Six hours after intracerebral administration. the central effects of metaraminol were examined with the following results. 1) Metaraminol in doses of 40 ?? 160 μg decreased spontaneous motor activity in mice as measured by the photo-cell counters method, the wheel cage method or the open-field test. Ptosis and catalepsy induced at these doses. 2) Metaraminol in doses of 40 ?? 80 μg which influenced the spontaneous motor activity in mice, blocked the avoidance behaviour but not escape. 3) Metaraminol in doses of 1.25 ?? 10 μg which did not influence the spontaneous motor activity in mice, markedly blocked the attacking response induced by the electroshock. 4) Ten min after intraventricular administration, metaraminol in a dose of 500 μg induced the arousal pattern of EEG in sensory cortex of cats and this pattern lasted for 30 min. Ninety min after administration, EEG tracings reverted to the drowsy pattern.

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Influence of metaraminol on behavioural changes in mice was studied with the following results. 1) When metaraminol was injected i.c., spontaneous motor activity as tested by either the photocell counters method or open-field test markedly increased within 90 min after injection, while on the contrary greatly decreased 3 hr later as compared with control group. Thus, these biphasic effects of metaraminol were clearly established. 2) 30 min after injection, metaraminol in doses of 160 μg did not alter brain catecholamines in mice, however, 6 hr after injection, brain dopamine and norepinephrine markedly decreased. 3) When metaraminol was injected into mice pretreated with reserpine or 6-hydroxydopamine, spontaneous motor activity tested by photo-cell counters method markedly increased and anti-6-hydroxydopamine activity of metaraminol was stronger than antireserpine. 4) Metaraminol completely antagonized ptosis and catalepsy induced by reserpine. 5) Six hr after injection, anti-methamphetamine activity was observed.

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As the extract of cattle prostate (PE) is clinically effective in treating prostatic hypertrophy, a study was carried out on urinary bladders of rat, guinea pig, rabbit and dog as well as on guinea pig ileum. Muscle strip of rat and/or dog bladder contracted with PE with increasing spontaneous movement, and was unaffected by atropine. The isolated ileum of guinea pig also contracted with PE, and the contraction was inhibited by papaverine, but not by atropine. A rise in intravesical pressure was observed with increasing spontaneous movement in guinea pig bladder treated with PE, as well as in rabbit bladder in vitro or in situ. The sphincter vesica of guinea pig was dilated by PE as well as by ACh and methacholine.

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The circadian rhythms of acute toxicity of N-methyl D-aspartic acid, picrotoxin, pentetrazol, strychnine, chlorpromazine and Na-methylhexabital in dd-mice were investigated. The drugs were injected into mice on the hour at 2, 6, 10, 14, 18 or 22 in one day, after which the cumulative mortalities were calculated for 72 hours. Regarding central stimulants, the mortality of mice injected at 22 (o'clock) was lowest, and when injections were given at 2, 10 or 18 (o'clock), the mortality was higher than at any other time. On the other hand, regarding central depressants, the mortality was lowest at 10, and highest at 14 or at 18 o'clock. Thus, the administration time of central stimulants showing the lowest mortality was shifted about 12 hours in comparison with central depressants. As compared to the central depressants, the mortality rate as the result of central stimulants showed a great contrast when injected at 10 o'clock.

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Effects of sympathomimetics and sympatholitics were studied on the biliary system of guinea-pigs (in vitro) and rabbits (in vitro and in vivo). Contractions and relaxations produced by sympathomimetic amines are mediated by α-excitatory and β-inhibitory adrenoceptors in the biliary system (gallbladder, common bile duct and sphinctor of oddi) of guinea-pigs. Sympathomimetic amines caused relaxations in the sphincter of oddi in rabbits (in vitro and in vivo) and responses were antagonized by a and p-blockade or a combination of both. Sympathomimetic amines caused contraction and relaxation on the common bile duct of rabbits. Transmural stimulation to guineapig gallbladder and rabbit common bile duct is mediated by cholinergic and adrenergic nerves. α-inhibitory adrenoceptor would thus be involved in the postanglionic cholinergic nerve endings in the gallbladder of guinea-pig. No difference was observed in mechanical responses to transmural stimulation in either the isolated sphincter of oddi or the duodenum of rabbits. It is concluded that the guinea-pig biliary system is functionally independent of the gastro-intestinal system and that the rabbit sphincter of oddi is functionally similar to the duodenal wall.

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Myocardial taurine level was found to be greater in the rat than in the guinea-pig. Taurine inhibited the development of arrhythmias caused by the i.v. infusion of ouabain in the rat. When ouabain induced arrhythmias, the myocardial taurine level decreased. Both effects were blocked by pretreatment of propranolol. The uptake of taurine into the heart did not necessarily result in the reversal of the PR interval prolonged by ouabain. The protecting effect of taurine against ouabain toxicity was not dependent upon the change in myocardial total ATPase activity.

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Rat mesenteric and hind limb arteries were perfused with the rat's own blood under constant perfusion rate, in situ. The effect of dopamine (DA) administered intraarterially was investigated and compared with effects of norepinephrine (NE), tyramine (Tyr), and phenylephrine (PHE). The magnitude of the vasoconstrictive maximum response of both vasculatures to NE and PHE was larger than those to DA and Tyr, and those to DA were larger than those to Tyr in hind limb, but those to Tyr were more potent than those to DA in the mesenteric artery. The vasoconstriction evoked by celiac ganglionic stimulation was much the same to that evoked by NE and PHE. Under cocaine infusion, the rise in perfusion pressure of both vasculatures evoked by NE was slight, but the duration was markedly potentiated. However, the effect of Tyr was suppressed and that of DA was not changed. In rats on α-methyl-p-tyrosine, the responses of both vasculatures to Tyr were reduced and those to NE and DA were not changed. In the reserpinized rat, the effect of NE was not changed and that of Tyr was reduced, while that of DA was more evident in both vasculatures. After phenoxybenzamine treatment, vasoconstrictive effect of DA was reversed in mesenteric and reduced in hind limb artery. Vasodilating effect of DA after phenoxybenzamine, was not changed by treatment with propranolol, atropine, and diphenhydramine but was reduced with reserpine and abolished with haloperidol. These results suggest that the vasoconstrictive effect of DA depends partly on indirect sympathomimetic action, and after phenoxybenzamine, DA acts by vasodilating the DA receptor. Potentiation with reserpine may depend on a postsynaptic mechanism and increase in dopamine-β-hydroxylase activity.

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General pharmacological effects of CEthyl p-(6-guanidinohexanoyloxy)benzoate) methanesulfonate (FOY), a new antiproteolytic agent, were studied and the following results were obtained. Acute administration of large doses of FOY in conscious dogs and rabbits caused a decrease in spontaneous motility, ataxia, cyanosis, collapse, mydriasis, and respiratory paralysis. The agent had no effect on the central nervous system and exhibited hypotensive effects in dogs in doses of more than 1 mg/kg. Hypotensive responses were not inhibited by treatment with atropine or hexamethonium. FOY had no effects on ECG in the rabbit at doses of less than 30 mg/kg and at doses from 10^-6 to 10^-4 g/ml, distinctly reduced the amplitude of the spontaneous and rythmic contractions of the isolated rabbit ileum, guinea-pig ileum and rat uterus preparation. The contractile response to nerve stimulation, noradrenaline and barium was suppressed in isolated guinea-pig vas deferens. FOY had no effects on the twitch response of gastrocnemius muscle to sciatic nerve stimulation in rats. The drug caused local irritant effects in rabbits and rats.

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Inhibitory effects of (Ethyl p-(6-guanidinohexanoyloxy)benzoate)methanesulf on ate (FOY) on kinin formation (in vitro and in vivo) and the fibrinolytic activity (in vivo) were examined and compared with other inhibitors. Inhibitory effect on kinin forming activity (in vitro) of various enzymes was measured in the guinea pig ileum. FOY and Trasylol inhibited the kinin forming activities of trypsin, pancreas kaliikrein and plasma kallikrein. Soybean trypsin inhibitor inhibited kinin forming activities of trypsin and plasma kallikrein, but not of pancreas kallikrein. Bradykininlike substance was formed in the perfusate when the rat's paw was heated at 46°C FOY and Trasylol added to the perfusion fluid produced a potent inhibition of the formation of bradykininlike substance. When administered i.v., FOY and Trasylol did not inhibit the formation of bradykinin-like substance. In the dog, activation of plasmin in the circulatory blood and increase of hemorrhagic tendency were caused by the i.v. administration of human serum plus streptokinase. Such responses were inhibited with a previous i.v. infusion of FOY and t-AMCHA. From the above findings, it may be concluded that FOY has inhibitory effects on kinin formation and fibrinolytic activity.

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In an attempt to develop an assay method for cardiotonic steroids (CS), a two compartment model was applied to the whole dog. As representative CS, g-strophanthin, digoxin and digoxigenin were infused continuously to the animal, and the minimal cardiotonic, irregularity and lethal doses were determined, together with indices K₁ and K₂, representing the rate of uptake and elimination, respectively, of these compounds into and out of a specific site within the myocardium. The order of cardiotonic potency was : g-strophanthin>digoxin>digoxigenin. The indices K₁ (and K₂) were the greatest with digoxigenin (digoxigenin), the second greatest with g-strophanthin (digoxin) and the smallest with digoxin (g-strophanthin). The order of the margin of safety as a ratio between the minimal irregularity and the minimal cardiotonic doses was: digoxin>g-strophanthin> digoxigenin, while it was: g-strophanthin>digoxin>digoxigenin as a ratio between the minimal lethal and the minimal cardiotonic doses. The cardiotonic, irregularity and lethal doses obtained in the present study coincided well with the values obtained in the canine heart-lung preparations, thus lending further support to the idea that effects of the CS appear when the substances accumulated to a definite amount at a specific site within the myocardium.

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The stomach, intestine and uterus were contracted by PGE₁. Stimulating effects of ACh and serotonin were augmented in some of these organs, especially in guinea pig uterus. ACh and serotonin-induced bronchial contraction, however, decreased after administration of PGE₁. Bronchial relaxation induced by adrenaline or noradrenaline was unaffected or increased. Antiadrenergic effects were not detected in the organs tested. ACh-induced contraction of frog rectus abdominus was augmented by PGE₁. The potentiating effect of PGEI was almost the same in degree as that of physotigmine, although cholinesterase inhibitory effect was not detected in PGE₁. Intravenous injection of PGE₁ (10 μg/kg) into rabbits caused a relaxation of the intestine, which was contrary to the result with the isolated organ. Administration of PGE₁(1 μg/100 g, i.p. or 0.1, 1 μg/100 g, i.v.) did not show any curative effects on intestinal paralysis in cecectomized rats. The mechanism of action of PGE₁ on rat uterus was found to be calcium-dependant.

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