RESUMEN
Mercury has been shown to be a significant health risk factor and is positively associated with cardiovascular diseases. Evidence reveals that men are more likely to develop cardiovascular diseases than women during reproductive age. However, the effects of mercury in females remain poorly investigated, despite the finding that female hormones demonstrate a cardioprotective role. In the present study, we evaluated whether chronic mercury chloride exposure could alter blood pressure and vascular function of the female rat aorta. Ten-week-old female Wistar rats were divided into two groups: control (vehicle) and mercury treated (first dose of 4.6 µg/kg, subsequent daily doses of 0.07 µg/kg), im. Mercury treatment did not modify systolic blood pressure (SBP) but increased vascular reactivity due to the reduction of nitric oxide bioavailability associated with the increase in reactive oxygen species from endothelial nitric oxide synthase (eNOS) uncoupling. Furthermore, increased participation of the cyclooxygenase-2 pathway occurred through an imbalance in thromboxane 2 and prostacyclin 2. However, the oestrogen signalling pathway was not altered in either group. These results demonstrated that chronic exposure to mercury in females induced endothelial dysfunction and, consequently, increased aortic vascular reactivity, causing vascular damage to the female rat aorta and representing a risk of cardiovascular diseases.
Asunto(s)
Ciclooxigenasa 2/efectos de los fármacos , Cloruro de Mercurio/toxicidad , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Presión Sanguínea/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Femenino , Cloruro de Mercurio/administración & dosificación , Óxido Nítrico/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Receptores de Estrógenos/metabolismoRESUMEN
Mercury is a metal widely dispersed in nature that when in contact with human organism, it damages the cardiovascular system. Long-term mercury exposure for 30 days induces endothelial dysfunction without blood pressure changes in normotensive adult rats. However, it is not known whether exposure to mercury can exacerbate endothelial dysfunction and hypertension development in predisposed animals. Thus, we aimed to investigate the effects of long-term mercury exposure on the blood pressure (BP) and in the isolated aortas of young normotensive and prehypertensive spontaneously hypertensive rats (SHRs). Four-week-old male Wistar rats and SHRs were treated daily with mercury chloride (HgCl2) (1st dose, 4.6 µg/kg; subsequent dose, 0.07 µg/kg/day, im, 30 days) or vehicle. BP was assessed weekly and the vascular reactivity to phenylephrine was evaluated in isolated aorta from rats exposed or not to mercury. Mercury exposure did not affect BP in young Wistar rats but accelerated the development of hypertension in young SHRs. Vascular reactivity to phenylephrine increased only in the aorta from mercury-exposed SHRs. While HgCl2 exposure in SHRs did not alter nitric oxide production, we observed increased superoxide anion production and decreased superoxide dismutase-1 protein expression, and enhanced cyclooxygenase-2 (COX-2) participation with increased prostaglandin (PGE2) production and decreased prostacyclin. In the Wistar group, mercury exposure did not alter superoxide anion production or the COX-2 pathway. Mercury exposure accelerated the natural course of hypertension in young SHRs and increased oxidative stress associated with reduced participation of antioxidant enzymes, an activated COX-2 pathway, thereby producing endothelial dysfunction, which is a risk factor in prehypertensive individuals.
Asunto(s)
Ciclooxigenasa 2/metabolismo , Endotelio Vascular/efectos de los fármacos , Hipertensión/inducido químicamente , Cloruro de Mercurio/toxicidad , Animales , Presión Sanguínea/efectos de los fármacos , Endotelio Vascular/metabolismo , Hipertensión/metabolismo , Masculino , Cloruro de Mercurio/administración & dosificación , Óxido Nítrico/biosíntesis , Estrés Oxidativo/efectos de los fármacos , Fenilefrina/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas WistarRESUMEN
Chronic exposure to mercury chloride (HgCl2) has been shown to promote oxidative stress and cell death in the central nervous system of adult rats displaying motor and cognitive impairments. However, there are no investigations about neurochemical function after this type of exposure in rodents that may be associated with those behavioral changes already reported. Thus, the aim of this study was to analyze glutamatergic and GABAergic dysfunctions in the motor cortex and hippocampus of adult rats, in a model of chronic exposure to HgCl2 in. Twenty rats were exposed to a daily dose of 0.375 mg/kg for 45 days. After this period, they were submitted to motor and cognitive functions tests and euthanized to collect the motor cortex and hippocampus for measurement of mercury (Hg) levels in the parenchyma and neurochemical assays for analysis of glutamatergic and GABAergic functions. It was observed that chronic exposure to HgCl2 promoted increase in total Hg levels in these two brain areas, with changes in glutamatergic transport, but without changes in GABAergic transport. Functionally this model of exposure caused the decrease of the spontaneous motor locomotion and in the process of learning and memory. In this way, our results provide evidences that glutamatergic neurochemical dysfunction can be pointed out as a strong causal factor of motor and cognitive deficits observed in rats exposed to this HgCl2.
Asunto(s)
Conducta Animal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Cloruro de Mercurio/toxicidad , Corteza Motora/efectos de los fármacos , Administración Oral , Animales , Hipocampo/metabolismo , Masculino , Cloruro de Mercurio/administración & dosificación , Corteza Motora/metabolismo , Ratas , Ratas WistarRESUMEN
This work investigated the preventive effect of diphenyl diselenide [(PhSe)2] against the toxic effects of mercury in silver catfish (Rhamdia quelen). The animals were treated during 30 consecutive days with a (PhSe)2 supplemented feed (3.0 mg kg-1) or commercial feed. During the last 5 days the animals received a daily intraperitoneal dose of HgCl2 (1.7 mg kg-1) or Saline (0.9%). Twenty-four hours after the last HgCl2 injection, the animals were euthanized by spinal cord section to biological material obtainment. Hepatic (AST and ALT) and renal (ammonia and creatinine) toxicity biomarkers, δ-ALA-D activity, TBARS, total and non-protein thiols levels and hepatic, renal and blood mercury (Hg) and zinc (Zn) content were evaluated. Considering renal parameters, HgCl2 exposition increased serum creatinine levels and decreased δ-ALA-D activity, total and non-protein thiols and TBARS levels. HgCl2 exposure also decreased blood δ-ALA-D activity. With exception of blood δ-ALA-D activity and total thiols levels, (PhSe)2 supplementation partially prevented mercury induced alterations. Animals exposed to HgCl2 presented an increase in liver and kidney Hg content and a decrease in liver and blood Zn content. The alteration in blood Zn content was partially prevented with (PhSe)2 supplementation. With the exception of mercury and zinc content, no effects of HgCl2 exposure on hepatic tissue were observed. These results show that (PhSe)2 supplementation can represent a promising alternative to prevent the toxic effects presented by Hg exposure.
Asunto(s)
Derivados del Benceno/farmacología , Intoxicación por Mercurio/tratamiento farmacológico , Intoxicación por Mercurio/prevención & control , Compuestos de Organoselenio/farmacología , Animales , Derivados del Benceno/metabolismo , Bagres/metabolismo , Creatinina/sangre , Dieta , Suplementos Dietéticos , Femenino , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Cloruro de Mercurio/administración & dosificación , Mercurio/sangre , Intoxicación por Mercurio/sangre , Compuestos de Organoselenio/metabolismo , Compuestos de Sulfhidrilo/sangre , Zinc/sangreRESUMEN
Mercuric chloride (HgCl2) induces kidney damage, in part, through oxidative stress. A role for angiotensin II (Ang II) in pro-inflammatory events in a model of acute HgCl2-induced nephropathy was reported. Ang II is a potent oxidative stress inducer; however, its role in oxidative/anti-oxidative events in HgCl2-induced nephropathy remains unknown. The aim of this study was to determine the role of Ang II in the oxidative stress and renal infiltration of CD8(+) T-cells after an acute HgCl2 intoxication. Three groups of Sprague Dawley rats were treated with a single subcutaneous dose of 2.5 mg/kg HgCl2: for 3 days prior to and for 4 days after that injection, rats in one group received Losartan (30 mg/kg), in another group Enalapril (30 mg/kg) or normal saline in the last group. Two other groups of drug-treated rats received saline in place of HgCl2. A final group of rats received saline in place of HgCl2 and the test drugs. All treatments were via gastric gavage. At 96 h after the vehicle/HgCl2 injection, blood and kidney samples were harvested. Renal sections were homogenized for measures of malondialdehyde (MDA), reduced glutathione (GSH) and catalase activity. Frozen sections were studied for the presence of superoxide anion ([Formula: see text]) and CD8(+) T-cells. HgCl2-treated rats had increased interstitial and tubular expression of [Formula: see text], high levels of MDA, normal catalase activity and GSH content, increased levels of interstitial CD8(+) T-cells and an increased percentage of necrotic tubules. Anti-Ang II treatments diminished the HgCl2-induced increases in interstitial [Formula: see text], CD8(+) T-cells and tubular damage and increased catalase and GSH expression above that due to HgCl2 alone; the HgCl2-induced high MDA levels were unaffected by the drugs. These data provide new information regarding the potential role of Ang II in the oxidative stress and renal CD8(+) T-cell infiltration that occur during HgCl2 nephropathy.
Asunto(s)
Angiotensina II/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Enfermedades Renales/inmunología , Riñón/metabolismo , Cloruro de Mercurio/administración & dosificación , Estrés Oxidativo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Animales , Linfocitos T CD8-positivos/inmunología , Catalasa/metabolismo , Enalapril/administración & dosificación , Glutatión/metabolismo , Riñón/inmunología , Riñón/patología , Enfermedades Renales/inducido químicamente , Losartán/administración & dosificación , Masculino , Malondialdehído/metabolismo , Cloruro de Mercurio/toxicidad , Necrosis , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
The aim of the study was to evaluate the effectiveness of preventive-detox preparation (P-dP) based on humic and aluminosilicate substances in the diet of laying hens (3% daily dose) previously intoxicated with methylmercury chloride (CH3ClHg, 5 mg Hg/kg feed mixture) for six weeks. Mercury content in the whole eggs of the group intoxicated with CH3ClHg increased compared to the control group: 488-fold after 1 wk, 622-fold after 2 wks, and 853-fold after 6 wks of intoxication. The use of P-dP in the group previously intoxicated with CH3ClHg reduced he mercury content of whole eggs by 18.4%, on average, whereas the average was 29.9% two weeks after the discontinuation of CH3ClHg and P-dP supply. Maximum Hg content in the whole egg was observed in group III (299.7 g), whereas the highest mercury level was obtained in the egg albumen.
Asunto(s)
Animales , Cloruro de Mercurio/administración & dosificación , Cloruro de Mercurio/toxicidad , Huevos/análisis , Huevos/toxicidad , Bioacumulación , PollosRESUMEN
The aim of the study was to evaluate the effectiveness of preventive-detox preparation (P-dP) based on humic and aluminosilicate substances in the diet of laying hens (3% daily dose) previously intoxicated with methylmercury chloride (CH3ClHg, 5 mg Hg/kg feed mixture) for six weeks. Mercury content in the whole eggs of the group intoxicated with CH3ClHg increased compared to the control group: 488-fold after 1 wk, 622-fold after 2 wks, and 853-fold after 6 wks of intoxication. The use of P-dP in the group previously intoxicated with CH3ClHg reduced he mercury content of whole eggs by 18.4%, on average, whereas the average was 29.9% two weeks after the discontinuation of CH3ClHg and P-dP supply. Maximum Hg content in the whole egg was observed in group III (299.7 g), whereas the highest mercury level was obtained in the egg albumen.(AU)
Asunto(s)
Animales , Huevos/análisis , Huevos/toxicidad , Cloruro de Mercurio/administración & dosificación , Cloruro de Mercurio/toxicidad , Bioacumulación , PollosRESUMEN
Right ventricle systolic dysfunction is a major risk factor for death and heart failure after myocardial infarction (MI). Heavy metal exposure has been associated with the development of several cardiovascular diseases, such as MI. The aim of this study was to investigate whether chronic exposure to low doses of mercury chloride (HgCl2) enhances the functional deterioration of right ventricle strips after MI. Male Wistar rats were divided into four groups: Control (vehicle); HgCl2 (exposure during 4 weeks- 1st dose 4.6 µg/kg, subsequent dose 0.07 µg/kg/day, i.m. to cover daily loss); MI surgery induced and HgCl2-MI groups. One week after MI, the morphological and hemodynamic measurements and isometric tension of right ventricle strips were investigated. The chronic HgCl2 exposure did not worsen the injury compared with MI alone in the morphological or hemodynamic parameters evaluated. At basal conditions, despite similar maximum isometric force at L-max, relaxation time was increased in the MI group but unaffected in the HgCl2-MI compared to the Control group. Impairment of the sarcoplasmic reticulum (SR) function and reduction in the sarcolemmal calcium influx were observed in MI group associated with SERCA2a reduction and increased PLB protein expression. Induction of MI in chronic HgCl2 exposed rats did not cause any alteration in the developed force at L-max, lusitropic function or -dF/dt except for a tendency of a reduction SR function. These findings could be partially explained by the normalization in the sarcolemmal calcium influx and the increase in NCX protein expression observed only in this group. These results suggest that chronic exposure to low doses of HgCl2 prevents the impaired SR function and the reduced sarcolemmal calcium influx observed in MI likely by acting on NCX, PLB and SERCA2a protein expression.
Asunto(s)
Calcio/metabolismo , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Cloruro de Mercurio/administración & dosificación , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Función Ventricular Derecha/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Hemodinámica , Masculino , Contracción Miocárdica/efectos de los fármacos , Infarto del Miocardio/patología , Ratas , Retículo Sarcoplasmático/efectos de los fármacos , Retículo Sarcoplasmático/metabolismoRESUMEN
This study investigated if lactating and nonlactating rats presented differences in relation to hepatic sensitivity to HgCl2 and the potential preventive role of ZnCl2. Lactating (days 3-12 of lactation) and nonlactating rats received 27 mg/kg ZnCl2 for five consecutive days and 5 mg/kg HgCl2 for five subsequent days. Lactating and nonlactating rats exposed to HgCl2 presented a decrease in food intake, a decrease in plasma alanine aminotransferase (ALT), and an increase in hepatic Hg levels when compared to the control group. Only lactating rats exposed to HgCl2 presented an increase in hepatic δ-aminolevulinic acid dehydratase activity. On the other hand, only nonlactating rats exposed to HgCl2 presented an increase in plasma aspartate aminotransferase (AST). ZnCl2 pre-exposure partially protected the increase in plasma AST activity presented by nonlactating rats and potentiated the liver Hg accumulation in lactating rats. Pups from the Sal-Hg and Zn-Hg groups showed a decrease in absolute liver weight and an increase in liver Hg levels. Summarizing, this study demonstrated that lactating rats presented distinct biochemical responses compared to nonlactating rats exposed to HgCl2 when hepatic parameters were evaluated.
Asunto(s)
Lactancia , Hígado/efectos de los fármacos , Hígado/enzimología , Cloruro de Mercurio/farmacología , Porfobilinógeno Sintasa/metabolismo , Animales , Aspartato Aminotransferasas/sangre , Aspartato Aminotransferasas/metabolismo , Cloruros/farmacología , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Femenino , Inyecciones Subcutáneas , Cloruro de Mercurio/administración & dosificación , Ratas , Ratas Wistar , Relación Estructura-Actividad , Compuestos de Zinc/farmacologíaRESUMEN
The present studies were conducted to changes arising from mercury poisoning in the central nervous system (CNS), with a focus on determining the receptors and neurotransmitters involved. Currently, little is known regarding the neurological basis of the cardiopulmonary effects of mercury poisoning. We evaluated changes in systolic arterial pressure (SAP), diastolic arterial pressure (DAP), respiratory rate (RR) and heart rate (HR) following a 5 µl intracisternal (i.c) injection of mercuric chloride (HgCl(2)) and the participation of the autonomic nervous system in these responses. 58 animals were utilized and distributed randomly into 10 groups and administered a 5 µL intracisternal injection of 0.68 µg/kg HgCl(2) (n=7), 1.2 µg/kg HgCl(2) (n=7), 2.4 µg/kg HgCl(2) (n=7), 60 µg/kg HgCl(2) (n=7), 120 µg/kg HgCl(2) (n=3), saline (control) (n=7), 60 µg/kg HgCl(2) plus prazosin (n=6), saline plus prazosin (n=6), 60 µg/kg HgCl(2) plus metilatropina (n=4) or saline plus metilatropina (n=4)HgCl(2). Anesthesia was induced with halothane and maintained as needed with urethane (1.2 g/kg) administered intravenously (i.v.) through a cannula placed in the left femoral vein. The left femoral artery was also cannulated to record systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and heart rate (HR). A tracheotomy was performed to record respiratory rate. Animals were placed in a stereotaxic frame, and the cisterna magna was exposed. After a stabilization period, solutions (saline or HgCl(2)) were injected i.c., and cardiopulmonary responses were recorded for 50 min. Involvement of the autonomic nervous system was assessed through the i.v. injection of hexamethonium (20 mg/kg), prazosin (1 mg/kg) and methylatropine (1 mg/kg) 10 min before the i.c. injection of HgCl(2) or saline. Treatment with 0.68, 1.2, 2.4 µg/kg HgCl(2) or saline did not modify basal cardiorespiratory parameters, whereas the 120 µg/kg dose induced acute toxicity, provoking respiratory arrest and death. The administration of 60 µg/kg HgCl(2), however, induced significant increases (p<0.05) in SAP at the 30°, 40° and 50° min, timepoints and DAP at the 5°, 10°, 20°, 30°, 40° and 50° timepoints. RR was significantly decreased at the 5°, 10°, 20°, 40° and 50° min timepoints; however, there was no change in HR. Hexamethonium administration, which causes non-specific inhibition of the autonomic nervous system, abolished the observed cardiorespiratory effects. Similarly, prazosin, a α(1)-adrenoceptor blocker that specifically inhibits sympathetic nervous system function, abolished HgCl(2) induced increases in SAP and DAP without affecting HR and RR. Methylatropine (1 mg/Kg), a parasympathetic nervous system inhibitor, exacerbated the effects of HgCl(2) and caused slow-onset respiratory depression, culminating in respiratory arrest and death. Our results demonstrate that increases in SAP and DAP induced by the i.c. injection of mercuric chloride are mediated by activation of the sympathetic nervous system.
Asunto(s)
Sistema Nervioso Autónomo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Cisterna Magna/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Frecuencia Cardíaca/efectos de los fármacos , Cloruro de Mercurio/toxicidad , Intoxicación del Sistema Nervioso por Mercurio/etiología , Frecuencia Respiratoria/efectos de los fármacos , Antagonistas de Receptores Adrenérgicos alfa 1/administración & dosificación , Análisis de Varianza , Animales , Sistema Nervioso Autónomo/fisiopatología , Cisterna Magna/fisiopatología , Relación Dosis-Respuesta a Droga , Contaminantes Ambientales/administración & dosificación , Masculino , Cloruro de Mercurio/administración & dosificación , Intoxicación del Sistema Nervioso por Mercurio/fisiopatología , Intoxicación del Sistema Nervioso por Mercurio/prevención & control , Microinyecciones , Antagonistas Nicotínicos/administración & dosificación , Parasimpatolíticos/administración & dosificación , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Oxidative stress is an important mechanism in mercury poisoning. We studied the effect of uric acid, a natural and potent reactive oxygen species and peroxynitrite scavenger, in HgCl( 2)-induced nephrotoxicity. Rats were injected with a unique dose of HgCl(2) (2.5 mg/kg body weight, subcutaneously) and then vehicle (for 3 days, twice daily) or HgCl(2) (unique dose) and intraperitoneal uric acid suspension (250 mg/kg body weight, twice daily, for 3 days), and then killed at 24, 48 and 72 hours after HgCl(2) administration (n = 5 for each group). At the end of the experimental study, kidneys and blood samples were taken. Tissues were prepared and examined under light microscopy. Uric acid significantly prevented the increase in plasma levels of creatinine and blood urea nitrogen (BUN); it helped maintain systemic nitrate/nitrite concentration and total antioxidant capacity. Uric acid attenuated the increase of renal lipid peroxidation and it markedly diminished nitrotyrosine signal and histopathological changes as early as 24 hours after HgCl(2) administration. Uric acid did not prevent a decrease in beta-actin signal caused by mercuric chloride, but it promoted a faster recovery when compared to the HgCl(2) alone group. Our results indicate that UA could play a beneficial role against HgCl(2) toxicity by preventing systemic and renal oxidative stress and tissue damage.
Asunto(s)
Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & control , Riñón/efectos de los fármacos , Cloruro de Mercurio/toxicidad , Ácido Úrico/farmacología , Lesión Renal Aguda/metabolismo , Análisis de Varianza , Animales , Western Blotting , Interacciones Farmacológicas , Inyecciones Subcutáneas , Riñón/metabolismo , Masculino , Cloruro de Mercurio/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Ácido Úrico/administración & dosificaciónRESUMEN
Mercury induces structural and functional damage in several organs, however the effects of subtoxic doses of the metal on the male reproductive system are not well defined. In order to analyze testicular and epididymal morphological alterations and changes in IL-4 or IFN-gamma serum levels, adult male Sprague-Dawley rats received 0.01, 0.05 or 0.1 microg/ml of mercuric chloride (HgCl(2)) in deionized water for 1 to 7 months by oral route. Controls received deionized water alone. Twenty rats, separated in four groups of five animals each, were used per time of exposure. Progressive degenerative lesions consisting of lack of germ cell cohesion and desquamation, arrest at spermatocyte stage and hypospermatogenesis were observed in seminiferous epithelium by light and electron microscopy. Leydig cells showed cytoplasmic vacuolation and nuclear signs of cell death. Loss of peritubular cell aggregation was evidenced in the epididymis. Mercury accumulation was detected in both organs by mass spectroscopy. Rats showed enhanced IFN-gamma serum levels as compared to controls but only reached significance after 7 months of mercury administration. Subtoxic doses of inorganic mercury could lead to reproductive and immunological alterations. The results demonstrate that sublethal concentrations of mercuric chloride are enough to induce morphological and ultrastructural modifications in male reproductive organs. These contribute to functional alterations of spermatogenesis with arrest at spermatocyte stage, hypospermatogenesis and possibly impaired steroidogenesis which together could affect male fertility.
Asunto(s)
Interferón gamma/sangre , Cloruro de Mercurio/toxicidad , Testículo/efectos de los fármacos , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Conducta de Ingestión de Líquido/efectos de los fármacos , Epidídimo/efectos de los fármacos , Epidídimo/patología , Epidídimo/ultraestructura , Conducta Alimentaria/efectos de los fármacos , Interleucina-4/sangre , Masculino , Cloruro de Mercurio/administración & dosificación , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Testículo/patología , Testículo/ultraestructuraRESUMEN
Heavy metals have received great attention as environmental pollutants mainly because once introduced in the biological cycle they are incorporated in the food chain. Especially the mercury toxicity due to a diversity of effects caused by different chemical species should be emphasized. Heavy metal intoxication has been treated with chelating agents such as 2,3-dimercapto-1-propanol (BAL). However, the efficacy of this treatment is questionable due to the lack of specific effect on the toxic metal. The present study examined the effects of HgCl2 exposure (five doses of 5.0 mg/kg between ages 8 to 12 days) on physiological parameters, on porphobilinogen synthase activity, and on mercury content in liver, kidneys and brain from suckling rats. The effect of BAL (one dose of 12.5-75 mg/kg) applied 24 hr after mercury intoxication on these parameters was also investigated. The results demonstrate that HgCl2 intoxication induced a decrease of corporal weight gain as well as brain weight and an increase in renal weight. The inhibition of porphobilinogen synthase from liver and kidney, is still significant and was not modified by subsequent BAL treatment. However, BAL altered two effects induced by mercury: increase in death percentage and decrease in mercury contents in liver and kidney. The increase of mortality induced by mercury was not promoted by metal redistribution to brain nor by the increase of porphobilinogen synthase inhibition induced by metal. More investigations are necessary to determine if the different effects of BAL on intoxication by metals are possibly related to other tissues and/or if the probable metal-chelating complex formed is more toxic than the metal itself.
Asunto(s)
Dimercaprol/farmacocinética , Riñón/química , Hígado/química , Cloruro de Mercurio/farmacocinética , Mercurio/antagonistas & inhibidores , Porfobilinógeno Sintasa/farmacocinética , Animales , Animales Recién Nacidos/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Química Encefálica , Muerte , Dimercaprol/administración & dosificación , Dimercaprol/efectos adversos , Esquema de Medicación , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Inyecciones Subcutáneas , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Cloruro de Mercurio/administración & dosificación , Cloruro de Mercurio/antagonistas & inhibidores , Mercurio/química , Tamaño de los Órganos/efectos de los fármacos , Porfobilinógeno Sintasa/efectos de los fármacos , Porfobilinógeno Sintasa/metabolismo , Ratas , Ratas Wistar , Aumento de Peso/efectos de los fármacosRESUMEN
Dimercaprol is a compound used in the treatment of mercury intoxication, however with low therapeutic efficacy. It is assumed that dimercaprol acts by reactivating target sulfhydryl-containing proteins. In the present investigation we studied the inhibitory effect of mercuric chloride treatment (3 days with 2.3 or 4.6 mg/kg HgCl2, sc) in mice on cerebral, renal and hepatic delta-aminolevulinate dehydratase (ALA-D) activity, and a possible reversal of the effect of mercury by dimercaprol (0.25 mmol/kg, 24 hr after the last mercury injection). Mercuric chloride did not inhibit cerebral ALA-D at the doses injected. Dimercaprol treatment did not restore the normal enzyme activity of the liver after the 25% inhibition caused by 4.6 mg/kg HgCl2. In the kidney, dimercaprol enhanced the inhibitory effect of 4.6 mg/kg mercuric chloride (from 35% after mercury treatment alone to 65% after mercury plus dimercaprol treatment). Mercury content increased in kidney after exposure to 2.3 or 4.6 mg/kg and the levels attained were higher than in any other organ Mercury accumulated in liver only after exposure to 4.6 mg/kg HgCl2, and dimercaprol further increased mercury deposition. Dimercaprol treatment also increased the levels of mercury in brain of animals exposed to 4.6 mg/kg HgCl2 The enzymes from all sources presented similar sensitivity to the combined effect of HgCl2 and dimercaprol in vitro. In the absence of preincubation, 0-500 muM dimercaprol potentiated the inhibitory effect of HgCl2 on ALA-D activity. In the presence of preincubation, and 100 and 250 muM dimercaprol enhanced ALA-D sensitivity to mercury, whereas 500 muM dimercaprol partially protected the enzyme from mercury inhibition. Dimercaprol (500 muM) inhibited renal and hepatic ALA-D when preincubated with the enzymes. These data suggested that the dimercaprol-Hg complex may have a more toxic effect on ALA-D activity than Hg2+. Furthermore, the present data show that dimercaprol did not acts by reactivating mercury-inhibited sulfhydryl-containing ALA-D, and that indeed it may have an inhibitory effect per se depending on the tissue.
Asunto(s)
Antídotos/farmacología , Dimercaprol/farmacología , Cloruro de Mercurio/toxicidad , Mercurio/metabolismo , Porfobilinógeno Sintasa/metabolismo , Análisis de Varianza , Animales , Antídotos/administración & dosificación , Antídotos/toxicidad , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Dimercaprol/administración & dosificación , Dimercaprol/toxicidad , Inyecciones Subcutáneas , Riñón/efectos de los fármacos , Riñón/enzimología , Dosificación Letal Mediana , Hígado/efectos de los fármacos , Hígado/enzimología , Cloruro de Mercurio/administración & dosificación , Ratones , Tamaño de los Órganos/efectos de los fármacos , Distribución TisularRESUMEN
We have examined the effects of mercuric chloride on renal glomerular structure. Isolated glomeruli from mercury-treated rats (HgCl2, 5 mg/kg body wt, s.c.) 1 hour post injection presented a diminished cross-sectional area as compared with control glomeruli [control (micron2) = 26,310 +/- 2,545, HgCl2 (micron2) = 18,474 +/- 1,828] and higher glomerular calcium content (control = 23 +/- 6 nmoles/mg prot, HgCl2 = 43 +/- 7 nmoles/mg prot). Renal sections prepared for immunohistochemical and histochemical analysis showed larger deposits of fibronectin and lipids and enhanced cellularity in glomerular structures from HgCl2-treated rats. Moreover, mieloperoxidase activity measured in isolated glomeruli were also increased as compared with control preparations [MPO (U/mg prot): control = 59 +/- 7, HgCl2 = 134 +/- 10]. When the animals were studied 24 hours post HgCl2 injection, glomerular cross-sectional area values were not different from control values (25,276 +/- 1,983 micron2), while calcium contents were higher than values observed 1 hour after treatment (92 +/- 9 nmoles/mg prot). A similar pattern was observed in fibronectin deposits. Hypercellularity in glomerular structures and the higher mieloperoxidase levels were maintained at this time (MPO HgCl2-rats 24 h = 148 +/- 31 U/mg prot). The effects observed in this study are consistent with an inflammatory response in the glomerular structure of HgCl2-treated rats that could explain the altered renal function described in previous reports in our laboratory.
Asunto(s)
Antiinfecciosos Locales/toxicidad , Glomérulos Renales/efectos de los fármacos , Cloruro de Mercurio/toxicidad , Animales , Antiinfecciosos Locales/administración & dosificación , Nitrógeno de la Urea Sanguínea , Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Fibronectinas/metabolismo , Inmunohistoquímica , Inyecciones Subcutáneas , Glomérulos Renales/enzimología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Laminina/metabolismo , Masculino , Cloruro de Mercurio/administración & dosificación , Neutrófilos/citología , Neutrófilos/efectos de los fármacos , Peroxidasa/metabolismo , Ratas , Ratas WistarRESUMEN
The sensitivity of developing rodents to toxic metals differs considerably from that of adults. In the present study, we investigated the in vivo and in vitro effects of inorganic mercury and lead on delta-aminolevulinic acid dehydratase (ALA-D) from brain, liver, kidney and blood of young rats. Eight day-old rats were injected with one or five doses of lead acetate (0, 3.5, or 7.0 mg/kg) or HgCl2 (0, 2.5, or 5.0 mg/kg). In vitro, the IC50 for mercury inhibition of cerebral, renal and hepatic ALA-D was in the 124 to 160 microM range, while values for lead acetate was in the 7 to 12 microM range. The IC50 of blood enzyme for lead (0.8 microM) and mercury (6.5 microM) was significantly lower than that observed for the other tissues. A single dose of lead did not affect the enzyme activity, but a single dose of HgCl2 (5 mg/kg) caused a significant inhibition of ALA-D from kidney (40%, P < 0.01) and liver (25%, P < 0.05). Five doses of lead acetate (3.5 or 7 mg/kg) caused an inhibition of about 25 and 40%, respectively (P < 0.01), of hepatic ALA-D, and an increase of 1.4-fold (P < 0.05) and 2.6-fold (P < 0.01) of blood enzyme, respectively. Treatment with five doses of HgCl2 (5 mg/kg) caused an inhibition of about 25, 60, 50, and 80% of ALA-D from brain, blood, liver and kidney, respectively (all P < 0.05). Five doses of 2.5 mg/kg HgCl2 caused an inhibition of ALA-D from liver (40%, P < 0.01) and kidney (45%, P < 0.01). These results demonstrate that ALA-D from young rat tissues show different sensitivities to mercury and lead. The enzyme was more affected by mercury than by lead in vivo, while in vitro lead was more potent that mercury as an ALA-D inhibitor.