There were marked differences among animal species between NADPH-dependent and ascorbic acid-Fe⁺⁺-dependent lipid peroxidation. In NADPH-dependent lipid peroxidation, this activity occurred to the greatest extent in rats followed by guinea pigs and rabbits and such was much lower in rabbits than in guinea pigs. On the other hand, rabbit microsomes exhibited higher lipid peroxidation activity than guinea pigs in ascorbic acid plus Fe⁺⁺ or Fe⁺⁺-dependent lipid peroxidation although the activity was still lower than in rats. The ascorbic acid plus Fe⁺⁺-stimulated lipid peroxidation produced a decrease in ethylmorphine N-demethylase activity which was closely related to ethylmorphine-enhanced NADPH-cytochrome P-450 reductase activity but was not related to the change of the apparent content of cytochrome P-450 in all animal species. These results indicate that decrease of NADPH-cytochrome P-450 reductase activity induces a decrease in ethylmorphine N-demethylase activity by lipid peroxidation.

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The types of interaction of mepyramine (M), diphenhydramine (D) and eprozinol (E), with histamine H₁-receptors of guinea pig ileal and tracheal smooth muscle, were comparatively studied in vitro. According to the concentrations used, all three substances showed an apparent dualist mechanism of action on both preparations when histamine (dihydrochloride) was used as the agonist. The competitive component of this mechanism (at low concentrations) was characterized by the following pA₂ values: 9.01 (M), 7.80 (D) and 5.64 (E) with the ileum; 8.06 (M), 7.00 (D) and 6.02 (E) with the trachea. The so called nonspecific component (at high concentrations) was of comparable intensity in the two organs. The pD'₂ values were 5.54-5.66 (M), 4.65-4.38 (D) and 3.82-3.55 (E) with ileal and tracheal muscle, respectively. At low concentrations the equi-active dose-ratio for M/D/E (1/16/2300 on the ileum) became 1 /12/110 when the trachea was used as the effector. This is surprising since histaminergic receptors of the two preparations are of the same H₁-type. It is suggested that only diphenhydramine and eprozinol are really dualistic, and that the non-specific mechanism of activity differs for each drug with that of eprozinol being effective on tracheal muscle.

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A quantitative method for measuring pain threshold by the use of ultrasonic stimulation in man was designed and the possibility of clinical application in assessing analgesics was investigated. Ultrasonic stimulus was given to Japanese subjects on the palmer distal part of the 2nd, 3rd and 4th fingers of both hands. The latent time between start of the stimulation and withdrawal of the hand when perceiving pain was considered the pain threshold. The ultrasonic evoked pain was a sharp pin-prick type, without sensations such as thermal and mechanical. The pain threshold lowered with increasing either stimulus intensity or water bath temperature when the hand of the subject was immersed during measurement. Normal threshold to ultrasonic stimulation measured in both 50 men and 50 women gave nearly normal distribution curves: women being more sensitive to ultrasonics than men. Analgesia with codeine phosphate (20 mg p.o.), aspirin (1.5, 1.0, 0.5 g p.o.), aminopyrine (100 mg p.o.) and mefenamic acid (500 mg p.o.) in volunteers of both sexes was demonstrated significantly using this method under double blind circumstances. Pentobarbital, diazepam, butylscopolamine, bromelain and placebo each in the usual dose used clinically failed to alter the pain threshold. Humans were at least 25 fold more sensitive than mice to the analgesics used herein.

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Pole climbing and shuttle box tests were employed to study conditioned avoidance response (CAR) and discrimination behaviour in Wistar male rats given extracts from Panax Ginseng root intraperitonealy. Neutral saponins (GNS), a water soluble fraction (GF₄) which does not contain saponins, and a lipid soluble fraction (GNo. 5) inhibited CAR and discrimination ability between 500 Hz sound with electric shock (S^D) and 1000 Hz sound without shock (S^Δ). Small doses of GNo. 5 and ginsenoside Rg fraction (GRg) produced a slight shortening of the response latency (RL) to the conditioned stimulus in CAR. GNo. 5 produced the incorrect response to S ^?? . Significant changes in the extinction of CAR were not evident with any fraction. Data from these tests indicate that Panax Ginseng root contains at least three sedative compounds.

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Effects of ID-540, a recently introduced benzodiazepine derivative, on the averaged photopalpebral reflex (PPR), subjective symptoms and serum levels of ID-540 and its principal metabolite, N-desmethyl-ID-540 following an oral dose of 0.5 mg were insvestigated in 4 healthy male Japanese students in their early twenties. Both the latencies of PPR, P₁ and P₂ latency, showed a prolongation and maximum level at 2-2.5 hours after administration and tended to decline thereafter to control levels. The serum concentration of ID-540 shossed a peak level at 2 hours after dosing, then showed a decline at 4 hours. The N-desmethyl-ID-540 exhibited a slow, gradual rise in the serum over the first 4 hours and there was a tendency toward a continued rise even at 24 hours. These parameters were of striking resemblance in the time-course of changes after oral dosing. Thus the PPR test nay be a useful means of determining the clinical effects of anxiolytic agents. ID-540 appears to be an agent with remarkable anxiolvtic effects.

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Studies were carried out to determine the relationship between metabolic and histopathological changes in the gastrocnemius muscle of rats in which an acute exudative inflammation had been induced by alkyldimethylbenzylammonium chloride (alkyl-DBAC, a cationic surfactant). Succinate respiration, Na⁺-K⁺-Mg²⁺ ATPasc activity and ATP, ADP and AMP levels were determined as the index of metabolic changes. Myofascial edematous swelling with the acceleration of succinate oxidation and Na⁺-K⁺-Mg²⁺ ATPase activity was noted at 30 minutes in the inflamed muscle. The ATP level was also transiently reduced. On the other hand, Na⁺-K⁺-Mg²⁺ ATPase activity and succinate oxidation were inhibited by alkyl-DBAC, at this concentration, in vitro. These results support the possibility that enhancement of energy metabolism is not directly initiated by alkyl-DBAC but may be the result of certain chemical mediators released by alkyl-DBAC. The enhancement of energy metabolism continued after 1 hour and this energy may initiate leukocyte migration as well as increase vascular permeability and edema.

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Dopamine-β-hydroxylase (DBH) activity in scrum, DBH and tyrosine hydroxylase (TH) activities in mesenteric vessels, and DBH and TH activities in locus coeruleus and hypothalamus of brain did not differ significantly between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKR) at 16 weeks of age when hypertension of SHR was fixed. In contrast, DBH and TH activities in vas deferens and adrenal glands were significantly higher in SHR than in WKR. These changes in SHR at 16 weeks of age after establishment of hypertension are directly opposite those reported previously in SHR at 3 weeks of age before the onset of hypertension.

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Bronchodilating actions of 7-hydroxy(I), 5, 7-dihydroxy(II), 5, 6, 7-trihydroxy (III) and 6, 7.8-trihydroxy(IV)-()-I-(3, 4, 5-trimethoxybenzyl)-12, 3, 4-tetrahydroisoquinolinc (TMI) were investigated in anesthetized cats and results were compared to those of AQ-110 (6, 7-dih)droxy-TMI) and isoproterenol. TMI derivatives given intravenously suppressed the bronchoconstriction induced by serotonin. These compounds also caused an increase in heart rate and a decrease in diastolic pressure. All of these actions sere inhibited by pretreatment vvith propranolol, suggesting that they were classified as β-sympathominictics. Bronchodilating activities of AQ-110, I, II, III and IV were 1 2.6, 136, 1 4.0, 1 7.7 and 1 23 that of isoproterenol, respectively. When compared with isoproterenol, I and the other TMI derivatives were about 9 and 2 times more potent in producing bronchodilation than in increasing heart rate. On the other hand, the bronchodilating activities of I, II and AQ-110 were 2-3 times as great as their depressor activities, while III and IV had no selectivity. When administered into the duodenum, II was the most potent in producing bronchodilation and the potency was followed by these of AQ-110, I, III, isoproterenol and IV in decreasing order. Duration of the bronchodilating action of TMI derivatives administered via either intravenous or intraduodenal route was considerably longer than that of isoproternol; especially I and II were long-acting. These results suggest that I and II exhibits a greater absorption efficiency or intraduodenal bioavailability than the other compounds tested.

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In an attempt to assess the effects of methylmercury on ethanol metabolism, Sprague-Dawley rats were treated with a daily dose (10 mg/kg i.p.) of methylmercuric chloride for 2 consecutive days and given a test dose (0.4 g/kg i.v.) of ethanol 24 hr after the last treatment. Blood ethanol levels were measured using gaschromatography by the direct introduction of blood samples into the sample vaporizing apparatus attached to the chromatograph. While treatment with methylmercury elicited a slight retardation in the ethanol elimination from the blood during 30 to 90 min, methylmercury did not essentially alter ethanol metabolism. There was no significant change in hepatic alcohol dehydrogenase activity of methylmercury-treated rats. By contrast, the activity of alcohol dehydrogenase purified from liver or yeast was remarkably inhibited by methylmercury and the type of inhibition proved to be non-competitive. Moreover, the inhibited activity was reactivated easily by sulfhydryl agents. From these results, it is conceivable that methylmercury has little influence on ethanol metabolism in vivo because of its non-specific binding with sulfhydryl groups in the organism.

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Using the redox potential of the myocardium ( ?? Eh) as a measure of the myocardial energy metabolism. the metabolic effects of three representative catecholamines, adrenaline (Adr). noradrenaline (Nor) and isoproterenol (Isp) were studied, in the canine heart-lung preparation supported by a donor. Adr and Nor produced an initial improvement of ?? Lh, followed by a sustained debasement, while Isp produced only a debasement. Pretreatment of the preparation with phentolamine or dibenamine, resulted in an abolishment of the initial irniprovement, while the effect of Isp remained unchanged. After pretreatment of the preparation with practolol, the positive inotropic and chronotropic effect and the associated increase in the myocardial oxygen consumption were no longer seen with all the catecholamines tested. Under these conditions. Adr and Nor produced a sustained improvement of ?? Lh, while Isp produced a transient debasement, which, in turn, was abolished by propranolol. When the heart was driven at a constant rate, the myocardial oxygen consumption did not increase with the catecholamines in most of the cases and a sustained improvement of ?? Eh was observed with Adr and Nor: Isp produced a transient debasement. These findings indicate that catecholamines produce an improvement of the myocardial energy metabolism through activation of the adrenergic α-receptor.

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The effects of phenylephrine and methoxamine were studied on pacemaker activity in the sinoatrial node and on atrial and ventricular contractility in isolated, blood-perfused atrial and ventricular preparations of dogs. Each drug was administered directly into the cannulated sinus node artery of an isolated atrium or the anterior descending branch of the isolated left ventricle over a period of 4 sec. Two response patterns to phenylephrine were observed in atrial preparations: monophasic positive chronotropic and inotropic effects; double peaked effects, positive effects were temporarily interrupted by negative effects. Phenylephrine-induced positive effects were blocked by an adrenergic beta-blocker, alprenolol or carteolol, but not by desipramine or phentolamine. Phenylephrine-induced negative effects were inhibited by atropine, tetrodotoxin or phentolamine. In ventricular preparations, phenylephrine usually induced a monophasic positive isotropic effect which was completely blocked by a beta-blocker but not by phentolamine. On the other hand, methoxamine usually induced negative chronotropic and inotropic effects in both preparations, and these negative effects were not blocked by atropine, tetrodotoxin and phentolamine. These results suggest that phenylephrine produces a cholinergic excitation which may occur through an adrenergic alpha-mechanism in parasympathetic nerve terminals, in addition to its adrenergic beta-stimulating effect.

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Crude mitochondrial P₂ fractions from bovine hypothalamus and substantia nigra, slices from rabbit spinal cord and mesencephalon and glial fractions from rabbit brain were incubated with [³H]-substance P and the uptake was measured and compared with those for 5-HT and GABA. Substance P was to some extent taken up into the fractions but this uptake was neither temperature nor time dependent and the pellet/ medium ratios were less than 1. Similar results were obtained in high potassium treated slices from rabbit mesencephalon. The rate of uptake for [³H]-substance P increased linearly in proportion to the medium concentration, suggesting a non-saturable binding. These results, together with our previous observations provide strong evidence that nerve terminals and glial cells lack a temperature sensitive, active uptake system capable of terminating transmitter action of substance P at the synapse.

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