European Journal of Pharmacology: Environmental Toxicology and Pharmacology最新文献

Long-term regulation of body weight and food intake were studied after rats were subjected to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which causes hypophagia and body weight loss, and to ventromedial hypothalamic lesion, which causes hyperphagia, metabolic changes and obesity. These two factors appeared to have an interaction, as ventromedial hypothalamic lesion initially aggravated the effects of TCDD on body weight and food intake. This was seen in both TCDD-resistant and TCDD-susceptible rat strains. In contrast, if TCDD was given several weeks before the lesion and body weight had stabilized to a low level, no aggravation was seen, but TCDD completely blocked the effects of ventromedial hypothalamic lesion. Thus, TCDD seems to affect the same regulation chain that is involved in the lesioning of the ventromedial hypothalamus. TCDD might serve as a tool in studying different mechanisms of long-term food intake and body weight regulation.

We studied the effects of ibuprofen on bronchial blood flow and myocordial function after inhalation injury. Sheep (n = 12) were chronically instrumented with cardiovascular and pulmonary catheters. After 5 days of recovery period, baseline data were collected and the sheep were divided into two groups. Group S (n = 6) were insufflated with 48 breaths of cotton smoke; while group I (n = 6) were pretreated with ibuprofen (12 mg/kg bolus followed by 3 mg/kg/h continuous infusion for 24 h) and challenged with the same dose of smoke. All the animals were studied for 24 h. Bronchial blood flow increased significantly in both groups throughout the experimental period; while stroke volume as well as right and left ventricular stroke work indices of both groups were significantly decreased (group I worse than group S) in the second half of the experimental period. These data suggest that vasodilatory prostaglandins do not play a major role in the bronchial vascular response to smoke inhalation injury and myocardial depression seen post injury is worse in animals treated with ibuprofen.

$\text{N}{}^{\mathrm{\omega }}\text{-}\text{nitro-}\text{L}\text{-arginine}$ methyl ester (L-NAME) is commonly used as a selective inhibitor for in vivo studies of brain nitric oxide (NO) synthase. We aimed to study the fate of $\text{N}{}^{\mathrm{\omega }}\text{-}\text{nitro-}\text{L}\text{-arginine}$ [¹¹C]methyl ester ([¹¹C]L-NAME) using position emission tomography in monkey and high performance liquid chromatography methods in dogs and rats. We found that [¹¹C]L-NAME was rapidly $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{= 2}\text{min}$) metabolized into $\text{N}{}^{\mathrm{\omega }}\text{-}\text{nitro-}\text{L}\text{-arginine}$ (L-NA) and [¹¹C]methanol which both had a slow rate of elimination. Although, in vivo L-NAME administration leads to long-lasting NO synthase inhibition by L-NA, methanol which is a potent neurotoxin in primate may produce detrimental effects unrelated to NO synthase inhibition.

The present findings provide experimental evidence for the hypothesis that an impairment of mitochondrial function may be involved in manganese neurotoxicity. Specifically, the treatment of dopaminergic neuronal-derived cell line (PC12) with MnCl₂ produced a significant inhibition of some mitochondrial complexes of the respiratory chain, while in the glial-derived cell line (C6) this effect was not observed. In PC12 the decrease in complex I activity was more pronounced than in other mitochondrial complexes. However treatment of cells with ZnSO₄ exerted no significant variations in enzymatic activities. A direct exposure of mitochondrial fraction to MnCl₂ reduced enzymatic activities of mitochondria in both cell lines adding further support to the proposed theory that the different sensitivity of the cells to manganese may be explained by a difference in uptake or intracellular storage. These data indicate that manganese neurotoxicity could be the result of a direct effect just on complex I activity or due to a secondary effect of oxidative stress induced by an excess of this transition metal.

To investigate the mechanisms underlying airway hyperresponsiveness a murine model was developed with several important characteristics of human allergic asthma. Mice were intraperitoneally sensitized with ovalbumin and after 4 weeks challenged via an ovalbumin aerosol. After aerosol, lung function was evaluated with a non-invasive forced technique. The amount of mucosal exudation into the airway lumen and the presence of mast cell degranulation was determined. Tracheal responsiveness was measured at several time points after challenge. At these time points also bronchoalveolar lavage and histology were performed. Sensitization induced high antigen-specific IgE levels in serum. Inhalation of ovalbumin in sensitized mice induced an immediate but no late bronchoconstrictive response. During this immediate phase, respiratory resistance was increased (54%). Within the first hour after ovalbumin inhalation increased mucosal exudation and mast cell degranulation were observed. At 12 and 24 h after ovalbumin challenge, mice showed tracheal hyperresponsiveness (29% and 34%, respectively). However, no apparent inflammation was found in the lungs or bronchoalveolar lavage. From these results it can be concluded that hyperresponsiveness can develop via mechanisms independent of an inflammatory infiltrate. Since mast cell degranulation occured after ovalbumin exposure, we hypothesize that mast cells are involved in the induction of airway hyperresponsiveness in this model.

These experiments were performed in an attempt to determine whether chronic stimulation of glomerular endothelial cells with recombinant human erythropoietin would alter mesangial cell proliferation. Glomerular endothelial cells in culture incubated with various concentrations of erythropoietin for up to 4 days exhibited dose-dependent endothelin-1 production. Moreover, the conditioned medium from erythropoietin-stimulated glomerular endothelial cells enhanced [³H]thymidine incorporation into mesangial cells. This enhancement was significantly attenuated in the presence of a endothelin. A receptor antagonist, BQ-123. These results suggest that endothelin-1 mediates erythropoietin-stimulated glomerular endothelial cell-dependent mesangial cell proliferation, resulting in the progression of glomerulonephritis.

We examined the effect of paracetamol treatment (650 mg/kg) on the function of the ATPase from rat hepatic mitochondria. The drug treatment caused an overall 35% decrease in ATPase activity, with a complete loss of the high affinity component as determined by substrate kinetic studies. The K_m for the intermediate and low affinity components decreased by about 30% without change in V_max, which may represent a compensatory mechanism. The drug treatment also resulted in a dramatic decrease in the phase transition temperature by about 19°C without affecting the energies of activation of the enzyme. Mitochondrial total phospholipid content increased significantly with a reciprocal decrease in the cholesterol content. The total phopholipid/cholesterol molar ratio increased by 50% after paracetamol treatment. However, phospholipid composition (as % of total) of the mitochondria was unaltered.

The aryl hydrocarbon (Ah) responsiveness of the T-47D, Hep G2, LS180, MCF-7, A431, C-4II and MDA-MB-231 human cancer cell lines was determined by the induction of CYP1A1 mRNA levels and ethoxyresorufin O-deethylase activity. With the exception of the MDA-MB-231 breast cancer cell line, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) significantly induced CYP1A1 mRNA levels and ethoxyresorufin O-deethylase activity in the remaining six cell lines and, based on their EC₅₀ values, for ethoxyresorufin O-deethylase induction, their Ah responsiveness followed the order T-47D > C-4II > MCF-7 > LS180 > Hep G2 > A431. In contrast, all the cell lines expressed the nuclear Ah receptor complex (167.1-24.5 fmol/mg protein) which bound to a ³²P-labeled consensus dioxin responsive element (DRE) in a gel mobility shift assay. The results of gel permeation chromatography and sucrose density gradient centrifugation studies showed that the calculated M_r values for the nuclear Ah receptor complex varied from 175 kDa (MDA-MB-231 cells) to 221 kDa (MCF-7 cells). In contrast, the photoaffinity labeled nuclear Ah receptor from all the cell lines gave a specifically labeled 110 kDa band and the apparent molecular weight of the nuclear Ah receptor complex cross-linked to a bromodeoxyuridine-substituted DRE was 200 kDa. The data show that the molecular properties and levels of the nuclear Ah receptor complex from seven different human cancer cell lines do not predict Ah responsiveness.

We studied the mechanism of antagonism of p-chloroamphetamine-induced neurotoxicity by dextromethorphan. The pretreatment with potent and selective σ receptor ligands, 4-phenyl-4-(1-phenylbutyl)piperidine (4-PPBP) and N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100), did not alter the reduction of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the cerebral cortex by repeated administration of p-chloroamphetamine. These results suggest that σ receptors might not play a significant role in the antagonism of p-chloroamphetamine-induced neurotoxicity by dextromethorphan.

Guinea pigs and mice infected with the parasitic worms Toxocara canis developed airway inflammation and tracheal hyporesponsiveness. Preceding inflammatory cell infiltration a brief hyperreactive response occurred in guinea pigs to histaminergic receptor stimulation at 3 days post infection (p.i.) and in mice to acetylcholine receptor stimulation at 1 day p.i. Few but large eosinophilic inflammatory foci developed in guinea pigs at 14 days p.i. Mice demonstrated progressive multifocal inflammation from 7 days p.i. In addition to eosinophils mouse airways were infiltrated by lymphocytes, forming perivascular and (partial) peribronchial infiltrates in an oedematous submucosa. The inflammation had resolved in guinea pigs at 35 days p.i., the trachea turning normareactive concurrently. The inflammation persisted in mice for ≥ 3 months and likewise persisted tracheal hyporeactivity. Incubation of trachea of non-infected mice with pulmonary inflammatory cells caused a significant decrease in cholinergic receptor responsiveness. This downward shift was prevented by 60% when a cyclooxygenase inhibitor was added to the incubation medium but not when inhibitors of lipoxygenase and superoxide formation were added, suggesting the involvement of prostaglandin E₂. This suggestion was supported by the finding of significantly increased prostaglandin E₂ concentrations in the bronchoalveolar lavage fluid at 14 and 28 days p.i.

It was concluded that tracheal hyporeactivity coincided with the presence of large numbers of eosinophils in the airways of both, guinea pigs and mice and that prostaglandin E₂ involvement was conceivable