The mechanism of vascular permeability of LPS was studied in rabbit skin with the following results : (1) LPS derived from E. coli enhanced the vascular permeability in rabbit skin, and although the activity was dependent on the dose of LPS, it was more clearly demonstrated with 0.5 % solution of Evans' blue. (2) At the site of the LPS injection, it was observed that polymorphonuclear leucocytes emigrated from the inner vein to the outer and the phenomenon was correlated to the exclusion of the dye. (3) In the leucopenic rabbit treated with nitrogen mustard, the reaction was partially reduced. (4) In the reserpinized rabbit, the reaction depended on the length of reserpinization time. (5) Cyproheptidin which is an inhibitor of histamine or serotonin, slightly reduced the initial phase of reaction. (6) LPS treated with 0.1 N-HCl lost about 10 % activity of the intact LPS. (7) The activity of LPS was inhibited by addition of calcium ion (0.001-0.01 μ mole/μg LPS), but potentiated of EDTA (0.01 μ mole/μg LPS). From these data covering various pharmacological activities of endotoxin, it is concluded that the mechanism of vascular permeability of LPS is complex.

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As one of the studies on the effects of ecdysterone on lipid metabolism, the effects of ecdysterone on experimental hyperlipemia, atherosclerosis and fatty liver in rabbits induced by cholesterol diet feed were studied. Forty-eight rabbits were divided equally into four groups. The animals in each group were fed a diet containing 1 % cholesterol together with 0, 0.5, 5 and 20 mg of ecdysterone per body per day, respectively. Blood samples were collected bi-weekly to determine lipid levels of various kinds in serum. All animals were sacrificed after 12 weeks, then aorta and liver were removed to observe the occurrence of atherosclerosis and fatty liver, or to measure liver weights and certain lipid levels in liver. Results obtained can be summarized as follows. Increases in serum total cholesterol and free cholesterol levels induced by cholesterol feeding were inhibited significantly by 5 ?? 20 mg oral administration of ecdysterone per body per day for 10 ?? 12 weeks, but significant inhibitory effects against the increases in total lipid, triglyceride, phospholipid and free fatty acid levels were not observed. Increases in liver total lipid, total cholesterol and triglyceride levels were inhibited by oral administration of ecdysterone (especially 20 mg per body per day) for 12 weeks. In the pathological examination, atherosclerosis and liver hypertrophy were not improved, but fat deposition in the liver was partially prevented by administration of ecdysterone for 12 weeks.

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Effects of 1, 2-propanediol-3-(p-chlorophenoxy)-1-carbamate (chlorphenesin carbamate, CC) on the motor systems were investigated in various animal species. CC decreased grip strength and inhibited cornea and pinna-reflexes in mice. Duration of the protective effects of CC against picrotoxin-, pentylenetetrazol and electro-shocks was longer than that of mephenesin. In addition, tremors induced by oxotremorine in mice were inhibited by CC as in the case of mephenesin. CC had no anti-strychnine effect in mice, whereas mephenesin clearly showed the effect. CC inhibited the spinal functions in rats, chicks and frogs, and the duration of action was longer than that of mephenesin. CC decreased the monosynaptic reflex component as well as polysynaptic component in rats when ventral root potentials were recorded following stimulation of the corresponding dorsal root. Intercollicular and ischemic decerebrate rigidities were depressed by CC as well as mephenesin. Administration of CC, except for large doses, had no effect on the muscle twitches in response to nerve stimulation and the refractory period of muscle twitches. CC caused a decrease of afferent discharges from the muscle spindle of rats in situ and frogs in vitro, which may in part contribute to the muscle relaxant effect of the drug. From these results, it is concluded that CC is a centrally acting muscle relaxant with a longer duration of action and that it differs in nature from mephenesin.

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Physico-chemical properties of the cerebrospinal fluid (CSF) drawn from a rabbit after the i.v. injection of thyphoid vaccine were studied. Results are as follows: When the CSF, obtained from the rabbit to which thyphoid vaccine had been given i.v., was intracerebrally injected into other rabbits, pyrogenecity was observed. Pyrogenecity of the CSF was inactivated by the addition of deoxycholate (DOC) and was reversed by dialysis or dilution with water. DOC showed no effect on the pyrogenecity of leucocytic pyrogen. Lipopolysaccharide (LPS) could be divided into several groups of molecular weights utilizing membrane filters. The LPS with higher molecular weights also shows high pyrogenecity with i.v. administration, and the molecular weights causing a similar activity when administrated intracerebrally ranged from 5.0 × 10⁴ to 10⁵. From these data, it is suggested that pyrogenecity of the CSF from febrile rabbits may be due to the LPS derived from the peripheral blood.

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Depressor responses to i.v. injection of hexamethonium (0.5 ?? 3 mg/kg) and tetraethylammonium (5 mg/kg) were attenuated by repeated administrations of ephedrine in the dog and rabbit. Those to hexamethonium were also reduced by repeated administrations of tyramine in the dog. Cardiovascular responses to nicotine (0.1 ?? 1 mg/kg), dimethylphenylpiperazinium (0.01 ?? 0.1 mg/kg) and tetramethylammonium (0.1 ?? 1 mg/kg) were modified by ephedrine (total, 35 ?? 80 mg/kg) in the dog and rabbit, i.e., the initial transient negative chronotropic and depressor actions were reduced, the subsequent marked pressor actions were attenuated while those durations were prolonged, and the late long lasting hypotensive actions were abolished. Pressor responses to carotid occlusion and splanchnic stimulation in the dog were reduced by repeated administrations of ephedrine (total, 35 mg/kg) or by pretreatment with syrosingopoine (0.05 ?? 1 mg/kg), although the reduction in the latter responses were not significant. Positive chronotropic responses to pre and post-ganglionic stimulation of the stellate ganglion were reduced by the same treatment, and the reductions in the former responses were more prominent than those in the latter. The decreases in caudal mesenteric blood flow response to pre- and post-ganglionic stimulation of the caudal mesenteric ganglion were attenuated by the treatment, though the attenuation in the former responses was not significant. From the results, it is suggested that ganglionic function may be altered by repeated administration of ephedrine or by pretreatment with syrosingopine.

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The influences of ephedrine, tyramine and norepinephrine on the blood pressure responses to dopamine were studied in the anesthetized dog. Dopamine (3, 10, 30 °Cg/kg), administered after a single administration of either ephedrine (1 mg/kg) or tyramine (0.5 mg/kg), or during their infusion (10 °Cg/kg/min), induced a diminished depressor response and a potentiated pressor response. Pressor responses to either ephedrine (40 °Cg/kg) or tyramine (40 °Cg/kg) were potentiated when these were administered after a single administration of dopamine (100, 200 °Cg/kg) or during infusion with dopamine (10 °Cg/kg). Depressor response to dopamine was abolished and its pressor response was potentiated when it was administered 30 min after the norepinephrine infusion (3 °Cg/kg/min). Thus dopamine, ephedrine and tyramine were synergistic in their pressor effects and this is presumed to be due to a facilitation of endogenous catecholamine release.

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The cardiovascular effects of a new beta-receptor blocking agent, 2-acetyl-7-(2-hydroxy-3-isopropylamino) propoxybenzofuran hydrochloride (BFE-60), were investigated in dogs, rats and guinea-pigs. In isolated guinea-pig atrial and tracheal preparations the effect of BFE-60 was 2 and 6.5 times more potent than that of propranolol in antagonizing the responses to isoproterenol. In anesthetized dogs, antagonistic action of BFE-60 on the effect of isoproterenol on systemic blood pressure and heart rate was 5 and 21 times stronger than that by propranolol, respectively. Acceleration of cardiac activities induced by isoproterenol or sympathetic nerve stimulation was effectively blocked by BFE60. In reserpinized rats, the drug in doses of 1 to 1, 000 μg/kg did not produce any significant increase in heart rate. BFE-60 in a dose of 30 μg/kg caused a reduction in heart rate and prolongation of ejection time. A significant decrease was observed in dp/dt by 3 μg/kg and tension time index by 100 μg/kg, while arterial pressure and left ventricular pressure declined with doses higher than 1 mg/kg. Maximum shortening velocity of cardiac contractile element in dogs was found to be decreased with doses of more than 100 μg/kg. In dog myocardium, BFE-60 decreased the oxygen consumption but did not significantly change the redox potential. Isoproterenol-induced tachycardia, increase in oxygen consumption and reduction in redox potential were completely suppressed in dogs on BFE-60. It is concluded that BFE-60 is a potent adrenergic beta-receptor blocking agent devoid of any intrinsic activity and is lacking in selectivity.

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Positive inotropic effects of dopamine were investigated in isolated left atria of the rat and compared with those of tyramine and norepinephrine. The following results were obtained. Norepinephrine was the most potent of these three sympathomimetic amines, and tyramine was more potent than dopamine, however the order of tyramine and dopamine was reversed in the reserpine or 6-hydroxydopamine-pretreated atria. Positive inotropic effects of tyramine and dopamine were reduced by reserpine while those of dopamine were regained by incubation of atria with cocaine. Effects of tyramine were reduced and those of dopamine were not altered by pretreatment with 6-hydroxydopamine. Effects of norepinephrine, tyramine, and dopamine were reduced to the same extent by lithium. Thus dopamine appears to be a direct and simultaneously indirect sympathomimetic amine, while the inhibitory effects of lithium depend mainly on postsynaptic inhibition.

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Interactions of glucofuranoside (GF) and vasoactive agents on isolated strips of inferior caval, femoral, colic and portal veins and femoral arteries from rabbits, dogs, miniature pigs and monkeys (Maccaca irus) were investigated. The resting tension of the vein strips from rabbits, dogs and miniature pigs was not influenced or was only slightly reduced by GF (2×10^-7 to 2 × 10^-4 M). In veins from one of 4 monkeys, GF caused contraction. Dose-contractile response curves of serotonin, noradrenaline, histamine, angiotensin, K⁺ and Ba⁺⁺ were moved right and downwards by GF (2 × 10^-6 to 2 × 10^-4 M) in a dose-dependent manner, the attenuation of the response to K⁺ and Ba⁺⁺ being appreciably greater than that with the other agents. Contractile responses of isolated strips of rabbit portal veins to transmural neural stimulation were also inhibited by GF. In portal vein strips depolarized by K⁺, the Ca⁺⁺-induced contractions were decreased by GF, the decrease being greater than thatby papaverine. It appears that GF attenuates the contractile response to vasoactive agents, mainly by interference with influxes of Ca⁺⁺ across cell membranes. There was no definite tendency for GF to induce greater inhibition in the response of veins than that of arteries.

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The effect of dehydrocorydaline chloride (DHC) on induction and healing of experimental gastric and duodenal ulcers was studied in rats and guinea-pigs. The following results were obtained. Ulceration induced by pylorus-ligation or by exposure to stress in rats was prevented by oral or s.c. administration of DHC, and s.c., intraduodenal and oral administration of DHC caused a reduction of gastric secretion (gastric volume and acid output) in pylorus-ligated rats. Ulceration produced by histamine injection in the guinea-pig duodenum was prevented by oral administration of DHC but not by s.c. administration. Gastric ulcers produced by reserpine injection in rats were also inhibited by oral administration of DHC but not by s.c. administration. Healing process of acetic acid-induced ulcers in rats was accelerated by oral administration of DHC but not by s.c. administration. On the basis of these results, DHC is a promising anti-peptic ulcer agent for clinical application.

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As the result of studying substrate specificity of cholinesterase (ChE) in rabbit liver and comparing it with that in cat, it was found that ChE hydrolysed acetyl-β-methyl choline (MeCh) markedly in rabbit liver but not so in the case of cat. Enzymic property of ChE in rabbit liver was compared with that in brain. Most of the enzyme was found in the nuclear and mitochondria fractions rather than in the soluble fraction, the latter of which contained approx. 50 % of ChE hydrolysing benzoylcholine (BzCh). When acetylcholine (ACh) or MeCh were used as substrates to ChE in liver and brain, pS curves showed the same patterns. When MeCh was used as a substrate, inhibitory patterns with propylene glycol, sumithion and eserin were almost identical in both cases of the liver and the brain. When MeCh was used as a substrate, Km values of ChE in liver and brain were identical. With ACh as a substrate, ChE activities in liver and brain were activated by NaCl Or MgCl₂. When MeCh was used as a substrate, NaCI had no effect on the ChE activity in liver, while marked inhibition was observed in brain. Marked inhibition by MgCl₂ was also observed on ChE activities in liver and brain when ACh or MeCh were used as substrates.

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Drug effects on the secretion of respiratory tract (S.R.T.) are investigated in pharmacological studies, however, satisfactory methods to measure S.R.T. have yet to be devised. The authors measured the electrical resistance (E.R.) by means of an inserted electrode and the effects of certain drugs on S.R.T. were determined. The correlation of secretion patterns between S.R.T. and saliva was investigated in dogs. As a result, pilocarpine (0.05 and 0.5 mg/kg i.v.) decreased E.R. considerably while atropine (1.0 mg/kg i.v), adrenaline (5 μg/kg i.v.) and isoprenaline (5 μg/kg i.v.) increased E.R.. Noradrenaline (5 μg/kg i.v.) had no effect. The pattern of secretion appeared to be different between S.R.T. and saliva. Such being the case, the method utilized herein may be useful in detecting relatively small changes in the S.R.T..

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When aggressive mice induced by isolation were grouped with four normal mice, spontaneous motor activity (SMA), emotional behaviour, brain polyamines and monoamines were examined with the following results. 1) SMA by photo-cell counters method in mice returning from isolation to a group did not alter, but by open-field test markedly increased in comparison with that of normal mice on the 14th day under the new grouped circumstances. 2) In mice returning to a group, aggressive behaviour including attacking and biting was rarely observed. 3) Brain spermidine (SPD) in non-aggressive mice returning to groups was markedly decreased in comparison with that of aggressive mice on the 3rd day under the grouped circumstnces. 4) The ratio of brain spermine/ SPD in normal and non-aggressive mice isolated for 3 ?? 6 weeks was 1.16±0.07, 1.20±0.04, respectively, while in aggressive mice induced by isolation the ratio was 0.84±0.04. The ratio in nonaggressive mice by aggregation and by LiCl (12.5 ?? 50 mg/kg) twice a day for ten days was 1.18±0.03, 1.15±0.04, respectively.

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Effects of naproxen on wet weight of granuloma, exudate volume and the amount of connective tissue components in granuloma were investigated using a proliferative inflammatory model in filter paper-implanted rats. The drug remarkably inhibited granuloma formation and exudate accumulation and strongly decreased 0.15 M NaCl extractable contents of total mucopolysaccharide, acid mucopolysaccharide, glycoprotein and non-collagen protein in granuloma, although this drug caused only a weak decrease of the total contents of these components. As a result, the ratio of soluble content to the insoluble one of these components was reduced. On the contrary, the collagen content was increased, that is this drug facilitated the fibrization of granuloma tissue. In these tests, the efficacy of naproxen was comparable to 1/4 the dose of indomethacin. Benzydamine HCl and prednisolone had a different mode of action, compared with that of naproxen : Benzydamine HCl failed to inhibit granuloma formation and exudate accumulation. Prednisolone did not change the ratio of soluble fraction to an insoluble one of granuloma ground substances. These results suggest that like indomethacin, naproxen may potentiate the structural stability of granuloma tissue.

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The anti-inflammatory activity and the general pharmacological properties of L-5418, a new nonsteroid compound, were assessed by a battery of standard tests. L-5418 was the same or half as active as phenylbutazone (PB) in inhibiting rat paw edema induced by various phlogistic stimulations, was similarly potent to PB in reducing granuloma formation and was less active than PB in adjuvant arthritis assay. L-5418 inhibited completely ultraviolet erythema at a dose of 200 mg/kg, but did not display significant inhibition on increased vascular permeability. L-5418 was weaker than aspirin and somewhat more potent than PB in analgesic activity. The compound had weak activities in hypothermic and antipyretic action and rotarod test, but did decrease spontaneous locomotion in mice, potentiated barbiturate hypnosis and inhibited markedly convulsions induced by strychnine, pentetrazol and electroshock. In a dose producing an anti-inflammatory effect, L-5418 had no effects on the cardiovascular and respiratory system, gastrointestinal tract, kidney and uterus. It was also free of any effects on blood coagulation and sugar level and did not have antagonistic actions on such substances as histamine, acetylcholine, 5-HT and BaCl2. Furthermore L-5418 lacked ulcerogenic action and the LD50 was over 10 g/kg when given orally. From the above results, it may. be considered that L-5418 has different properties from the known anti-inflammatory agents and is a new type of drug.

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