ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb01923.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:The selective dopamine (DA) D2receptor antagonist raclopride was found to attenuate operant lever‐pressing with water as reward in a dose dependent manner and more potently than the corresponding consummatory act, i.e. the unconditioned water intake. This is the same way as previously reported for other DA D2antagonists. In screening experiments raclopride has been selected on the basis of great separation between antagonism of DA‐agonist induced hyperactivity, stereotypies and production of catalepsy. We found that attenuation of lever‐pressing and water intake by raclopride were not more separated in dose than after, for example, haloperidol. We further found that attenuation of lever‐pressing and water intake occured in doses relatively lower than those producing catalepsy, thus excluding catalepsy as a cause for the attenuation. Decreased water intake in thirsty animals caused by a low dose of apomorphine (APO) was counteracted by raclopride. This has previously been found with DA D2, but not with D1, antagonists, which further supports that this apomorphine‐effect is mediated via D2receptors. However, raclopride only showed this antagonism in a narrow dose‐range, like haloperidol. The selective profile previously found for sulpiride, proposed to be related to low incidence of extrapyramidal side‐effects in the clinic, was thus n

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb01117.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:The purpose of this study was to apply our earlierin vitrofindings for extracorporeal complexation combined with haemodialysis toin vivoconditions, for the enhancement of cadmium (Cd) removal from dogs. The results showed that ethylenediaminetetraacetic acid (EDTA), glutathione (GSH) and combination of the two agents (EDTA+GSH) facilitated efficient elimination of cadmium. GSH, EDTA and EDTA+GSH treatments brought about the clearance of 2.2., 14.7 and 18.2 μg Cd/kg body weight/hr haemodialysis, respectively. Treatment with EDTA+GSH brought about the most rapid extravascular redistribution of the metal

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb01118.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:To investigate the effect of L‐neutral amino acids on tissue levels of methyl mercury in the adult animal, rats were infused into the external jugular vein with solutions containing a) 0.05 mM203Hg‐MeHgCl and saline, b) 0.05 mM203Hg‐MgHgCl‐0.1 mM L‐cysteine, c) 0.05 mM203Hg‐MeHgCl‐0.1 mM L‐cysteine‐0.1 mM L‐methionine, d) 0.05 mM203Hg‐MeHgCl‐0.1 mM L‐leucine, or e) 0.05 mM203Hg‐MeHgCl‐0.1 mM L‐cysteine‐0.1 mM L‐leucine. Groups of animals were sacrificed at 3 min. 7 hr, and 96 hr. Brain, kidney, and liver203Hg radioactivity was measured by means of gamma‐scintillation spectrometry. Brain203Hg concentrations L‐cysteine treated animals were significantly higher compared with saline treated animals (P<0.05) at 3 min., 7 hr and 96 hr. The coinjection or coinfusion of methyl mercury with L‐cysteine and L‐methionine abolished the L‐cysteine‐mediated brain203Hg uptake (P<0.05), at each sacrifice time. Kidney and liver203Hg concentrations were not significantly different in any of the treatment groups compared with controls, irrespective of the sacrifice time. Furthermore, the percentage of diffusible203Hg (non‐protein bound) at each sacrifice time was not statistically different irrespective of the treatment assigned. These results suggest that methyl mercury L‐cysteine conjugates in the plasma may share a common transport step with the L‐neutral amino acid carrier transport system and indicate the presence in brain capillaries of a transport system capable of selectively mediating methyl mercury

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb01119.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:The effects of several diuretics, including tienilic acid and indacrinone, on isolated rat heaptocytes were examined. Addition of tienilic acid and indacrinone at 1 mM to a suspension of freshly isolated cells caused dose‐dependent loss of cell viability as judged by the LDH‐latency test. Survey of 19 structurally related compounds revealed that the extent of cell injury and chemical structure were correlated, and an intense adverse effect was attributed to the 2‐thienylcarbonyl moiety. Several other factors influencing cell viability are also disclosed. Further study revealed that tienilic acid and indacrinone were toxic to the primary culure of hepatocytes at a lower dose than that to freshly isolated hepatocytes. Thus, an isolated hepatocyte system can be used to select compounds displaying low hepatotoxicity, as for example is needed when screening diur

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb01120.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:The guinea‐pig ileum longitudinal muscle‐myenteric plexus preparation, preincubated with3H‐choline or3H‐noradrenaline, was mounted in an organ bath and superfused with Tyrode's solution. Alaproclate (2‐(4‐chlorophenyl)‐1,1‐dimethyl 2‐aminopropanoate) (0.01‐0.5 mmol/l) reduced (IC50= 0.1 mmol/l) and at about 0.5 mmol/l completely blocked the electrically evoked3H‐acetylcholine secretion. The depressing effect of alaproclate (0.2 mmol/l) was not counteracted by atropine (0.01, 1 or 10 μmol/l), hexamethonium (0.1 mmol/l), phentolamine (1 μmol/l) yohimbine (1 μmol/l), haloperidol (1 μmol/l), 8‐phenyltheophylline (10 μmol/l), cyproheptadine (1 μmol/l), metitepine (1 μmol/l), bicuculline (10 μmol/l), picrotoxinin (0.1 mmol/l), forskolin (25 μmol/l), 3‐isobutyl‐1‐methylxanthine (5 mmol/l), nifedipine (1 μmol/l), verapamil (1 μmol/l), dilitiazem (1 μmol/l), high calcium (6 mmol/l), high potassium (10 or 15 mmol/l), tetraethylammonium (2 mmol/l), 4‐aminopyridine (0.5 mmol/l), apamin (0.5 μmol/l), barium (0.5 mmol/l) or quinine (0.1 mmol/l). Among the potassium channel blockers tested only quinine (at 0.5 or 1 mmol/l), in the same manner as lidocaine, reduced the evoked secretion of3H‐acetylcholine. The results are in agreement with the hypothesis that the effect of alaproclate on the evoked3H‐acetylcholine secretion is not mediated by a neurotransmitter receptor, or a potassium channel sensitive to tetraethylammonium, 4‐aminopyridine, apamin, barium or quinine, but is due to a local anaesthetic effect. In contrast to the evoked secretion, the spontaneous release of3H‐acetylcholine was enhanced by high concentrations of alaproclate (0.4‐1 mmol/l). The mechanism underlying the effect of alaproclate on the spontaneous release remains to be established. Alaproclate (0.25 or 0.5 mmol/l) also enhanced the spontaneous release and red

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb01121.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:The haemodynamic effects of the Ca‐agonist BAY K 8644 alone and in combination with the selective β‐1‐adrenoceptor agonist dobutamine were studied in the isolated rabbit heart. BAY K 8644 produced a concentration‐dependent increase in contraction amplitude and shortening velocity, oxygen consumption and heart rate. In combination with a small fixed concentration of dobutamine (40 nM), Bay K 8644 produced similiar alterations. When Bay K 8644 was infused at a fixed concentration (38 nM), dobutamine likewise produced similiar increments in contraction amplitude, shortening velocity and heart rate, whereas oxygen consumption was considerably augumented. Both BAY K 8644 and dobutamine showed definite positive inotropic effects in the isolated rabbit heart. Combination of the two drugs did not yield a stronger positive inotropic effect than that seen on single drug administration, and oxygen consumption was even i

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb01122.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:The urinary excretion of amitriptyline (AT) as N‐glucuronide was studied in healthy volunteers after single oral doses of AT and in patients on continuous treatment with AT. In the volunteers, 8±3% of a 25 mg dose of AT was recovered in urine as glucuronide during 108 hr. No difference between slow and rapid debrisoquine hydroxylators with respect to the excretion of AT glucuronide was seen. 0.08 to 1.68% of the given AT dose was recovered in urine in unchanged form. The excretion of unchanged AT correlated with the debrisoquine metabolic ratio (rg=0.61; p<0.01). In 5 patients on continuous treatment with AT (125‐150 mg/day), 8 ± 5% of the daily dose was recovered in 24‐hr urine as AT glucuronide. The present study shows that direct glucuronidation is a minor metabolic pathway of AT in manin vivoboth after single low doses and during continuous treatment with therapeuti

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb01123.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:Demethoxydaunorubicin was compared to other anthracyclines (daunorubicin, doxorubicin, epirubicin) on its ability to generate free oxygen radicals when mixed with Fe2+in solution and on its ability to reduce clonogenic survival of fibroblasts in culture. Oxygen electrode measurements of free radical generation showed that most of the consumed oxygen entered the monovalet oxygen reduction pathway. Catalase and superoxide dismutase additions inhibited oxygen consumption for all tested anthracyclines and diethylenetriaminepentacetic acid (DTPA) was also inhibitory except for demethoxydaunorubicin. Demethoxydaunorubicin and epirubicin dose‐dependently reduced the clonogenic survival of fibroblasts. Addition of catalase or superoxide dismutase was without effect, whereas metal chelators DTPA, desferrioxamine and EDTA all protected against epirubicin‐induced toxicity. Of the chelators, only desferrioxamine protected against demethoxydaunorubicin toxicity. Testsin vivowill further elucidate whether demethoxydaunorubicin also differs from the other anthracyclines in therapeutic effect as well as in side effects such as myocardial toxic

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb01124.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:The apparent kinetic deuterium isotope effect (I) on the oxidation of ethanol to acetaldehyde by washed rat liver microsomes was measured with (1‐R)‐[1‐2H2, 1‐14C]‐ethanol (I1) and [1‐2H2, 2‐14C]‐ethanol (I2) as substrates by a competitive technique involving only measurements of radioactivity. The average values were for non‐induced rats, I1= 1.57 and I2= 2.23. When these two substrates were used with stereospecific enzymes (alcohol dehydrogenase and catalase) a small secondary effect was observed, causing I2to be about 10% higher than I1. With non‐stereospecific systems I2was much larger than I1, and the values were connected by a simple formula. This relation in combination with use of the inhibitors, sodium azide and thiourea, made it possible to calculate tentatively the contribution to microsomal ethanol oxidation of catalase, a non‐identified stereospecific enzyme, and non‐stereospecific catalytic systems, as well as the isotope effects of the latter two systems. Measurements were made in microsomes from normal, phenobarbital treated, and acetone treated rats. For the stereospecific component an isotope effect of 1.4‐1.5 was calculated for all three groups. For the non‐stereospecific enzyme in acetone treated rats a value of 4.0 was found. Both the other groups showed a value about 2.7. The activity of the non‐stereospecific system was about twice the normal in barbiturate treated, and 3 times the normal in the acetone treated group, where it contributed 70% of the total activity. The isotope effects on the changes in ethanol oxidation (the ‘differential isotope effect’) caused by inhibitors and activators were utilized to decide whether inhibitors were specific for a single reaction. Thus azide while inhibiting catalase completely, also inhibited other reactions. The large increase (5‐6 times) in rate caused by Fe‐EDTA had an I2of 1.6, equal to that for oxid

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb01125.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY