Inhibitory effects of quinidine and quinine on liver microsome oxidation enzymes in man and rat

AIM: To compare the inhibitory effects of quinidine and quinine on liver microsome bufuralol 1'-hydroxylase (BH), aryl hydrocarbon hydroxylase (AHH), and 7-ethoxycoumarin O-deethylase (ED) activities in man and rat. METHODS: A normal phase HPLC and the fluorescence spectrometry were used to assay the enzyme activities. RESULTS: Both quinidine and quinine produced a concentration-dependent inhibition to liver microsome BH, AHH, and ED in man and rat. Their median inhibitory concentrations (IC50) on liver microsome BH, AHH, and ED low and high affinity phases were 0.2, 378, 2952, and > 5000 mumol.L-1 for quinine in man, 290, 613, 1465, 1595, mumol.L-1 for quinidine in rat; 29, 207, 808, and > 5000 mumol.L-1 for quinine in man, and 31, 54, 597, and 2508 mumol.L-1 for quinine in rat, respectively. CONCLUSION: Quinidine is a species- and stereo-selective potent inhibitor to human liver microsome BH.     

The effects of certain drugs on the uptake and release of [3H]noradrenaline in rat whole brain homogenates

Twelve drugs were studied with respect to their effects on inhbition of neuronal uptake of [3H]noradrenaline ([3H]NA) and on release of this amine from presynaptic nerve terminals. An in vitro method, using a crude synaptosomal homogenate prepared from rat whole brain, was employed. All drugs tested were found to produce some release of [3H]NA although tyramine was by far the most potent drug in this respect; tripelennamine and cocaine were observed to produce the least release. Studies of inhibition of NA uptake again demonstrated tyramine to be the most potent of the 12 drugs although in this case it did not differ significantly from cocaine and tripelennaine. The remaining compounds also showed decreased accumulation of [3H]NA and all 12 drugs produced uptake inhibition at a lower dose than that required for release of the amine. A correlation between releasing potency and lipophilicity of the compounds indicated that tyramine seemed to be acting in a different manner from the remaining compounds. A correlation between inhibitory potency and lipophilicity could be demonstrated for only six of the drugs, with tyramine, tripelennamine and cocaine showing the greatest deviation from this relationship.     

Links between temperamental dimensions and brain monoamines in the rat.

In 27 female Wistar rats, the authors obtained composite scores on harm avoidance and novelty seeking, as well as 57 measures of monoamines and metabolites from 10 different brain regions. A multivariate regression method was used to discover associations between individual differences in temperament and neurochemistry. Harm-avoidant subjects had low levels of striatal dopamine and high levels of cortical norepinephrine and amygdaloid 5-hydroxyindoleacetic acid. High novelty-seeking scores were linked to low levels of brainstem serotonin and dopamine and to low levels of 5-hydroxyindoleacetic acid in amygdala and accumbens. Moreover, rats scoring high on novelty seeking had higher-than-average levels of norepinephrine in the thalamus and amygdala and of serotonin in the amygdala. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of ketamine anaesthesia on the content of monoamines and their metabolites in the rat brain

The effects of ketamine anaesthesia (100 mg/kg i.p.) on the content of brain 5-hydroxytryptamine (5HT), 5-hydroxyindoleacetic acid (5HIAA), noradrenaline (NA), dopamine (DA) and homovanillic acid (HVA) were studied in male Wistar rats. Fifteen min after ketamine injection, when the rats were deeply anaesthetized, the 5HT content in many brain regions tended to be increased. An opposite tendency was found in the brain 5HIAA content. In rats treated with probenecid, which markedly lengthened ketamine anaesthesia, the accumulation of 5HIAA was significantly reduced by ketamine. In addition to ketamine anaesthesia, probenecid was found to lengthen thiopental anaesthesia. One hour after the ketamine administration, when the rats were no longer anaesthetized but were excited, the brain NA concentration was increased by 17% (P less than 0.02). The brain DA content was unchanged, but at 15 min and 1 hour after ketamine administration the striatal HVA content was increased by about 55% (P less than 0.05), suggesting an increased turnover of DA. The results suggest that during recovery from ketamine anaesthesia the increased NA content and the increased DA turnover may be associated with the postanaesthetic excitement of the rat, whereas the decreasamine anaesthesia.     

Amyloid beta-peptide and its fragments induce acetylcholine release in in vitro basal forebrain tissue slices of rat brain, but do not affect the choline uptake

OBJECTIVE: Although stressor uncontrollability has been shown to suppress immune responses in animals and for human subjects, the results have been inconsistent. We reanalyzed results of our previous study regarding stress-related immune deviation in man, to establish whether perceived uncontrollability of an acute stressor acts as a co-determinant in the observed changes in immunological parameters. METHOD: Three types of cognitive reactions to an acute interpersonal stressor were assessed: "motivation," "uncontrollability," and "guiltiness." Stress-induced changes in the number of several types of immune cells in peripheral blood and proliferative responses of lymphocytes to antigens and mitogens were assessed. RESULTS: In comparison with control subjects and with subjects perceiving high control over the experimental stress situation, the subject perceiving low control showed a stressor-induced decrease in the number of T helper cells. Reversely, subjects perceiving high control showed an increase in the number of B cells as opposed to the other two groups. The effects of perceived uncontrollability could not be accounted for by mood changes, but they were related to previously experienced life stress. CONCLUSIONS: Perceived uncontrollability of an acute stressor can have immuno-modulating effects over and above those of the stressor per se.     

Differential presynaptic modulation of noradrenaline release in human atrial tissue in normoxia and anoxia

1. Presynaptic modulation of noradrenaline release in human atrial tissue specimens was investigated under normoxic and anoxic conditions. 2. Noradrenaline release was induced by electrical stimulation and release during experimental intervention (S2) was compared with release during a preceding control stimulation (S1). The results were expressed as the geometric means and 95% confidence intervals of the S2/S1 ratio. 3. The alpha 2-adrenoceptor agonist, UK 14304 (0.1 mumol-1) significantly inhibited noradrenaline release, resulting in a S2/S1 ratio of 0.49 (0.40-0.59), and the a 2-adrenoceptor antagonist, yohimbine (1 mumol l-1) increased noradrenaline release (S2/S1 1.83 [1.43-2.35]) during normoxia. Both compounds were ineffective during anoxia. 4. Adenosine (30 mumol-1) inhibited noradrenaline release with a S2/S1 ratio of 0.54 (0.42-0.66). The adenosine antagonist, 8-phenyltheophylline, alone had no effect during normoxia. During anoxia, neither adenosine nor 8-phenyltheophylline altered noradrenaline release. 5. The beta 2-adrenoceptor agonist, terbutaline (1 mumol l-1) increased (1.53 [1.14-2.01]) and the beta-adrenoceptor antagonist, pindolol (1 mumol l-1) suppressed noradrenaline release (0.62 [0.49-0.79]) under normoxic conditions. During anoxia, pindolol significantly inhibited noradrenaline release with a S2/S1 ratio of 0.66 (0.51-0.85), whereas terbutaline did not influence noradrenaline release. 6. Angiotensin II (0.1 mumol l-1 enhanced noradrenaline release resulting in a S2/S1 ratio of 1.44 (1.34-1.54), while the angiotensin II antagonist, losartan (1 mumol l-1) had no effect on noradrenaline release during normoxia. Conversely, angiotensin II did not increase noradrenaline release and losartan significantly inhibited noradrenaline release to a S2/S1 ratio of 0.60 (0.46-0.77) during anoxia. 7. In conclusion, human cardiac tissue possesses presynaptic inhibitory alpha 2-adrenoceptors and adenosine receptors, as well as facilitatory beta 2-adrenoceptors and angiotensin II receptors regulating noradrenaline release under normoxic conditions. During anoxia the responses to alpha 2-adrenoceptors and adenosine receptor stimulation are lost, whereas facilitatory responses to beta 2-adrenoceptors and adenosine II receptor stimulation are maintained and these receptors appear to be maximally stimulated. This differential presynaptic modulation in anoxia may contribute to enhanced sympathetic activity in ischaemia.     

Electroconvulsive shock and norepinephrine uptake kinetics in the rat brain

1 The effect of isoprenaline on gastric secretion evoked by various means has been studied in conscious rats provided with Pavlov and Heidenhain pouches. 2 Interdigestive acid secretion in the Pavlov pouch was reduced by isoprenaline, whereas pepsin secretion was unaltered. 3 Central vagal stimulation effected by 2-deoxy-D-glucose injection evoked a gastric secretory response that was substantially reduced by isoprenaline. 4 2-Deoxy-D-glucose increased the mobilization of gastric mucosal histamine, an effect that was prevented by isoprenaline. 5 Isoprenaline infusion alone induced a slight increase in histamine mobilization and also a considerable elevation of immunoreactive serum gastrin concentration. 6 The secretory response to food in the Pavlov pouch was almost abolished by isoprenaline. 7 Although the acid response to histamine in the Heidenhain pouch was susceptible to isoprenaline inhibition, that to methacholine was not. 8 Pepsin secretion in the Heidenhain pouch preparation stimulated by histamine or methacholine seemed to be enhanced by isoprenaline.     

Chloroquine, quinine and quinidine inhibit calcium release from macrophage intracellular stores by blocking inositol 1,4,5-trisphosphate binding to its receptor

Endocrine and exocrine pancreatic morphogenesis is known to occur from ductal epithelium, but the factors that regulate this process are unknown. Vascular endothelial growth factor (VEGF)/vascular permeability factor has recently been reported to affect fetal islet ontogenesis. VEGF is an angiogenic factor with a growth-promoting effect that is thought to be restricted to vascular endothelial cells. We demonstrated that VEGF is also a mitogen for adult rat pancreatic duct epithelial cells in primary culture. VEGF supplementation to a serum-free culture medium increased the 5-bromo-2'-deoxyuridine-pulse labeling index of ductal cells more than 2-fold. Immunohistochemical staining and protein blots revealed that pancreatic duct cells express fetal liver kinase-1 high-affinity receptors for VEGF. In pancreatic tissue, immunohistochemistry shows that VEGF peptide is expressed in normal pancreatic islet cells. In duct ligation-induced acute pancreatitis, numerous inflammatory leukocytes containing VEGF were seen to infiltrate between hyperplastic ducts. In the latter model, islet neogenesis has previously been observed. Our data indicate the possibility that VEGF plays a role in the paracrine regulation of ductal growth and differentiation in vivo, eg, in pancreatitis. In vitro, however, VEGF did not induce endocrine differentiation of ductal cells, indicating that it is not the only factor required for the activation of islet neogenesis.     

On the release of glutamate and aspartate in the basal ganglia of the rat: interactions with monoamines and neuropeptides

Experiments were designed to determine the in vivo cell-cycle phase of lymphocytes in secondary lymphoid follicles, and whether B-cell proliferation and apoptosis occur within follicular dendritic cell (FDC)-associated clusters. Using frozen serial sections of human tonsils, lymphoid follicles were stained to reveal histone H3 mRNA, as an S-phase marker, using in situ hybridization, and stained immunohistochemically with antibodies against cyclin E as a late G1 phase marker, cyclin B1 and p34cdc2 as S-G2-M phase markers, and Ki-67 as a marker of cycling cells. Each LF was divided into five zones: mantle zone, outer zone, apical light zone, basal light zone and dark zone, with the help of haematoxylin and eosin staining, and a CD23 immunostain. The rate of occurrence of positively labelled cells was calculated by dividing the number of positive cells by the number of all cells in each zone. The cells that were positive for cyclin E, histone H3 mRNA, cyclin B1, p34cdc2, and Ki-67 were found most frequently in the dark zone (54.5 +/- 6.6%, 22.0 +/- 5.7%, 36.7 +/- 14.5%, 40.0 +/- 10.2%, and 59.0 +/- 13.4%, respectively), followed by the outer zone (52.7 +/- 7.8%, 14.9 +/- 4.1%, 22.9 +/- 9.7%, 24.9 +/- 7.9%, and 44.6 +/- 12.3%, respectively), showing that both the outer zone and the dark zone contain many proliferating lymphocytes. Furthermore, FDC-associated clusters and free lymphocytes were obtained from enucleated germinal centres, using enzymatic digestion. The rates of occurrence of cells that were positive for cyclin B1 and Ki-67 within the clusters (7.2 +/- 1.9% and 37.9 +/- 10.5% respectively) were significantly lower than those of free lymphocytes outside the clusters (22.2 +/- 4.0% and 62.8 +/- 14.0%, respectively). The rates of occurrence of apoptotic bodies and cells within the clusters, as detected by in situ tailing or in situ nick translation (0.2 +/- 0.4% and 0.4 +/- 0.4%, respectively) were significantly lower than those outside the clusters (1.1 +/- 0.3, 1.6 +/- 0.5%, respectively). These results suggest that FDC-associated clusters are not the site of proliferation, and that they rarely contain apoptotic bodies and cells of B lymphocytes.     

Pharmacological analysis of local anaesthetic tolycaine-induced convulsions by modification of monoamines in rat brain

The effects of a local anaesthetic, tolycaine, on brain monoamine levels were investigated during the convulsive process in rats. The influence of central monoamine modifications on tolycaine-induced convulsions was also examined. Tolycaine (140 mg/kg, intraperitoneally) produced a significant elevation of noradrenaline and 5-hydroxytryptamine levels in all brain regions in the convulsive state from the levels in the non-convulsive state. Their levels returned to normal during the postconvulsive state. Dopamine levels were depleted in the cerebral cortex, the striatum, and the ponsmedulla oblongata during the convulsive process and increased in the cerebellum. Pretreatment with alpha-methyl-p-tyrosine, which depletes brain catecholamine, suppresses the tolycaine-induced convulsions, as shown by a decrease in the incidence; L-3,4-dihydroxyphenylalanine and bis-(1-methyl-4-homopiperazinyl-thiocarbonyl)-disulfide, which increase brain catecholamine, intensified the convulsions, as shown by shortening of the latency and increase in the mortality. Antagonists of beta-adrenergic and dopamine receptors, such as propranolol, chlorpromazine and pimozide, markedly suppressed the convulsions, but an antagonist of alpha-adrenergic receptor, phenoxybenzamine, had no effect. Furthermore, 5-hydroxytryptophan, which increases brain 5-hydroxytryptamine, suppressed the convulsions, and DL-p-chlorophenylalanine, which depletes brain 5-hydroxytryptamine, intensified them. Antagonists of 5-hydroxytryptamine receptor, methysergide and methiothepin, suppressed the convulsions. These results suggest that brain noradrenaline and 5-hydroxytryptamine are major regulators in the tolycaine-induced convulsive process and that central catecholaminergic neurones act in a stimulatory way on the tolycaine-induced convulsions, while serotonergic neurones act suppressively.     

Identification of some volatile endogenous constituents in rat brain tissue and the effects of lithium carbonate and chloral hydrate

Nine endogenous volatile compounds were found in rat brain tissue, and were identified by mass spectrometry as chloroform, a 5-C-aldehyde, dimethyl disulphide, 2,5-dimethyl tetrahydrofuran, a 8-C-alkane, xylene, 2-heptanone, heptaldehyde and 2-n-pentylfuran. Using gas chromatographic and gas chromatographic mass spectrometric techniques, it was established that lithium carbonate did not induce the production of detectable amounts of any new volatile compounds in brain tissue. However, after administration of chloral hydrate, trichloroethanol, a compound not normally present in rat brain tissue, was found to be present.     

Training effects on maternal and fetal glucose uptake following acute exercise in the rat

The purpose of the present study was to determine the effects of chronic maternal exercise on glucose uptake in maternal tissues after one bout of treadmill running during late gestation in the rat and to determine the effects on glucose accumulation in the fetus and placenta. Trained pregnant animals (PR) ran at 30 m.min-1, on a 10 degrees incline for 1 h on day 20 of gestation with a similarly treated trained nonpregnant group (NPR). Immediately after the run the animals were infused with a bolus of 1 g.kg-1 body wt as a 50% dextrose solution mixed with 2-deoxy-D-[1-3H] glucose through a carotid catheter. Sedentary pregnant (P) and nonpregnant animals (C) were also infused with the solution after no food and water for the same time frame. After 60 min, tissues were analyzed for radioactivity. Radioactive tracer was augmented in the red gastrocnemius and soleus of the PR group and the soleus of P rats. However, tracer accumulation in the fetus and placenta of the trained animals was not different than P animals. These results indicate that acute exercise in trained animals increased glucose uptake in maternal skeletal muscles without compromising conceptus glucose accumulation.     

The effect of sulfhydryl reagents on the tityustoxin-induced acetylcholine release in rat brain slices

The effect of breast feeding on serum FSH and LH concentrations was studied in 13 puerperal women. Despite the collateral increase in serum prolactin levels, nursing was not followed by significant changes in serum FSH or LH levels during a 30-min observation period. Our data indicate that nursing has no significant effect on pituitary FSH and LH release.     

The effect of steroid contraceptives on the concentrations of brain monoamines in rats and mice

The effect of three estrogen-progestin combinations on biogenic amines in discrete brain areas of rats and mice has been investigated. With the exception of a significant decrease of brain 5-hydroxyindolacetic acid in the rats treated for 30 days with the combination norethynodrel + mestranol, no significant changes in the levels of serotonin, noradrenaline or dopamine in the rat brain were found following the administration of the compounds under study. On the other hand, in mice moderate but significant changes in the levels of serotonin, dopamine, noradrenaline and 5-hydroxyindolacetic acid were found in various brain areas depending on the estrogen-progestin combination used. The potential importance of these effects for the contraceptive as well as for some central actions of these compounds is discussed.