Catcholamine and nitric oxide systems as targets of chronic lead exposure in inducing selective functional impairment

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.

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

“…Vassallo et al www.bjournal.com.br endothelial release of endothelin (10,11). The participation of free radicals reducing nitric oxide bioavailability (12) and depletion of antioxidant reserves (4) or its upregulation (13) has been reported.…”

Section: Introductionmentioning

confidence: 99%

“…Carmignani et al (11,15) reported increased myocardial inotropism and increased activity of the angiotensin-converting enzyme in rats exposed to 60 ppm lead acetate for 10 months. On the other hand, Williams et al (16) reported negative inotropic effects on perfused hearts caused by acute lead administration.…”

Section: Introductionmentioning

confidence: 99%

Lead reduces tension development and the myosin ATPase activity of the rat right ventricular myocardium

Vassallo

Lebarch

Moreira

et al. 2008

Lead (Pb 2+ ) poisoning causes hypertension, but little is known regarding its acute effects on cardiac contractility. To evaluate these effects, force was measured in right ventricular strips that were contracting isometrically in 45 male Wistar rats (250-300 g) before and after the addition of increasing concentrations of lead acetate (3,7,10,30, 70, 100, and 300 µM) to the bath. Changes in rate of stimulation (0.1-1.5 Hz), relative potentiation after pauses of 15, 30, and 60 s, effect of Ca 2+ concentration (0.62, 1.25, and 2.5 mM), and the effect of isoproterenol (20 ng/mL) were determined before and after the addition of 100 µM Pb 2+ . Effects on contractile proteins were evaluated after caffeine treatment using tetanic stimulation (10 Hz) and measuring the activity of the myosin ATPase. Pb 2+ produced concentration-dependent force reduction, significant at concentrations greater than 30 µM. The force developed in response to increasing rates of stimulation became smaller at 0.5 and 0.8 Hz. Relative potentiation increased after 100 µM Pb 2+ treatment. Extracellular Ca 2+ increment and isoproterenol administration increased force development but after 100 µM Pb 2+ treatment the force was significantly reduced suggesting an effect of the metal on the sarcolemmal Ca 2+ influx. Concentration of 100 µM Pb 2+ also reduced the peak and plateau force of tetanic contractions and reduced the activity of the myosin ATPase. Results showed that acute Pb 2+ administration, although not affecting the sarcoplasmic reticulum activity, produces a concentration-dependent negative inotropic effect and reduces myosin ATPase activity. Results suggest that acute lead administration reduced myocardial contractility by reducing sarcolemmal calcium influx and the myosin ATPase activity. These results also suggest that lead exposure is hazardous and has toxicological consequences affecting cardiac muscle.

“…Peripheral or central nervous mechanisms, such as the increase of sympathetic nerve activity, the reduction of baroreflex sensitivity and the reduction of parasympathetic tone (33), are also involved in lead-induced hypertension. In addition, Carmignani et al (32,41) reported increased myocardial inotropism and increased ACE activity in rats exposed to 60 ppm lead acetate for 10 months.…”

Section: Leadmentioning

confidence: 99%

“…Lead-induced hypertension is reported to result from the inhibition of NKA (39) and from the reduced bioavailability of NO plus an increased endothelial release of endothelin (40,41). Free radicals reducing NO bioavailability (42) and depletion of antioxidant reserves (8,43) or their up-regulation (39) have also been reported.…”

Section: Leadmentioning

confidence: 99%

Toxic effects of mercury, lead and gadolinium on vascular reactivity

Vassallo

Simões

Furieri

et al. 2011

Heavy metals have been used in a wide variety of human activities that have significantly increased both professional and environmental exposure. Unfortunately, disasters have highlighted the toxic effects of metals on different organs and systems. Over the last 50 years, the adverse effects of chronic lead, mercury and gadolinium exposure have been underscored. Mercury and lead induce hypertension in humans and animals, affecting endothelial function in addition to their other effects. Increased cardiovascular risk after exposure to metals has been reported, but the underlying mechanisms, mainly for short periods of time and at low concentrations, have not been well explored. The presence of other metals such as gadolinium has raised concerns about contrast-induced nephropathy and, interestingly, despite this negative action, gadolinium has not been defined as a toxic agent. The main actions of these metals, demonstrated in animal and human studies, are an increase of free radical production and oxidative stress and stimulation of angiotensin I-converting enzyme activity, among others. Increased vascular reactivity, highlighted in the present review, resulting from these actions might be an important mechanism underlying increased cardiovascular risk. Finally, the results described in this review suggest that mercury, lead and gadolinium, even at low doses or concentrations, affect vascular reactivity. Acting via the endothelium, by continuous exposure followed by their absorption, they can increase the production of free radicals and of angiotensin II, representing a hazard for cardiovascular function. In addition, the actual reference values, considered to pose no risk, need to be reducedResearch supported by CAPES and CNPq/FAPES/ FUNCITEC (#39767531/07), Brazil, and MCINN (#SAF 2009-07201) and ISCIII (Red RECAVA, #RD06/0014/0011), Spai