ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01833.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:The effect of intraperitoneal injections of 0, 30, 60 and 100 mg/kg of carbamazepine (CBZ), twice a day for 4 days, was studied in 4 groups of 6 male Sprague‐Dawley rats per group to evaluate its hepatic enzymatic induction, toxicity and metabolism. Rats were sacrificed on the fifth day and the urines of the last 24 hours were collected. While the activities of hepatic microsomal aminopyrine N‐demethylase and epoxide hydratase tended to increase with the dose of CBZ, the cytochrome P‐450 content and the activity of aniline hydroxylase however reached a maximum at 60 mg/ kg. The percentage of the administered daily dose of CBZ excreted as unchanged CBZ in the urine increased considerably with the dose, while that of metabolites such as carbamazepine‐10,11‐epoxide (CBZ‐E), trans‐10,11‐dihydrodihydroxycar‐bamazepine (TDC), and thioethers (T) did not markedly change. These data not only corroborate a maximum in enzyme induction but also suggest a saturation of the induced hepatic enzymes. Urinary T and TDC, representing more than 50% and less than 10%, respectively of the total amount recovered, tend to demonstrate that the glutathione conjugation with the intermediates of CBZ leading to the formation of higher mercapturates could be more important than the epoxide‐diol pathway for the metabolism of CBZ under conditions

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01834.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:The effect of thapsigargin (Tg) was studied in rat thoracic aorta. Tg (10‐8—10‐5M) had a dual effect on rat aorta. Thus, Tg induced a concentration dependent increase in basal tone in normal physiological salt solution (PSS), while Tg in potassium (K+) precontracted aortic rings caused a concentration related relaxation and shifted the K+‐concentration response curve to the right and depressed the maximal response to K+. Removal of vascular endothelium abolished the relaxant response to Tg and increased the sensitivity of the preparations to the contractile effect of Tg. The contractile response to Tg was resistent to wash‐out in drug‐free PSS and was not affected by phentolamine, indomethacin or mepyramine but partly reduced by the calcium‐antagonist nitrendipine and eliminated by wash‐out in calcium‐free PSS. Atropine eliminated the endothelium dependent relaxant effect of carbachol, but had no effect on the Tg or on the calcium ionophore A 23187 evoked relaxation. Ultraviolet radiation decreased the relaxant effect of Tg and A 23187 without affecting the carbachol induced relaxations. The results showed that vascular endothelium depressed the contractile effect of Tg and that Tg like A 23187 had an endothelium dependent relaxant effect on rat aorta different from that of carbachol. The results indicate that Tg in vascular smooth muscle acts by stimulating the transmembranal influx of extr

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01835.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:Mouse N1E‐115 neuroblastoma cells were used to study carbachol induced changes in muscarinic cholinergic parameters. Cells were treated with carbachol (1 mM) for up to 96 hours. The number of muscarinic receptors, measured in3H‐3‐quinuclidinyl benzilate binding experiments, decreased approximately 50% after 4 hours exposure to carbachol. This was followed by an increase in binding sites, and after 24 hours the number of binding sites was the same as in control cells. The changes observed in the choline esterase activity followed the same pattern. The increase in number of binding sites was not dependent on protein synthesis, while the increase in choline esterase activity was. The muscarinic receptor‐stimulated uptake of45Ca2+showed an initial decrease, which was followed by a significantly increased basal uptake of45Ca2+. It is suggested that all these changes are adaptations of long time exposure to ca

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01836.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:Vasoconstrictor responses to prostaglandin F2a and noradrenaline were investigated in ring segments of feline femoral, coronary and cerebral arteries incubated in calcium‐free solutions containing different concentrations of magnesium (1.2, 4.4 and 13.2 mM). Contractions produced by prostaglandin F2a and noradrenaline were depressed when calcium was omitted from the incubation solution. The presence of raised concentrations of magnesium (4.4 or 13.2 mM) in the tissue bath further depressed the prostaglandin f2a and noradrenaline contractions in calcium‐free medium. In a separate set of experiments the vessel wall contents of cAMP and cGMP were measured before and after the additions of 4.4 or 13.2 mM magnesium; stable relaxations by magnesium were noted but there was no parallel change in the vessel content of cAMP or cGMP. The results indicate that magnesium may interfere with the release of calcium from intracellular depots, and that neither adenylate cyclase, nor guanylate cyclase are involved in the dilator activity of magnesium in isolated arter

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01837.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:We have studied the influence of endothelium on BAY K 8644, CGP 28392, potassium, noradrenaline and calcium induced responses in isolated thoracic aorta from rats. In aortic preparations with intact endothelium BAY K 8466 and CGP 28392 (10‐9‐10‐5M) had a concentration dependent contractile effect, but BAY K 8644 was more effective in contracting the vessels than CGP 28932. Removal of endothelium increased the contractile response to both substances without affecting the difference in contractile effect between the two calcium agonists. In high concentrations (10‐4M) BAY K 8644 and CGP 28392 had an equal relaxing effect on potassium precontracted preparations, which was unaffected by removal of endothelium. Removal of endothelium caused a shift to the left of the potassium and noradrenaline concentration response curves without any change in maximal contractile response. The contractile response to calcium in BAY K 8644 and potassium activated vessels was unaffected by removal of endothelium. We conclude that endothelium derived factor(s) depress the contractile response to calcium agonists, potassium, and noradrenaline but has no influence on the relaxant effect of BAY K 8644 and CGP 28392 in rat aorta. The influence of endothelium on the contractile effect on BAY K 8644 and potassium seems not to be due to a direct effect on calcium influx but rather to an influence on the membrane potential of the smooth muscl

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01838.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:The time course of resensitization of the down‐regulated β‐adrenoceptor system of rat myometrium was studied. The isoprenaline‐induced decrease of myometrial cAMP reversed rather rapidly and after 4 and 8 days no significant change of the cAMP level was demonstrated, however, the cAMP level was higher than in the control myometrium after 12 days. The elevated phosphodiesterase activity dereased to 80% of control activity after 4 days, but returned to control activity after 8 days. The decreased number of β‐adrenoceptors increased gradually after discontinueing the treatment and reached the number of the controls after 12 days. Our results suggest that the resensitization of the β‐adrenoceptor‐cAMP‐system is rather complex, the normalization of the cAMP content and the phosphodiesterase activity is more rapid than the normalization of the β‐adrenoceptor number which is a rather slow process i

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01839.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:A chicken limb bud micromass system measuring the production of cartilage proteoglycans and the incorporation of radiolabeled thymidine and leucine was used to calculate potential developmental hazard. This hazard index was based upon the 50% inhibitory concentration (IC50) for these parameters and enabled classification of substances according to their intrinsic ability to inhibit differentiation at concentrations which were not cytotoxic. All‐trans‐retinoic acid, a potent teratogen, inhibited cartilage proteoglycan synthesis at a concentration which was more than 100 times lower than those affecting the incorporation of14C‐thymidine and14C‐leucine. On the other hand, sodium valproate, salicylate and isoniazid inhibited cartilage proteoglycan synthesis only near concentrations which were also cytotoxic. The results from testing with chicken limb bud micromass compared favorably, both with respect to effective concentrations and ratios describing developmental hazard to those from rodent micromass

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01840.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:The rate of development of tolerance to the benzodiazepines clorazepate and clonazepam against pentetrazole‐induced seizures in mice was compared. Treatment with clorazepate (0.1% solution as drinking water) for 21 days led to tolerance beginning at day 7. When mice were treated with clonazepam (0.5 mg/kg twice daily intraperitoneally), tolerance was evident already at the fourth day of treatment. Twenty‐four hours after cessation of treatment the seizure threshold was significantly decreased after treatment with both drugs. Clorazepate, a prodrug of the main metabolite of diazepam, desmethyldiazepam, regards further interest for anticonvulsant therapy because of a relatively slow onset of tolera

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01841.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:In the present paper the acute actions primarily of the tricyclic antidepressants amitriptyline and desipramine, the atypical antidepressant zimeldine and the potential antidepressant alaproclate were evaluated in six models used for studying antidepressant agents. These included the forced swim test, a modified learned helplessness procedure, the clonidine hypothermia test, the social dominance test (using the interaction with clonidine), a differential‐reinforcement‐of‐low‐rates (DRL‐72s) schedule and conditioned avoidance response. The results showed desipramine to be effective in all the tests employed. Zimeldine was effective in the learned helplessness, DRL‐72s and domination tests, but also caused notable deficits in two‐way active avoidance response. Alaproclate was effective in all the tests except the domination paradigm. Amitriptyline was effective in all tests employed. The results are discussed in relation to the possible mechanism of action of these compounds in the test mo

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb01842.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY