue baths with Krebs' bicarbonate solution, then tested sequentially for vasoreactivity to 68 mmol/L K+, followed by graded concentrations of phenylephrine (PE), 0.01 to 0.3 micromol/L, acetylcholine (Ach), 0.001 to 3 micromol/L, nitroprusside (SNP), 0.0001 to 0.1 micromol/L, norepinephrine (NE), 0.001 to 300 micromol/L. There were no differences between L and C animals with respect to either vasoconstrictors (PE and NE) or vasodilators (Ach and SNP). The tissue levels of cGMP measured with and without phosphodiesterase inhibition, and in the absence and presence of either Ach or SNP, were comparable in the two groups. We conclude that the intrinsic vascular responsiveness is unchanged in lead-treated animals. The elevation of MBP is due to the presence of circulating factor(s) and hemodynamic changes.

Lead-induced hypertension is not associated with altered vascular reactivity in vitro

Lead-induced hypertension is not associated with altered vascular reactivity in vitro

Lead-induced hypertension is related to accumulation of reactive oxygen species

Lead-induced hypertension is related to accumulation of reactive oxygen species

Lead acetate-induced contraction in rabbit mesenteric artery: Interaction with calcium and protein kinase C

Animal studies have demonstrated that low-level lead exposure produces hypertension and that lead can cause contraction of vascular smooth muscle directly. The physiological effects of lead have been associated with both stimulation and inhibition of protein kinase C (PKC). Given that vascular smooth muscle contractility is generally enhanced when protein kinase C is activated, we have tested the hypothesis that lead contracts vascular smooth muscle via stimulation of PKC. Helically-cut strips of rabbit mesenteric artery were mounted in muscle baths for measurement of isometric force development. Cumulative addition of lead acetate (10 −10–10 −3 M) to the muscle bath produced contractions (concentration necessary to produce half-maximal response −log EC 50 = 5.16 ± 0.07). Maximal contraction to lead acetate in arteries denuded of endothelium did not differ from those in intact vessels, supporting the hypothesis that lead-induced contraction is an endothelium-independent event. Contractions to lead acetate were potentiated by the PKC activators, phorbol 12-myristate 13-acetate (TPA; 3 × 10 −7 M) and mezerein (3 × 10 −7 M), as indicated by leftward shifts in the concentration-response curve and increase in the potency of lead (−log EC 50 with TPA: 6.94 ± 0.07; −log EC 50 with mezerein: 6.07 ± 0.04). H-7 (6 × 10 −6 M), an inhibitor of PKC, decreased maximal contraction to lead ~65% and slightly, but insignificantly, decreased the potency of lead (−log EC 50 = 4.82 ± 0.1). The inactive phorbol ester, phorbol 12-myristate 13-acetate 4-0-methyl ether (1 × 10 −6 M), did not alter contractile responses to lead (−log EC 50 = 4.92 ± 0.09). Vascular contraction to lead partially depends on extracellular calcium as the L-type voltage-gated calcium channel antagonist, verapamil (3 × 10 −6 M), decreased leadinduced contractions by 50%. These data indicate that lead interacts with PKC in an endothelium-independent, calcium-dependent manner to cause vascular smooth muscle contraction and suggest that lead-induced increases in vascular contractility may play a role in lead-induced hypertension.

Lead-induced hypertension: possible role of endothelial factors.

The results of this study confirm that low lead (0.01%) but not high lead (0.5%) administration results in increased blood pressure in rats treated for up to 12 months. This effect appeared to be related to an imbalance of endothelially-derived vasoconstrictor and vasodilator compounds in low lead-treated animals but not in high lead-treated animals. In low lead-treated rats, measurement of plasma endothelins 1 and 3 (ET-1 and ET-3) revealed that ET-3 concentration increased significantly after both 3 months (Experimental, 92.1 +/- 9.7 v Control, 46.7 +/- 12.0 pmol/mL; P < .001) and 12 months (Experimental, 105.0 +/- 9.3 v Control, 94.1 +/- 5.0 pmol/mL; P < .01) while ET-1 was unaffected. Plasma and urinary cGMP concentrations (as a reflection of endothelium-derived relaxing factor (EDRF)) decreased significantly at 3 months (plasma, Experimental, 1.8 +/- 0.9 v Control, 4.2 +/- 1.6 pmol/mL; P < .001) and 12 months (plasma, Experimental, 2.2 +/- 0.7 v Control, 4.2 +/- 0.9 pmol/mL; P < .001). Thus, the path to development of hypertension in low lead rats may be through an increase in the concentration of the vasoconstrictor hormone, ET-3, and a decrease in the vasodilator hormone, EDRF. High levels of lead exposure did not result in hypertension, perhaps because plasma concentrations of ET-1, ET-3 and cGMP were unaltered at 3 months, while ET-1, ET-3 and cGMP concentrations were coordinately and significantly decreased at 12 months.

Rapid hypertensinogenic effect of lead: studies in the spontaneously hypertensive rat.

Chronic lead exposure may cause hypertension in normotensive rats. This hypertensinogenic effect has been attributed to perturbations in the renin-angiotensin axis, the contractile response of the vascular smooth muscle, or the intracellular Ca2+ homeostasis as a consequence of the inhibition of Na(+)-K(+)-ATPase activity. In this study we examined the short-term effect of lead exposure on blood pressure, plasma renin activity, vascular contractility, and renal Na(+)-K(+)-ATPase activity and abundance in the spontaneously hypertensive rat. Our data indicate that modest lead exposure caused blood pressure elevation within two weeks in this rat strain that is genetically susceptible to the development of hypertension. This rapid blood pressure-elevating effect did not appear to depend on the mechanisms described in hypertension associated with more chronic lead exposure listed above. This acute model provides an additional approach to the study of lead-induced hypertension.

19F-NMR study of the effect of lead on intracellular free calcium in human platelets

Lead has been shown to affect calcium homeostasis. However, there is no prior evidence to indicate an effect of low concentrationsof lead in the environment (≈1 μM) on the intracellular free Ca 2+ concentration in any human tissue. We have investigated the effect of lead on the intracellular free Ca 2+ concentration of human blood platelets using 19F-NMR and a fluorinated intracellular Ca 2+ indicator. We report a basal intracellular free Ca 2+ value of 172 ± 8 nM. Treatment with 1, 5, 10 and 25 μM Pb 2+ resulted in average increases in intracellular free Ca 2+ of 39%, 91%, 135% and 172%, respectively. The percent increase in intracellular free Ca 2+ was linearly and positively correlated with the log of Pb 2+ concentration. Using atomic absorption spectroscopy, a significant increase in total calcium of approx. 10 nmol/mg protein was found in 25 μM Pb 2+ treated platelets. This indicates that influx of external Ca 2+ contributes to the observed increase in free Ca 2+. The results provide an explanation for the previously reported effects of lead on platelet function, and suggest a mechanism for low level lead-induced hypertension.

Lead increases red cell sodium-lithium countertransport.

The effect of 1, 3, 5, and 20 mumol/L lead on normal red cell sodium-lithium countertransport was studied in vitro. Red cell suspensions incubated with lead had increased sodium-lithium countertransport at all concentration levels compared with paired, unleaded controls when all groups were evaluated by analysis of covariance (F = 19.2, P less than 0.001). The effect of lead was concentration dependent (r = 0.998, P less than 0.001). These observations suggest that abnormalities in sodium transport are involved in the pathogenesis of lead-induced hypertension. Because increased red cell sodium-lithium countertransport is characteristic of essential hypertension, these observations further suggest that lead-induced and essential hypertension may share common pathophysiological mechanisms.

Effects of lead on vascular reactivity.

Considerable controversy exists concerning the possible role of lead in the etiology of human hypertension. In animal studies, there is convincing evidence that lead alters cardiovascular responsiveness; rats drinking water containing 100 ppm lead develop a chronic, significant 15 to 20 mm Hg elevation in systolic blood pressure. Pressor responsiveness to catecholamines is enhanced in animals chronically exposed to lead, and the responsiveness of isolated vascular smooth muscle to adrenergic agonists is increased in rats with lead-induced hypertension. Experimental evidence suggests that alterations in the cellular mechanisms that regulate intracellular calcium concentration may contribute to the abnormal vascular function in lead-induced hypertension. Recent work in our laboratory indicates that increased vascular reactivity in genetic hypertension is associated with altered activity of the protein kinase C branch of the calcium messenger system. Contractile responses to lead in rabbit mesenteric artery are potentiated by activators (phorbol esters) of this enzyme complex, and a selective inhibitor of protein kinase C inhibited contractions induced by lead. Based on these results, it is proposed that a cellular component of the action of lead to increase vascular reactivity may relate to the role of protein kinase C in smooth muscle contraction.

Effects of Lead on Vascular Reactivity

Considerable controversy exists concerning the possible role of lead in the etiology of human hypertension. In animal studies, there is convincing evidence that lead alters cardiovascular responsiveness; rats drinking water containing 100 ppm lead develop a chronic, significant 15 to 20 mm Hg elevation in systolic blood pressure. Pressor responsiveness to catecholamines is enhanced in animals chronically exposed to lead, and the responsiveness of isolated vascular smooth muscle to adrenergic agonists is increased in rats with lead-induced hypertension. Experimental evidence suggests that alterations in the cellular mechanisms that regulate intracellular calcium concentration may contribute to the abnormal vascular function in lead-induced hypertension. Recent work in our laboratory indicates that increased vascular reactivity in genetic hypertension is associated with altered activity of the protein kinase C branch of the calcium messenger system. Contractile responses to lead in rabbit mesenteric artery are potentiated by activators (phorbol esters) of this enzyme complex, and a selective inhibitor of protein kinase C inhibited contractions induced by lead. Based on these results, it is proposed that a cellular component of the action of lead to increase vascular reactivity may relate to the role of protein kinase C in smooth muscle contraction.

Lead and hypertension in a mortality study of lead smelter workers.

Hypertension has been associated with occupational lead exposure and may in part be a consequence of renal injury. To assess the epidemiology of death potentially associated with lead-induced hypertension, the authors have reviewed data from a larger study. This study evaluated the mortality of a cohort of white, male, hourly workers hired at a lead smelter in Idaho between January 1, 1940, and December 31, 1965, and employed for at least 1 year. Mortality was determined as of December 1, 1977. Of the 1987 males qualifying for the study group, 1281 were known to be alive, 665 were known to be deceased, and the remainder (2.1%) were lost to follow-up. The findings of renal disease and cancer are more suggestive of an association with lead exposure.

Lead-induced hypertension: blunted beta-adrenoceptor-mediated functions.

Lead-induced hypertension: blunted beta-adrenoceptor-mediated functions.