The influence of dopamine, levodopa and apomorphine on maximal electroconvulsive seizure was studied in young chicks, adult cocks and rats. The susceptibility of chicks to maximal electroshock seizure increased with age between 1 to 7 days. Low to moderate doses of dopamine (12.5-150 mg/kg, i.p.), levodopa (6.25-25 mg/kg, s.c.) and apomorphine (0.25-2.0 mg/kg, s.c.) significantly (P<0.005) protected chicks against electroshock seizure, while high doses (200-400 mg/kg, i.p. of dopamine, 50-200 mg/kg, s.c. of levodopa and 2.5-5 mg/kg, s.c. of apomorphine) enhanced electroshock seizure in 1 to 7 day old chicks. However, when 14 day old chicks were used, these dopaminoceptor agonists protected the chicks against maximal electroshock seizure. Noradrenaline (1-40 mg/kg, i.p.) had no significant effect on electroshock seizure in chicks. Both pimozide (4 mg/ kg, i.p.) and haloperidol (0.4 mg/kg, i.p.) antagonized the effects of levodopa (12.5 and 50.0 mg/kg, i.p.) and apomorphine (0.5-5 mg/kg, s.c.) on maximal electroshock seizure. The seizure susceptibility of both adult rats and fowls to electroshock was not altered by dopamine (12.5-400 mg/kg, i.p.). Central dopamine neurotransmission might be involved in the biphasic dose-dependent effects of dopamine, levodopa and apomorphine on maximal electroshock seizure in young chicks.

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The regulatory roles of intracellular taurine and glycine, transported and biosynthesized in hepatocytes, on the formation of conjugated bile acids were studied using freshly isolated hepatocytes (fresh hepatocytes) and hepatocytes in primary culture (cultured hepatocytes). Transported taurine significantly increased the rate of taurocholic acid formation both in fresh hepatocytes and cultured hepatocytes. Similarly, the addition of cysteine and hypotaurine, which were metabolically converted to taurine in hepatocytes, facilitated the formation of taurocholic acid in these cells. On the other hand, exogenous glycine into the incubation medium had no effect on the formation of glycocholic acid both in fresh and cultured hepatocytes. In contrast, the addition of serine and threonine, which are metabolically converted to glycine in hepatocytes, significantly increased the formation of glycocholic acid in fresh hepatocytes, although little effect of the additions of serine and threonine on the formation of glycocholic acid was noted in the case of cultured hepatocytes. The present results indicate that the formation of taurine-conjugated bile acids in hepatocytes is maintained by both transported and intracellularly formed taurine in hepatocytes, while that of glycine-conjugated bile acids is regulated by glycine formed within hepatocytes, but not by transported glycine.

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Nipradilol but not desnitro nipradilol ((N-) nipradilol) inhibited the norepinephrine (NE) -induced depolarization and contraction of the rabbit portal vein. The NE-induced contraction and depolarization were also blocked by prazosin, but not blocked by yohimbine. Therefore, nipradilol possesses an α₁-blocking action. The order of potency was prazosin >nipradilol >yohimbine> (N-) - nipradilol=0. With applications of field stimulations to muscle tissues, the smooth muscle membrane was depolarized with a latency of several seconds, and the action potential was generated. These phenomena were blocked by tetrodotoxin (TTX), prazosin or nipradilol, but not by yohimbine. Isoproterenol (Isop) inhibited the 30 mM K-induced contraction, and this inhibitory action was blocked by (N-), nipradilol, nipradilol or propranolol, dose-dependently. The potency of β-blocking actions of nipradilol was much the same as that observed by propranolol and (N-) nipradilol. When nipradilol (10^-5 M) was applied to the tissue, the amplitude of the 30 mM K contraction was slightly reduced. Such inhibitory action was not observed by application of (N-) nipradilol. The K₁ values of nipradilol for blocking actions on the NE-induced contraction and Isop-induced relaxation were of the same order of 10^-7 M. Therefore, the potencies of α₁ -blocking and β-blocking actions of nipradilol may be the same in the rabbit portal vein. These findings suggest that the vasodilating action of nipradilol on the rabbit portal vein is mainly due to the α₁-blocking action and that the nitrate action of this agent may be weak.

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A new model of a microwave device was developed with a power of 10 kW at 2450 MHz. In order to accomplish even distribution of heating with minimum trauma and with a maximum certainity about enzyme inactivation, a modified magnetic field distribution was utilized rather than the conventional electric field. An integrated tuning system was used to increase efficiency and distribution of microwave energy absorption. This increased the ability of the instrument to properly inactivate the enzymes in the brain of both mice and large rats. In general, the time of irridiation for the rat was 600 to 900 msec and for the mice, 100 to 330 msec. The animal chambers used were designed so as not to impair breathing or too severely restrict movement. The effects of these improvements on microwave irradiation were confirmed by 1) observation of brain appearance, 2) effects on succinic dehydrogenase and cholinesterase activity, 3) measurement of regional temperatures in the animal's brain, 4) thermograms of the brain, 5) electron microscopic examination of brain tissue and 6) measurement of endogenous acetylcholine and catecholamines.

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The anti-ulcer effect of sofalcone, an isoprenyl chalcone derivative, on acetic acid-induced gastric ulcers in rats was studied histologically and histochemically. After administrations of sofalcone at 50 and 200 mg/kg twice daily for 10 days, contraction of the ulcer, mucosal regeneration, accelerated development of the collagen fibers in the granulation tissue at the base of the ulcer, and increase of acid mucopolysaccharides, an alcian blue stain-positive substance covering the regenerated mucosa, were noted. The healing effect of sofalcone was balanced in mucosal regeneration and connective tissue proliferation (formation of the collagen fibers). Sofalcone of 50 mg/kg showed a greater healing effect than gefarnate at the same dose and had a similar healing effect as L-glutamine at 200 mg/kg.

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In vitro effects of racemomycin-D on cellular metabolism were examined in rat kidney. Racemomycin-D decreased the concentration gradient of Na⁺ and K⁺ across the cell membranes, but failed to influence water content and ATP concentration of kidney cortical slices. The antibiotic inhibited microsomal (Na⁺+K⁺) - ATPase. Preincubation of the microsomes with racemomycin-D enhanced the inhibition about 1.8-fold. Succinoxidase activity of mitochondria remained unaltered in the presence of racemomycin-D, but the antibiotic potently decreased ATP-dependent Ca²⁺ and Mg²⁺ uptakes by mitochondria. These results suggest that racemomycin-D probably disorders intracellular homeostasis of Na⁺, K⁺ and Ca²⁺.

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Effects of neuroactive peptides on the release of labeled 5-hydroxytryptamine (5-HT) from preloaded rat spinal cord slices were investigated. The 5-HT release was significantly stimulated by somatostatin (10-50 μM) and substance P (10-50 μM), but not by neurotensin (50 μM), 8-endorphin (30 μM) and methionine-enkephalin (met-enk) (100 μM). Somatostatin-stimulated 5-HT release was markedly inhibited by γ-aminobutyric acid (GABA) (30 μM), but not by baclofen (30 μM) and met-enk (100 μM). Substance P-stimulated 5-HT release was strongly inhibited by GABA (30 μM) and baclofen (30 μM), but not by met-enk (100 μM). High concentrations (20 mM) of potassium also stimulated 5-HT release. The high potassium-stimulated 5-HT release was not affected by GABA (30 μM) and met-enk (100 μM). These results suggested further evidence on the important role of somatostatin and substance P as modulators of serotonergic neurones.

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The effect of prostaglandin E₁ α-cyclodextrin host molecule (PGE₁·CD) was estimated by using a model of immune complex glomerulonephritis induced in rats by i.v. injection of 1 mg of rabbit serum albumin every other day. PGE₁·CD was given subcutaneously for 10 days after nephritis was definitely induced and resulted in a rapid restoration of various biochemical parameters, especially in plasma. The continuous s.c. administration of PGE₁·CD (300 μg/rat/day) with a mini osmotic pump provoked a therapeutic effect similar to that obtained with twice daily s.c. administration of PGE₁·CD (300 μg/rat×2/day). Both PGE₁·CD groups revealed less glomerular damage and fewer locations of immune complexes in glomeruli as demonstrated by light and immunofluorescence microscopy. The beneficial effect of PGE₁·CD may be associated with reduced immune complex deposits in glomeruli. The present studies suggest that PGE₁·CD may enhance the clearance of immune complex deposits from the glomeruli rather than inhibiting the formation of immune complex in the circulation.

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The positive inotropic effect of TA-064, (-) - (R) -1- (p-hydroxyphenyl) -2- [(3, 4-dimethoxyphenethyl) amino] ethanol, was studied in the anesthetized dog and isolated guinea pig heart. An intravenous administration of TA-064 dose-dependently increased the cardiac contractile force with little effect on blood pressure in dogs. The positive inotropic activity of TA-064 was 1/100 that of isoproterenol and similar to that of dobutamine. This effect of TA-064 was stereospecific, and it was blocked by practolol. Thus TA-064 has beta1 -adrenoceptor agonistic action. The positive inotropic effect of TA-064 was more pronounced than the positive chronotropic effect, compared with those of isoproterenol. Similar effect of TA-064 was observed in the reserpinized dog and in the isolated perfused heart of the guinea pig as well. TA-064 administered intraduodenally at a dose of 0.1 mg/kg increased contractile force by 120% of the control, and the effect lasted for more than 160 min. TA-064 given in the femoral artery demonstrated a very weak vasodilating effect on the artery. TA-064 is an orally active, positive inotropic agent. The selective positive inotropic action of TA-064 may result from its beta₁ -adrenoceptor agonistic property.

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The activities of monoamine oxidase (MAO) in a homogenate and the mitochondrial fraction of monkey (Macaca facicularis) heart were measured with labelled benzylamine, serotonin (5-HT), tyramine and β-phenylethylamine (PEA) as substrates. The effects of clorgyline, deprenyl and semicarbazide on MAO were also investigated. Benzylamine deamination was more sensitive to deprenyl than to clorgyline, although it was not completely inhibited by a high concentration of either, and the remaining activity was completely inhibited by pretreatment with semicarbazide. The activities of 5-HT and tyramine were both more sensitive to clorgyline than to deprenyl, and both inhibitors gave single-sigmoidal inhibition curves. Experiments with increasing concentrations of PEA as substrate and clorgyline and deprenyl as inhibitors indicated that at higher concentrations, PEA was a substrate for MAO-A as well as MAO-B in monkey heart. These results suggest that monkey heart mitochondria contain not only MAO-A and MAO-B, but also clorgyline resistant amine oxidase (CRAO). The ratio of MAO-A, MAO-B and CRAO was determined from plots of inhibitions with each substrate. The kinetic constants of MAO in monkey heart were compared with those of MAO in hearts of other animals. The enzymic properties of MAO in monkey heart were discussed on the basis of these results.

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Addition of liver cytosol from 16 hr-starved rats treated with 6-aminonicotinamide to rat liver microsomes caused potentiation of the anti-carboxylesterase action of ethyl-p-nitrophenyl phenylphosphonothioate (EPN). This was not found when liver cytosol from non-pretreated rats after 16 hr-starvation was used. This potentiation of EPN-induced inhibition of carboxylesterase may be, at least in part, explained by the fact that treatment of rats with 6-aminonicotinamide resulted in a significant increase in NADPH level in liver cytosol which, in turn, stimulated formation of an EPN oxygen analog, a potent inhibitor of carboxylesterase, through cytochrome P-450-coupled monooxygenase.

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Effects of trimebutine maleate (TM-906) on the smooth muscles of isolated guinea pig gallbladder were investigated. TM-906 inhibited the contractile responses to cholinergic nerve stimulation (5 Hz) and to acetylcholine (3×10^-8 g/ml) to the same extent, both of which produced much the same amplitude of contraction. TM-906 noncompetitively antagonized the contractile response to methacholine, and it caused a parallel shift of dose-response curves for the contractile response to CaCl₂ to higher concentrations. Moreover, TM-906 inhibited the contractile response to 50 mM KCl in a dose-dependent manner. On the other hand, TM-906 itself evoked a slight contractile response in a dose-dependent manner. The contractile response induced by TM-906 was prevented by exposure to Ca⁺⁺-free solution, but not by tetrodotoxin or atropine. From these results, it was suggested that TM-906 inhibited the contractile responses to cholinergic nerve stimulation, acetylcholine, methacholine and 50 mM KCl by reducing the influx of calcium ion across the cell membrane, while it was assumed that TM-906 itself evoked a slight contractile response by increasing in some way the concentration of the intracellular free calcium ion available for the contractile systems.

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The in vivo effect of bromhexine on secretory activities of tracheal submucosal glands was investigated with a histological/histochemical technique with reference to a role of the vagal reflex. When bromhexine was given at 5, 10 or 20 mg/kg into the stomach of anesthetized dogs, the ratio of acinar inner diameter of the submucosal gland to wall thickness (A^IWR) markedly increased in a biphasic manner; the early transient increase was seen 0.5 hr after administration, and the second prolonged increase occurred during 2 to 6 hr after administration. The early stimulant phase was almost abolished by atropine, 1 mg/kg i.v., or bilateral cervical vagotomy, whereas the second stimulant phase was not affected by these treatments. Emetine also induced a similar early increase in A^IWR at 0.5 hr after administration, the change also being abolished by atropine or surgical vagotomy in this case. The number of submucosal glandular cells which stained blue and purple with a combination of alcian blue at pH 2.5 and periodic acid-Schiff was decreased by bromhexine, but the cell number which stained red was markedly increased. These histochemical changes in glandular cells were not influenced by treatment with atropine or surgical vagotomy. In the present study, it was found that bromhexine exerts both a secretagogic action on submucosal glands and a mucolytic action toward acid glycoproteins inside the cells in vivo. Also, the secretagogic action of bromhexine occurs biphasically; the first phase results from the vagal reflex probably through a gastrointestinal irritation, and the second phase results from a direct action on the glands.

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Temporal changes in the avoidance responses and serum prolactin levels were investigated for a 360 min period after s.c. administration of antipsychotic drugs such as chlorpromazine (2 mg/kg), prochlorperazine (2 mg/kg), haloperidol (0.035 mg/kg), droperidol (0.03 mg/kg), YM-09151-2 (0.005 mg/kg) and sulpiride (80 mg/kg) in rats. Male adult rats of the Wistar strain were trained under a continuous lever-press avoidance schedule (Sidman type) to observe avoidance-suppressing effects of the drugs. The avoidance response was suppressed after administration of chlorpromazine, prochlorperazine, haloperidol, droperidol and YM-09151-2, showing significant decrease in response rate and significant increase in shock rate when compared with those after saline administration, while it was scarcely suppressed within 150 min after sulpiride. On the other hand, serum prolactin levels were increased after administration of all the drugs used. Furthermore, parallelism between temporal changes in the avoidance responses and those in serum prolactin levels was observed after administration of the antipsychotic drugs, except for sulpiride. These results suggest that the prolactin-increasing effects of antipsychotic drugs are applicable for predicting antipsychotic efficacies in humans, excluding sulpiride therapy.

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