摘要:

Abstract:The 5‐HT3receptor antagonists such as ondansetron have been shown to have anxiolytic‐like activity in a wide range of preclinical tests: in the mouse black: white test, the rat social interaction test, the rat elevated X‐maze and the marmoset human threat test. Ondansetron, like other 5‐HT3receptor antagonists appears to have important advantages over existing anxiolytic therapies. Thus, the 5‐HT3receptor antagonists are not sedative, they do not have addictive liabilities, there are no problems of withdrawing from chronic treatment and they can be used following benzodiazepine withdrawal. Such compounds even inhibit the behavioural syndrome associated with withdrawal from drugs of abuse, nicotine, alcohol, cocaine, opiates. The preclinical data, therefore, indicates the 5‐HT3receptor antagonists as novel anxiolytics of the future, and there is new clinical work in support of this

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00448.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:To compare the function of sodium transport between intestine and renal tubule, we studied the effect ofE. coliSTa enterotoxin and 8‐bromo cyclic GMP in perfused rat kidneys. Infusion of STa enterotoxin (0.017 and 0.1 μg/ml) caused a dose and time dependent decrease in total renal sodium tubular transport. The major site of STa effect was at the renal proximal tubule. Similar to Sta enterotoxin, 8‐bromo cyclic GMP (10–5M) caused a significant decrease of fractional renal sodium proximal tubule transport. In contrast to STa enterotoxin, infusion of 8‐bromo cyclic GMP resulted in a significant but short lasting (30 min.) increase in glomerular filtration rate. STa enterotoxin also decreased significantly the renal tissue potassium. This STa effect was related to a significant decrease in renal potassium tubular transport, resulting also in an increase of urinary potassium excretion. These studies demonstrate the specific functional effect of STa enterotoxin in promoting the decrease in renal proximal tubular sodium transport, similar to 8‐bromo cyclic GMP. In perfused rat kidneys STa also decreased tissue potassium, mainly by a decrease in potassium transport and increase in urinary potassium excretion. These effects suggest the existence of an endogenous peptide resembling STa enterotoxin, that regulates the function of renal sodium tubular

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00449.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:We studied the onset and offset of use‐dependent block (UDB) of maximum rate of rise of action potential (V̇max) with 3 × 10–5M mexilietine in guinea pig left atrium. A large decrease of V̇max was observed between the first and the second excitation when the preparations were stimulated at 4Hz after two minutes of rest period. UDB after the second excitation developed slowly to reach steady state within 30 sec. These two onset rates were 1.016 ± 0.055 and 0.070 ± 0.009/action potential. Recovery process was also fitted with two exponential equations. The time constant of the fast recovery was 528 ± 23 msec, and the slow one was 3099 ± 435 msec. The relative contribution of the slow component was 38.3 ± 2.6% in the onset and 29.7 ± 3.1% in the recovery. In spite of elevated maximum diastolic potential at 4 Hz stimulation, the relationship between resting membrane potential and V̇max disclosed voltage‐dependent block of V̇max was no more than 5%. It is concluded that mexiletine has a slow kinetic component as well as a fast one. When atrial muscle is depolarized, V̇max decreases further. Therefore, mexiletine may be more effective against the atrial arrhythmias than pre

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00450.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Aluminium (A1) accumulation occurs in the liver of renal patients and in patients on parenteral nutrition. Human hepatotoxicity is not proven. The role of the liver in storage and biotransformation of A1 and in development of osteo‐ and neurotoxicity is not clarified as yet. The aim of the present investigation was to study the storage of A1 in total liver and in subcellular liver fractions, and its association with soluble cytosolic molecular species. Therefore, rats were loaded with A1 prior to liver fractionation by ultracentrifugation, and equilibrium gel filtration chromatography of the cytosol, using a previously described method for A1 speciation in serum. A1 accumulated dose‐dependently in liver and subcellular liver fractions, the lowest levels occurring in the cytosol. A dose‐dependent elevation of A1 in the blood was also observed. Gelfiltration of the cytosol indicated that A1 was associated with a low molecular weight form which was not a citrate complex, and a high molecular weight form, which was larger than transferrin. No induction of and association with metallothionein occ

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00451.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:We examined the possibility of predicting the extent of hepatic drug‐oxidizing capacity by determination of caffeine, trimethadione and their metabolites in three groups of rats with chemically induced liver injuries. Trimethadione (4 mg/kg) and caffeine (10 mg/kg) were simultaneously administered as two probe drugs. In rats with chemically induced liver injuries pretreated with carbon tetrachloride (CCl4: 0.25 ml/kg), α‐naphthylisothiocyanate (ANIT: 40 mg/kg), or D‐galactosamine (GalN: 400 mg/kg), the half‐life (t1/2) of caffeine and trimethadione was significantly (P<0.01) prolonged compared to those of control groups total body clearance as dramatically reduced (P<0.01), whereas apparent volumes of distribution (Vds) were increased in ANIT and GalN groups. In rats with liver damage the production of three metabolites (theobromine, paraxanthine and theophylline) of caffeine as well as the only metabolite (dimethadione) of trimethadione after oral administration of both drugs were significantly decreased compared to those of controls. In rats with liver injuries, total body clearance of caffeine and trimethadione showed a strong correlations (r = 0.99, P<0.01); also total body clearance of caffeine correlated well with the ratio of dimethadione/trimethadione after 1, 2, and 4 hr of trimethadione administration (r = 0.93, P<0.01; r = 0.97, P<0.01 and r = 0.97, P<0.01 respectively). Besides, total body clearance of caffeine also correlated well (coefficients ranging from 0.74 to 0.96; P<0.01) with the ratio of theobromine/ caffeine, paraxanthine/caffeine and theophylline/caffeine after 1, 2 and 4 hr) of caffeine administration. These findings indicate that the hepatic drug‐oxidizing capacity can be evaluated by measuring the plasma concentration ratios of caffeine or trimethadione to their metabolites using single blood sampling within a short time (1 or 2 hr) after administration of caffeine or trimethadione to rats with chemically induced live

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00452.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The effect of various solvents on the central nervous system was studied by using rat brain synaptosomal membranes as anin vitromodel. The activity of (Ca2+/Mg2+) ATPase and the membrane fluidity was determined. The alteration of the ATPase activity depended on the physio‐chemical characteristics of the solvent in question. Incubation with aliphatic alkanes caused a stimulation of the ATPase activity whereas mixed hydrocarbons as kerosene, white spirit and gasoline inhibited the enzyme. Incubation with chlorinated hydrocarbons caused a biphasic response dependent on the concentration. Oxygen‐containing hydrocarbons exhibited various effects as found after incubation with hydrocarbons. The different effects of the solvents on the ATPase activity suggest that the lipophilicity of the solvents is one of more parameters affecting the membrane. Furthermore, the biphasic response following the incubation with chlorinated hydrocarbons indicates that more mechanisms are involved in the enzyme effect. The membrane fluidity is increased with higher concentrations of the solvents. From the results it is concluded that the ATPase activity depends not only on the membrane fluidity and volume, but also on the hydrophilic vicinity of the enzyme molec

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00453.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:We have investigated the effect of non‐immunosuppressive cyclosporin A (CS‐A) doses on glucose tolerance, pancreatic insulin content, insulin content of isolated islets and insulin secretionin vitroin response to glucose. Within 12 weeks animals treated permanently with a dose of 2.5 mg CS‐A/kg b.wt. developed glucose intolerance (but not hyperglycaemia) accompanied by a decrease of pancreatic insulin content due to a decrease of islet insulin content, whereas the relative B‐cell volume density was.not changed. Isolated islets obtained from rats treated for 4 weeks had a diminished sensitivity for glucose, whereas islets obtained from animals treated for>4 weeks showed a diminished half‐maximum and maximum secretion rate. Rats treated for 12 weeks with 1.25 mg CS‐A/kg b.wt. developed an impaired glucose tolerance after 8 weeks accompanied by a diminished pancreatic insulin content. Despite continued treatment the pancreatic insulin content was able to increase and the glucose tolerance to normalize, indicating an adaptation of pancreatic B‐cells to CS‐A. The results support the theory that a potential toxic effect of cyclosporin A can be diagnosed by functional tests (e.g. insulin secretion in response to a stepwise increase of glucose) before the irreversible (e.g. morphological) al

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00454.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:In the absence of GTP or its analogues, the β‐adrenoceptor agonist (H), the receptor (R) and the stimulatory guanine nucleotide‐binding regulatory protein (Gs‐protein) form a slowly dissociable complex (HRGSGDP). It is presumed that the agonist in this ternary complex is bound to the receptor with high affinity while its binding to the receptor in the HR‐complex is of low affinity. We have studied the effect of Mg2+on the formation of these two complexes by the displacement of (‐)‐[3H]CGP‐12177 with (‐)‐isoprenaline in cell membranes prepared from guinea‐pig lung parenchyma. In the absence of Mg2+, only monophasic displacement curves were obtained with a dissociation constant not differing from that obtained in the presence of Gpp(NH)p and Mg2+. In the presence of Mg2+and absence of Gpp(NH)p, a shallow binding curve was obtained that fitted a two site model best. One of the dissociation constants agreed well with that obtained in the presence of Gpp(NH)p and Mg2+but the other one was 27 times smaller. It was concluded that Mg2+is necessary for the coupling between the HR‐complex and the Gs‐protein. The two dissociation constants obtained in the absence of Gpp(NH)p represent the dissociation constants of the HR‐ and HRGSGDP‐complexes and may correspond to those named KLand KHin the literature. According to our study, there may be no difference in affinity between the agonist and receptor in the HR‐ and HRGSGDP‐complexes. The two dissociation constants obtained in the absence of GTP or its analogues re

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00455.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:W84 (hexamethylene‐bis‐[dimethyl‐(phthalimidopropyl)‐ammonium bromide]) is an experimental antidote against organophosphorus poisoning and has been found to affect muscarinic cholinoceptors allosterically. The attempt was made to test whether the W84‐action on muscarinic cholinoceptors depends on the species. For this purpose, the effect of W84 on the binding of [3H]N‐methylscopolamine ([3H]NMS) was investigated in membrane‐suspensions from the hearts of guinea pigs, rats, and pigs in 3mM MgHPO4, 50 mM Tris, pH 7.3, at 23°. W84 inhibited [3H]NMS‐binding in the three membrane suspensions with similar potency (half‐inhibitory concentration IC50: 2‐5μM). To evaluate the allosteric activity of W84, its effect on the dissociation of [3H]NMS was determined. At 3μM, W84 diminished the rate of [3H]NMS‐dissociation to about 20% of the control in the three suspensions. At 3μM of W84, [3H]NMS‐dissociation was almost prevented. In conclusion, W84 acted equally on the cardiac cholinoceptors of guinea pigs, rats, and pigs, respectively. It can be anticipated that M2‐cholinoceptors of other species woul

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00456.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The goal of our study was to examine the effects of amiloride on distal renal tubule calcium and sodium absorption at low and high luminal pH.In vivomicroperfusion of distal convoluted tubules were performed on rats. Total Ca and Na concentrations in perfusion and collected fluids were measured by atomic absorption spectrometry. When tubules were perfused with low pH perfusate (pH = 5.6), net calcium absorption (JCa) averaged 5.4 pmol/min. With high pH perfusate (pH = 7.1), JCawas significantly higher averaging 8.9 pmol/min. (P<0.01). In contrast, net sodium absorption (JNa) was not affected by luminal pH (231 pmol/min. versus 237 pmol/min.). At low luminal pH, 10–4M amiloride analogue (5‐N‐methyl‐N‐isobutyl amiloride) (MIA) inhibited sodium absorption but stimulated calcium absorption. At high luminal pH MIA still inhibited Na absorption but it had no effect on calcium absorption. Thus, the natriuretic effect of amiloride appears to be independent of luminal pH, while the amiloride‐stimulated distal calcium absorption is observed at low but not at high

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00457.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY