Interactions of Cadmium and Nickel with K Channels of Vascular Smooth Muscle (original) (raw)
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Biological trace element research, 2017
Cadmium is an environmental pollutant closely linked with cardiovascular diseases that seems to involve endothelium dysfunction and reduced nitric oxide (NO) bioavailability. Knowing that NO causes dilatation through the activation of potassium channels and Na(+)/K(+)-ATPase, we aimed to determine whether acute cadmium administration (10 μM) alters the participation of K(+) channels, voltage-activated calcium channel, and Na(+)/K(+)-ATPase activity in vascular function of isolated aortic rings of rats. Cadmium did not modify the acetylcholine-induced relaxation. After L-NAME addition, the relaxation induced by acetylcholine was abolished in presence or absence of cadmium, suggesting that acutely, this metal did not change NO release. However, tetraethylammonium (a nonselective K(+) channels blocker) reduced acetylcholine-induced relaxation but this effect was lower in the preparations with cadmium, suggesting a decrease of K(+) channels function in acetylcholine response after cadmi...
Cadmium Toxicity on Arterioles Vascular Smooth Muscle Cells of Spontaneously Hypertensive Rats
International Journal of Environmental Research and Public Health, 2006
Cadmium (Cd) is frequently used in various industrial applications and is a ubiquitous environmental toxicant, also present in tobacco smoke. An important route of exposure is the circulatory system whereas blood vessels are considered to be main stream organs of Cd toxicity. Our previous results indicate that cadmium chloride (CdCl 2 ) affects mean arterial blood pressure in hypertensive rats. We hypothesized that Cd alters the intracellular calcium transient mechanism, by cadmium-induced stimulation of MAPKs (ERK 1 & 2) which is mediated partially through calcium-dependent PKC mechanism. To investigate this hypothesis, we exposed primary cultures of vascular smooth muscle cells (VSMCs) from wistar kyoto (WKY) and spontaneously hypertensive rats (SHR) to increased concentrations of CdCl 2 on cell viability, expression of mitogen-activated protein kinases (MAPKs/ERK 1 & 2), and protein kinase C (PKC) which are activated by Cd in several cell types. The results from these studies indicate that CdCl 2 decreased cell viability of both SHR and WKY VSMCs in a concentration dependent-manner. Viability of both cell types decreased 33±5.3 (SHR) and 39±2.3% (WKY) when exposed to 1 µM CdCl 2 , whereas, 8 and 16 µM reduced viability by 66±3.1 and 62±4.5% in SHR cells. CdCl 2 increased ERK 1 & 2 in a biphasic manner with maximum increase occurring when cells are exposed to 1 and 4 µM in SHR VSMCs, whereas, a reduction in ERK 1 and 2 is observed when WKY cells are treated with 2 µM. The results also indicate that CdCl 2 increased PKC a/ß in both SHR and WKY VSMCs with a greater increase in expression in SHR VSMCs. In addition, the [Ca 2+ ] i chelator, BAPTA, suppressed the CdCl 2 effect, whereas, the PKC inhibitor, GF109203X, reduced the CdCl 2 induced-effect on PKC expression. The present studies support the hypothesis that Cd can be a risk factor of hypertension through dysfunction of vascular smooth muscle cells under certain conditions.
Aim: To investigate the mechanism of nickel augmented phenylephrine (PE)-induced contraction in isolated segments of Wistar rat aorta. Materials and Methods: Effect of varying concentrations of nickel on PEinduced contraction were investigated in isolated segments of Wistar rat aorta using an organ bath system. Aortic rings were pre-incubated with verapamil (1 µM and 20 µM), gadolinium, apocynin, indomethacin or N-G-nitro-L-arginine methyl ester (L-NAME) separately before incubation with nickel. Results: Endothelium intact aortic rings incubated with 100 nM, 1 µM or 100 µM of nickel exhibited 80%, 43% and 28% increase in PE-induced contraction, respectively, while no such enhancing responses were observed in endothelium denuded aorta. Incubation of aortic rings with 1 µM and 20 µM verapamil suggested an involvement of influx of calcium through T-type calcium channels in smooth muscle cells, while aortic rings pre-incubated with gadolinium showed no role of store operated calcium channels in the nickel effect on PEinduced contractions. The enhancing effect of nickel on PE-induced contractions was inhibited by apocynin, indomethacin or L-NAME. Conclusion: Nickel has caused augmentation of PE-induced contractions as a result of the endothelial generation of reactive oxygen species (ROS) and cyclooxygenase 2 (COX2) dependent endothelium contracting factors (EDCFs), which increases the influx of extracellular calcium through T-type Ca 2+ channels in smooth muscle cells.
The vascular endothelium as a target of cadmium toxicity
Life Sciences, 2006
Cadmium (Cd) is an important industrial and environmental pollutant that can produce a wide variety of adverse effects in humans and animals. A growing volume of evidence indicates that the vascular endothelium may be one of the primary targets of Cd toxicity in vivo. Studies over the past 20 years have shown that Cd, at relatively low, sublethal concentrations, can target vascular endothelial cells at a variety of molecular levels, including cell adhesion molecules, metal ion transporters and protein kinase signaling pathways. The purpose of this review is to summarize the results of these recent studies and to discuss the implications of these findings with regard to the mechanisms of Cd toxicity in specific organs including the lung, liver, kidney, testis and heart. In addition the possible roles of the vascular endothelium in mediating the tumor promoting and anticarcinogenic effects of Cd are discussed.
Free Radical Biology and Medicine, 2013
Cadmium is an environmental pollutant that is closely linked with cardiovascular diseases, such as atherosclerosis and hypertension. Moreover, cadmium can induce an increase in oxidative stress. One of the main sites affected by oxidative stress is the aorta, which consequently develops atherosclerosis. However, there are few reports demonstrating aortic effects induced by small concentrations of cadmium that are similar to those found in the blood resulting from occupational exposure. Furthermore, several studies have reported on chronic cadmium exposure, and the results of these studies may have been influenced by the secondary effects induced by this metal, such as hypertension. Therefore, we investigated the effects of acute cadmium exposure on the vascular reactivity to phenylephrine of aortic rings isolated from male Wistar rats. Cadmium increased phenylephrine reactivity without changing the vasorelaxation induced by acetylcholine and sodium nitroprusside. Endothelial damage or incubation with L-NAME shifted the phenylephrine concentration-response curves leftward in arteries incubated with or without cadmium, but the curves were shifted to a lesser degree after cadmium incubation. Enalapril, losartan, the nonselective COX inhibitor indomethacin, the TXA(2) synthase inhibitor furegrelate, the selective COX-2 inhibitor NS 398, the TP receptor antagonist SQ 29.548, the EP1 receptor antagonist SC 19.220, superoxide dismutase, and the NADPH oxidase inhibitor apocynin partially reverted the cadmium-induced effects on the reactivity to phenylephrine. Cadmium exposure increased vasoconstrictor activity by reducing NO bioavailability owing to the increased production of ROS by NADPH oxidase. The results of the tested cadmium concentration, which is below the reference values, suggest that acute cadmium exposure may induce vascular injury through endothelial oxidative stress. These data contribute to the evidence indicating that cadmium is a high risk to public health.
Cadmium Feeding: Apparent Depression of Atrioventricular-His-Purkinje Conduction System
Acta Pharmacologica Et Toxicologica, 2009
Abstract Male rats were exposed to 0,10 and 130 p.p.m. cadmium administered in 0.5% saline drinking water for 71 days. Biweekly records of ECGs, Hct, body weight and blood levels of cadmium were made. Rats exposed to 130 p.p.m. cadmium showed slower growth rates and declining Hct indicative of acute cadmium poisoning. At the end of the experimental period, carotid artery blood pressures and whole heart cadmium levels were determined. Although no significant blood pressure changes were observed in the experimental groups, the cadmium content of the hearts of the higher dose group was significantly higher than in the hearts of the lower dose group. The PR interval of the ECG was lengthened progressively and to the same extent in both experimental groups with continued cadmium feeding. These experiments offer evidence that the accumulation of even moderate amounts of cadmium will be manifested in marked changes in cardiac conduction without overt signs of cadmium poisoning.
British Journal of Pharmacology, 1998
1 In the rat, intracerebroventricular (i.c.v.) injection of cadmium, a pollutant with long biological halflife, causes a sustained increase in blood pressure at doses that are ineective by peripheral route. Since cadmium inhibits calcium-calmodulin constitutive nitric oxide (NO) synthase in cytosolic preparations of rat brain, this mechanism may be responsible for the acute pressor action of this heavy metal. 2 To test this possibility, we evaluated the eect of i.c.v. injection of 88 nmol cadmium in normotensive unanaesthetized Wistar rats, which were i.c.v. pre-treated with: (1) saline (control), (2) L-arginine (L-Arg), to increase the availability of substrate for NO biosynthesis, (3) D-arginine (D-Arg), (4) 3-[4morpholinyl]-sydnonimine-hydrochloride (SIN-1), an NO donor, or (5) CaCl 2 , a cofactor of brain calcium-calmodulin-dependent cNOS I . In additional experiments, the levels of L-citrulline (the stable equimolar product derived from enzymatic cleavage of L-Arg by NO synthase) were determined in the brain of vehicle-or cadmium-treated rats.
Biological Trace Element Research, 2015
Cadmium exposure causes health problems that may result from increased oxidative stress and from changes in enzyme metalloproteases activities as angiotensinconverting enzyme (ACE). In fact, cadmium produces inhibition of serum ACE but is not known how cadmium acts on tissue ACE activity and whether following acute exposure tissue cadmium content is increased. In order to elucidate these issues, a cadmium bolus was injected intravenously in Wistar rats, and the cadmium content and the ACE activity were measured in the serum, lungs, aorta and kidneys. Moreover, in order to clarify if the cadmium affects directly tissue ACE activity, acute metal exposure in vitro was performed. Our results demonstrated that 120 min following cadmium administration, blood and organ cadmium content were both increased. Serum and lung ACE activity were reduced following acute cadmium exposure, but aortic and kidney ACE activities were not affected. The inhibitory effects induced by cadmium on ACE activity were also observed in the serum, as well as the lungs and the aorta, but not in the kidneys following in vitro exposure. Moreover, the inhibitory effects induced by cadmium on ACE activity were partially restored in vitro by zinc supplementation, suggesting a possible interaction or competition between cadmium and zinc by at the active site of ACE. Summarising, our results suggest that acute cadmium exposure promotes an increase in the tissue metal content that was accompanied by direct inhibition of serum, aorta and lung ACE activity, an effect that is cadmium concentration-dependent and is partially reversed by zinc.
The Vascular System as a Target of Metal Toxicity
Toxicological Sciences, 2007
Vascular system function involves complex interactions among the vascular endothelium, smooth muscle, the immune system, and the nervous system. The toxic metals cadmium (Cd), arsenic (As), and lead (Pb) can target the vascular system in a variety of ways, ranging from hemorrhagic injury to subtle pathogenic remodeling and metabolic changes. Acute Cd exposure results in hemorrhagic injury to the testis, although some strains of animals are resistant to this effect. A comparison of Cd-sensitive with Cd-resistant mouse strains showed that expression of the Slc39a8 gene, encoding the ZIP8 transporter, in the testis vasculature endothelium is responsible for this difference. Endogenously, ZIP8 is a Mn 21 / HCO 3 symporter that may also contribute to Cd damage in the kidney. Chronic Cd exposure is associated with various cardiovascular disorders such as hypertension and cardiomyopathy and it is reported to have both carcinogenic and anticarcinogenic activities. At noncytotoxic concentrations of 10-100nM, Cd can inhibit chemotaxis and tube formation of vascular endothelial cells. These angiostatic effects may be mediated through disruption of vascular endothelial cadherin, a Ca 21-dependent cell adhesion molecule. With regard to As, ingestion of water containing disease-promoting concentrations of As promotes capillarization of the liver sinusoidal endothelium. Because capillarization is a hallmark precursor for liver fibrosis and contributes to an imbalance of lipid metabolism, this As effect on hepatic endothelial cells may be a pathogenic mechanism underlying As-related vascular diseases. With regard to Pb, perinatal exposure may cause sustained elevations in adult blood pressure, and genetically susceptible animals may show enhanced sensitivity to this effect. Taken together, these data indicate that the vascular system is a critical target of metal toxicity and that actions of metals on the vascular system may play important roles in mediating the pathophysiologic effects of metals in specific target organs.