The last decade has been the most prolific and stimulating period in the area of prostaglandin (PG) study. Since PGs were found in the hypothalamus and cerebrospinal fluid, and were released from the central nervous system (CNS) spontaneously and in response to chemical or electric stimulation, many investigators have been engaged in studying their effects in the CNS. In fact, PGs have a wide range of pharmacological actions in the CNS. Relatively large doses of PGs have to be given centrally to produce some effects. On the other hand, some types of PGs, when applied centrally in doses of a few ng, stimulate the hypothalamus or the pituitary gland to increase secretion of hypothalamic and anterior and also posterior pituitary hormones. Physiological investigations of PGs have been aided by the use of inhibitors of their synthesis; aspirin, indomethacin etc. These compounds inhibit secretion of the hormones from the hypothalamus as well as the pituitary, suggesting that endogenous PGs exert a functional role for the hormone secretion. To produce fever, PGEs have to act on the preoptic anterior hypothalamus, and aspirin and indomethacin decrease fever produced by pyrogens but not PGEs. Pyrogens produce fever by increasing synthesis and release of PGEs. Hypothalamic PGEs play a role as a central transmitter or modulator in temperature regulation.

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The IgE mediated reactions such as 48 hr homologous passive cutaneous anaphylaxis (PCA) and active anaphylactic bronchoconstriction in rats were inhibited in a dose dependent manner by treatment with 7-acetyl-5-oxo-5H-[I]benzopyrano[2, 3-b] pyridine (Y-9000) and disodium cromoglycate (DSCG) given intraperitoneally. The inhibitory activity of Y-9000 was to the same extent as that seen with DSCG. The IgE mediated reactions were also inhibited by oral treatment with Y-9000 but not with DSCG. In addition, the treatment with Y-9000 resulted in inhibition of IgG mediated reaction such as anaphylactic asthma in the passively sensitized guinea pigs and 4 hr heterologous PCA in rats. However, DSCG failed to prevent these reactions. Y-9000 also inhibited the active systemic anaphylaxis of the mouse and non-immunological reactions in rats such as histamine release after an intraperitoneal injection of dextran, anaphylactoid reaction and paw edema induced by the dextran, egg white or carrageenin. This agent had a stimulating effect on the adrenals, and showed glucocorticoid like activity, but bronchodilator and antagonistic activities on chemical mediators were nil. These results suggest that the anti-allergic activities of Y-9000 are elicited by inhibiting the release of allergic mediators in a manner similar to DSCG, and are partially mediated by stressor activity.

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The inhibitory effect of D-penicillamine on the denaturation of human γ-globulin induced by heat and Cu⁺⁺ was compared with the action of other agents such as antirheumatic drugs, anti-inflammatory drugs, SH reagents, SH inhibitors and chelating reagents. The denaturation of human γ-globulin was induced by Cu++ at 10 μM (“Cu⁺⁺ induced denaturation”) and was further increased by heating at 63°C for 3 hr in the presence of Cu⁺⁺ (“total denaturation”). Thus the value obtained by subtracting “Cu⁺⁺ induced denaturation” from “total one” was designated as “thermal denaturation”. D-Penicillamine enhanced “thermal denaturation” at a low concentration but inhibited it with increasing the concentration as well as L-cysteine. SH reagents such as thiomalic acid, 6-mercaptopurine inhibited “total” and “thermal” denaturation. SH inhibitors and protein binding reagents such as N-ethylmaleimide, trinitrobenzenesulfonic acid inhibited the “total” and “thermal” denaturation of the protein. Chelating reagents such as ethylenediamine tetraacetic acid, 8-hydroxyquinoline inhibited “total”, “Cu⁺⁺ induced” and “thermal” denaturation of the protein. Au⁺ inhibited “total denaturation”, but not “Cu⁺⁺ induced denaturation”. On the other hand, Au⁺⁺⁺ denaturated the protein considerably with or without heating, in the absence of Cu⁺⁺ but dithiothreitol did so only with heating in the same condition. The anti-inflammatory drugs used herein had no effect on the protein denaturation. D-Penicillamine apparently prevents the denaturation of human γ-globulin by the chelate formation with Cu⁺⁺ and the binding to free protein SH, initiator for sulfhydryldisulfide interchange reaction.

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Influence of estrone on uterine contraction and increase of internal pressure of uterus induced by PG were studied in the rat. The sensitivity of the uterus to PG was increased after estrone injection, the maximum effect being observed 72 hours after the administration. Regarding uterine contraction and increase of internal pressure induced by PGE₂ or PGF_2α, the amplitude was enlarged but the frequency was decreased with estrone injection. Contraction and increase of internal pressure induced by PG were well correlated in the rat uterus treated with estrone. Progesterone inhibited the stimulatory action of estrone on uterine contraction induced by PG. These results suggest that estrone may play an important role in action of PG in rat uterus.

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To clarify the mode of action of loperamide, the interaction with various agonists was investigated in guinea pig intestines. The following results were obtained. Prostaglandin E₁ (0.1 μg) or acetylcholine (1 ?? 3 μg) injection into the mesenteric artery at 10 min intervals caused a constant rise of intraluminal pressure of the intestinal loop in situ. Loperamide (0.01 ?? 0.1 mg/kg i.v.) markedly suppressed the response induced by prostaglandin E₁. Morphine (0.1 ?? 1.0 mg/kg i.v.) and atropine (0.01 mg/kg i.v.) also suppressed the response. The intestinal response induced by acetylcholine was inhibited markedly by atropine and slightly by loperamide (0.1 mg/kg i.v.) but not by morphine. Contractions of the isolated ileum induced by coaxial stimulation, BaCl₂, nicotine and serotonin were suppressed by loperamide (10^-9 ?? 2 × 10^-7 g/ml). Morphine, methadone and codeine showed the same effect as loperamide but the activity was weaker than that of loperamide. Contractions of isolated ileum induced by acetylcholine, histamine and bradykinin, and Ca-contraction in the depolarized taenia coli were inhibited by relatively high concentrations of loperamide (2 × 10^-7 g/ml or above). These results suggest that loperamide suppresses the function of cholinergic neurons in the intestines.

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Effects of cholinergic agonists and serotonin were examined on the chronically denervated stomach fundus. We developed a new method of adrenergic denervation (sympathectomy), which was confirmed chemically, histochemically and functionally. Vagotomy was performed by the usual method. The sensitivity of the longitudinal muscle of the fundus to cholinergic agonists and serotonin was not modified by chronic sympathectomy or vagotomy when determined from the ED50 of the dose-response curve. The maximum contractile response of vagotomized fundus to each cholinergic agonist and to serotonin was significantly decreased, whereas only a slight decrease was observed in sympathectomized fundus. Ca²⁺-contracture in Ca²⁺-free isotonic K⁺ Ringer's solution was markedly decreased in chronically vagotomized or sympathectomized fundus. Efflux of ⁴⁵Ca in Ca²⁺-free isotonic K⁺ Ringer's solution was significantly lowered by vagotomy but only slightly by sympathectomy. No significant change in ATP content was observed in the vagotomized or sympathectomized fundus.

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Renal effects of metolazone (MET), a new diuretic agent, were compared with those of hydrochlorothiazide (HCT) in rats. MET in an oral dose of 0.01 ?? 0.5 mg/kg resulted in a dose-related increase in urine flow, sodium excretion and osmolal clearance in male rats. The natriuretic action of MET was not enhanced by administration of an increased dosage (1 ?? 5 mg/kg). Urinary excretion of potassium was significantly increased after MET, but was less than that of sodium. Therefore, the ratio of urinary concentration of sodium to potassium was markedly increased. Similar results were obtained when MET was intraperitoneally administered. In female rats, MET also proved to be an effective natriuretic. The diuretic effects of HCT were qualitatively similar to those of MET, but MET was 10-20 times as potent as HCT on a basis of minimal effective dose. In the renal clearance experiments, MET did not influence the renal plasma flow and glomerular filtration rate. From these findings, it is concluded that MET exerts a diuretic effect by inhibiting the reabsorption of electrolytes in the renal tubules.

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Clonazepam at two doses of 1 mg/kg i.p. significantly decreased 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) contents in the rat caudatus and cortex but no so in the olfactory tubercle, septum and hypothalamus. The drug decreased dopamine (DA) turnover rate in the caudatus, but did not inhibit tyrosine hydroxylase activity. The drug significantly enhanced stereotyped behavior induced by apomorphine and d-methamphetamine. Clonazepam enhanced apomorphine-induced decrease in striatal HVA, and cortical DOPAC and HVA contents, and d-methamphetamine-induced decrease in cortical DOPAC content. Reserpine pretreatment did not affect apomorphine-induced stereotypy and its enhancement with clonazepam. The drug did not activate adenylate cyclase nor DA-sensitive adenylate cyclase in the striatal homogenates and did not change cyclic AMP content in the caudatus. The drug inhibited phosphodiesterase activity in caudate and cortical homogenates but not in vivo. Clonazepam did not alter ChAc and AChE activities in the caudatus, 6 other cerebral regions and the spinal area. Clonazepam also decreased NE turnover in the caudatus and 5-HIAA contents in the brainstem area. These neurochemical and behavioral effects of clonazepam indicate probable postjunctional DA stimulation in the striatum and cortex of the type not linked with adenylate cyclase and phosphodiesterase but probably due to activation of inhibitory γ-amino butyric acid (GABA) neurons on the strio-nigral pathway.

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Biological activity of 1α-hydroxycholecalciferol was studied in rats. 1α-Hydroxycholecalciferol was found to be more potent and rapidly active than vitamin D in stimulating intestinal calcium transport and calcium mobilization from bone both in normal and vitamin D deficient rats. 1α-Hydroxycholecalciferol was also active in nephrectomized and/or thyroparathyroidectomized rats both in intestine and bone. Although it is well known that 1α-hydroxycholecalciferol is metabolized to lα, 25-dihydroxycholecalciferol in the liver, there is the possibility that the former is active without further metabolism. In rats in which hepatitis was induced by CCl₄, 1α-hydroxycholecalciferol was active both in the intestine and in the bone, while it was inactive in hepatectomized rats. These data clearly demonstrate that 1α-hydroxycholecalciferol is not active by itself and must be metabolized in the liver. This idea also shows the lag time in response of rats to 1α-hydroxycholecalciferol as compared with that of 1α, 25-dihydroxycholecalciferol. It was also demonstrated that 1α-hydroxycholecalciferol has more potent antirachitic activity than vitamin D and does not lose its activity with chronic oral administration. In view of these findings, 1α-hydroxycholecalciferol appears to have a good potential for clinical application in cases of renal failure and metabolic bone diseases.

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γ-Oryzanol has been reported to inhibit gastric secretion and experimental ulcers in rats. In this paper, the inhibitory effects of γ-oryzanol on gastric secretions caused by three stimulants have been compared. γ-Oryzanol was slightly effective for histamine-stimulated acid secretion, non effective for carbachol-stimulated secretion and significantly inhibited the tetragastrin-stimulated secretion. The effect of γ-oryzanol on acid secretion stimulated by tetragastrin was prevented by vagotomy but not by splanchnicotomy. It is assumed that the gastric antisecretory effect of γ-oryzanol is mediated by the vagus nerve which plays a role in the action of gastrin.

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Membrane stabilizing effects of cholesterol on the permeability of K⁺ and change in membrane potential induced with lysolecithin were investigated. Cholesterol inhibited K⁺ release from rabbit red blood cells treated lysolecithin. 3.3 × 10^-6M of cholesterol was the optimum concentration required to inhibit K⁺ release from rabbit red blood cells treated with lysolecithin (1.25 μg/ml) at the level of 100 percent. Change in membrane potential was evident with lysolecithin by the method of fluorescent dye and, cholesterol inhibited the change which was dose dependent. These inhibitory effects of cholesterol on the K⁺ release and changes in membrane potential served as the membrane stabilizing action on red blood cell membrane. It is assumed that cholesterol acts as an inhibitor to increase membrane fluidity and permeability of malignant transformed cells such as tumor and lymphoid cells.

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A single administration of ifenprodil at the doses of 100, 200 and 400 mg/kg (p.o.), and 50 and 100 mg/kg (i. m.) produced a moderate CNS depression in rats, such as, sedation, ptosis, systemic muscle relaxation and decrease in motor activity. These symptoms appeared dose-dependently and persisted for about 4 hours following administration. In a direct physical dependence test, 5 groups of rats were fed the ifenprodil-admixed food together with drinking water ad libitum for 24 hours daily for 53 ?? 103 days (mean ifenprodil intake, 43-240 mg/kg/day), on the gradedly increased dosage schedule with a dosage level of 0.5 vs. 1 mg/g food to 4 mg/g food. In the natural withdrawal following administration, no significant withdrawal signs were observed in any group. In a substitution test either for phenobarbital or morphine, no suppression of withdrawal signs during the period of cross-administration of ifenprodil and no maintenance of dependence were observed. In a physical dependence-producing test, the rats fed ifenprodil never manifested withdrawal signs such as diarrhea, “wet shakes”, sudden loss of body weight as in the levallorphan precipitation test. Ifenprodil apparently has no physical dependence liability.

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