摘要:

Abstract:Over the past several years, angiotensin I converting enzyme (ACE) inhibitors, compounds that block the formation of angiotensin II (ANG II), have become widely used in the treatment of cardiovascular disease. Recently, a new class of orally active, non‐peptide inhibitors of the renin‐angiotensin system, the ANG II receptor antagonists have also become available. Since both classes of compounds block the renin‐angiotensin system, although at different sites, it remains to be determined whether blockade of ANG II receptors will have any specific advantage over inhibition of ACE. The following review assesses the actions of ANG II antagonists and suggests ways in which blockade of ANG II receptors may differ both pharmacologically and clinically from inhibition o

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00977.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Recently, decreased gastrointestinal β‐adrenergic responses in experimental diabetes have been demonstrated. Gastrointestinal responses to β‐adrenoceptor agonists are impaired in both insulin‐dependent and non‐insulin‐dependent diabetic rat. Insulin treatment improves the impaired gastrointestinal β‐adrenergic responsiveness of diabetic rats. The improvement seen with insulin treatment on β‐adrenergic responsiveness is closely related to protein biosynthesis. The decreased β‐adrenergic responses in diabetic rat gastrointestinal tract seem to result from a decrease in the number of β‐adrenoceptors. It is most likely that the decreased gastrointestinal β‐adrenergic responsiveness is related to an impairment in the turnover of β‐adrenoceptors as a consequence of diabetes and that insulin has a beneficial effect on t

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00978.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The deteriorative effects after chronic endosulfan exposure on muscle coordination, learning and memory of rats were compared with that produced by aldrin which has been reported to have similar effects in experimental animals. A rota‐rod apparatus was used to study the muscle coordination and learning and memory were tested by recording the response to unconditioned and conditioned stimuli using a pole‐climbing apparatus. Aldrin but not endosulfan inhibited motor coordination in both sexes. A greater motor deterioration occurred in male group. This finding, together with the previous data which shows inhibition by its metabolite of motor activity, suggests that its metabolic product is responsible for this action. Like aldrin, endosulfan inhibited both learning ability and conditioned avoidance response. A change in the activities of brain monoamines or inhibition of perception and reflexes or both were proposed for these behavioural effects, since the former was reported to be produced by both compounds and the latter was found to occur in aldrin treated r

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00979.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:A previous study has demonstrated that the urinary level of 6 β‐hydroxycortisol is a marker of liver CYP3A content after induction by rifampicin. To put in evidence an eventual genetic polymorphism for this cytochrome, the frequency distribution of 6 β‐hydroxycortisol excretion was investigated in 102 healthy Caucasians before and after 6 days of oral rifampicin administration (600 mg daily). After rifampicin treatment, a wide interindividual distribution was observed but no clear bimodality. Moreover the mean 6 β‐hydroxycortisol level was higher in women (n = 38) than in men (n = 64). These observations do not favour the existence of a CYP3A genetic polymorphism based on 6 β‐hydroxycortisol excretion but evoke a sexual dimorphism. However, CYP3A is composed of at least four enzymes and as the enzyme(s) responsible for Cortisol 6 β‐hydroxylation is (are) not perfectly known, it can not be excluded that a genetic polymorphism does exist for one enzyme

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00980.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Whole‐body autoradiography in rainbow trout (Oncorhynchus mykiss) after oral and intravenous administration of3H‐labelled anatoxin B1showed labelling of several extrahepatic tissues, such as the uveal melanin and the vitreous humour of the eyes, the trunk and head kidney, the olfactory rosettes and the pyloric caecae. Liquid chromatography of extracts of the vitreous humour showed that unmetabolized3H‐AFB1was the main labelled material present at this site. Liquid chromatography of extracts of the uveal melanin showed presence of aflatoxicol and aflatoxin B1in proportions of about 3:1. The binding to the pigment is probably due to a hydrophobic type of interaction with the melanin. Microautoradiography showed that melanin‐containing cells in the trunk and head kidney and in the olfactory rosettes also accumulated high amounts of radioactivity. In the trunk kidney there was, in addition, a labelling of the second segment of the proximal tubules and of the distal tubules and the collecting ducts. Studiesin vitrowith microsomal and 12,000 x g supernatant preparations of the trunk kidney showed formation of DNA‐ and protein‐bound metabolites from the aflatoxin B1. It is probable that the bioactivation of the aflatoxin B1is confined to the second segment of the proximal tubules. The labelling of the distal tubules and the collecting ducts, which was confined to the cytoplasm of the cells, may be related to excretion and/or absorption processes. Microautoradiography of the olfactory rosettes, showed labelling of the sensory epithelium, but not the indifferent epithelium. A low formation of protein‐bound aflatoxin B1‐metabolites was found in incubations with microsomal preparations of this tissue. The same observation was made in incubations with microsomal preparations of the head kidney. In the pyloric caeca bound metabolites were observed in vivo at a level comparable to that found in the trunk kidney. Our results suggest that retention and metabolism in some extrahepatic tissues might be of importance as concerns the toxicologic potential of aflatoxin B1in th

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00981.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The actions of and interaction between formoterol and salmeterol were studied on guinea‐pig tracheain vitro.Tracheal strip preparations were contracted by 1 μmol/1 carbachol giving a near maximal contraction. Salmeterol in concentrations from 0.1 to 3 μmol/1 relaxed the tracheal smooth muscle by about 30 per cent of the maximum relaxation produced by theophylline. Formoterol caused a concentration‐dependent and almost complete relaxation with a pD2of 8.56. In the presence of salmeterol there was a rightward shift of the concentration‐response curve for formoterol. The pA2for salmeterol was estimated to 7.42. Similar experiments with isoprenaline indicated that salmeterol has a low affinity for β1‐adrenoceptors. Formoterol and salmeterol both inhibited in a concentration‐dependent manner the contractions evoked by stimulation of the vagus nerve in a tracheal tube preparation. The degree of inhibition decreased with increasing stimulation frequency. Complete inhibition was attained with salmeterol, but not with formoterol, at the highest frequency employed (45 Hz). The inhibiting effect of 10 μmol/1 salmeterol was not blocked by 10 μmol/1 sotalol, a β‐adrenoceptor antagonist. It is concluded that salmeterol, in comparison to formoterol, is a partial pradrenoceptor agonist and has, at high concentrations, an additional unspecific

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00982.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Isolated perfused livers from rats fasted overnight were subjected to 30 min. of hypoxia followed by reoxygenation for 60 min., resulting in marked cytotoxicity as evidenced by an enhanced release of cytosolic enzymes (lactate dehydrogen‐ase: 14‐fold over controls, glutamate‐pyruvate‐transaminase: 12‐fold over controls) and glutathione (twofold over controls) into the perfusate, by calcium accumulation (by a Factor of 1.4) in the tissue and by an 80% inhibition of bile secretion. Virtually no mitochondria1 injury became apparent and no evidence for lipid peroxidation could be found. In the presence of ascorbate, an augmentation of hepatic injury was observed. This might be due to the pro‐oxidant activity of ascorbate in the presence of ionized iron, which is easily released from high molecular weight stores under reductive (e.g. hypoxic) conditions. The water soluble vitamin E analogue trolox C as well as propyl gallate clearly protected the liver against hypoxiaireoxygenation injury, yielding further evidence for a causative role of oxidative stress in this model. Due to their water solubility and their high efficacy as free radical scavengers, these antioxidants might be of therap

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00983.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The neurobehavioural effects of a single non‐lethal dose (1000 μg/kg intraperitonelly) of 2,3,7,8‐tetrachlorodi‐benzo‐p‐dioxin (TCDD) were assessed in young male Han/Wistar rats, highly resistant to acute lethality of TCDD. TCDD decreased body weight significantly compared withad libitumfed controls. TCDD did not change the behaviour or the motility of rats in the open field test 8 days after the treatment nor did it affect the spontaneous motor activity up to 27 days after the exposure. In the elevated plus‐maze test for anxiety, TCDD‐treated rats did not differ from eitherad libitumfed controls or pair‐fed controls. In the 24‐hr passive avoidance test, the learning of TCDD‐treated rats did not differ significantly from that ofad libitumfed controls or pair‐fed controls from 8 hr to 16 days after the treatment. TCDD did not affect the motor coordination or the maintenance of balance on the rotating rod but it impaired them slightly in the elevated horizontal bridge test 16 hr after exposure. It did not affect nociception in the hot plate test 16 hr or 8 days after the injection. The results suggest that a single sublethal dose of TCDD does not alter markedly the general behaviour of Han/Wistar rats, in contrast to its striking effect on feeding behaviour which results in a marked decrea

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00984.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The effects of exogenous guanosine 5′‐triphosphate (GTP), guanosine, adenosine 5′‐triphosphate (ATP) and adenosine on platelet aggregation, serotonin secretion and cyclic nucleotide accumulation were studied using thrombin‐stimulated washed human platelets. GTP (10 μM‐1 mM) dose‐dependently inhibited thrombin‐induced aggregation and serotonin secretion. The inhibition of aggregation was accompanied by an increase in platelet cyclic GMP. GTP did not affect cyclic AMP concentration. Adenosine (1 μM‐1 mM) dose‐dependently inhibited thrombin‐induced aggregation and serotonin secretion, and increased cyclic AMP. ATP at high concentrations (100 μM‐1 mM) inhibited aggregation and serotonin secretion, and 1 mM ATP increased cyclic AMP. Guanosine was relatively ineffective in preventing aggregation and serotonin secretion and did not affect cyclic GMP. The rank order of inhibition of thrombin‐induced aggregation of washed human platelets was adenosine>GTP>ATP>guanosine. In conclusion, exogenous GTP inhibits thrombin‐induced aggregation and serotonin secretion of washed human platelets by increasing cyclic GMP. The results raise the possibility of a cell membrane site of action for GTP in platelets which mediates the activation of soluble guanylate cyclase suggesting that GTP may have a local ant

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00985.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Contrary to the general belief that cimetidine and ranitidine spare glucuronidation of drugs, some authors have indicated that both cimetidine and ranitidine could inhibit the glucuronidation of paracetamol (acetaminophen) by cultured rat hepatocytes. Thus, we tested the effect of three histamine H2‐receptor blockers (cimetidine, ranitidine and famotidine) on the glucuronidation of 7‐hydroxy‐4‐methylcoumarin (7‐OH‐4‐MC) by human liver microsomes. None of the drugs studied produced significant inhibition of the glucuronidation of 7‐OH‐4‐MC when used at concentrations up to 1.5 mM. Thus, even the new H2‐receptor blocker, famotidine, spares glucuronidation. These findings further support the previous reports which suggest that glucuronide conjugation in humans is spared by

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00986.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY