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Biomedical subjects

V Saano

Publications and source records attributed to V Saano.

67 records · Page 4Linked to original sources
PubMed1984

Binding of beta-carbolines and tetrahydroisoquinolines by opiate receptors of the delta-type.

Effects of various beta-carbolines (BC's) and two tetrahydroisoquinolines (TIQ's) on the specific binding of a natural opiate delta-receptor ligand, leucine enkephalin, have been studied in rat synaptosomal membranes, and compared with the effects on the binding of mu-receptor ligands dihydromorphine and naloxone. Harmaline (7-MeO-1-Me-dihydro-BC) was the most potent compound studied (Ki value 3.5 microM), while the two TIQ's (salsolinol and salsolidine) were less potent than BC's (Ki greater than 100 microM) in inhibiting the binding of delta-receptors. In general, BC's showed more affinity for delta-receptors than for mu-receptors; salsolinol was more potent against the binding of mu-receptors. Inhibition of binding was generally of the competitive type: Kd values increased and Bmax values were not altered. The Na dependence suggests that BC's and salsolinol are antagonists or partial agonists of opioids. Since the binding affinity of BC's and TIQ's was on the micromolar level only, the opiate receptors do not appear to be the major sites of action for BC's or TIQ's.

Animals↗
PubMed1983

Tofizopam enhances the action of diazepam against tremor and convulsions.

Tofizopam, an anxiolytic 3,4-benzodiazepine, increases the affinity of benzodiazepine receptors for 1,4-benzodiazepines. In this study we investigated whether this increased affinity of the receptors alters the sensitivity of mice to tremor and to convulsions. Convulsions induced by harmane were not affected by tofizopam (50-300 mg/kg), but diazepam (15 mg/kg) increased the ED50 of harmane from 9.9 to 25.1 mg/kg. Tofizopam did not alter the threshold for electroshock-induced convulsions, while a dose of 10 mg/kg diazepam protected mice from convulsions. Low doses of tofizopam (12.5-25 mg/kg) sensitized mice to the tremorogenic effect of harmaline. Diazepam inhibited tremor: the ED50 of harmaline increased by 153% after 50 mg/kg of diazepam. In contrast to 1,4-benzodiazepines, tofizopam has no anticonvulsive effect. It sensitises mice to the tremor induced by harmaline. In combination with diazepam, however, tofizopam enhanced the anticonvulsive and antitremorogenic actions of this 1,4-benzodiazepine by 12-65%. This effect probably results from a tofizopam-induced increase in the occupation of benzodiazepine receptors.

Animals↗
PubMed1982

Tofizopam modulates the affinity of benzodiazepine receptors in the rat brain.

Tofizopam, a 3,4-benzodiazepine, lacks the sedative action common to 1,4-benzodiazepines, but has anxiolytic activity. In this study we administered tofizopam (50 mg/kg) to rats perorally twice a day for six days, and analyzed the binding of [3H]flunitrazepam to benzodiazepine receptors of these drug-treated rats. The effect of tofizopam treatment was compared to that brought about by treatment with diazepam (12 mg/kg twice a day for six days) and to binding in controls treated with vehicle. Compared to the controls, the diazepam group had a marked decrease in binding of [3H]flunitrazepam to benzodiazepine receptors both in the forebrain and in the hindbrain. As a result of the increased affinity of the receptors tofizopam slightly, but statistically significantly, enhanced binding. With both drugs the number of receptors was unaltered. The effect of tofizopam in the hindbrain was similar to that in the forebrain. The results of this study support our earlier finding from single-dose studies that tofizopam acts indirectly on benzodiazepine receptors.

Animals↗
PubMed1982

Binding of beta-carbolines and caffeine on benzodiazepine receptors: correlations to convulsions and tremor.

Compounds from both the beta-carboline (BC) and xanthine groups have been suggested to be the natural ligands for benzodiazepine (BZ) receptors. In this study we examined the effects of several BC's and caffeine, 1,3,7-trimethylxanthine, on the binding of 3H-flunitrazepam (3H-FZ) and beta-3H-carboline-3-carboxylic acid ethyl ester (3H-BCCE) to the BZ receptors of rat and mouse brain. In mice, convulsion-producing doses of caffeine (120 mg/kg intravenously) and harmane (30 mg/kg intravenously) lowered the specific binding of 3H-FZ in vivo by 12-31%. A tremorogenic dose of harmaline (30 mg/kg intravenously) increased binding by 31%. Caffeine and harmane also slightly decreased the in vivo binding of 3H-BCCE, a compound that binds preferentially to the cerebellar type of BZ receptors. Harmaline stimulated the binding of 3H-BCCE only in the forebrain. Both harmaline and harmane increased by 41-111% the amount of 3H-BCCE that was distributed to the brain. In vitro BC's and caffeine displaced 3H-FZ from receptors in the rat brain with various Ki values (4.7 to 206.9 microM). The antagonism for BZ binding was competitive and in Scatchard analysis produced linear plots. Exceptions were harmaline and caffeine in the forebrain: both exhibited curvilinear plots for 3H-FZ binding. Harmaline increased the binding, and caffeine decreased it by altering the affinity of a subgroup of BZ receptors. In the hindbrain both harmaline and caffeine inhibited binding and produced linear plots. BC-induced tremor and convulsions unveil a large number of spare receptors in the brain, and these seem to be of the cerebellar type of BZ receptors. In addition, our results show that tremorogenic and convulsive BC's act differently on BZ receptors: during harmaline-induced tremor the affinity of some BZ receptors is increased, while harmane-induced convulsions are connected to direct occupation of BZ receptors.

Animals↗
PubMedDate not supplied

Changes in GABA-benzodiazepine receptor complex and in peripheral benzodiazepine receptors in male mice after copulation.

We studied the effect of copulation on GABA and benzodiazepine (BZD) receptors in the male mouse. After copulation, there was an 18% increase in the in vitro number of [3H]muscimol binding sites in frontal cortex. No changes were observed in central BZD binding sites labelled either in vivo by [3H]flunitrazepam or in vitro (in olfactory bulbs and in frontal cortex) by [3H]flumazenil, but further in vitro studies demonstrated that the GABA-stimulated [3H]flunitrazepam binding was reduced in both frontal cortex and olfactory bulbs. Copulation increased the number of peripheral BZD binding sites labelled by 3H-Ro 5-4864 in olfactory bulbs by 22% and in heart by 36%, but not in frontal cortex or in testes. The changes of GABA/BZD and peripheral BZD receptors in mouse suggest that the GABAergic system may be affected by copulation.

Animals↗
PubMedDate not supplied

Decreased GABA, benzodiazepine, and picrotoxinin receptor binding in brains of rats after cobalt-induced epilepsy.

In previous studies of experimental and human epilepsy, defects have been shown in the gamma-aminobutyric acid (GABA) receptors. We further investigated the role of the GABA/benzodiazepine/picrotoxinin receptor complex in the epileptic focus and also in other regions of the rat brain. The focus was induced by cobalt implantation to the right motor cortex, and the brains were dissected 16-19 days after the operation. Benzodiazepine (using [3H]flunitrazepam as a ligand; FLU), GABA [3H]muscimol; MUS), and picrotoxinin [( 35S]t-butylbicyclophosphorothionate; TBPS) receptor bindings were measured in different brain areas and the values were compared with glass-implanted controls. In the focal area, the specific receptor binding decreased in the order TBPS greater than FLU greater than MUS. In the perifocal area only TBPS binding decreased, and Scatchard analysis showed a decrease in the number of binding sites (p less than 0.05) without any effect on binding affinity. No change was seen in the binding characteristics of the other areas studied. According to our results, in cobalt-induced epilepsy the GABA/benzodiazepine/picrotoxinin receptor complex is modulated in the focal area; this may lead to a defect in chloride conductance, which in turn induces disturbed control of neuronal activity in the epileptic focus.

Animals↗
PubMedDate not supplied

Effects of vigabatrin (gamma-vinyl GABA) on neurotransmission-related amino acids and on GABA and benzodiazepine receptor binding in rats.

The effect of 12-day intraperitoneal i.p. administration of vigabatrin (GVG, gamma-vinyl GABA) to rats on the neurotransmission-related amino acids in various brain regions (cortex, hippocampus, cerebellum, and spinal cord), cisternal fluid (CSF) and blood was studied. Results showed that GVG administration increased the levels of GABA in cortical and subcortical regions of the brain and CSF without affecting GABA and benzodiazepine receptors in the cortex. In addition, a dose-dependent decrease was noted in the concentration of glutamate in the hippocampus and in the concentrations of aspartate and glutamine in the cortex, hippocampus, and cerebellum. The changes in the levels of amino acids in the brain, except for that of GABA, were not reflected in the CSF, however, and the levels of amino acids in discrete brain regions did not show any correlation with those in the serum or in the CSF. The results suggest that GVG administration might suppress development and spread of seizures not only by elevating the level of the inhibitory amino acid GABA, but also by decreasing the levels of excitatory amino acids in the brain.

Amino Acids↗
PubMedDate not supplied

Possible interaction between oxcarbazepine and an oral contraceptive.

The effect of oxcarbazepine (OCBZ) on the kinetics of an oral contraceptive containing ethinyloestradiol (EE) and levonorgestrel (LNG) was investigated in 13 healthy female volunteers who had previously received the contraceptive for at least 3 months. After 15 days of the first study cycle, each subject received, in addition to the oral contraceptive, 300 mg OCBZ on day 16, 300 mg twice daily on day 17, and 300 mg three times daily from day 18 of the first cycle to day 18 of the next menstrual cycle. The area under the curve values for both EE and LNG decreased when OCBZ was given with the oral contraceptive (p = 0.006, analysis of variance). The results indicate that OCBZ, like most antiepileptic drugs (AEDs), decreases the bioavailability of EE and LNG, perhaps by affecting metabolism or protein binding.

Adult↗
PubMedDate not supplied

3H-atipamezole binding sites in mouse cerebral cortex: possible involvement of alpha 2-adrenoceptors in sexual behavior.

Atipamezole is a new specific alpha 2-adrenoceptor antagonist. In this study, first, the presence of specific 3H-atipamezole binding sites in the sagittal and coronal sections of mouse brain was established using autoradiography. In vitro experiments with mouse cerebral cortex membranes indicated that d-medetomidine, a new alpha 2-adrenoceptor agonist structurally related to atipamezole, displaces labelled atipamezole more potently than noradrenaline. The saturation isotherm with d-medetomidine demonstrated high affinity binding with the apparent number of binding sites KD 1.36 nM and 760 fmol/mg, respectively. In the next series of experiments male mice were sacrificed immediately after copulation and cerebral cortex 3H-atipamezole and 3H-flumazenil binding was studied. Oxymetazoline and prazosin are known to label preferably alpha 2A and alpha 2B subtypes of alpha 2-adrenoceptors. Therefore, parallelly with noradrenaline both these compounds were used to determine non-specific binding of 3H-atipamezole. When noradrenaline or oxymetazoline were used as displacing agents copulation caused a significant increase of 3H-atipamezole binding sites. No significant changes were observed when prazosin was used. 3H-Flumazenil binding remained unchanged by copulation. The up-regulation of 3H-atipamezole binding sites indicates that not only alpha 2-adrenoceptors in the periphery but also in the CNS may participate in the regulation of sexual behavior. Moreover, in regulation of sexual behavior central alpha 2-adrenoceptors may be more important than benzodiazepine receptors.

Adrenergic alpha-Antagonists↗
PubMedDate not supplied

Highly selective and specific antagonism of central and peripheral alpha 2-adrenoceptors by atipamezole.

The potency, selectivity and specificity of atipamezole [MPV-1248, 4-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole], as an alpha 2-adrenoceptor antagonist was studied. In receptor binding studies [( 3H]-clonidine and [3H]-prazosin displacement) an alpha 2/alpha 1 selectivity ratio of 8526 was obtained for atipamezole, while idazoxan and yohimbine showed ratios of 27 and 40, respectively. Atipamezole had also about a 100 times higher affinity on alpha 2-adrenoceptors than the reference compounds. In the electrically stimulated prostatic portion of rat vas deferens, atipamezole showed potent competitive antagonistic activity against clonidine (pA2 8.6) and medetomidine (pA2 8.7) at presynaptic alpha 2-adrenoceptors. In the epididymal portion of the rat vas deferens, atipamezole had only weak competitive antagonistic activity against phenylephrine (pA2 5.0). In binding studies and studies with isolated organs, atipamezole had no effect on beta 1-, beta 2-, H1-, H2-, 5-HT1-, 5-HT2-, muscarine, DA2-, tryptamine, GABA, opiate and benzodiazepine receptors. In the pithed rat, atipamezole, like idazoxan, had partial alpha 1-adrenoceptor-mediated vasoconstrictor effects in addition to potent alpha 2-adrenoceptor blocking activity. In mice, medetomidine-induced sedation was effectively antagonized by atipamezole. These results show that atipamezole is a potent, selective and specific antagonist of both centrally and peripherally located alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗