摘要:

Abstract:This study was investigated to clarify the role of intracellular Ca2+following endotoxin treatment (1 mg/kg, intraperitoneally) toD‐galactosamine‐sensitized mice (400 mg/kg, intraperitoneally), and to observe lipid peroxide levels, an index of hepatotoxicity, in endotoxin/galactosamine (Ga1N)‐challenged mice under activation of macrophages, especially Kupffer cells, by zymosan. The liver lipid peroxide level and serum glutamic pyruvic transminase activity in mice 18 hr after administration of endotoxin/Ga1N were markedly higher than those in mice treated only with endotoxin. In spite of an increase in lipid peroxide formation, there was little or no effect of Ga1N administration on xanthine oxidase and superoxide dismutase activities in mice given endotoxin. However, the injection of verapamil (10 mg/kg, subcutaneously) markedly decreased lipid peroxide levels in liver of endotoxin/Ga1N‐injected mice. In the mice given a Ca2+‐deficient diet, lipid peroxide level in liver after endotoxin/Ga1N injection was markedly decreased compared to that in mice fed a normal diet. Administration of dexamethasone (200 μg/kg, intraperitoneally) in mice 1 hr before treatment with endotoxin/Ga1N did not induce lipid peroxide formation. Administration of endotoxin to Ga1N‐treated mice resulted in a higher level of liver cytosolic free Ca2+([Ca2+]i) than that in endotoxin‐treated mice. On the other hand, Ca2+‐ATPase activity in liver plasma membrane in the endotoxin/Ga1N‐treated mice was markedly decreased as compared with endotoxin alone. On the contrary, the Ca2+‐ATPase activity in liver mitochondria was higher in endotoxaemic mice treated with Ga1N than in mice given endotoxin alone. State 3 respiration and respiratory control index, which are parameters of mitochondrial function, were decreased more in the liver of mice treated with endotoxin/Ga1N than in the endotoxin‐treated group. These findings suggest that [Ca2+]imay participate in the lipid peroxide formation which results from endotoxin/Ga1N‐induced hepatotoxicity under conditions of zymosan‐activated macrophages, and that the increases of endotoxin‐sensitivity caused by Ga1N challenge may greatly contribute to Ca2+‐

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00993.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:To determine the roles of the alternatively spliced short and long forms of the γ2 subunit in the effect of ethanol on the GABAAreceptor function, picrotoxin‐sensitive [35S]t‐butylbicyclophosphorothionate ([35S]TBPS) binding was studied in recombinant rat α1β2γ2 and α6β2γ2 receptors expressed in human embryonic kidney 293 cells. Ethanol (10–500 mM) in the absence of added GABA had only minor effects on [35S]TBPS binding irrespective of the γ2 splice variant, its effects being greater in α6β2γ2 than in α1β2γ2 receptors. Ethanol (100 mM) decreased the binding in all four subunit combinations at various concentrations of GABA, again an effect independent of the γ2 variant. The two γ2 variants had different effects on GABA modulation of the binding, with the long γ2 variant decreasing the efficiency of GABA inhibition in α6β2γ2 receptors and enhancing the biphasic GABA stimulation and inhibition in α1β2γ2 receptors. The findings confirm the importance of the α subunits in the allosteric interactions between the convulsant binding site and other effector sites, which can be modified only to a minor extent by the

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00994.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:2,5‐Hexanedione is a n‐hexane metabolite with neurotoxic properties. We have previously demonstrated that acute administration of 2,5‐hexanedione causes analgesia in the tail‐flick test in rats. In the present investigation, we examined the possible involvement of a cholinergic component in the 2,5‐hexanedione‐induced antinociception, since literature data indicate that this hexacarbon compound may act as a competitive inhibitor of acetylcholinesterase and that cholinesterase inhibitors are analgesic to rodents. Rats were treated with saline or with 5 or 25 mg/kg atropine (intraperitoneally) 10 min. before the injection of vehicle or 800 mg/kg 2,5‐hexanedione (intraperitoneally). 2,5‐Hexanedione caused a significant increase in tail‐flick latencies at 10, 30, 60 and 90 min. after hexacarbon injection. Atropine (5 or 25 mg/kg) partially reversed the analgesia caused by 2,5‐hexanedione at 60 and 90 min. When effects of 2,5‐hexanedione on brain acetylcholinesterase was assessedin vitro, the results demonstrated that a competitive component is involved in enzyme inhibition. Taken together, these data support the involvement of a cholinergic (muscarinic) component in 2,5‐hexane

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00995.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:The subtype of the functional presynaptic autoreceptor in adrenergic nerves of the male guinea‐pig urethra was pharmacologically characterised. The urethra was incubated with3H‐noradrenaline and superfused with Tyrode solutionin vitroand the fractional secretion of3H‐noradrenaline evoked by 300 electrical shocks at 5 Hz was measured. α‐Adrenoceptor antagonists enhanced the3H‐noradrenaline secretion. The effects of BRL 44408 ((±)‐2‐[(4,5‐dihydro‐1H‐imidazol‐2yl)methyl]‐2,3‐dihydro‐1‐methyl‐1H‐isoindole), BRL 41992 ((‐)‐1,2‐dimethyl‐2,3,9,13b‐tetrahydro‐1H‐dibenzo[c,f]imidazo[1,5‐a]azepine), and WB‐4101 (2‐([2,6‐dimethoxyphenoxyethyl]aminomethyl)‐1,4‐benzodioxane) were tested. The rank order of apparent EC50values was BRL 44408

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00996.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:The cardiotoxic effects of catecholamines have been explained in part by the generation of oxygen free radicals and aminochromes. The role of aminochromes remains however controversial. It has previously been demonstrated that adrenochrome, an oxidation product of adrenaline, shows cardiotoxic properties only at very high concentrations, and it has been suggested that the deleterious effects observed may be caused by a worsening in myocardial perfusion. The functional properties of adrenochrome were examined in isolated spontaneously‐beating rabbit hearts with depleted catecholamine stores (reserpin 7.0 mg/kg 16–24 hr before preparation, Langendorff, constant pressure: 70 cm H2O, Tyrode solution, [Ca++]sol1.8 mmol/l, 37°). Cumulative concentration‐response curves show an adrenochrome‐concentration‐dependent increase of contractility (left ventricular pressure, EC50= 3.6×10‐6M; +dp/dtmax, EC50= 1.6×10‐5M), whereas myocardial relaxation was impaired (‐dp/dtmax, EC50= 2.6×10‐5M; ‐dp/dtmax/+dp/dtmax= 0.68 at 10‐4M). Heart‐rate was only slightly enhanced (+10% at 10‐4M), and the coronary flow was markedly influenced only by adrenochrome 10‐4M (‐17%). The relative coronary flow (=global coronary flow/pressure‐rate product) was concentration‐dependently reduced (EC50= 10‐5M; −49% at 10‐4M). We conclude that in isolated rabbit hearts, adrenochrome has a positive inotropic action but impairs myocardial relaxation, and coronary constrictor activity prevents an increase of myocardial oxygen supply, thus worsen

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00997.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:This investigation aimed at examing the hypothesis that furosemide elicits renal sympathoexcitation through stimulation of renal renin release, which in turn produces increased plasma angiotensin II levels, causing centrally mediated sympathoexcitation. In addition, direct central nervous actions of furosemide on central control of mean arterial pressure, heart rate, and efferent renal sympathetic nerve activity were examined. Furosemide (300 mg/kg intravenously) was administered to four groups of rats: (1) control; (2) nephrectomized; (3) with intravenous losartan blockade (10 μmol/kg); and (4) with intracerebroventricular losartan blockade (10 nmol). In a fifth group of rats, furosemide was administered intracerebroventricularly (0, 2.5, 25 or 250 μg). To eliminate reflex control of mean arterial pressure, heart rate and efferent renal sympathetic nerve activity, all experiments were performed in rats with sinoaortic denervation and bilateral vagotomy. Experiments were performed during Saffan anaesthesia (0.9% alphaxalone/0.3% alphadolone), and rats were paralyzed with pancuronium and artifically ventilated. Furosemide produced an immediate 40% increase in efferent renal sympathetic nerve activity while the furosemide vehicle, 2 vol.% ethanolamine, did not affect efferent renal sympathetic nerve activity. The furosemide‐induced increase in efferent renal sympathetic nerve activity was abolished in rats with bilateral nephrectomy but it was not affected by intravenous or intracerebroventricular losartan blockade. Intracerebroventricular angiotensin II produced an increase in mean arterial pressure and efferent renal sympathetic nerve activity whereas intravenous angiotensin II produced a pressor response in absence of increased efferent renal sympathetic nerve activity. Losartan effectively blocked responses to intravenous or intracerebroventricular angiotensin II. Intracerebroventricular administration of furosemide produced no changes in mean arterial pressure, heart rate or efferent renal sympathetic nerve activity. It is concluded that intravenous administration of furosemide elicits an immediate increase in efferent renal sympathetic nerve activity via a renal mechanism independent of angiotensin II. Intracerebroventricular furosemide has no effect on central nervous control of mean arterial pressure, heart rate or efferent renal sympathetic nerve activ

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00998.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:This study assesses the contribution of metabolism for the disposition of pentamidine in the rat. With the use of14C‐labelled compound, the excretion of radioactivity in urine and faeces has been studied in four rats during 44 days after a single intravenous injection of the drug. The urinary and faecal excretion of the radioactivity were of equal importance; 22±2% (mean±S.D.) and 25±4% being detected in urine and faeces, respectively. The activity in organs and tissues at 44 days after drug administration was also measured and amounted to 21±5% of the administered dose. Using HPLC the proportion of metabolites in urine in relation to unchanged pentamidine increased with time after dose, being 76±15% (mean±S.D.) of the total excreted radioactivity on day 1 and 97±1% on day 6. HPLC ‐ tandem mass spectrometry was used for identification of metabolites in urine obtained from four rats given unlabelled pentamidine. Using synthetic reference compounds and the selective MS/MS mode four oxidized metabolites of pentamidine were identified either by direct injection into the system or by analyses of extracted urine. Thus, a substantial part of pentamidine is excreted as metabolite

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00999.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:This study was carried out to determine the effect of renal ischaemia on transport systems for organic compounds in the rabbit kidney proximal tubule. Ischaemia for 30 or 60 min. induced glucosuria and phosphaturia, which was accompanied by polyuria and natriuresis. The Na+‐dependent uptake of glucose, succinate and L‐glutamate by brush‐border membrane vesicles was not altered by 30 or 60 min. of ischaemia, while the H+/tetraethylammonium antiport was significantly inhibited after 30 min. of ischaemia. When the duration of ischaemia was extended to 120 min. the uptake of glucose and succinate by brush‐border membrane vesicles was also significantly attenuated, but the L‐glutamate uptake was not altered. The uptake of glucose, succinate and L‐glutamate by basolateral membrane vesicles was not impaired even with 120 min. of ischaemia, suggesting that transport systems for organic compounds in the brush‐border membrane are more sensitive to ischaemia than those in the basolateral membrane. Ouabain‐sensitive oxygen consumption in renal cortical slices was not depressed by 60 min. of ischaemia. When kidneys were reperfused for 60 min. following 60 min. of ischaemia, the Na+‐glucose and Na+‐succinate cotransport and the H+/tetraethylammonium antiport were not different from the control, but the recovery of alkaline phosphatase was significantly reduced. When kidneys were subjected to ischaemia for 60 min., a loss of brush‐border microvilli and plasma membrane was observed after 5 or 60 min. of reflow in the proximal convoluted tubule. After 3 hr of reflow, focal necrosis appeared although the microvilli were partially regenerated. These results indicate that renal ischaemia induces selective impairments of transport systems in the rabbit renal proximal tubule, and that the glucosuria and phosphaturia induced by transient ischaemia are results, at least in part, from a diminution of brush‐border surface area rather than a direct defect in the function of the mem

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb01000.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:Pregnant Syrian golden hamsters were given a single oral dose of203Hg‐labelled methyl mercury (MeHg), 1.6 μmol/kg body weight, on day 12 of gestation. The uptake, retention and tissue distribution of203Hg in the dams and pups was studied by γ‐counting during the following three weeks. The average transplacental transfer of203Hg was 1.1% of the administered dose per pup, corresponding to 11% of the administered dose to a whole litter. This was considerably more than in our previous studies when the dams were treated on gestational day 2 (1.3%) or 9 (4.6%). The amount of203Hg transferred to each pupin uterowas independent of the litter size. The average additional transfer of203Hg to a litter via milk was 1.7% of the administered dose. In the pups, the content of203Hg in the liver and brain decreased, while the content in the kidneys and pelt increased during the second and third week. The highest amount of203Hg was generally found in the pelt, which indicated that unweaned hamster pups primarily excrete MeHg by binding to hair. The chemical form of mercury in the liver and kidneys of the pups was determined by ion‐exchange separation of inorganic Hg and MeHg followed by γ‐counting. The amount of inorganic Hg in the liver of the pups remained constant throughout the experiment, while it increased in the kidneys after one week due to the demethylation of MeHg. The inorganic Hg in the liver of newborn pups was probably due to maternal demethylation of MeHg and transplacental transfer of inorganic Hg. This hypothesis was supported by the observed transplacental transfer of inorganic Hg in pregnant dams administered203HgCl2on day 12 of

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb01001.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:Untreated rabbit liver microsomes demonstrated the highest content of cytochrome P450 and activity of NADPH cytochromecreductase compared to rat and monkey. The sodium dodecyl sulfate polyacrylamide gel electrophoresis of microsomes from untreated rabbit demonstrated a greater quantity of 50 KDa polypeptide than in rat and monkey. The activity of glutathione‐S‐transferase towards 1‐chloro‐2,4‐dinitrobenzene and the band intensity of 26 KDa polypeptide was found to be at maximum in untreated rabbits, while rat liver demonstrated the highest activity of glutathione‐S‐transferase towards ethacrynic acid. The extent of hepatic microsomal lipid peroxidation was at maximum in untreated rats. The activity of catalase was higher in untreated monkeys compared to untreated rats and rabbits. Lindane at a dose of 10 mg kg‐1body weight for a period of six days increased the hepatic content of cytochrome P450 and the activities of NADPH cytochromecreductase, aminopyrine N‐demethylase, glutathione‐S‐transferases, haem oxygenase and lipid peroxidation, decreased non‐protein thiols and concomitantly intensified the 50 and 26 KDa polypeptides in the microsomes and 100,000xg supernatants respectively, in the rat but not in the rabbit or monkey. The results demonstrate that lindane is a bifunctional inducer in the rat and non‐functional in rabbit and monkey. It also increased the activities of hepatic drug metabolizing enzymes with concomitant production of oxidative stress in the rat, whereas in rabbit and monkey it did not alter the drug metabolizing enzymes nor prod

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb01002.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY