The characteristics of neuronal and paraneuronal muscarinic inhibition and excitation were analyzed using rat caudate nucleus (CN) slices and isolated chromaffin cells obtained from the rat adrenal medulla. In CN neurons, either acetylcholine (ACh), carbachol, or muscarine inhibited orthodromically activated firing, while nicotine had no effect on neuronal activity. Muscarine decreased the amplitude of EPSPs without altering the resting membrane potential (RMP), input impedance and EPSP time courses. These results indicate that muscarinic receptors produce the pre-synaptic inhibition of synaptic transmission in the CN. In adrenal chromaffin cells, it was found that ACh, muscarine, and nicotine all increased extracellularly recorded firing. During voltage clamp recording at the RMP, ACh induced a transient inward current (fast response) followed by a long-lasting current (slow response). Muscarine induced the slow response, whereas nicotine induced the fast response. Muscarine reduced the inward K⁺ current produced by the application of a high K⁺ medium to cells. During patch clamp recording, muscarine decreased the opening rate of the single K⁺ channels. These results indicate that the muscarinic excitation of adrenal chromaffin cells was triggered by a reduction in the number of active K⁺ channels at the RMP.

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-Quantum chemical studies were applied to analyze the activities of catechol O-methyltransferase (COMT) inhibitors. Molecular orbital calculations of inhibitor molecules were made by semi-empirical molecular orbital calculations, CNDO/2 (complete neglect of differential overlap) methods. Regression analysis among theoretical reaction indices based on the frontier electron theory and COMT inhibitory activities were carried out. The COMT inhibitory actions of two series of inhibitors, a series of 1, 5-substituted 3, 4-dihydroxy benzenes and a series of substituted 3-hydroxy-4-methoxy benzenes, were investigated. The resulting regression equations contain two common reaction indices as regression variables: the electron density on the oxygen atom of the hydroxyl group and the super-delocalizability on the 5th carbon atom of the benzene ring. These two atomic positions are considered to play an important role in the interaction of these inhibitors with COMT. The hydroxyl of atomic position 3 is probably indispensable to the COMT inhibitory action by these inhibitors.

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-The antiarrhythmic effects of MS-551, which prolongs cardiac action potential duration without affecting the maximum upstroke velocity of the action potential, were assessed in three different canine ventricular arrhythmia models: 1) ventricular tachycardia (VT) induced by electrical stimuli 3-5 days after myocardial infarction, 2) spontaneous ventricular tachyarrhythmias 24-48 hr after two-stage coronary ligation and 3) ventricular tachyarrhythmias induced by digitalis. Intravenous administration of MS-551 (0.1-1 mg/kg) decreased the susceptibility in 10 dogs out of 13 to VT or ventricular fibrillation evoked by programmed electrical stimulation (PES) delivered to the ventricular septum 3-5 days after myocardial infarction. Oral administration of MS-551 (3 mg/kg) also decreased the susceptibility to VT evoked by PES in 7 out of 10 conscious postinfarction dogs. Concurrently, intravenous (0.1-1 mg/kg) or oral (3 mg/kg) administration of MS-551 produced increases in the ventricular effective refractory periods (ERP) by 7 ± 1%-17 ± 3% or 13 ± 2%, respectively. Similarly, d-sotalol (0.3-3 mg/kg, i.v. and 10 mg/kg, p.o.) decreased the susceptibility to VT with increased ERP. However, MS-551 (1 and 10 mg/kg, i.v.) failed to inhibit both canine two-stage coronary ligation arrhythmia and digitalis arrhythmia. These results suggest that MS-551 is a pure class III antiarrhythmic drug which may be effective in the treatment of life-threatening reentrant tachyarrhythmias, but not in automaticity arrhythmias.

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Central cholinergic hypofunction causes the disruption of spatial cognition, while cholinomimetics improve this disruption in rats. Scopolamine (0.5 mg/kg, i.p.) has also been reported to disrupt radial maze performance in rats. Nebracetam (WEB 1881 FU), a new nootropic candidate, was able to correct this scopolamine-induced disruption of spatial cognition at the dose of 10 mg/kg, p.o. Furthermore, nebracetam enhanced oxotremorine-induced tremors in mice. These results indicate that nebracetam has a cholinergic enhancing effect. The scopolamine-induced disruption of spatial cognition has been previously reported to improve not only by cholinomimetics but also by brain noradrenergic drugs such as L-threo-DOPS and amantadine. Nebracetam reversed the change of brain noradrenaline contents in the frontal cortex and hippocampus in which the noradrenaline content decreased by treatment with scopola mine. Nebracetam also decreased the Δ⁹-tetrahydrocannabinol (6 mg/kg, i.p.)-induced disruption of spatial cognition, which was reported to be related to the lymbic noradrenergic function. These results suggest that the cognitive enhancing effect of nebracetam involves not only cholinergic mechanisms but also involves lymbic and hippocampal noradrenergic mechanisms.

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The effects of oxiracetam on the reduction of brain metabolism induced by focal cerebral ischemia were investigated by measuring local cerebral glucose utilization (LCGU) in rats 24 hr after left middle cerebral artery occlusion. Focal cerebral ischemia reduced LCGU in the entire ipsilateral cortex, the greatest reduction being in the lateral parts of the frontoparietal cortex. LCGU was slightly reduced in the contralateral cortex; this reduction was considered to be caused by diaschisis. Oxiracetam was administered intraperitoneally for 3 days prior to middle cerebral artery occlusion. In the ipsilateral cortex, LCGU reduction was minimized in the ischemic center areas by oxiracetam at a dose of 400 mg/kg and in more extensive areas, by a dose of 800 mg/kg. Moreover, oxiracetam at a dose of 800 mg/kg enhanced metabolism impaired by diaschisis in the caudal areas of the contralateral cortex. These findings suggest that oxiracetam minimizes the reduction of brain function induced by ischemia and may therefore be useful in the treatment of cerebrovascular disease.

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We evaluated the effects of a potent cholecystokinin (CCK)-B/gastrin receptor antagonist, L-365, 260 (3R(+)-N-(2, 3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4-benzodiazepin-3-yl)-N''-(3-methylphenyl)urea); a selective CCK-A receptor antagonist, devazepide (L-364, 718); and cimetidine on gastric acid secretion induced by pentagastrin, histamine and bethanechol in anesthetized rats. We also evaluated the effects of L-365, 260 and cimetidine on acid secretion in pylorus-ligated rats. Intravenous administration of L-365, 260, L-364, 718 and cimetidine dose-dependently reduced acid secretion induced by pentagastrin (20 nmol/kg/hr), with ED₅₀ values of 0.63, 19.1 and 2.5 μmol/kg, respectively. Of interest was the finding that L-365, 260, like cimetidine, dose-dependently inhibited acid secretion induced by histamine (100 μmol/kg/hr) and bethanechol (5 μmol/kg/hr) with ED₅₀ values of 5.9 and 4.3 μmol/kg, respectively. L-364, 718, even at 30 μmol/kg, i.v., had only a slight effect on histamine or bethanechol-induced acid secretion. Gastric acid secretion was suppressed by treatment with L-365, 260 (3-100 μmol/kg, i.v.) and cimetidine (11.9-396.4 μmol/kg, i.v.) in pylorus-ligated rats, with ED₅₀ values of 13.3 and 96.9 μmol/kg, respectively. These results indicate that L-365, 260 suppresses acid secretion induced by histamine and bethanechol in rats and that the gastrin receptor plays an important role in acid secretion in pylorus-ligated rats.

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The present experiments were designed to evaluate the importance of nitric oxide in the regulation of renal hemodynamics and the autoregulation of renal blood flow (RBF) in anesthetized dogs. RBF was measured by an electromagnetic flowmeter, and renal arterial pressure (RAP) was varied by an adjustable aortic clamp. The RAP-RBF relations were examined during the intrarenal infusion of saline or agents. The intrarenal infusion of L-N^G-nitro-arginine (L-NNA, 40 μg/kg·min) at normal RAP decreased RBF and urine flow (UF), while the infusion of L-arginine·HCI (1 mg/kg.min) increased RBF and UF. Both agents did not affect the glomerular filtration rate and mean arterial pressure. The autoregulation of RBF was impaired during the L-NNA infusion. The L-arginine infusion did not affect autoregulatory efficiency. When L-NNA (40 μg/kg·min) and L-arginine were infused simultaneously into the renal artery, the autoregulation of RBF was maintained. However, a higher dose of L-NNA (200 μg/kg·min) impaired the autoregulation of RBF. These results suggest that the basal production and/or the release of nitric oxide contributes to the regulation of renal hemodynamics and urine formation. During the reduction of RAP, nitric oxide may play an important role in the autoregulation of RBF.

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The role of mucosal sulfhydryl (SH) in the pathogenesis of indomethacin-induced gastric lesions was investigated in rats. Indomethacin (25 mg/kg, s.c.) caused high-amplitude gastric contractions, resulting in linear hemorrhagic lesions in the corpus mucosa within 4 hr, but did not induce any changes in the mucosal SH levels. These lesions were prevented significantly by prior s.c. administration of cysteamine, glutathione (GSH) or diethylmaleate (DEM), irrespective of whether the mucosal SH was increased by the former two agents or reduced by the latter. N-Ethylmaleimide (NEM) tended to worsen such lesions without any effect on the mucosal SH contents. Gastric hypermotility caused by indomethacin was inhibited significantly by DEM, cysteamine and GSH, while acid secretion was reduced by DEM and NEM. Both cysteamine and GSH prevented the indomethacin-induced linear lesions even in the stomach perfused with 150 mM HCl, whereas in the animals treated with DEM, non-linear damage was induced exclusively in the antrum by indomethacin in the presence of acid. We conclude that the mucosal SH has no relation to the ulcerogenicity of indomethacin in the gastric corpus mucosa.

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We investigated the effects of disulfiram (DS) on ovarian carbonyl reductase activity in rats to determine the influence of DS on female reproductive function. Three consecutive treatments with DS significantly inhibited ovarian carbonyl reductase activity as well as ovulation, dose-dependently. Single treatment with DS had no effect on ovarian carbonyl reductase activity. Our observations indicate that consecutive treatment with DS has an inhibitory action on female reproductive function, although DS is well-known to inhibit aldehyde dehydrogenase and dopamine β-hydroxylase.

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Using a three-panel runway task, the influence of dorsal hippocampal lesions on working and reference memory in rats was investigated. Despite 20 postoperative training sessions, rats with hippocampal lesions were unable to perform the working memory task. In the acquisition process of the reference memory task, however, there was no significant difference between hippocampal- and sham-lesioned rats. On the other hand, rats trained preoperatively with a working memory procedure, and then subjected to hippocampal lesions, showed more errors (pushes made on the two incorrect panels of the three panel-gates located at four choice points) than did sham-lesioned rats. The increase in working errors induced by hippocampal lesions was not reduced during 10 subsequent re-training sessions. Hippocampal lesions had no effect on retention of the reference memory performance. The increase in working errors in hippocampal-lesioned rats was significantly reduced by treatment with the cholinesterase inhibitor physostigmine at 0.1 mg/kg and the cholinergic activating drug minaprine at 10 mg/kg. These findings suggest that lesions of the dorsal hippocampus selectively impair the ability to carry out the working memory task whether rats are trained preoperatively or postoperatively, and that the working memory loss in hippocampal-lesioned rats is mediated by lowering of the cholinergic function.

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The effect of quinidine on the transient outward current (I_A) in rat hippocampal neurons was studied. Quinidine at 1 × 10^-6 M or more dose-dependently decreased the I_A without affecting the current-voltage relationship. Quinidine accelerated the decay phase of the I_A, suggesting the blockade of open channels. This result may have an implication on the side effects of quinidine in the central nervous system, since the I_A is involved in the control of rhythmic electrical activity of the neurons.

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Dibutyryl cyclic AMP (dBcAMP)-treatment of cultured rat astrocytes induced changes in astrocyte morphology followed by the potentiation of prostaglandin F_2α (PGF_2α)-stimulated phosphoinositide (PI) hydrolysis. The potentiation was observed in astrocytes of the cerebral cortex, cerebellum, and hippocampus. The dBcAMP-treatment induced agonists-specific changes in PI hydrolysis; e.g., the potentiation of norepinephrine-effect and the reduction of the carbachol-effect. Coincubations of carbachol or norepinephrine with PGF_2α produced additive responses.

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Selectivity of bevantolol hydrochloride (NC-1400) towards α- and β-adrenoceptor subtypes of rat cerebral cortex was examined in binding experiments and compared with propranolol. Bevantolol biphasically displaced the ³H-dihydroal-prenolol binding. The affinity of bevantolol to β₁-adrenoceptor was equal to that of propranolol. Bevantolol displaced ³H-prazosin binding monophasically but not ³H-p-aminoclonidine binding. These results suggest that bevantolol is a β₁-adrenoceptor antagonist with a relatively high affinity to α₁-adrenoceptor subtypes.

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Effects of clomiphene and/or estrogen on uterine prostaglandin (PG) F_2α fluctuations in ovariectomized rats were examined. Uterine PGF_2α fluctuations were measured at the indicated times after injection of clomiphene and/or estradiol. Antiestrogenic effects of clomiphene on urine weight and PGF_2α levels were observed at 6 hr, and its effect on uterine 13, 14-dihydro-15-keto-PGF_2α forming capacity was observed at 24 hr. At 48 and 72 hr, additive effects were recognized in all parameters. These results indicate that clomiphene possesses agonistic-antagonistic actions on the PGF_2α fluctuations in the uterus.

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