I. Action of spasmogens. Evidence has been obtained suggesting that (1) for all spasmogens tested, phasic contraction is produced by Ca release, the tonic contraction chiefly being maintained by the energy-dependent active influx of Ca, that (2) only in the case of Ba, a direct stimulation to the contractile system of muscle is also partly concerned with contraction, which is implied by the residual contraction by Ba in the Ca-free bath solution, and that (3) K and acetylcholine release Ca from the store of easily releasable Ca, whereas Ba does so, in addition, from the store of less easily releasable Ca.
II. Action of relaxants. Summing up the results of various experiments, it is concluded that (1) the relaxing action of isoproterenol on the normal tonus is due chiefly to the pseudo-competitive (or functional) inhibition of Ca influx and Ca release and (2) those of papaverine and Mg to the competitive inhibition of Ca influx and the non-competitive inhibition of the contractile system of muscle, the inhibition of Ca influx being more concerned with the relaxation by Mg than with that by papaverine.

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The pharmacological activity of CoQ in relation to structure and the mechanism of potentiation in synaptic reflex were studied.
1. CoQ enhanced SR, eminently MSR, as contrasted to strychnine, in which PSR was dominant.
2. The effect of CoQ was dependent on the number of isoprenoid units, the more the numbers of isoprenoid units, the lower was the effective dose.

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Cardiotonic effect of proscillaridin A, cardiac glycoside derived from a squill, was tested in some methods.
1. Lethal doses (Hatcher doses) of proscillaridin A were 0.142mg/kg in cats, 0.152mg/kg in dogs, and 0.484mg/kg in rabbits, whereas the dose of g-strophanthin was 0.104mg/kg in cats.
2. 3.16×10^-8 Molar concentration of proscillaridin A showed a persistent 60% increase of contractile force in cat papillary muscle preparation.
3. Contractile force of left ventricular muscle showed 9% increase after the second administration (total proscillaridin A 0.04mg/kg) in phenobarbital induced myocardial depression.
4. The ratio between the maximum rate of development isometric tension (dp/dt) and a constant fraction of the integrated isometric tension developed (IIT) showed 12% increase after the second administration of proscillaridin A.

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This investigation was undertaken to clarify the relationship between lipolysis, glycogenolysis and calorigenesis induced by catecholamines. The effects of thyroidectomy, phentolamine and propranolol on adrenaline-induced calorigenesis, lipolysis and glycogenolysis in rats were examined. It was found that there is a dissociation of adrenaline-induced calorigenesis from lipolysis and glycogenolysis. These results suggest that the rise in plasma FFA, glucose and lactic acid is not related to the increased oxygen con-sumption.

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After determining suitable conditions for the use of the thermoelectrical method, by which changes in the blood flow rate in a vary small area can be measured, the basal blood flow level and changes in various areas of cat brain were investigated.
Results obtained are as follows: basal blood flow level and changes are not uniform in various areas of the brain, and adrenergic innervation is apparently involved with these effects. Vasodilators such as isoproterenol and acetylcholine, however, had almost the same effects in all brain areas.

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Effects of butoxybenzyl hyoscyamine bromide (BBHB) on contractile response of isolated guinea-pig gallbladder to specific and non-specific stimulants were examined. Results are as follows:
1) BBHB, in low concentrations (10^-9_??_10^-6M), exerted an atropine-like competitive blocking action against the acetylcholine (ACh)-induced contraction. The affinity to muscarinic receptor of BBHB (pA₂=8.79±0.08, molar unit) was greater than that of atropine (pA₂=7.64±0.12, molar unit).
2) BBHB, in high concentrations (5×10^-6_??_4×10^-4M), showed non-competivity blocking action against the KCl-induced contraction (pD₂'=3.30±0.06) and the BaCl₂-induced contraction (pD₂'=3.12±0.15). The affinity of BBHB was somewhat less than that of papaverine (pD₂'=4.80±0.11 to BaCl₂ and 4.81±0.05 to KCl).
3) In the Ca⁺⁺-free medium, high concentrations of BBHB inhibited noncompetitively the BaCl₂-induced contraction, the pD₂' value being 3.05±0.12, however BBHB, even in a high concentration, did not affect the Ca⁺⁺-induced contraction of K⁺-depolarized preparation in Ca⁺⁺-free medium. On the other hand, papaverine antagonized noncompetitively the Ba⁺⁺-induced contraction (pD₂'=4.56±0.21) and the Ca⁺⁺-induced contraction (pD₂' =4.75 ±0.03).
These results suggest that BBHB, in low concentrations, antagonizes competitively the ACh-induced contraction at muscarinic receptors, whereas in gigh concentrations reduced K⁺-induced and Ba⁺⁺-induced contractions, presumably by interfering with the K⁺- and Ba⁺⁺-induced inward release of membrane-bound calcium, by decreasing the Ba⁺⁺-influx and/or by preventing the barium ion from being utilized by the contractile proteins.

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The central effects of LiCl were examined with the following results.
1) LiCl in doses of 600_??_800mg/kg i. p. or 40_??_80μg i. c. decreased spontaneous motor activity in mice as measured by either the wheel cage or the photocell counters methods.
2) LiCl in doses of either 400mg/kg i. p. or 20μg i. c., which did not influence the spontaneous motor activity in mice, markedly blocked the conditioned avoidance response but not the unconditioned.
3) LiCl in doses of 100mg/kg or 20μg i. c. blocked the biting, attacking and vocalization in the electroshock induced aggressive behavior including attacking, biting, vocalization, jumping and piloerection.
4) LiCl in doses of 600mg/kg i. p. or 80μg i. c. did. not influence catecholamines or 5-HT in mouse brain.

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The behavioral and electroencephalographic effects of Clozapine were investigated in mice, rats and rabbits, and compared with chlorpromazine and perphenazine.
Clozapine showed in general the pharmacologic properties characteristic to neuroleptics, such as decrease in exploratory behavior, suppression of conditiond avoidance response, taming effects, anti-methamphetamine and so on.
These effects were less potent and shoter in duration than those of chlorpromazine and perphenazine.
Clozapine, however, lacked cataleptogenic propeties and depressed the EEG arousal responses induced not only by auditory but also by mesencephalic reticular stimulation, differently from chlorpromazine and perphenazine.

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The mechanism of inflamed dermal tissue permebility in filter paper-implanted rats and the inhibitory effect of anti-inflammatory drugs were investigated. In order to elucidate the mechanism, quantitative changes of connective tissue components [acid mucopolysaccharide (AMPS), glycoprotein (GP) and collegen (C)] in inflamed tissues and the effect of anti-inflammatory drugs were tested.
1) When inflamed tissue was divided into skin side upper fiilter paper and the under muscle one, AMPS content in the muscle side and the GP in both tissues increased very rapidly and markedly. Peaks of both component levels were reached at day 5 or 7. Later AMPS level decreased slightly and thereafter remained at a constant level (almost twice the normal level) until day 25. On the other hand, the GP level thereafter followed a slow reduction, which was more pronounced on the skin side than in muscle one, the level on the skin side fallen to the normal level by day 25. C content in the muscle side of filter paper-implanted rats increased progressively until day 25, while the level on the skin side became markedly lower than normal.
2) The effect of anti-inflammatory drugs (acetylsalicylic acid, aminopyrine, phenylbutazone, bucolome, flufenamic acid, benzydamine HCI, indomethacin, prednisolone and dexamethasone) administered orally once a day for 3 days was examined 3 days after implantation. The increase of AMPS content on the muscle side was inhibited significantly by all these drugs. Acetylsacylic acid, phenylbutazone, flufenamic acid indomethacin and prednisolone also inhibited significantly the increase of GP content in both tissues, whereas benzydamine HCl and dexamethasone effected only in the skin side and bucolome only in muscle side. The decrease of C content in skin side was inhibited remarkably by predni-solone, dexamethasone and indomethacin.
3) The inflamed dermal tissue permeability and GP content in the same region, following a similar pattern, changed during an inflammatory process. A correlation was proved between the inhibitory effect of anti-inflammatory drugs on this two parameters.

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In order to elucidate the mechanism of the increase of inflamed dermal tissue permeability in filter paper-implanted rats and the inhibitory effect of anti-inflammatory drugs, the author attempted a determination of the changes in mucopolysaccharase (M) activities in inflamed tissue and the effect of anti-inflammatory drugs. Enzymes determined were β-glucuronidase (β-G), N-acetyl-β-glucosaminidase (NA-β-G) and lysozyme (LZ).
1) When inflamed tissue was divided into skin side upper filter paper and the under muscle one, β-G and NA-β-G activities in both tissues elevated slowly until day 7, thereafter rapidly and markedly. LZ activity elevated remarkably, especially on the muscle side after day 10.
2) From 7 to day 25, the inflamed region was divided further into exudate, granuloma, skin and muscle and these three enzyme activities changed with a similar pattern in each region. These enzyme activities in exudate continued to elevate even after day 15, while those in granuloma, skin and muscle reached a maximum at days 15, 10 and 7 respectively and thereafter declined.
3) The drug effect on M activities in inflamed tissues (skin and muscle sides) 3 days after implantation was examined by a daily, oral administration for 3 days. The elevations of β-G and NA-β-G activities in inflamed tissues were inhibited remarkable by prednisolone, dexamethasone, indomethacin and phenylbutazone. Bucolome, flufenamic acid and benzyd-amine HCl showed only a weak inhibitory effect. All non-steroids tested remarkably inhibited the elevation of LZ activity in inflamed tissues, whereas steroids exibited only a weak inhibitory effect.
4) The drug effect on M activities in exudate and inflamed tissues (granuloma, skin and muscle) 10 days after implantation was tested by an oral, daily administration for 10 days. β-G and NA-β-G activities in exudate and granuloma were inhibited significantly by prednisolone, dexamethasone and indomethacin, while LZ activity was inhibited in both regions by bucolome, benzydamine HCl and indomethacin. These three enzyme activities in skin and muscle were inhibited significantly by almost all drugs tested.
5) From these results, the increase of inflamed dermal tissue permeability could by partially due to the elevated M activities. It can be assumed, therefore, that the inhibitory effect of anti-inflammatory drugs on the increase of tissue permeability is to some degree caused by the inhibition of anti-inflammatory drugs on M activities.

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It was reported in our 4th paper that there was a biorhythm witn one cycle of 4_??_5 months in inducing El-mice-convulsion.
The biorhythm in El-mice born for 3 consecutive days was quite similar to the rhythm in the group without age-limitation.
Additionally, El-mice-convulsions had a circadian rhythm with 2 peaks in TSC (thre-shold of shaking-number for convulsions) at 10a.m. and 10p.m., with one of the lowest TSC peak at 2a.m. and the 2nd lowest level of TSC peak at 6p.m.
At 6p.m., influence of central-acting drugs as related to El-mice in convulsions was hardly observed, though it was observed at 10a.m.
There was a biorhythmic change in numbers of eosinophile of mice, and the cycle was 35_??_42 days in dd-mice and 42_??_49 days in El-mice.

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Genesis of coughing were studied electrophysiologically in cats, using a new antitussive drugs (Oxymetebanol, 14-Hydroxy-dihydro-6β-thebainol-1-4-methyl ether). Results are as follows:
1. Codeine and oxymetebanol depress the cough reflex evoked by repetitive stimulation (20Hz) of the superior laryngeal nerve (SLN). The depressive effects represented by ED₅₀ (i. v.) were 0.08 (0.02_??_0.27)mg/kg for oxymetebanol and 1.4 (0.88_??_2.24)mg/kg for codeine.
2. Codeine and oxymetebanol depress the centrally-induced cough reflex evoked by the stimulation of the nucleus tractus solitarius.
3. Synaptically evoked potentials recorded within the nucleus tractus solitarius follow-ing stimulation of the SLN were not influenced by either drug at the dose mentioned above. Spike discharges also, evoked by a single stimulation of SLN were not influenced by either codeine or oxymetebanol.
4. The negative synaptic potentials induced in the ipsilateral hypoglossal nucleus (20 msec latency) by the stimulation of the SLN were not influenced by codeine up to 8.0mg/kg or by oxymetebanol up to 2.0mg/kg.
5. Oxymetebanol and codeine with stimulation of the SLN had no influence on synaptic potentials recorded at the caudal portion of the ambiguus nucleus, the high density region of expiratory neurons.
6. Burst discharges of the ambiguus motoneurons induced by 20Hz repetitive stimulation of the SLN were depressed by 1.0mg/kg of oxymetebanol and 2.0mg/kg of codeine, however the short latency response of these neurons evoked by a single shock stimulation was not influenced when the dosages mentioned above were utilized.
Central inter-relationships between cough reflex and the evoked potential in the medulla oblongata have been discussed.

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This paper describes an experimental study of effects of GA-56 on the central nervous system, respiratory and circulatory system, smooth muscle and urinary volume,
1) GA-56 did not effect the central nervous system, such as was seen regarding the sleeping time of hexobalbital, convulsions of strychnine, pain sensation and body temperature.
2) GA-56 revealed little effect on the respiratory and circulatory system, such as respiration, blood pressure, electrocardiogram, isolated atrial, isolated heart, whole heart, peripheral blood vessels.
3) GA-56 showed no remarkable effect on smooth muscle, such as isolated intestine of guinea-pig and rabbit and whole intestine of rabbit. GA-56 did not effect on the urinary volume.
By way of summarization, it has been demonstrated that GA-56 is a safe drug provided it is administrated orally.

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This paper describes an experimental study of the acute toxicity of GA-56.
In rats, mice and rabbits GA-56 revealed no toxicity with oral administration even when the maximum dose was administrated.
Moreover, no pathological changes were observed intestine following an intraintestinal administration of GA-56 in a large dose.

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The experiment were carried out ascertain the added arsenite in diet and resulting content in each organ, as well as the effect on diet.
1) When rats were raised on an arsenite-added diet (1, 000 p. p. m.), the rats died in two weeks while on milk or cereal. There was little body weight gain in one week. When rats were raised on an arsenite-added diet (50 or 200 p. p. m.), there were no differences in body weight gain as compared with rats on a non-arseniteadded diet of milk or cereal.
2) A milk or cereal diet resulted in the same content in each rat organ when the rats had been raised on an arsenite-added diet (1, 000 p. p. m.) for one week. Regarding the whole organ, the order of arsenite content was: liver, kidney, spleen and brain. In organ per g the order was: spleen, kidney, liver and brain. The quantity of arsenite in the brain was little in either the whole organ or organ per g.
3) When rats were raised on an arsenite-added diet of 50, 200, 650 p. p. m. for 35 days, the content of arsenite in the whole organ was estimated as most in the liver, least in the brain. In the kidney and spleen a change was observed depending on the volume of arsenite and diet. The content of arsenite in organ per g was the highest in the spleen, next in the liver and lowest in the brain and kidney. When rats were raised on cereal rather than milk the content in each organ greater.
4) The increase of added arsenite corresponded to the increased amount of arsenite in each organ.

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1) A relationship was determined among flight behavior, stimulus parameters and sites.
2) Utilizing tracing apparatus of behavior using the photometric technique, characteristics of flight behavior were recorded. Difficulties in the twisting wire were removed by using a special type rotating connector through which the electrical signals induced in the stimulator were transmitted into the brain.
3) Nitrazepam in the amount of 1_??_10mg/kg (i. p.) caused a depression in the flight behavior, and at the same time the appearance of general behavior including muscle relaxation, sedation and ataxia. When the same drug, as much as 1_??_50mg/kg (p. o.), was administrated, the flight depression, which was not always dose dependent, was resulted.
4) The administration of diazepam as much as 1_??_10mg/kg (p. o.) resulted in a moderate depression of flight behavior, and the less depression in the general behavior as compared with nitrazepam.
5) Chlordiazepoxide showed a marked increase of threshold at 50mg/kg (p. o.), but a lower dose of 10_??_20mg/kg (p. o.) did not result in any significant action.
6) Degree of provocated flight behavior or each drug in the following order; diazepam>nitrazepam>chlordiazepoxide.

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Rearing circumstances and shaking conditions were considered from the standpoint of behavioral-scientific pharmacology concerning El-mice-convulsion. Rate of non-convulsion (RNC) and threshold of shaking-number for convulsion (TSC) were used as indexes, and results are as follows.
(1) The area of living space had no direct influence on TSC or RNC.
(2) RNC increased markedly when each mouse was reared in an isolated condition, as compared to those in groups. This increase of RNC as seen with isolation recovered to the control level when the mice were re-grouped again. RNC in grouped mice was hardly influenced by the number of mice in one cage, i.e. 2, 5, 10 or 12.
(3) When each El-mouse was reared with 1 or 7 dd-mice, the RNC of El-mice increased remarkably as compared to the case of rearing only El-mice together. The RNC also recovered when the El-mice were grouped.
(4) Relation between TSC or RNC and the environmental temperature was studied. Both TSC and RNC increased at 8°C, but at 30_??_34°C hardly differed from those placed in a 22_??_26°C situation.
(5) TSC increased with the increase of shaking-frequency, cycle/min, but the time, that is seconds until El-convulsive seizure was observed, hardly differed. Induction of El-convulsion was prevented when the shaking movement was stopped midway.

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