摘要:

Abstract:The anaesthetic properties of pregnanolone emulsion, which is a new pharmaceutically and clinically acceptable preparation of pregnanolone, have been evaluated and compared with those of thiopentone in the mouse. “Loss of the righting reflex” for 15 sec. was used as a criterion for the anaesthetic effect. The range for the optimal infusion rate to reach the threshold anaesthetic dose was 0.25–1.0 mg/kg/min. for pregnanolone and 10–40 mg/kg/min. for thiopentone. Potency, measured at the optimal infusion rate as the mean anaesthetic dose, AD50, or as the threshold anaesthetic dose, was about six times higher for pregnanolone than for thiopentone. The induction of anaesthesia, which ensured directly after a complete dose was given, and the duration of anaesthesia were similar for pregnanolone and thiopentone in equipotent doses. The approximate therapeutic index for pregnanolone was about four times higher than that for thiopentone. The range for the time of anaesthesia was about 150 min. for pregnanolone emulsion but only about 50 min. for thiopentone. Recovery of the mice from anaesthesia occurred within minutes after pregnanolone, whereas it took hours following thiopentone. In conclusion, these results show that the advantage of pregnanolone emulsion over thiopentone include a higher therapeutic index, a wider range for the duration of anaesthesia and a shorter recovery

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb00929.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:Noradrenergic (NA) and serotonergic (5‐HT) receptor profiles were compared in the cerebral cortex of young adult (3 months old) and aged (24 months old) male Sprague Dawley rats. β and α‐1 receptors were significantly decreased in 24 month old rats, whereas α‐2 receptors remained unchanged. 5‐HT‐2 Postsynaptic receptors and 5‐HT high affinity uptake were reduced in aged animals; on the other hand the number of3H‐imipramine (3H‐IMI) recognition sites located on serotonin nerve terminals and labelled also by3H‐paroxetine (3H‐PAR), were significantly higher in the cerebral cortex of old rats. The ratio 5‐hydroxyindoleacetic acid (5‐HIAA)/5‐HT, an index of serotonin turn‐over, increased in some brain areas of senescent rats. There were no age‐related changes in the responsiveness of investigated binding sites to subchronic desipramine treatment; the density of β‐noradrenergic and 5‐HT‐2 serotonergic receptors and that of3H‐IMI binding sites was

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb00930.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:The effects of H1‐blockers (pyrilamine, diphenhydramine and promethazine) and H2‐blockers (cimetidine, ranitidine) on the postsynaptic potentials of the bull‐frog sympathetic ganglion were studied by means of the sucrose gap method. All the H1‐blockers tested, at concentrations of 10−6‐10−4M, depressed the amplitudes of both action and slow postsynaptic potentials in positive and negative directions in a concentration‐dependent manner; these drugs had more potent inhibitory effects on postsynaptic potentials. In the case of H2‐blockers, action and postsynaptic potentials were slightly depressed as perfusion continued at 10−4M. From the present experiments, it was concluded that H1‐blockers directly inhibit postsynaptic potentials of the sympathetic ganglions, and that this inhibition may be responsible for various autonomic disturbances attr

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb00931.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:W84 (hexamethylene‐bis‐[dimethyl‐(3‐phthalimidopropyl)‐ammonium bromide]) protects overadditively against an organophosphate‐intoxication when applied in combination with atropine. Further experimental evidence led to the hypothesis that W84 exerted an allosteric effect on muscarinic acetylcholine receptors. In order to investigate the action of W84 on the receptor level, binding studies with3H‐N‐methylscopolamine were performed in homogenized and intact guinea‐pig myocardium. For sake of comparison three bispyridinium oximes were included, i.e. Uno3 (trimethylene‐bis‐[4‐hydroxyiminomethyl‐pyridinium] dibromide mono‐2,6‐dichlorobenzylether), obidoxime, and TMB4. In cardiac membrane suspensions, all compounds inhibited3H‐NMS‐binding after 2 hrs of incubation concentration‐dependently by reducing its affinity, whereas leaving the number of binding sites unaltered. However, with increasing concentrations W84 suppressed3H‐NMS‐binding less than expected for a competitive antagonist. Kinetic studies revealed that W84 did not only slow the association of3H‐NMS, but additionally retarded its dissociation over the entire range of concentrations that inhibited3H‐NMS‐binding. At ImM, W84 augmented the half life time of the3H‐NMS‐receptor complexes from a control value of 4 min to more than 120 min. The stabilization of the radioligand‐receptor complexes is indicative of an allosteric effect of W84. Obidoxime, TMB4 and Uno3 at low concentrations acted like competitive inhibitors of3H‐NMS‐binding. From 10‐−5M onwards, Uno3 retarded3H‐NMS‐dissociation concentration‐dependently. It is concluded that the effect of bisquaternary compounds on3H‐NMS‐association and‐dissociation is mediated via binding to two separate sites, i.e. the muscarinic receptor site and an allosteric effector site, respectively. Also in intact beating left atria, W84 retarded3H‐NMS‐dissociation concentration‐dependently. The stabilizing effect of W84 on antagonist‐receptor complexes may explain the overadditive protective action exer

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb00932.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:When thyroid hormone secretion in vivo was studied by the release of125I from thyroid to blood after TSH in mice preloaded with the isotope, only 54.4 ± 2.0% (± SE) of plasma125I was butanol extractable, indicating low specificity for thyroid hormones. To improve specificity plasma125I was bound to anti‐T4 rabbit antibodies and precipitated with goat antirabbit serum. The intraassay coefficient of variation was 2.5%, and anti‐T4 bound radioactivity correlated well with that extractable with butanol (r = 0.95, P<0.001). The effect of 40–1000 μU TSH intravenously in mice pretreated with 1 μg T3 3 times during 2 days to suppress endogenous TSH was evaluated 2 hrs after the injection of TSH by 1) conventional radioimmunoassays of total and free stable T4 in plasma (no preloading with125I), 2) total blood125I in mice preloaded with125I, and 3) anti‐T4 bound125I in plasma in mice preloaded with125I. Stable T4 increased with TSH doses of 70 μU or higher, but the slope was low and the relation between error variance and slope did not permit a useful bioassay. Total blood125I responded significantly to 40 μU TSH and showed a favourable relation between error variance and slope, but the specificity may be questioned. Anti‐T4 bound125I in plasma also responded significantly to 40 μU TSH and showed a very good relation between error variance and slope. The new technique of measuring anti‐T4 bound radioactivity seems to combine the specificity of radioimmunoassay with a precision and sensitivity well comparable to that of the conventional radioiodine

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb00933.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:Intraperitoneal administration of cadmium chloride to 8–12 weeks old CBA‐mice enhanced hepatic lipid peroxidation. A positive correlation between cadmium chloride dose and level of peroxidation was observed in both male and female mice. A sex‐related difference in mortality was not observed but at a dose of 25 μmol CdCl2/kg the level of hepatic lipid peroxidation was higher in male mice than in female mice. The hepatic lipid peroxidation was not increased above the control level in 3 weeks old mice, while 6 weeks old mice responded with increased peroxidation as did 8–12 weeks old mice. The mortality after an acute toxic dose of cadmium chloride was the same in the three age groups. Pretreatment of mice with several low intraperitoneal doses of cadmium chloride alleviated cadmium induced mortality and lipid peroxidation. The results demonstrate both age dependency and a protective effect of metallothionein induction on cadmium chloride induced hepatic lipid pero

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb00934.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:In spinal cord slices isolated from guinea‐pig and preincubated with3H‐adenine, 0.3–30 μM forskolin induced a dose‐dependent increase in the content of3H‐cAMP, the maximal increase being about 8‐fold. The selective α2‐adrenergic agonist UK‐14,304 (10 μM) reduced both the basal and the forskolin stimulated levels of3H‐cAMP by 18–32%. Dose response curves of the effect of UK‐14,304 on cAMP production in the spinal cord slices, stimulated with 3 μM forskolin, showed an IC50 of 37 nM and a maximally inhibitory effect of 27%. A number of other α2‐adrenergic agonist (clonidine, guanfacine, B‐HT 920 and B‐HT 933) also inhibited the forskolin stimulated3H‐cAMP production; clonidine and guanfacine being almost equipotent with UK‐14,304, but their maximal inhibitory effects being only about 6–7%. B‐HT 920 and B‐HT 933 were less potent and their maximal inhibitory effects about 16–21%. The dose response curve of UK‐14,304 on inhibition of forskolin stimulated cAMP production was shifted almost 50‐fold to the right by 0.3 μM yohimbine. Prazosin (0.3 μM) did not affect the UK‐14,304 dose resonse curve. It is concluded that α2‐adrenoceptor stimulation mediates inhi

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb00935.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:The direct effects of theophylline and enprofylline, a new anti‐asthma xanthine derivative without adenosine receptor blocking action, were studied in the isolated, spontaneously beating rabbit heart. At increasing concentrations from 2 × 10−5–5 × 10−4M both drugs produced increases in heart rate up to 143% and 162% and in contractility up to 135% and 147% from control values (100%), respectively. At concentrations higher than 10−3M contractures and heart block occured. Enprofylline showed a potency about 2.3 times higher than theophylline. Coronary flowrate did not increase. Myocardial oxygen consumption was moderately increased by the drugs. The myocardial pharmacokinetics showed two‐compartment characteristics for both drugs. Half‐times of the two phases of accumulation were for theophylline 0.28 and 0.98 min. and for enprofylline 0.31 and 0.78 min. The terminal disposition half‐time for enprofylline was, however, 2.7 times higher than that of 0.91 min. for theophylline, apparently due to a stronger binding of the former drug intracellularly. Both xanthines accumulated against a concentration gradient showing myocardial tissue‐perfusion liquid ratios of about 2.9 for theophylline and 3.7 for enprofylline. The drugs seem to exert their primary action on sarcolemmal binding sites which probably are unrelated to

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb00936.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:Earlier studies have shown that selenium and vitamin E are important in maintaining normal cardiac function. The present study was designed to test the effect of sole selenium deficiency on electrophysiological and mechanical characteristics of the rat heart. Male weanling rats were fed a standardized vitamin E adequate but selenium deficient diet, or a control diet. Deficiency of selenium was verified by direct (tissue selenium analyses) and indirect (glutathione‐peroxidase tissue analyses) methods.In vivoelectrocardiographic recordings as well asin vitroelectrophysiological and mechanical recordings did not reveal abnormalities in any of the two groups. In conclusion, earlier studies have shown that the combined deficiency of selenium and vitamin E leads to abnormal cardiac function. Selenium deficiency alone, however, does not appear to significantly affect cardiac function in the ra

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb00937.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Abstract:A convenient method for screening for drugs that block acetylcholine‐activated ion channels, using the isolated chick biventer cervicis preparation is described. Since most of these drugs can only gain access to their site of action when the ion channel is in the open configuration, their effects are potentiated by prior treatment of the preparation with neostigmine. By preventing hydrolysis of acetylcholine, neostigmine enhances the possibility that ion channels will be in the open configuration. Potentiation of their neuromuscular blocking effects by neostigmine is apparently specific for drugs acting this way, other non‐depolarizing neuromuscular blocking drugs are usually antagonized by neostigmine. The chick biventer cervicis preparation also contains a second set of accessible ion channels, the so‐called voltage‐gated channels in the nerve axons which are the site of action of local anaesthetic compounds. It has been observed that addition of local anaesthetics to the bathing solution causes an increase in the potential required to elicit indirect muscle contractions i.e. they induce a shift to the right of the voltage‐response curve, a property which may be included in screening procedures with the isolated chick biventer cervicis pr

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1988.tb00938.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY