Medizin - Open Access LMU - Teil 09/22 Archiv
249 Episoden
1 minute
1 minute
Torasemide is a new loop diuretic with a longer half-life and longer action than furosemide in healthy subjects. In order to evaluate the pharmacodynamic effects, single oral doses of furosemide (80 mg) and torasemide (20 mg), which were equipotent in healthy subjects, were given to 14 patients with cirrhosis and ascites. Before the study patients underwent an equilibration period of 4 days without diuretics. The drugs were alternated following a randomized double-blind cross-over design after a wash-out period of at least 2 days. Urine was collected at defined intervals for 24 h after drug administration and blood samples were taken before, 6 h and 24 h after medication. Torasemide induced greater cumulative 24 h diuresis (2863 ± 343 vs. 2111 ± 184 ml, p < 0.01) than furosemide. Torasemide did not differ from furosemide for cumulative 0–6 h sodium excretion (96 ± 17 vs. 92 ± 23 mmol sodium) but caused a more pronounced cumulative 6–24 h natriuresis (38 ± 11 vs. 17 ± 4 mmol, p < 0.05). Five patients exhibited a weak response to furosemide (0–36 mmol sodium/24 h, median 24 mmol; 690–1460 ml urinary volume/24 h, median 1325 ml). These patients showed significantly higher natriuresis and diuresis following torasemide (26–136 mmol sodium/24 h, median 78 mmol, p < 0.05; 1670–3610 ml urinary volume/24 h, median 2200 ml, p < 0.05). Twenty-four hours after administration of both drugs there were no significant changes in hemodynamic, renal or hormonal parameters. No adverse effects were noted with either treatment. These findings suggest that torasemide might be more advantageous than furosemide in the treatment of ascites due to cirrhosis.
1 minute
Previous studies suggested the expression of mRNA, coding for CNP, exclusively in the central nervous system. In the present study, using the polymerase chain reaction (PCR) technique instead of the less sensitive Northern blot hybridization, CNP-specific sequences have also been detected in rat atria and ventricles of the heart as well as in organs of the immune system (thymus, spleen and lymph nodes). Parallel PCR-assays documented ANP-mRNA in these tissues. To verify specificity of the PCR-products, Southern blots have been hybridized with a third internal oligonucleotide and amplification products have been sequenced. The relative level of CNP-mRNA in these tissues was estimated to be in the range of 1-9% of total brain CNP transcripts. The results suggest that the peptide may have a peripheral as well as a central site of action. In light of its pronounced effect on cell proliferation, particular interest should focus on a possible role of CNP in the immune system.
1 minute
Isolated ventral and dorsal rat spinal roots incubated in normal (2.5 mM) or high glucose (25 mM) concentrations or in high concentrations of other hexoses were exposed transiently to hypoxia (30 min) in a solution of low buffering power. Compound nerve action potentials, extracellular direct current potentials, and interstitial pH were continuously recorded before, during, and after hypoxia. Ventral roots incubated in 25 mM D-glucose showed resistance to hypoxia. Dorsal roots, on the other hand, revealed electrophysiological damage by hyperglycemic hypoxia as indicated by a lack of posthypoxic recovery. In both types of spinal roots, interstitial acidification was most pronounced during hyperglycemic hypoxia. The changes in the sensitivity to hypoxia induced by high concentrations of D-glucose were imitated by high concentrations of D-mannose. In contrast, D-galactose, L-glucose, D-fructose, and L-fucose did not have such effects. Resistance to hypoxia, hypoxia-generated interstitial acidification, and hypoxia-induced electrophysiological damage were absent after pharmacological inhibition of nerve glycolysis with iodoacetate. These observations indicate 1) that enhanced anaerobic glycolysis produces resistance to hypoxia in hyperglycemic peripheral nerves and 2) that acidification may impair the function of peripheral axons when anaerobic glycolysis proceeds in a tissue with reduced buffering power.
1 minute
Exposure of nervous tissue to hypoxia results in interstitial acidification. There is evidence for concomitant decrease in extracellular pH to the increase in tissue lactate. In the present study, we used double-barrelled pH-sensitive microelectrodes to investigate the link between lactate transport and acid-base homeostasis in isolated rat spinal roots. Addition of different organic anions to the bathing solution at constant bath pH caused transient alkaline shifts in extracellular pH; withdrawal of these compounds resulted in transient acid shifts in extracellular pH. With high anion concentrations (30 mM), the largest changes in extracellular pH were observed with propionate >l-lactate ≈ pyruvate >62; 2-hydroxy-2-methylpropionate. Changes in extracellular pH induced by 10 mMl- andd-lactate were of similar size. Lactate transport inhibitors α-cyano-4-hydroxycinnamic acid and 4,4′-dibenzamidostilbene-2,2′-disulphonic acid significantly reducedl-lactate-induced extracellular pH shifts without affecting propionate-induced changes in extracellular pH. Hypoxia produced an extracellular acidification that was strongly reduced in the presence of α-cyano-4-hydroxycinnamic acid and 4,4′-dibenzamidostilbene-2,2′-disulphonic acid. In contrast, amiloride and 4,4′-di-isothiocyanostilbene-2,2′-disulphonate were without effect on hypoxia-induced acid shifts. The results indicate the presence of a lactate-proton co-transporter in rat peripheral nerves. This transport system and not Na+/H+ or C1−/HCO−3 exchange seems to be the dominant mechanism responsible for interstitial acidification during nerve hypoxia.
1 minute
Na+ channel currents of rat motor and sensory nerve fibres were studied with the patch-clamp technique on enzymatically demyelinated axons. Differences between motor and sensory fibres in multi-channel inactivation kinetics and the gating of late single-channel currents were investigated. In the axon-attached mode, inactivation of multi-channel Na+ currents in sensory axons was best fitted with a single time constant while for motor axons two time constants were needed. Late single-channel currents in sensory axons were characterized by short openings whereas motor axons exhibited additional long single-channel openings. In contrast, in excised, inside-out membrane patches, no differences between motor and sensory fibres were found: in both types of fibre inactivation of multi-channel Na+ currents proceeded with two time constants and late single-channel currents showed short and long openings. After application of the reducing agent glutathione to the cytoplasmic side of excised inside-out patches, inactivation of Na+ currents in both motor and sensory fibres proceeded with a single, fast exponential time constant and late currents appeared with short openings only. These data indicate that the axonal metabolism may contribute to the different inactivation kinetics of Na+ currents in motor and sensory nerve fibres.
1 minute
The import of proteins into mitochondria is an intricate process comprised of multiple steps. The first step involves the sorting of cytosolically synthesized precursor proteins to the mitochondrial surface. There precursor proteins are recognized by specific receptors which deliver them to the general import site present in the outer membrane. The second stage of import involves a series of complex intraorganelle sorting events which results in the delivery of the proteins to one of the four possible submitochondrial destinations, namely the outer and inner membranes, the matrix and intermembrane space. Here in this review, we discuss the current knowledge on these intramitochondrial sorting events. We especially focus on targetting of proteins to the intermembrane space. Sorting to the intermembrane space represents a particularly interesting situation, as at least three separate targetting pathways to this subcompartment are known to exist.
1 minute
The phenotype of a fully differentiated, mature Schwann cell is appar-ently largely determined by Schwann cell-axon interactions. In vitro, elevation of intra-cellular cAMP levels in Schwann cells induces a phenotype which resembles that of a mature, i.e., axon-related, Schwann cell. Therefore, an important role for cAMP as a second messenger of axon-Schwann cell interactions in vivo is assumed. However, the effects of cAMP on Schwann cells are not restricted to induction of features of a mature phenotype. For example, elevation of intracellular cAMP levels results of also in a markedly increased synthesis of nerve growth factor (NGF) mRNA, which is barely detectable in intact sciatic nerves of adult animals. Furthermore, since cAMP induces myelin gene expression in cultured Schwann cells, additional regulatory mechanisms have to be postulated for the induction and maintenance of a mature non-myelinating Schwann cell phenotype. Here we show that a soluble protein growth factor can partially induce a non-myelinating mature Schwann cell phenotype in vitro. Treatment with transforming growth factor 1 (TGF-1) results in a marked and rapid downregulation of the low affinty NGF receptor (NGFR) on cultured Schwann cells without induction of PO gene expression. In contrast, in agreement with previous studies, an increase in PO mRNA levels and a reduction in NGFR mRNA after cAMP elevation is much slower when compared with the effect of TGF-1, suggesting the involvement of different intracellular mechanisms. Consistent with this hypothesis, we did not observe an induction of mRNA coding for TGR- isoforms after cAMP elevation in cultured Schwann cells which constitutively synthesize TGF-1 mRNA
