摘要:

Abstract:The renal metabolism of sulindac‐sulphide was studied in subcellular fractions from human kidney. It was shown that renal microsomes, in the presence of NADPH, effectively catalyzed the sulphoxidation of sulindac‐sulphide. Also the mitochondrial fraction catalyzed the reaction but at a ten‐fold lower rate than the microsomes. Carbon monoxide, metyrapone and n‐octylamine did not inhibit renal sulphoxidation of sulindac‐sulphide and the reaction could occur in a monooxygenase containing fraction free from NADPH‐cytochrome P‐450 reductase. Hydroxylation of lauric acid was studied in microsomes and in the purified monooxygenase containing fraction under the same experimental condition as sulindac‐sulphide sulphoxidation. Lauric acid is a substrate known to be metabolized by a renal cytochrome P‐450 to 11 and 12‐hydroxylated products. This reaction was sensitive to carbon monoxide and did not occur in the absence of NADPH cytochrome P‐450 reductase. Based on these results we conclude that cytochrome P‐450 plays at the most a limited role in human kidney metabolism of sulindac‐sulphide. In contrast, sulphoxidation of sulindac‐sulphide was substantially reduced in the presence of methimazole suggesting a role of the flavin‐containing monooxygenase in the renal biotransformatio

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01868.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:Amperozide, a novel psychotropic agent, in concentrations lower than 10 μM caused a homogenous prolongation only of the action potential in both guinea‐pig and rabbit papillary muscle. In concentrations ≥ 10 μM, amperozide caused a flattening of the action potential plateau and the later part of the repolarization phase became slower (longer), probably reflecting an impaired repolarizing Na‐Ca exchange current. The overshoot (OS) and the rate of rise of the action potential (dV/dtmax) were depressed. It is concluded that amperozide has a blocking action on the transmembrane calcium current since Isi(second inward current), DIA (depolarization induced automaticity) and the peak force of contraction were depressed. The blocking of the Isiwas use‐dependent resembling the actions of calcium‐antagonists like verapamil, except that it was less potent at equimolar concentrations. Amperozide in concentrations where it acted as an Isi‐blocker (above 10 μM), had depressing effects only on ouabain‐induced oscillatory events. No major differences in the effects of amperozide were apparent between guinea‐pig, ferret or rabbit

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01869.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:In ferret and guinea pig papillary muscles enprofylline (10 μM‐10 mM) and theophylline (0.1‐2 mM) alone or in combination with terbutaline (0.05 μM‐0.1 μM) decreased the action potential duration and increased the plateau height, increased the peak force of contraction and facilitated the depolarization‐induced automaticity. In voltage clamp, the xanthines alone or in combination with terbutaline increased second inward currents, ICa,fand ICa,2, but had relatively less effect on the time‐dependent outward current. No qualitative differences between enprofylline and theophylline could be detected but the former was about 5 times more potent in increasing ICa,f.In clinically relevant concentrations, enprofylline and theophylline alone, or in combination with terbutaline caused a small (2‐5%) shortening of the ac

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01870.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:The binding characteristics of125I‐iodocyanopindolol (125I‐ICYP) and3H‐CGP‐12177 to intact hepatocytes and a particulate fraction prepared from hepatocytes from sham‐operated and partially hepatectomized rats were compared. In the paticulate fraction, the β‐adrenoceptor number increased 4‐10‐fold after partial hepatectomy.125I‐ICYP binding to intact cells demonstrated a high fraction of non‐specific binding, although phentolamine was included in the assay to reduce non‐specific binding.3H‐CGP‐12177 binding to intact cells also demonstrated a higher fraction of non‐specific binding than in most cell types. In intact cells, the β‐adrenoceptor number increased 5‐6‐fold after partial hepatectomy. The number of receptors was comparable in intact cells and the broken cell preparation, indicating that receptors are conserved during the prep

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01871.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:Plasma concentrations of morphine were followed for 24 hours in eight patients after intravenous and rectal administration of 10 mg morphine chloride. The plasma levels of morphine were determined by a sensitive and specific radioimmunoassay based upon an extraction procedure which separates morphine from its major polar metabolites. The bioavailability of morphine after rectal administration was found to be 53.3 ± 17.8% (mean ± S.D.). Peak concentrations of 16.3 ± 8.7 ng ml‐1were reached after 59 ± 16 min. The study indicates that first pass elimination of morphine may be partially avoided by rectal administr

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01872.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:The influence of the actual glycaemic level on the kinetics of insulin disappearance from plasma was studied in 16 type I diabetic patients. Constant intravenous infusion of insulin (1‐5 mU · kg‐1· min.‐1) was used to achieve different levels of steady state plasma free insulin concentrations, while the blood glucose level was clamped at normoglyc‐aemia, 4.1 ± 0.1 mmol/1 (mean ± S.E.M.), and mild hyperglycaemia, 8.2 ± 0.1 mmol/1. The experimentally determined data were compared using a previously validated model of first order kinetics for insulin disappearance from plasma in diabetic patients. At the physiological insulin concentration range the median clearance rate of insulin was 23 ml · kg‐1· min.‐1(range 16‐26) at normoglycaemia and 23 ml · kg‐1min.‐1(19‐35) at hyperglycaemia (P = 0.45). At supraphysiological levels, insulin was cleared at a lower rate at normoglycaemia than at hyperglycaemia. No correlation was observed between the insulin clearance rate and the duration of diabetes or the haemoglobin A1clevel (both Spearman's rho = 0.08). In conclusion, the insulin clearance rate from plasma is independent of the actual glycaemic level and hardly influenced by the long‐term glycaemic leve

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01873.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:The effect of 32 weeks' alcohol treatment on the number and affinity of dopamine and muscarinic receptor sites in rat striatum were measured using3H‐spiperone and3H‐quinuclidinylbenzilate (3H‐QNB) as radioligands. The number of dopamine receptor sites was 38 per cent and the number of muscarinic receptor sites 36 per cent lower in the alcohol group than in control rats. The differences in receptor affinities were less marked. In conclusion, a long‐term alcohol intake with rather moderate doses seems to induce a pronounced down‐regulation in dopamine and muscarinic receptor systems in rat

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01874.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:Previous studies from these laboratories have revealed that 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) induced acute profound release of dopamine together with a marked reduction in dopamine synthesis. The present study was undertaken in an attempt to further elucidate these acute alterations. MPTP produced dose‐dependent marked reductions in the concentrations of dopamine and noradrenaline in mouse brain 2 hours as well as 7 days after the administration. Both the acute and long‐term reductions in dopamine were most pronounced in the striatum, whereas the reductions in noradrenaline (acute and long‐term) were most pronounced in the cortical region. Contemporaneous with the acute reduction in the catecholamines, MPTP increased the levels of the dopamine metabolites 3‐methoxytyramine and homovanillic acid (HVA), and the noradrenaline metabolite normetanephrine. In contrast, the levels of the dopamine metabolite 3,4‐dihydroxyphenylacetic acid (DOPAC) were reduced. These data are indicative of a profound release of both dopamine and noradrenaline from the storage sites into the extraneuronal space. Pretreatment with the monoamine oxidase inhibitor pargyline totally prevented the acute reduction in dopamine and partially also the reduction in noradrenaline produced by MPTP. However, MPTP increased the levels of 3‐methoxytyramine and normetanephrine also in pargyline treated mice. The selective dopamine uptake inhibitor GBR 13098 antagonized the MPTP‐induced reduction in dopamine and increase in 3‐methoxytyramine, but had no effect on the MPTP‐induced reduction in noradrenaline. MPTP produced a marked acute reduction in tyrosine hydroxylation in the dopamine predominated areas striatum and limbic region, whereas a slight increase in tyrosine hydroxylation was noted in the noradrenaline predominated cortical region. Similar effects of MPTP were observed in reserpine pretreated animals. Pargyline prevented the MPTP‐induced reduction in dopamine synthesis. Recentin vitroobservations indicate that MPP+, the toxic metabolite of MPTP, is capable of inhibiting the electron‐transport carrier, an action which may account for the neurotoxicity of the compound. It appears possible that this effect of MPP+could explain the currently observed acute chan

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01875.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:5‐Aminosalicylic acid seems to be the active moiety of sulfasalazine in the treatment of chronic inflammatory bowel disease. Even if the precise mode of action is obscure, it is assumed that two of the main mechanisms are inhibitory effects on the lipoxygenation of arachidonic acid and interaction with free radicals. As 4‐aminosalicylic acid has been claimed to be beneficial in the topical treatment of ulcerative colitis, it was tested whether this drug possesses any influence on the 5‐lipoxygenase activity in human neutrophilsin vitroor whether it acts as a radical scavenger. The change of the amino residue from carbon‐5 to carbon‐4 abolished the effect in the two systems tested. The reported clinical observations on 4‐aminosalicylic acid in the treatment of chronic inflammatory bowel disease remain to be confirmed and cannot be explained by interference with arachidonic acid metabolism or free oxyg

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01876.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:Uptake of3H‐choline and the binding of3H‐hemicholinium‐3 in the cerebral cortex was investigated in male Wistar rats of different ages. The effect of Al3+‐ions on3H‐choline uptake was also studied. Na‐dependent high affinity uptake of3H‐choline and3H‐hemicholinium binding were lower in 10‐ to 11‐month‐old rats than in 3‐ to 4‐month‐old rats. There was no further decline in these parameters from 10‐ to 11‐month‐old to 24‐ to 25‐month‐old rats. Al3+‐ions had no effect on the uptake of3H‐choline. The present study supports the hypothesis that there is a relationship between Na‐dependent high affinity uptake of3H‐choline and the binding of3H‐hemicholinium in the crude

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01877.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY