The effects of six inducers and malotilate on 7-alkoxycoumarin 0-dealkylase activities in rat liver microsomes were examined. Phenobarbital (PB) (100 mg/kg) was administered intraperitoneally to rats for 6 days; 3-methylcholanthrene (3-MC) (40 mg/kg), β-naphthoflavone (β-NF) (40 mg/kg), isosafrole (150 mg/kg) and polychlorinated biphenyls (PCB) (100 mg/kg) were administered intraperitoneally for 3 days; isoniazid (INH) (50 mg/kg) was administered intraperitoneally for 10 days; and malotilate (500 mg/kg) was administered orally for 3 days. The 0-dealkylase activities toward 7-methoxycoumarin (7-MC), 7-ethoxycoumarin (7-EC) and 7-propoxycoumarin (7-PC) were examined 24 hr after the final administration of the drugs. The ratios of 7-EC 0-deethylase and 7-PC 0-depropylase to 7-MC 0-demethylase activity in the control and six inducer treated groups were compared. The ratios in the groups treated with the six compounds, each of which induces a different form(s) of cytochrome P-450 (P-450), were clearly different from each other. Therefore, the measurement of 7-alkoxycoumarin 0-dealkylase activities should be extremely useful for the routine determination of the molecular species of P-450. On the other hand, the ratio in the malotilate-treated group was different from that in any other inducer-treated group, so that there might be a possibility that malotilate induced a form(s) of P-450 that is different from any of the already known species.

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In order to elucidate the biological role of T-kininogen, it's levels in plasma, exudate, and liver were measured by radioimmunoassay in rats following the induction of carrageenin pleurisy. T-kininogen level in the liver microsomes was increased markedly at 8-24 hr after the carrageenin injection, and its plasma level increased at 24-48 hr with a delay. Pretreatment with dexamethasone suppressed the pleural exudate accumulation almost completely, but inhibited the T-kininogen level in plasma or liver only partially. When rats were pretreated with carrageenin injection into a paw 2 days prior to intrapleural injection of carrageenin, the pretreatment did not affect the pleurisy development, even though the plasma level of T-kininogen was greatly increased. Increased level of T-kininogen correlated well with the thiol protease inhibitor activity found in the plasma and exudate. These results indicate that an increase in the T-kininogen level does not influence the exudation, but might act as an inhibitor of thiol proteases that could be released at the inflammatory site.

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The effect of superior cervical ganglionectomy or long term treatment with guanethidine on the mechanical response of dilator muscle of the rat iris to several stimulants was examined. The dose-response curve for noradrenaline (NA) was significantly shifted to the left 7 days after denervation (ca. ×1O) or by treatment with guanethidine (ca. ×10), but those for methoxamine (Meth) and acetylcholine (ACh) were not. Cocaine did not further sensitize the denervated muscle to NA, but it sensitized the normal muscle to an extent similar to that caused by denervation. Cocaine did not affect the sensitivity to Meth in both control and denervated muscles. The maximum response to NA decreased by about 30% or 20% after surgical or chemical denervation, respectively, while those to Meth, ACh and Ca²⁺ did not alter significantly. These results indicate that in the dilator muscle, the sympathetic denervation caused a purely specific supersensitivity to NA which was simply explained by a presynaptic mechanism: an impairment of the neuronal uptake process.

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The effects of a brief hypoxic episode on synaptic activity in the CA1 region of the hippocampus were studied using the in vitro slice prepared from dietary Mg-deficient mouse. After 5 min of hypoxia, the synaptically evoked population spike was increased in amplitude and developed to an epileptiform discharge. The induction of the epileptiform discharge following hypoxia was prevented in the presence of DL-2-amino-5-phosphonovaleric acid (APV), a N-methyl-D-aspartate (NMDA) receptor antagonist, at a concentration of 30-50 μM. The post-hypoxic epileptiform discharge, however, was reduced but not blocked completely by the application of APV (concentration up to 100 μM). These results show that a brief hypoxic episode induces APV-sensitive epileptiform activity in the CA1 region of dietary Mg-deficient mouse, suggesting the involvement of NMDA receptors in post-hypoxic changes of synaptic transmission in the hippocampus.

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Effects of 12 compounds including 5-lipoxygenase (5-LO) inhibitors and antiallergic drugs on the activity of 5-LO from the polymorphonuclear leukocytes (PMN) of guinea pigs, rats, rabbits, monkeys and humans were examined. The 5-LO activity was inhibited by the drugs according to the following orders of efficacy: Guinea pig 5-LO, 5-HDHDMF>TZI-2721>NDGA>AA861>FPL55712>isoproterenol; rat 5-LO, 5-HDHDMF>AA861>TZI-2721>NDGA>FPL55712>KP-136>MCI-826>benoxaprofen; and rabbit 5-LO, 5-HDHDMF>TZI-2721>NDGA> AA861>FPL55712>KP-136>MCI-826. The 5-LO activity from the rhesus monkey was dose-dependently inhibited by only 3 compounds, 5-HDHDMF> NDGA>TZI-2721, in this order, but the other compounds, except for AA861, did not show any effect on this activity. In humans, 5-LO activity was inhibited in the following order: TZI-2721>5-HDHDMF>NDGA>AA861>FPL55712. From these results, it was strongly suggested that there is a species difference of this enzyme in its sensitivity to drugs.

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Effects of N-(2, 6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide (DM-9384) on learning and memory were studied using four different experimental rat models. In electroconvulsive shock- or scopolamine-induced amnesia in the step-through passive avoidance task, DM-9384 improved both types of amnesia when administered before the training trial. Aniracetam also showed similar but somewhat weaker effects. Furthermore, in the scopolamine amnesia mode!, an improvement was confirmed with arecoline. The dose-response curves for these compounds were bell-shaped. In the shuttle box active avoidance task, DM-9384 administered daily 1 hr before each training session facilitated the acquisition process of the avoidance response. In addition, the experiment of light-dark discrimination task with positive reinforcement showed that this compound administered daily after each session slightly accelerated the acquisition process of the correct response. These results suggest an ability of DM-9384 to enhance cognitive functions.

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The effects of isofloxythepin, a dibenzo[b, f]thiepin derivative, on the central and peripheral histamine systems were compared with those of chlorpromazine and haloperidol. The three drugs examined all inhibited both the histamine-induced contraction of guinea pig ileum and the specific[³H]mepyramine binding to guinea pig brain membranes in a dose-dependent manner. The effectiveness in inhibiting these reactions was in the order of: chlorpromazine>isofloxythepin> haloperidol. The histamine-induced relaxation of rat uterus, which is mediated by H₂-receptors, was not affected by isofloxythepin. The effect of isofloxythepin on the pargyline-induced accumulation of tele-methyl histamine in the mouse brain was indicative of a decrease in histamine turnover, whereas chlorpromazine and haloperidol were devoid of such effects. Isofloxythepin inhibited both the lethal effect of histamine injected i.v. in mice and histamine-induced edema in rat hind paws far more strongly than chlorpromazine or haloperidol did. These results show that isofloxythepin is a neuroleptic with H₁-antagonist properties, which are intermediate in potency between those of chlorpromazine and haloperidol, and also it may have an inhibitory action on histamine turnover in the brain. Protection against the lethal effect of histamine and the inhibition of histamine edema by isofloxythepin may largely be due to mechanisms other than the blocking of H₁-receptors.

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Effects of subcutaneous administration of psychoactive drugs: methamphetamine (0.13-1 mg/kg), chlorpromazine (0.5-2 mg/kg), physostigmine (0.05-0.2 mg/kg), scopolamine (0.031-0.5 mg/kg), pentobarbital (5-20 mg/kg), diazepam (0.5-2 mg/kg) and morphine (1.3-5 mg/kg) on discrete lever-press and shuttle avoidance responses were investigated in Mongolian gerbils that had received a brief (5 min) bilateral brain ischemic operation. Although some of the ischemic animals tended to show a retardation of acquisition of the avoidance responses, the established baselines were almost identical between the sham-operated and ischemic groups. In the lever-press task, morphine increased the response rate, whereas chlorpromazine, physostigmine, pentobarbital and diazepam decreased both the response and avoidance rates in a dose-dependent manner. In the shuttle avoidance task, both the response and avoidance rates were dose-dependently increased by methamphetamine, scopolamine and morphine, but chlorpromazine, physostigmine, pentobarbital and diazepam dose-dependently decreased them. These drug effects were almost the same between the sham-operated and ischemic groups. However, the ischemic-operation produced a significant loss of pyramidal cells in the CA1 sector of the hippocampus, the remaining level being less than 10% that of the sham-operated control animals.

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Potentiating effects of β-eudesmol on neuromuscular blockade were investigated in phrenic nerve-diaphragm muscles of normal and alloxan-diabetic mice. Pretreatment with β-eudesmol potentiated the blocking effects of succinylcholine to a greater extent in diabetic muscles than in normal ones. This effect was saturated after 30-min pretreatment in normal muscles. Further potentiation was observed after 60-min pretreatment in diabetic muscles. These results suggest that β-eudesmol modifies the sensitivity of diabetic mice to depolarizing blockers so that they have a higher susceptibility to these compounds.

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We studied the effect of plasmin inhibitor on ethanol and ammonia-induced gastric mucosal lesions in rats using an ex vivo chamber. Tranexamic acid and aminocaproic acid significantly inhibited macroscopic gastric hemorrhagic necrosis and attenuated the decrease of gastric transmucosal potential difference induced by 50% ethanol and 1 % ammonia. The protection of gastric mucosa afforded by tranexamic acid and aminocaproic acid was not affected by pretreatment with indomethacin (5 mg/kg). These results suggest that plasmin inhibitor plays an important role in the prevention of gastric deep necrosis following exposure of the stomach to a damaging agent.

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(±)-Higenamine (Hig, demethylcoclaurine) is a cardiotonic principle from aconite root. (+)-R-Coclaurine (Coc) and (+)-S-reticuline (Ret) are compounds contained in the dried buds of Magnolia salicifolia MAXIM. All of these alkaloids possess a common chemical structure: tetrahydroisoquinoline. Coc and Ret showed negative inotropic effects in contrast to the positive inotropic effects of Hig in papillary muscles of guinea pigs. Coc and Ret shifted to the right the concentration-contraction curves of Hig. Hig shifted in parallel to the left the Ca²⁺ curve, and it tended to shift to the left the isoproterenol (Isp)-induced response curve. In contrast, Coc and Ret inhibited the Ca²⁺ curve and the low concentration range of the Isp-induced curve, and it potentiated the high concentration ranges of Ca²⁺ and Isp. Coc and Ret showed actions that were reversed in direction to those of Hig, as clearly demonstrated in the Ca²⁺ curve.

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Effect of castration on [³H]-spiperone binding in the striatum of mid-life /mature rats was investigated. Four weeks after castration an increase in D-2 dopamine receptors was noted, and this was partially reduced by testosterone. These results suggest that testosterone may regulate striatal D-2 dopamine receptors in an age-dependent manner.

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²²Na⁺ uptake into capillaries isolated from the cerebral cortex of adult (20 to 26-week-old) sustained-hypertensive spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) was compared with findings in age-matched Wistar Kyoto rats (WKY). In the presence of 1.0 mM ouabain, 1.0 mM furosemide and 2.0 mM LiCl, ²²Na⁺ uptake into the isolated cerebral capillaries of WKY and SHR was significantly reduced to 38% and 65% of the control values, respectively, when 0.1 μM α-rat atrial natriuretic peptide (rANP) was added to the uptake buffer. The rANP-induced inhibition observed in SHR was significantly less, as compared with that in the WKY. Noteworthy was the observation that the Na⁺ uptake into the cerebral capillaries of SHRSP was not inhibited by rANP. As this peptide is thought to regulate amiloride-sensitive Na⁺ transport from the blood to brain by interacting with specific receptors, the present finding may relate to the etiology of dysfunction of the blood-brain barrier, in the presence of hypertension.

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