ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb01708.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Clearance experiments were performed in conscious rats in order to investigate whether intravenous infusion of the non‐selective α‐adrenoceptor antagonist phentolamine could block compensatory sodium reabsorption during furosemide‐induced volume contraction. By measuring inulin clearance, urinary excretion rates of sodium and water, and lithium clearance, the effects on proximal and distal nephron segments were dissociated. The renal effect of intravenous infusion of 0.3 mg/kg/hr phentolamine (n=6) was compared with time control animals (n=9). Furosemide was administered as constant intravenous infusion (7.5 mg/kg/hr) with simultaneous phentolamine infusion at four dose levels: 0 (n=9), 0.3 (n=6), 1.0 (n=7) and 3.0 mg/kg/hr (n=6). Phentolamine infusion reduced noepinephrine‐induced increase in blood pressure at all three dose levels (n=5). Phentolamine infusion induced transient antidiuresis and a prolonged antinatriuretic response. Compared with rats given furosemide only, phentolamine attenuated dose‐dependently the diuretic and natriuretic peak response to furosemide. This effect was associated with dose‐dependent reductions in mean arterial pressure. The reduced natriuretic response was due to a reduced fractional sodium excretion in the distal nephron segment (at all doses of phentolamine) and a reduction of the glomerular filtration rate (1.0 and 3.0 mg/kg/hr phentolamine). The fractional lithium excretion (FELi) increased to 65±3% at 0.3 mg/kg/hr phentolamine during the natriuretic peak response of furosemide, while it only increased to 52±3% during furosemide alone. At steady‐state conditions (120–180 min. after start of furosemide infusion) after infusion with furosemide plus 0.3 mg/kg/hr phentolamine the animals were still volume‐depleted, but the compensatory tubular Na reabsorption in the proximal tubules was inhibited (FELi=48±2% versus 39±1%>in rats given furosemide alone). During furosemide infusion plasma epinephrine increased 700% and plasma norepinephrine increased 50%. These results are compatible with increased systemic sympathetic nervous activity and a contributory role of proximal tubular α‐adrenoceptors in mediating compensatory sodium reabsorption during acute furosemide

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00417.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:A significant loss of human cytochrome P‐450 was observed during the anaerobic incubation of NADPH‐reduced human liver microsomes obtained from surgical samples, in presence of carbon tetrachloride or halothane. In order to prevent any interference in the classical spectrum of cytochrome P‐450 with CO, the method of Johannesen&DePierre (1978) was modified to obtain cytochrome P‐450 determination. The enzyme inactivation reaction showed pseudo‐first order kinetics and was accompanied by destruction of the haem tetrapyrrolic structure, as indicated by a significant loss of its porphyrin fluorescence. Values of about 200 and 700 were calculated for the partition ratio between metabolic turnover of the substrate and enzyme inactivation during reductive incubation of one of these microsomal preparations with limiting concentrations of CCl4and halothane, respectively. The results indicate that human liver cytochrome P‐450 can be inactivated reductivelyin vitroby CCl4and halothane reactive metabolites and suggest that a suicide type of mechanism, similar to that which was recently demonstrated to occur, for both substrates, with rat liver microsomes (Mannoet al.1988a&1991), may also be involved in the inactivation of the huma

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00418.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The effects of (+)‐S‐12967 and (—)‐S12968, isomers of a new dihydropyridine (1, 4‐DHP) derivative [2(7‐amino 2, 5‐dioxaheptyl) 3‐ethoxycarbonyl 4‐(2, 3‐dichlorophenyl) 5‐methoxycarbonyl 6‐methyl 1, 4‐dihydropyridine] were studied on contractile responses of isolated thoracic aortas from rats and compared to that of nifedipine. The maximal relaxant effect of both isomers was reached in about 2 hr whereas the maximal relaxant effect to nifedipine was obtained within 30 min. The two 1, 4‐DPH isomers and nifedipine had a far more potent inhibitory effect on potassium (K+) than on noradrenaline (NA) induced contractions. They shifted the K+, Ca2+and NA‐concentration response‐curves to the right and depressed the maximal vessel response to these agonists. Nifedipine was about 10 times more potent than the (—)‐isomer which again was about 100 times more potent that the (+)‐isomer. In contrast to nifedipine (–)‐S‐12968 and (+)‐S‐12967 had a dual action on K+and Ca2+‐induced contractions as both isomers in low concentrations, 3×10–9M and 3×10–7M, respectively, shifted the K+‐concentration response curves to the left and increased the maximal response. In K+‐depolarized preparations they increased the response to low Ca2+‐concentrations without affecting the maximal vessel response at the highest Ca2+‐concentrations. The result indicates that (+)‐S‐12967 and (—)‐S‐12968 possess Ca2+‐agonistic as well as Ca‐antagonistic properties. Compared to nifedipine both isomers are slow acting vasodilators. Their action as regards their pot

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00419.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:In order to compare characteristics of benzomorphan and phencyclidine receptors, binding of the ligands [3H]SKF10047 and [3H]phencyclidine (PCP) was measured in intact rat synaptosomal membranes and in membranes treated with a detergent (CHAPS, a twitterionic derivative of cholic acid). Ligand binding was quantified in the particle containing fractions and in particle‐free supernatants. About 20% of the SKF binding sites could be solubilized from the membranes by CHAPS under the conditions used here, while all PCP binding sites remained associated to particles. This observation and the inhibition patterns found for the two ligands indicate that the PCP receptors and the SKF receptors as delineated in this paper are indeed separat

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00420.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Acute and long term changes in nociception after administration of 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP) 80 mg/kg (four injections of 20 mg/kg given at two hr intervals) were investigated in mice. MPTP caused shivering, lacrimation, salivation, teeth chattering and fur erection a few minutes after drug injection, but all these behavioural changes were normalized within 30 min., when the first behavioural testing was performed. No significant alteration in general behaviour, sensorimotor performance or body temperature could be detected at the time of nociceptive testing. The acute effects of MPTP on nociception were a reduced response latency in the tail flick test and a prolonged response latency compared to controls in the constant temperature hot plate test. No significant effects of MPTP were found in the increasing temperature hot plate test. The long term effects were a reduced response latency both in the tail flick test and the constant temperature hot plate test, indicating that the MPTP induced lesions of dopaminergic pathways result in hyperalgesia. In the increasing temperature hot plate test and the formalin test, no significant long term changes were demonstrated. Seven days after injection, the dopamine content was reduced to 62% of control values in striatum, to 51% in the rest of the forebrain, and to 41% in the spinal cord. Noradrenaline levels were only slightly and transiently reduced. Serotonin levels were not affected 7 days after injection, but 14 days after injection, a great increase was found in the forebrain and in the spinal cord. The results suggest that dopaminergic systems tonically inhibit nociception. A functional adaptation starts to take place about one week after lesion, making an investigation of the time course important in studies of the functional effects of MPTP induce

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00421.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Previous work in our laboratory has demonstrated that sodium polystyrene sulfonate (SPS) significantly lowered serum lithium (Li) concentrations when administered in a single oral dose after an oral dose of lithium in a mouse model. The present study was designed to determine whether: 1) repetitive doses of SPS are effective in lowering serum lithium concentrations, 2) the effect of SPS on lithium concentration is dose related and 3) SPS enhances the elimination of lithium. Mice (N=144) were given orogastric LiCl (250 mg/kg) and then divided into 4 groups: Controls received water 0, 30, 90, 180, and 360 min. after LiCl; the Full‐Dose SPS Group received SPS (5 g/kg/dose) at equivalent times; the Half‐Dose SPS Group received SPS (2.5 g/kg/dose) at the same times; and the Elimination Group received water at 0 and 30 min. after LiCl and SPS at 90, 180 and 360 min. after LiCl. Subgroups of each group were sacrificed at 1, 2, 4 and 8 hr post‐treatment and serum analyzed for lithium concentrations. Statistical analyses revealed that, when compared to Controls: 1) SPS significantly lowered serum lithium concentrations; 2) this effect was dose‐related; 3) repetitive dosing of SPS appears to enhance the elimination of

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00422.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:A study was undertaken to examine the relationship between blood acetaldehyde levels and clinical responses in volunteers receiving the anti‐alcohol drugs disulfiram and calcium cyanamide. In the first part of this study volunteers received different doses of disulfiram (125 mg and 500+250 mg), of calcium cyanamide (25 mg, 50 mg and 100 mg) and of ethanol (0.2 g/kg orally and 0.5 g/kg intravenously). The ensuing interactions ranged from no reaction at all to an intense hypotensive cyanamide‐ethanol reaction (CER). A blood acetaldehyde concentration‐effect relationship was suggested. In the second part of this study seven subjects received 50 mg of calcium cyanamide 4 hr prior to an intravenous ethanol dose of 0.2 g/kg. The maximum blood level of acetaldehyde ranged from 16 to 241 μM. Aversive interactions started to occur at acetaldehyde levels around 40–60 uM. Changes in flushing reaction and diastolic blood pressure appeared best to reflect changing blood acetaldehyde levels. As a rule, however, the expected cyanamide‐ethanol and disulfiram‐ethanol reactions are more clearly registered as an increase in acetaldehyde levels than as the ensuing physiologic

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00423.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Concentration‐relaxation profiles for pinacidil, verapamil, terbutaline and theophylline were studied in guinea‐pig trachealis contracted by two commonly applied techniques for K+depolarization. All drugs were much less effective on contractions induced by hyperosmolar 124 mM K+solution (added KCl) than on contractions elicited by an isoosmolar 124 mM K+Krebs solution (substituted KCl). The maximal relaxant responses were (isoosmolar K+/hyperosmolar K+): pinacidil 100%/40%, verapamil 100%/60%, theophylline 100%/0%, terbutaline 50%/0%. Addition of mannitol to establish the same hyperosmolarity as with 124 mM KCl also produced contraction of guinea‐pig trachealis. Concentration‐relaxation curves for the drugs on mannitol‐induced contractions had close resemblance to those obtained in hyperosmolar 124 mM K+solution. When contraction was elicited by 30 mM K+, pinacidil showed seven times higher relaxant potency in hyperosmolar compared to isoosmolar solution, whereas the relaxant responses to verapamil, theophylline and terbutaline were not influenced by osmolality. When K+depolarization is used as a tool for evaluation of drug action in airway smooth muscle, the two different techniques produce dissimilar results. The influence of hyperosmolarity pec se appears to be an important and unwanted feature when K+depolarization is produced by additi

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00424.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:In the present study the effect of acutely administered (—)‐nicotine on locomotor activity was measured after direct bilateral microinjections into the nucleus accumbens (Acb) or into the ventral tegmental area (VTA) of rats. Intrategmental (—)‐nicotine (either 0.02 or 2 μg/side) increased locomotor activity, the effect being greatest after the lower dose. The stimulation began almost immediately and was shortlasting with peak activity occurring at 30 min. after injection. Intra‐accumbal (—)‐nicotine (either 0.02, 2 or 20 μg/side) caused only a marginal short enhancement of activity which was not dose‐dependent. The time course of enhanced activity was similar to that observed after intrategmental injection. Our results indicate that the nicotine‐induced hyperlocomotion may arise primarily from activation of VTA nicotinic cholinoceptors (nAchRs), whereas activation of the accumbal nAchRs is less significant in re

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00425.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY