Background: Nondepolarizing neuromuscular blocking agents (NMBAs) are extensively used in the practice of anesthesia and intensive care medicine. Their primary site of action is at the postsynaptic nicotinic acetylcholine receptor (nAChR) in the neuromuscular junction, but their action on neuronal nAChRs have not been fully evaluated. Furthermore, observed adverse effects of nondepolarizing NMBAs might originate from an interaction with neuronal nAChRs. The aim of this study was to examine the effect of clinically used nondepolarizing NMBAs on muscle and neuronal nAChR subtypes.
Methods: Xenopus laevis oocytes were injected with messenger RNA encoding for the subunits included in the human [alpha]1[beta]1[varepsilon][delta], [alpha]3[beta]2, [alpha]3[beta]4, [alpha]4[beta]2, and [alpha]7 nAChR subtypes. The interactions between each of these nAChR subtypes and atracurium, cisatracurium, d-tubocurarine, mivacurium, pancuronium, rocuronium, and vecuronium were studied using an eight-channel two-electrode voltage clamp setup. Responses were measured as peak current and net charge.
Results: All nondepolarizing NMBAs inhibited both muscle and neuronal nAChRs. The neuronal nAChRs were reversibly and concentration-dependently inhibited in the low micromolar range. The mechanism (i.e., competitive vs. noncompetitive) of the block at the neuronal nAChRs was dependent both on subtype and the NMBA tested. The authors did not observe activation of the nAChR subtypes by any of the NMBAs tested. 相似文献
The article presents results of treatment of 21 patients with a surgical pathology and diabetes mellitus who had intraportal allotransplantation of cultures of islet cells of the pancreas and 316 patients with the similar surgical pathology without such transplantation. It was found that the intraportal introduction of islet cell cultures into the liver can result in an early and considerable drop of the injected insulin dose which is very important in the postoperative period. This method allowed to make the period of treatment at the hospital approximately 15 days shorter. 相似文献
The mechanisms by which ethanol inhibits testicular testosterone synthesis in rats were studied in vitro using isolated rat Leydig cells. The ethanol-induced inhibition was reversed by 4-methylpyrazole, an alcohol dehydrogenase inhibitor, suggesting that ethanol metabolism was responsible for this inhibition. L-glutamate and pyruvate, when added to the Krebs-Ringer incubation medium, reversed the inhibition by ethanol. The membrane glutamate receptor agonists kainic acid and quisqualic acid had no effects, indicating metabolic mechanisms for the L-glutamate action. This was verified also by observations that the metabolic transaminase inhibitors aminooxyacetate and cycloserine inhibited testosterone synthesis. In the amino acid supplemented Krebs-Ringer, pyruvate could not fully prevent inhibition by ethanol alone, but addition of L-glutamate to this medium abolished ethanol-induced inhibition. Experiments performed using a new inhibitor of testosterone biosynthesis in intact Leydig cells, triethylcitrate, indicated that active citrate metabolism, and/or efflux from mitochondria, was essential for the steroidogenic pathway from pregnenolone to testosterone in the smooth endoplasmic reticulum. The early steps of hCG stimulation before pregnenolone formation were most sensitive to its effect. Our results indicate that the inhibition of steroidogenesis by ethanol results from decreased availability of the metabolites involved in the substrate shuttles maintaining the NAD(P)H redox states between the mitochondrial and the smooth endoplasmic reticulum compartments, and that the inhibition can be overcome by a proper selection of exogenous sources for these metabolites. 相似文献
The histamine-storing neural system in adult and developing zebrafish (Danio rerio) was studied with immunocytochemical and chromatographical methods. Furthermore, the gene for histidine decarboxylase was partially cloned and its expression mapped with in situ hybridization. The histamine-storing neurons were only seen in the caudal hypothalamus, around the posterior recess of the diencephalic ventricle. Almost all parts of the brain, except the cerebellum, contained at least some histamine-immunoreactive fibres. The ascending projections had the rostral part of the dorsal telencephalon as a major target. Descending projections terminated in the torus semicircularis, central grey and inferior olive. A prominent innervation of the optic tectum, which has not been reported in other fish, was seen. The in situ hybridization gave a strong signal in cells with the same anatomical position as the histamine-immunoreactive neurons. The first histamine-immunoreactive neurons appeared in the ventral hypothalamus at about 85 h post-fertilization, and at 90 h, immunoreactive fibres terminated in the dorsal telencephalon. The embryonic histamine production described in mammals was lacking in this species. Both immunocytochemical and chromatographical studies indicated that histamine is absent in all other parts of the zebrafish body, and no specific hybridization was seen in any other part of the fish than the hypothalamus. The zebrafish could therefore be a very useful model for pharmacological in vivo studies of the histaminergic system of the brain, since the powerful peripheral actions of histamine should be lacking in this species. 相似文献
Abstract: Polycythaemia vera (PV) is a myeloproliferative disorder characterized by haematopoietic progenitor cells being hypersensitive to cytokines such as erythropoietin, interleukin-3, stem cell factor and insulin-like growth factor 1, which results in an increased production of mature blood cells. The pathogenetic cellular mechanism(s) behind this hypersensitivity to cytokines is unknown, but the number of cytokine receptors and the interaction between ligand and receptor are normal in PV. Interest has therefore focused on post-receptor mechanism(s). Haematopoietic cell phosphatase (HCP) is an intracellular tyrosine phosphatase that has been demonstrated to regulate proliferative signals negatively induced by the cytokines mentioned above. Moreover, motheaten mice that genetically lack HCP have an increased amount of erythroid progenitors that are hypersensitive to Epo, and patients with familial polycythaemia have been shown to exhibit a mutation of the Epo receptor gene that includes the docking site for HCP. We therefore studied mRNA expression of HCP in pure populations of CD34+ cells, granulocytes, platelets and lymphocytes from patients with PV, chronic myeloid leukaemia (CML) or essential thrombocythemia (ET), as well as healthy controls. Using a polymerase chain reaction analysis employing specific primers for HCP, we failed to detect any abnormalities of HCP expression in PV in any of the cell populations that were examined. Moreover, HCP mRNA expression was similar in ET and CML compared to controls. Finally, Western blot analysis revealed a normal HCP protein content in PV granulocytes and platelets. We therefore conclude that neither an impaired expression of the HCP gene nor a defect in HCP protein synthesis is present in PV, and does not seem to play a role in the aetiology of this disorder. 相似文献