Effects of 2-(4-methylaminobutoxy) diphenylmethane hydrochloride (MCI-2016) were studied on gastric lesions induced by conditioned emotional stimulus (CES) in mice. The gastric lesions were produced by the communication box reported by Ogawa et al. The communication box was divided into 48 compartments by transparent plastic walls. Twenty-four mice in each compartment were subjected to footshock through the grid on the floor (sender), and the other 24 mice were not (responder). The mice were subjected to CES for 12 hr. The incidences of the gastric lesions in the responder and sender groups were 72.9 and 98.8%, respectively. MCI-2016 at doses of 20-50 mg/kg (×2), p.o., reduced the incidence of gastric lesions in the responder group; and diazepam at a dose of 2 mg/kg (×2), imipramine at doses of 10 and 20 mg/g (×2), p.o., amitriptyline at doses of 5 and 10 mg/kg, (×2), p.o., and sulpiride 100 mg/kg (×2) reduced the incidences of gastric lesions in the responder group. These findings have indicated that MCI-2016 has an antiulcerative action against gastric erosion induced by CES.

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The present experiments were designed to study the renal effects of propranolol and atenolol in rats. Wistar rats were anesthetized with urethane and continuously hydrated with saline solution. In one group of the rats, the drugs were injected into the jugular vein. In the other group of the rats, the drugs were injected into the abdominal aorta through a canula which was inserted from the left carotid artery into the aorta up to the middle between forking points of left and right renal arteries. Intravenous infusion of propranolol and atenolol increased urine voulme (UV), urinary sodium excretion, urinary potassium excretion and urinary chloride excretion. Propranolol and atenolol, which were intraaortally injected, produced an increase in UV and sodium concentration in the urine, inducing a more marked increase in total sodium amount excreted from both kidneys by propranolol than by atenolol. However, the natriuretic response was far more marked in the left kidney than in the right kidney in the case of atenolol administration as compared to that in the case of propranolol. It was speculated, therefore, that the natriuresis induced by these drugs was the first pass effect on the rat kidneys. It was also noted that the first pass effect of atenolol on kidneys was more marked than that of propranolol.

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Traxanox at the upper dose of 300 mg/kg, p.o., showed no effect on the central, somatic and autonomic nervous systems in the various tests. This agent caused some relaxation of the guinea pig tracheal strip in the resting tone at a concentration of 10^-6 M or more; however, its activity was less potent than that of isoproterenol and paraverine. Traxanox had no competitive antagonistic action against chemical mediators. Treatment of rats with this agent (3 mg/kg, i.v., or 10 mg/kg, s.c.) resulted in an inhibition of gastric (acid) secretion. Intravenous injections of traxanox (1-10 mg/kg) in dogs caused an immediate but transient inhibition of gastric and jejunal movement, and after a short time, slight potentiation of the latter; however, pretreatment with atropine prevented this latter potentiation. In the in vitro test, 10^-4 M traxanox caused contraction of the guinea pig ileum, a response which was inhibited by atropine. Traxanox (300 mg/kg, p.o.), however, did not show any effects on gastrointestinal propulsion in mice, nor did it have any effect on the gastrointestinal mucosa, gastric ulcers or bile secretion in rats. Traxanox (300 mg/kg, p.o.) showed a diuretic action in both normal and adrenoectomized rats. This action, however, was not observed in the rats treated with indomethacin (1 mg/kg, i.p.). This agent (10 mg/kg, i.v.) suppressed the spontaneous uterine contractions of pregnant rats in some cases. These findings suggest that traxanox at doses (1-5 mg/kg, p.o.) showing antiallergic activity has little effect on the central, somatic and autonomic nervous systems, digestive system, urinary organs and reproductive organs.

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It has been demonstrated that the administration of large doses of dopa or 5-hydroxytryptophan (5-HTP) affected not only dopamine (DA) or serotonin (5-HT) neurons but also other neurons. This report concerns the effects of tryptophan, 5-HTP or dopa on concentrations of 5-HT, DA, norepinephrine, and their metabolites in p-chlorophenylalanine-, 5, 7-dihydroxytryptamine (5, 7-DHT) or non-treated rat brain. The results were as follows: 1) When the brain DA levels increased more than six-fold after the i.p. administration of 1-dopa, the brain 5-HT levels significantly decreased, and 5-hydroxyindoleacetic acid (5-HIAA) levels significantly increased. 2) In the nerve ending fraction of rat brain, the administration of 1-dopa induced the largest increase of DA levels in the striatum, while administration of dl-5-HTP produced the largest increase of 5-HT levels in the hypothalamus. These results suggest that the distribution of newly synthesized 5-HT or DA after the administration of 5-HTP or dopa, respectively, depends not only on that of aromatic I-amino acid decarboxylase, but also on that of nerve cells which selectively take up 5-HTP or dopa or that of synaptic vesicles which selectively take up 5-HT or DA. 3) The large doses of 5-HTP administration to 5, 7-DHT pretreated rats induced the largest increase of 5-HT levels in the striatum. Thus, results in the present study indicate that the distribution of DA or 5-HT after the administration of dopa or 5-HTP, respectively, depends on the doses of dopa or 5-HTP given as well as the presence or absence of the lesioned 5-HT or DA neurons.

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Effects of dl-2 {3-(2'-chlorophenoxy)phenyl} propionic acid (CPP) on the nociceptive response induced by injection of bradykinin (BK) into rabbit femoral artery were studied. When drugs were administered intravenously, the analgesic activity of morphine was 2 to 10 times more potent than that of CPP; but when it was injected into the femoral artery, CPP was approximately 5 times more potent than morphine. Intraventricular injection of a small dose of 10 pg/head morphine produced a prominent analgesic activity, while even a large dose of 500 pg/head CPP had little effect. Prostaglandin E₁ (PGE₁) alone in a dose range of 0.1 to I μg i.a. produced no nociceptive response, but an intra-arterial pre-injection of PGE₁ enhanced BK-induced nociceptive response. Morphine suppressed the BK-response pretreated with PGE₁, but CPP as well as indomethacin had little effect. These results suggest that CPP suppresses BK-induced nociceptive response at the periphery, probably at the paravascular “pain receptor”, and the analgesic effect of CPP may be due to inhibition of endogenous PG synthesis. On the other hand, CPP in a dose range of 2.5 to 20 mg/kg, i.v. produced antipyretic effects on the fever induced by typhoid vaccine. Intraventricular injection of 500 μg/head CPP produced a slight antipyretic effect. CPP had no effect on PGE₁ -induced fever. These results suggest that CPP produces the antipyretic effect acting on the central nervous system, probably due to inhibition of endogenous PG synthesis.

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The effects of oxatomide, an anti-allergic drug, on the actions of chemical mediators were investigated in guinea pigs, rats and cats; and the following results were obtained: Studies on the guinea pig ileum revealed oxatomide to be a potent antagonist of histamine with a dual type of action, being competitive at low doses and noncompetitive at higher doses. Oxatomide at concentrations of 0.1 μM or higher inhibited the contractile responses evoked by crude SRS-A from sensitized guinea pig lung. Oxatomide (0.1 to 10 μM) did not inhibit the chronotropic effect of histamine in guinea pig atrium. In anaesthetized guinea pigs, serotonin-induced bronchoconstriction was antagonized by oxatomide (0.1 to 1 mg/kg, ix.) as effectively as histamine-induced bronchoconstriction. However, oxatomide (up to 1 mglkg, i.v.) did not inhibit acetylcholine-induced or arachidonic acid-induced bronchoconstriction. Oxatomide given orally in the range of 5 to 30 mg/kg markedly inhibited the increased vascular permeability by histamine, serotonin, and bradykinin in rats. Oxatomide at doses of 0.03 mg/kg (i.v.) or higher also prevented the contraction of the nictitating membrane induced by serotonin in cats. Oxatomide (0.3 μM and 1 μM) inhibited competitively the calcium-induced contracture of fullydepolarized taenia coli of guinea pigs. From these results, oxatomide appears to have potent antagonistic activities on the actions of various chemical mediators. These properties of oxatomide may contribute to its anti-allergic activity.

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It was investigated whether the analgesic effects of eptazocine were antagonized by treatment with naloxone, one of the opiate antagonists, and whether morphine-induced effects were affected by eptazocine. The analgesic effects of eptazocine, similar to those of morphine, were completely antagonized by treatment with 0.5 mg/kg naloxone, s.c., as determined by the hot plate and pressure methods in mice and by the tail-flick method in rats. In contrast, as tested by the acetic acid-induced writhing method in mice, the analgesic effect of eptazocine, similar to that of pentazocine, was not antagonized by treatment with 1.0 mg/kg naloxone, s.c., while that of morphine was antagonized by 0.5 mg/kg naloxone, s.c. Using the acetic acid-induced writhing method in mice, the pA₂ values of naloxone were found to be the following order: eptazocine<pentazocine <morphine. In addition, the analgesic effect of morphine was dose-dependently antagonized by the treatment with eptazocine as determined by the pressure method. Furthermore, the stimulating effect of morphine on spontaneous locomotor activity was also antagonized by eptazocine. These results suggest that eptazocine may be classified as one of the opiate agonist-antagonists.

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Anti-anoxic effects of MCI-2016 were compared with those of drugs for cerebrovascular diseases, tricyclic antidepressants and physostigmine in mice. Minimal effective doses of MCI-2016 which significantly increased the survival time or gasping duration were 12.5 mg/kg, p.o. for hypoxia, 50 mg/kg, p.o. for KCNinduced anoxia, and 100 mg/kg, p.o. for decapitation-induced gasping. As a whole, these effects of MCI2016 were superior to those of reference drugs for cerebrovascular diseases. MCI-2016 was also shown to be effective under a consecutive administration schedule. In marked contrast to the effect of MCI-2016, tricyclic antidepressants significantly shortened the survival time under hypoxia. Considering that atropine shortened and physostigmine markedly increased the survival time under hypoxia, involvement of anti-cholinergic action may be postulated for the shortening effect of tricyclic antidepressants. The anti-hypoxic effect of MCI-2016 as well as physostigmine was diminished by atropine treatment. Furthermore, MCI-2016 exhibited a combination effect with physostigmine at optimal doses. Although the influence of norepinephrine uptake inhibitory action on the hypoxic condition are not clear in the present study, these results may suggest that activation of CNS cholinergic system is involved as one of the causative mechanisms for anti-anoxic effect of MCI-2016.

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Effects of piroxicam on allergic inflammation were investigated with allergic air pouch inflammation and antigen-induced arthritis in rats. In allergic air pouch inflammation, piroxicam exerted a dose-dependent inhibition (1 ?? 10 mg/kg, p.o.) of the exudate production, the migration of leukocytes and the release of lysosomal enzyme into the exudate; and its potency was superior to that of indomethacin and equivalent to that observed with prednisolone. In contrast with this, the suppressive effect of piroxicam on non-allergic air pouch inflammation was as weak as indomethacin. Prednisolone showed a similar effect on both types of air pouch inflammation. In antigen-induced arthritis, piroxicam showed a dose-dependent (0.3 ?? 3 mg/kg, p.o.) inhibitory effect on knee joint swelling and an improving action on the functional disorder of the inflamed joint. On this model, piroxicam was 3 to 4 times more active than both indomethacin and prednisolone. In non-allergic joint inflammation induced with croton oil in rats, however, the anti-inflammatory potency of piroxicam was almost equal to those of indomethacin and prednisolone. Piroxicam showed more potent inhibition than indomethacin on heterologous passive cutaneous anaphylaxis in rats, but showed only a slight inhibition on the increased vascular permeability caused by histamine and bradykinin. Piroxicam had no influence upon the plaque-forming cell response and the delayed hypersensitivity reaction in mice; furthermore, the hemolytic activity of complement in guinea-pig serum was scarcely affected by piroxicam in vitro. These results indicate that piroxicam possesses prominent efficiency on allergic inflammation and may function on several activities of inflammatory cells.

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Acetylcholine produced an elevation of the atrial pressure and decreased the systemic output dose-relatedly at 30 fig or more without producing any change in the heart rate. Negative chronotropic effects were observed only with doses of more than 600 μg. These effects of acetylcholine were enhanced by physostigmine and antagonized by atropine, while pindolol and 6-hydroxydopamine exerted no influence. Acetylcholine-induced elevation of atrial pressure and decrease of systemic output were similarly observed even when the heart was paced at a constant rate. Carbachol and methacholine produced qualitatively similar changes in the atrial pressure and systemic output. However, carbachol was unique in that it produced a dose-related negative chronotropic effect. Vagal stimulation induced an elevation of atrial pressure and a decrease of systemic output associated with bradycardia. Effects of vagal stimulation on atrial pressure and systemic output were abolished in the paced heart. These findings suggest that exogenous acetylcholine cannot reach the pacemaker site because of the abundant presence of cholinesterase in the region of the pacemaker, while acetylcholine released by vagal stimulation can reach the pacemaker site before being degraded by cholinesterase. The elevation of the atrial pressure and a decrease in the systemic output produced by exogenous acetylcholine can be ascribed to activation of the receptors in the ventricular myocardium, while the negative inotropic effects of vagal stimulation are due to an inhibition of atrial functions.

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Pepsin enhanced phagocytosis of heterologous red blood cells by macrophages, but suppressed phagocytosis of homologous red blood cells. Antigen-presenting ability of the macrophages pulsed with heterolcgous red blood cells was augmented by pepsin, but not those pulsed with homologous red blood cells. On the other hand, an acid protease was found in macrophages that had biochemical and immunochemical properties which were quite close to those of pepsin. Along with phagocytosis of heterologous red blood cells by macrophages, the activity of this pepsin-like enzyme in macrophages showed an increase and extracellular release was also observed. Such changes were not observed in the macrophages that phagocytized homologous red blood cells or non-antigenic materials. Inhibition of this enzyme activity by pepstatin resulted in suppression of the phagocytosis of heterologous red blood cells. These results indicate that pepsin modulates macrophage functions and that a pepsin-like enzyme in macrophages plays an important role in the facilitation of phagocytosis and antigen-presentation by macrophages.

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The effect of methamphetamine on preference for morphine was studied in rats by the drug-admixed food (DAF) method. The preference rates for morphine-admixed food gradually increased by the repetition of choice and forced trials and then became stable at the level of 70%. On the other hand, the preference rates for morphine-admixed food combined with methamphetamine did not so increase compared with the case of morphine alone. From the taste aversion test, it was assumed that combination of morphine and methamphetamine did not enhance taste aversion, although methamphetamine suppressed development of preference for morphine. In the case of combination of morphine and cocaine or caffeine, preference rates for these drugs increased like the case of morphine. This result indicated that the suppression of the preference for morphine which was induced by methamphetamine was not produced by the general effect of CNS stimulants. We found that methamphetamine suppressed the development of the preference for morphine. These findings suggest that the suppression resulted from neither taste aversion nor the general effect of CNS stimulants. Furthermore, acute toxicity and other effects were enhanced by the combination of morphine and methamphetamine, and it might participate with the suppression.

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