In rats anaesthetised with pentobarbitonc, somatosensory evoked potentials, produced by stimulation of contralatcral or ipsilateral forepaws were used tc measure the activity in different neuronal pathways. Computer derived averages of 32 consecutive responses yielded a stable and consistent measurement of the evoked potentials. The drugs were applied to the cerebral cortex by using cortical cup technique and changes were measured in evoked potentials. Coriical application of alloferin increased the amplitude of the early negative wave of the cortical evoked potentials. This effect of alloferin was blocked by prior treatment of the cortex with eserine. It appears that the excitant effect of alloferin on the cortex was the result of disinhibition of cortical cholinergic inhibitory mechanism.

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Pharmacological profile of a new sympathomimetic agent, compound 70-352, is reported herein. This compound was found to directly stimulate a-adrenergic receptors in the cat, guinea pig, rabbit and rat. Activity was similar to that of noradrenaline (NA) but it was only 0.032% as potent as NA on isolated rat uterus. Duration of action of the compound was, however, much longer. Compound 70-352 had no effect on the central nervous system and the acute LD₅₀ in mice was 1000.0 mg/kg i.p.

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Observed to be associated with impairment of liver function in aged rats were: increased lipid peroxides in the liver and serum, diminishing hepatic glutathionc and decreases in mitochondrial respiratory activity and cytochrome content. Spontaneous failure of hepatic functions in aged animals was significantly ameliorated by the administration of cytochrome c. It is suggested that the underlying mechanism lies in the versatile ability of cytochrome c to reduce lipid peroxides, increase the hepatic glutathione content and activate mitochondrial function.

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The actions of chinoform and oxine on isolated phrenic nerve-diaphragm preparation of the rat and the uptake of chinoform by rat diaphragm strip were investigated. Chinoform and oxine decreased both twitch responses to indirect and, to a lesser extent, to direct stimuli in the rat phrenic nerve-diaphragm preparation. The depressant action of oxine was reversible whereas that of chinoform was irreversible and always accompanied by a marked rise in muscle tone. The neuromuscular block caused by these drugs was enhanced rather than antagonized by eserine and KCl. The depressant action and the rise in muscle tone caused by chinoform disappeared in vitro by lowering muscle temp., by suspending the drug in dog serum and also by conjugating it with glucuronic acid. When rat diaphragm strips were incubated aerobically in Krebs-bicarbonate solution containing chinoform for 1 to 5 hr at 37°C, the drug was accumulated against a concentration gradient until concentration ratio (muscle/medium) of up to 36: 1 had been attained. These findings indicate that rat diaphragm strips accumulate chinoform largely by intracellular binding and that the drug can act intracellularly as a metabolic poison.

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Effects on motor activities of normal and exhausted mice were studied on fractions obtained from Panax Ginseng root consecutively administered orally in small doses. Effects on motor activities were measured utilizing: hole cross (HC) test, and tests using phototransister (PT) and spring (ST) recorders. Significant decreases in motor activities were observed in the GNS 100 mg/kg treated groups in the HC test and in 400 mg/kg treated mice in the PT test. Significant increases of motor activity were absent in both HC and PT tests, however, 10 mg/kg of GNo. 4 and TRg slightly increased locomotor activity in the PT test. A significant increase of locomotor activity in the ST test, was noted after the administration of GNo. 5 at a dose of 10 mg/kg. In the test using an activity wheel apparatus, GRg slightly decreased the number of light beam interruptions, and locomotor and rotating activities in the PT test. GF₄ significantly increased the number of interruptions in the activity wheel, and decreased both activities in the PT test. Ten mg/kg of GNo. 3 and GNo. 5 significantly increased locomotor activity of the exercised mice.

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While the increase in cardiac work, force and rate are known to be a function of beta-adrenergic receptor stimulation, the mechanism of metabolic actions is uncertain. This study was undertaken to clarify the “calorigenic” action of epinephrine and its relation to hemodynamic changes. In a group of canine heart-lung preparations, the intra-atrial infusion of 0.01, 0.03 and 0.1 μg/kg of epinephrine did not change the cardiac work, force and rate, of the myocardial oxygen consumption, as compared to the control. However, intra-atrial infusion of 0.5 μg/kg of epinephrine caused an increase in cardiac work, cardiac isometric contraction, coronary flow and a marked elevation in the myocardial oxygen consumption above and beyond the rate of its effect on the cardiac hemodynamic parameters. Addition of 0.5 mg/kg of Sotalol did not cause depression of these parameters of left ventricular functions, including the coronary flow. However, 0.5 mg/kg of Sotalol effectively blocked the “calorigenic” action of 0.5 μg/kg of epinephrine. Apparently, more oxygen is being extracted by the myocardium after 0.5 μg/kg of epinephrine. Sotalol blocks this calorigenic action of epinephrine. Since the metabolic effects of epinephrine have not been shown to be beta-adrenergic receptor-mediated changes, it is concluded that Sotalol has the unique property of blocking the metabolic action of epinephrine.

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Secretory and vascular responses to various biogenic and foreign substances of the isolated blood-perfused canine pancreas were investigated. The majority of cholinergic drugs such as acetylcholine, methacholine, carbachol, bethanechol pilocarpine, neostigmine, lobeline, nicotine, TMA and McN-A-343, and gastrointestinal hormones such as secretin, pancreozymin, gastrin, glucagon caused an increase of output of pancreatic juice with vasodilatation. Bradykinin and kallikrein inhibited the secretion with vasodilatation, and DMPP, physostigmine and dopamine increased the secretion with vasoconstriction. Dibutyryl cyclic AMP, histamine, nitroglycerin and methylxanthines such as caffeine, theophylline and theobromine also caused a secretion with vasodilatation. Vasopressin inhibited the secretory rate of pancreatic juice with vasoconstriction. Most adrenergic drugs such as noradrenaline, adrenaline, phenylephrine, methoxamine, ephedrine, tyramine and isoprenaline except dopamine, had no effect on secretion. Vascular responses of the pancreas to various drugs were found to be similar to those of the mesenteric vessels. Since the secretion of pancreatic juice did not change in parallel with the rate of local blood flow, the mechanism of pancreatic secretion appears to be independent of the blood supply to the pancreas.

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The present study regarding the effects of 8-chloro-6-phenyl-4H-s-triazolo [4, 3-a] [1, 4] benzodiazepine (D-40TA) on the EEG arousal and sympathetic excitatory responses evoked spontaneously or by stimulation of the midbrain reticular formation, posterior hypothalamus, thalamus and sciatic nerve in the curarized, intact brain or cerveau isolé cats provided the following conclusion: D-40TA reduced the central sympathetic excitability by depressing the hypothalamus and its related structures, and limited the persistence of the EEG arousal by selective depression of the hypothalamic and probably midbrain mechanism relevant to a “tonic” EEG component with much less influence upon a “phasic” EEG component related to waking ability itself. These dual effects may be responsible for hypnogcnic action of D-40TA.

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In vitro incorporation of radioactive precursors into protein or nucleic acids and corticosterone production in the adrenals of morphine treated rats were examined, and the results were compared with those of ACTH treatment. An increase in incorporation of radioactive precursors into nucleic acids with concomitant decrease in corticosterone production was observed with repeated morphine treatment, indicating an enhanced synthesis of nucleic acids in the glands. On the other hand, incorporation of labelled amino acids into protein decreased after an initial increase. With repeated ACTH treatment, decreased incorporation of labelled precursors was observed in both protein and nucleic acids in parallel with the gradual increase in the rate of corticosterone production during the course of ACTH treatment. When adrenals were incubated with 5 μg/flask of corticosterone, the incorporation of radioactive precursors into nucleic acids was decreased markedly. These results suggest an interference of corticosterone which accumulates in the medium with the synthesis of nucleic acids in vitro.

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The mechanism of blockade by bufahn at the neuromuscular junction was examined by using the isolated diaphragm of the rat. Bufalin appears to reduce acetylcholine sensitivity at the motor end-plate by causing prolonged depolarization. According to the results of the studies of the post-tetanic potentiation, bufalin appears to have both stimulant and depressant phases of action on the motor nerve terminals, i.e., in smaller doses, it acts as a stimulant and in larger doses (corresponding to the doses of blockade), as a depressant. The amount of acetylcholine release was considerably increased immediately after washing out of bufalin treatment (incubated for 30 min with 10^-4 g/ml), whereas in the presence of the same concentration of bufalin, obviously decreased. With regard to blocking effect, bufalin added to the bathing fluid was more potent than infused i.v. which indicates that the pre-junctional effect of this agent is essential for its blockade at the neuromuscular junction.

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Crude preparations of protease and culture filtrate of Serratia piscatorum IFO 12527 contained a heat-resistant, large molecular and non-proteinous anti-inflammatory ingredient(s) (PLS). The active ingredient was precipitated with Rivanol or Cetavton, and purified by extraction with n-butanol or by adsorption with Lloyd's reagent. From these and other chemical data, PLS is considered to be an acid polysaccharide. PLS injected i.m. inhibited the edema induced by carrageenin and anti-serum in rat feet. The effect on carrageenin edema was 37 times as potent as that of indomethacin and 200 times that of hydrocortisone acetate. These anti-edema effects were not observed by oral administration. PLS, i.m., inhibited cotton pellet granuloma more markedly than hydrocortisone acetate, without decreasing the weight of the adrenals and thymus. It had weak activating effect on kinin-forming systems in the rat plasma in vitro. Additional pharmacological properties of PLS are also described.

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Effects of extracts obtained from Panax Ginseng root on recovery frorr exhaustion, were studied using six methods: exploratory movement (EM), hole cross (HC), rotating rod (RR), sliding angle (SA), spring balance (SB) and rectal temp. (RT) tests. Four hr oscillation movements were used as enforced exercise. Drugs were injected i.p. immediately following the exercise. Water extract significantly accelerated the recovery of exploratory movements, increased motor activity index in EM test and elevated rectal temp. However, water extract decreased the index in HC test and grip tone in SB test. Anti-fatigue effects of Ginsenoside RgI were obvious in every test. Lipophilic fraction significantly speeded up recovery from fatigue in EM, RR, RT and SB tests, but delayed recovery in HC and SA tests. Neutral saponins fraction had no effect on recovery in the 6 tests. In the EM tests, devised to measure two kinds of exploratory movements of fatigued mice and their spontaneous movement, methamphetamine (2 mg/kg), caffeine (25 and 50 mg/kg), 2-dimethylaminocthanol (25 mg/kg) and glucose (100 and 200 mg/kg) significantly speeded up the recovery of these two exploratory movements, and increased the spontaneous movement.

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The presence of cyclic adenosine 3', 5'-monophosphate (cAMP) in the ciliated protozoan, Tetrahymena pyrifurmis W, was demonstrated by thin-layer chromatography (TLC). The content of cAMP in the cell increased abruptly in the early exponential phase, and then diminished with further culture. When cells in the exponential or stationary growth phase were cultured in a fresh medium, growth was inhibited by addition of dibutyryl cAMP (Bt₂-cAMP) or methylxanthines. In synchronized cultures of Tetrahymena, Bt₂-cAMP inhibited protein and RNA syntheses in the G₁ phase and DNA synthesis in the S phase. These results indicate that cAMP regulates the growth of the protozoan in the G₁ phase.

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Inhibitory effects of chlorpromazine (CP) and its free radical (CP•) on the tonic component of the K-contraction of vas deferens isolated from guinea pig were studied by the Magnus method. CP and CP. were equally effective at concentrations higher than 2×10^-7 g/ml for selective inhibition of the tonic component in neutral media (pH 7.4). The effect of CP• was 100 times greater than that of CP in acidic media (pH 5.0). These findings can be explained in terms of the increased stability of CP•, since the absorption spectral analysis showed that CP• was apparently stable in acidic media. Among reducing agents studied, 2-mercaptopropionylglycine was the most potent in restorative activity for the above inhibition.

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DAO was partially purified from hog kidney by a procedure involving differential centrifugation, heat treatment and ammonium sulfate fractionation. The enzymic properties of partially purified DAO were studied with cadaverine and histamine as substrates and the following results were obtained. The specific activities of hog kidney DAO at the final step of purification were 183-fold and 125-fold those of the crude homogenate with histamine and cadaverine, respectively, as substrates. With cadaverine and histamine the pS maxima values were 3×10^-3 M and 1×10^-3 M and the pH optima were 7.1 and 6.5, respectively. All the diamines tested, (i.e. cadaverine, putrescine, hexamethylenediamine, histamine, ethylenediamine and agmatine) were oxidized with this enzyme, while monoamine, (i.e. tyramine, benzylamine, serotonin, β-phenylethylamine, n-amylamine and n-propylamine) were not. DAO activity was inhibited by aminoguanidine, hydroxylamine, MPH and semicarbazide. The inhibitory effects were similar when either cadaverine or histamine was used as substrate. SH-reagents, such as PCMB and iodoacetoamide, did not affect DAO activity, but various metal ions, such as CuCl, Cu(NO₃)₂, Zn(NO₃)₂, AlCl₃ and Fe(NO₃)₃ were inhibitory. The inhibitory effect of AgNO₃ on DAO activity differed greatly, when using cadaverine and histamine as substrates. The temperature-in-activation curves of DAO measured with cadaverine and with histamine were different.

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The effects of cold storage (2°C) on the uptake of ³H-norepinephrine (³H-NE) by the rabbit aortae were studied. The cold storage progressively decreased the uptake of norepinephrine by strips exposed to low concentration (10^-7 M) of ³H-NE. By the 7th day of storage, the uptake became constant and was not affected by further treatment. Cocaine (10^-5 M) or desipramine (10^-6 M) failed to decrease this residual norepinephrine uptake in the strips stored for more than 5 days. Although cocaine potentiated the norepinephrine response of aortae from young (5 wk.) and old (over 10 months) rabbits equally, the cocaine sensitive norepinephrine uptake of old rabbit aortae was approx. half the value observed in the aortae of young rabbits. Study on ³H-metabolites indicated that the major portion of the radioactivity in the fresh and cold stored tissue was ³H-NE. The content of total ³H-metabolites formed by monoamine oxidase was less in the medium for the cold stored tissue than for the fresh tissue. These results indicate that cocaine sensitive neuronal uptake of norepinephrine by the rabbit aortae disappears after cold storage. These studies, together with previous experiments, strongly support the view that the cocaineinduced potentiation in the aorta involves a postsynaptic component.

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