摘要:

Alloxan inhibited hexokinase activity in cytoplasmic fractions of transplantable radiation‐induced rat islet cell tumours, ob/ob mouse pancreatic islets, rat liver and rat kidney. Half maximal inhibitory concentrations of alloxan were greater than those previously found for half maximal inhibition of pancreatic islet or liver glucokinase. D‐glucose, preferentially the α‐anomer, and D‐mannose protected hexokinase activity against alloxan inhibition. 1,4‐Dithiothreitol completely protected against and partially reversed the alloxan inhibition of hexokinase. The ability of various dithiols to reverse the inhibition of hexokinase by alloxan was dependent on the spacing between the SH (thiol) groups. Only dithiols with intermediate spacing between the SH groups were effective. Dithiols with two vicinal SH groups such as 1,2‐dimercaptoethane and 2,3‐dimercaptopropanol (BAL) and dithiols with more widely spaced SH groups such as 1,5‐dimercaptopentane were ineffective. Thus a reaction of alloxan with two SH groups in the sugar binding site of the hexokinase with the formation of a disulfide bond may be involved in the reversible inhibition of the enzyme. Ninhydrin also inhibited hexokinase from all four tissues studied. The half maximal inhibitory concentrations of ninhydrin were lower than those of alloxan. Inhibition of hexokinase may be an important factor in the general cytotoxic action of ninhydrin. However, inhibition of pancreatic islet hexokinase is unlikely to be the initial event in the pancreatic B‐cell toxic action of alloxan, even if inhibition of hexokinase by high concentrations of alloxan may contribute to the B‐cell toxic action. Accordingly transplantable radiation‐induced rat islet cell tumours, in which glucose metabolism is primarily based on a high affinity glucose phosphorylating enzyme (hexokinase) activity, show resistance to alloxan toxicity. This contrasts with normal pancreatic B‐cells, which display high sensitivity to alloxan action and have a glucose metabolism critically dependent on the availability of low affinity glucose phosphorylating enzym

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00725.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

Serum verapamil and metabolite concentrations were determined by HPLC in 29 patients in routine treatment with verapamil, and 23 were in steady state. Dosage levels and corresponding mean trough levels (± S.D.) were as follows: 120 mg daily: 79.1 (±77) nmol/1, 240 mg daily: 173.3 (±200.1) nmol/1, 360 mg daily: 204 (±110.2) nmol/1 and 480 mg daily: 361.0 (±231.4) nmol/1. The variation coefficients were 97.3, 115.4, 54.0, and 62.1, respectively, thus showing considerable interpatient variation. Repeated determination of trough levels showed, in contrast, only small intrapatient variation (variation coefficient 35.8, 1.9, and 7.4, at the dosage levels 120, 240 and 340 mg per day). No significant correlation was found between serum verapamil levels age, sex, or weight. No significant effect of digoxin on the concentration of serum verapamil was found. No relation was observed between serum verapamil concentrations and desired effect or side‐effects. Two patients showed no measurable serum verapamil, but one of these had detectable levels of metabolites. Such patients may represent subgroups of fast metabolizers or non‐absorbers. Measurements of the metabolites nor‐verapamil, D 620 and D 617 indicated saturation of the first‐pass metabolism. In conclusion, therapeutic drug monitoring is not indicated during routine verapamil treatement, whereas single measurements of verapamil may be warranted in patients not responding to treatment in order to identify fast metabolizers or n

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00726.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

The high affinity binding of3H‐alaproclate to membranes in liver homogenates from naive rats and those treated with phenobarbital sodium, 75 mg/kg intraperitoneally, alaproclate hydrochloride, 40 mg/kg intraperitoneally proadifen hydrochloride, 40 mg/kg intraperitoneally once daily for 7 days and killed 24 hr after the last injection was examined. The treatment increased the normal number of alaproclate binding sites (Bmax: 1.1 nmol/g tissue, KD: 0.6 nM) by factors of about 10, 4 and 6, respectively. About 80% of the binding was localized to the microsomal fraction in both normal and phenobarbital treated rats. Ninety % of the alaproclate displaceable binding in a microsomal preparation of the normal liver was inhibited by low (nM) concentrations of proadifen whereas only about 20% in the liver preparations from phenobarbital treated rats was inhibited by low concentrations of proadifen. Thus, the main part of the induced binding sites was insensitive to proadifen. The same was found for the alaproclate and proadifen‐induced alaproclate binding sites. The stereoselectivity of alaproclate enantiomers for binding to the normal and the induced binding sites was different: the S–(–) form was 100 times more potent than the R–(+)‐ enantiomer in inhibiting binding of racemic alaproclate to the normal sites, whereas the latter form was 3 times more potent than the former in inhibiting the binding to the phenobarbital‐induced proadifen insensitive binding sites. High affinity for the alaproclate binding sites in normal liver seems to require an ester function since the keto analogues 2‐amino‐6‐(4‐chlorophenyl)‐5,5‐dimethyl‐3‐hexanone and especially 5‐amino‐1‐(4‐chlorophenyl)‐2,2‐dimethyl‐3‐hexanone were much less active than alaproclate, the isopropyl analogue 2‐(4‐clorophenyl)‐1,1‐dimethyl 2‐amino‐3‐methylbutanoate and proadifen. All other compounds tested had quite low affinity for the alaproclate binding sites in the liver. Quinidine was the most potent of these compounds in normal liver and desipramine in livers from phenobarbital treated rats. High or moderate high affinity alaproclate binding s

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00727.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

The influence of x‐opioid receptor agonists and antagonists on release of oxytocin and vasopressin was examined in isolated rat neurointermediate lobes. Electrically evoked release of oxytocin and vasopressin was concentration‐dependently inhibited by the specific x‐receptor agonist U69593, whereas bremazocine only inhibited the secretion of oxytocin markedly. Treatment with naloxone enhanced the evoked release of oxytocin significantly without effect on vasopressin secretion. The U69593‐mediated inhibition of oxytocin release was abolished by naloxone, whereas that of vasopression was unaffected. Naloxone did not reverse the bremazocine‐induced inhibition of hormone release. The data support the theory of an inhibiting endogenous control over oxytocin secretion and show that the release of oxytocin and vasopresin is differentially affected by the two K‐recept

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00728.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

The effects of o,p'‐DDD on the DNA synthesis in the C57B1 mouse lung and liver were studied. As determined by3H‐thymidine incorporation into DNA, a selective increase in the lung DNA synthesis (+59%) was observed 2 days after a single intraperitoneal injection of 100 mg/kg o,p'‐DDD. Microautoradiography showed that the incorporated3H‐thymidine was confined to a restricted number of heavily labelled cells, presumably proliferating type II cells. At the most, a 9 times higher rate of cell proliferation was observed in the lung 4 days after an intraperitoneal injection of 500 mg/kg o,p'‐DDD. Using mouse lung or liver S‐9 as activating system, no mutagenic activity of o,p'‐DDD was detected in the Ames test. The induced cell proliferation may indicate a tissue‐selective promotor activity of o,p'‐DDD

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00729.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

Morphine‐3‐glucuronide (M3G) is the major metabolite of morphine and is present in the circulation of persons treated with morphine or abusing heroin. This project was designed to study the kinetics of M3G in the foeto‐maternal compartment, since this metabolite may be of relevance for the abstinence syndrome observed in neonates of pregnant abusers. The kinetics of M3G were studied in two non‐pregnant and four pregnant Rhesus monkeys. M3G was given as a bolus injection in four of the animals and as a long‐term infusion for 12 hr in two animals. M3G passed slowly across the placenta to the foetus and amniotic fluid. After 10 hr of M3G infusion, the foetal plasma M3G concentration was measured in two cases and found to be 37% and 72%, respectively, of the maternal conc

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00730.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

The effects of ethanol on two types of bulbar expiratory neurones, post‐inspiratory (early expiratory) and expiratory (late expiratory) neurones, were studied in decerebrated, paralyzed and artificially ventilated cats. Intravenous injection of ethanol (300 mg/kg) depressed the efferent activity in the phrenic and recurrent laryngeal nerves which displayed the augmenting discharge during inspiration and the decrementing discharge during the early stage of expiration (stage I expiration). It reduced the duration of expiration, with a preferential effect on stage I expiration. Out of 22 medullary respiratory neurones consisting of 14 post‐inspiratory and 8 expiratory neurones, 12 neurones were depolarized by ethanol and 10 neurones were hyperpolarized. In both cases, the respiratory fluctuations of membrane potential diminished and synaptic noises decreased. Input resistances of these neurones remained unchanged. Ethanol depressed the spike activity during stage I expiration of the post‐inspiratory neurones. In expiratory neurones, a suppression of firing was greater in stage I expiration than in later stages of expiration. The present results demonstrate that ethanol reduces the expiratory period mainly through the depression of the post‐inspiratory neuronal activity in the bulbar respiratory control me

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00731.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

Myocardial accumulation of GBR 12909 showed monophasic exponential kinetics with a half‐life of 93 min. The disposition followed a three‐phasic exponential time‐course with half‐lives of 1.1, 17 and 98 min., respectively, which was interpreted as three‐compartment kinetics. The drug accumulated 430 times in the myocardium at steady‐state with 8, 30 and 61% of the drug amount referable to a central, superficial and two deeper myocardial drug pools. GBR 12909 produced concentration dependent (range 0.01 to 12400 nM) biphasic negative inotropic and chronotropic effects. The inhibitory Em‐values with regard to contraction velocity were 42 and 105% with corresponding EC50‐values of 29 and 688 nM and the related Hill‐exponents were 0.6 and 1.1, respectively. Frequency and contraction amplitude related inhibitory Em‐values were of similar size. Apparent dynamic steady states developed within about 17 min. Very marked monophasic negative dromotropic effects were observed with computer‐derived inhibitory Em‐values related to the electrocardiographic PQ‐ and QRS‐intervals exceeding 100%. The frequency‐corrected QTc‐interval showed an initial increase of 10% but decreased to about 20% below control level at the highest two drug concentrations. Coronary flow‐rate increased about 30% and then gradually decreased to near the control value. Oxygen consumption only decreased at the three highest concentrations. Our findings seem compatible with the view that GBR 12909 may possibly act in the myocardium as a membrane‐stabilizer which causes inhibition of Na+‐ and Ca++‐influx over sarcolemma. Intracellular inhibition of Ca++‐liberation from organelles and

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00732.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

The aim of the study was to analyse the β2‐adrenoceptor selectivity earlier found in two series of catecholamines and one series of resorcinolamines (Johanssonet al.1986). The affinity of the compounds was assessed in binding studies in preparations from the guinea‐pig left heart ventricle (β1‐adrenoceptors) and the soleus muscle (β2‐adrenoceptors) using3H‐CGP‐12177 as radioligand. Further, the activation of the adenylate cyclase by the compounds was studied in the same preparations. Selectivity quotients were obtained from both functional effects and from affinity and adenylate cyclase activating studies. There was a good correlation between the selectivity quotients obtained in these two ways. Tertiary butyl substitution on the amino nitrogen gave the highest β2‐adrenoceptor selectivity in both the catechol and resorcinol series. In comparison with their isopropyl substituted analogues the β2‐adrenoceptor selectivity of these compounds (KWD 2026 and terbutaline) was mainly due to a change in affinity for the β1‐ and β2‐adrenoceptors and, to a lesser degree, a ch

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00733.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

Tyrosine exerts potent cardiovascular effects: smaller doses induce tachycardia and hypertension while higher doses induce bradycardia and hypotension. However, the direct cardiac effects of this amino acid have not been characterised. In the present study increasing doses of L‐tyrosine were administered to the perfusate of isolated rat (0.01–10.0 mg) and rabbit (0.5–40.0 mg) hearts. Heart rate and isometric force of contraction or amplitude of contractions, and either perfusion pressure or flow of perfusate were recorded. In rat hearts L‐tyrosine decreased heart rate and isometric force of contraction. In rabbit hearts L‐tyrosine also decreased heart rate and amplitude of contractions. The effects on coronary vasculature were variable. In rat hearts, high doses of L‐tyrosine induced bi‐phasic changes with initial coronary dilatation, followed by vasoconstriction. In rabbit hearts the predominant effect of L‐tyrosine was coronary artery constriction. These results show that the inhibitory cardiovascular effects of L‐tyrosinein vivomay be at least in part, explained by direct cardiac effects o

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00734.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY