The present study was designed to elucidate influences of hypothermia on gastric secretory response to secretagogues (bethanechol, histamine and tetragastrin) in rats exposed to restraint plus water immersion (36 and 25°C) stress. In vagotomized rats provided with a pH microelectrode, decrease in intragastric pH by bethanechol (75 μg/kg, i.p.)was markedly produced under the water-immersion at 25°C and the extent of the pH decrease was significantly greater than that observed under the water-immersion at 36°C. However, intragastric pH decrease by histamine (1 mg/kg, i.v.) or tetragastrin (60 μg/kg/20 min, i.v) was not affected by varying water temperatures. Using a technique of pyloric ligation, gastric acid and pepsin responses to bethanechol were measured at doses of 50-100 μg/kg in vagotomized rats and also at doses of 0.5-1.0mg/kg in vagally intact rats. Stimulation of acid and pepsin secretion by bethanechol was provoked only under the water-immersion at 25°C. As compared with the values obtained under the water-immersion at 36°C, a significant augmentation of bethanechol-stimulated secretion was seen for acid and pepsin output in vagotomized rats and seen for acid output in vagally intact rats under the water-immersion at 25°C. These results suggest that hypothermia may operate some mechanism for increasing the secretory responsiveness of the stomach to cholinomimetics.

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To clarify the mechanism of enhanced absorption of indomethacin (IND) when dosed with magnesium silicate, reported previously, magnesium (IND-Mg) and calcium (IND-Ca) salts of IND were prepared, and the bioavailability in rat and physical properties of these salts were studied in comparison with IND. The mean plasma levels after a single oral dosing of IND-Ca and IND-Mg were significantly higher than those after IND (6mg/kg). The absolute bioavailability calculated was 63.7% for IND, 83.2% for IND-Mg and 96.8% for IND-Ca. The area (AUC) under the plasma concentration curve after multiple oral dosing of IND-Ca and IND-Mg was also significantly larger than that after IND multiple dosing (p<0.001). Thus, the increased absorption of the salts made it possible to decrease their dosage. The mean plasma levels and the AUC after multiple dosing of the salts in the decreased doses (4.16 mg/kg for IND-Ca and 4.74 mg/kg for IND-Mg) were significantly high as compared with those in IND dose (6 mg/kg) group (p<0.05). In IND-salt multiple dose groups, the drug-metabolizing enzyme activities were only slightly decreased as compared with the control, while activities in IND dose group were substantially decreased. There was no significant change in the plasma protein binding between the IND- and the salt-treated rats. The partition coefficient (n-octanol-water) for IND-Ca and IND-Mg was higher than that of IND. The rank order of solubility in 2% taurocholate solution was IND-Mg>IND>IND-Ca, and the solubility of IND-Mg was 3 times higher than that of IND-Ca. Therefore, the mechanism of increased absorption of these salts was probably ascribed to the enhanced lipid solubility and increased solubility in bile and intestine juice.

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A novel organogermanium compound, Ge-132, carboxyethylgermanium sesquioxide, showed enhancement of 0.5 mg/kg morphine analgesia in both administration routes of oral administration (p.o.) and intraperitoneal injection (i.p.) in the Tail-Flick test, and the effect was completely abolished by 0.5 mg/kg Naloxone, stereospecific opiate antagonist. Ge-132 alone, 250 mg/kg i.p., did not show any antinociceptive action by assessing the Tail-Flick test and the Hot-Plate test. By the intracerebral injection of Ge-132, 100-1000 μg, prolongation of Tail-Flick latency was observed and the action was abolished by 50 μg CaCl₂ injection. Although bestatin which is reported to enhance the morphine analgesia inhibits enkephalinase and enkephalin aminopeptidase, Ge-132 did not show any inhibition on both enkephalin degrading enzymes. The possibility for the mode of action of Ge-132 was discussed

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The effect of phenobarbital (PB) and 3-methylcholanthrene (3-MC) on the metabolic behavior of aminopyrine (AM) was studied using an isolated hepatocyte system prepared from male Wistar rats. The formation of 4-formylaminoantipyrine (FAA) was increased after pretreatment with PB, but not 3-MC. However, the total amounts of AM and its main metabolites recovered from hepatocyte system after the incubation for 30 min were considerably reduced both by PB and 3-MC-pretreatment. Furthermore, when using 4- monomethylaminoantipyrine (MAA), the first metabolite of AM, as a substrate, 3-MC-pretreatment resulted in a more significant decrease in the total amounts of MAA and its further metabolites recovered than did PB. Present observation suggests the participation of cytochrome P-448 as well as cytochrome P-450 in the metabolism of AM.

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The effect of chlorpromazine (CPZ) on the intestinal absorption of sulfamethoxazole (SMZ) was studied in isolated perfused rat small intestine by comparing two determinants, i.e. the epithelial permeability and the intestinal blood flow. The appearance rate of SMZ in blood in the presence of CPZ decreased to one-half of the control without CPZ. The pH of perfusion solution was significantly decreased by CPZ after 10 min perfusion. According to the Winne's absorption model, CPZ did not change the apparent epithelial permeability of SMZ, but decreased the epithelial permeability of unionized SMZ due to the decrease in the pH of perfusion solution by CPZ. It was also suggested that CPZ decreased the fraction of the total blood flow rate in the subepithelial capillaries to less than one-half.

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After a dose of 800 μg of hydroxyurea (HU) was administered to day-4 chick embryos in ovo, the limb deformity including micromelia was observed. We examined the teratogenic mechanism of the action for HU by using histochemical and biochemical techniques. The present study provides histological evidence for the cell death and the depression of cell proliferation just after the treatment with HU and the retardation in periosteal ossification during the of repair and/or recovery from cell death. On the other hand, the incorporation of [³H]glucosamine and [³⁵S]sulfate into glycosaminoglycan was inhibited at day-7 and day-9, when the embryos are in the process of repair and/or recovery The cartilage specific proteglycan, an index of chondrogenesis, appeared at day-7, but the ratio of cartilagenous proteoglycan/noncartilagenous proteoglycan in the treated limbs was depressed. These results suggest that the slight retardation in chondrogenesis and/or the incomplete function of chondrocyte were induced by the treatment with HU in chick embryos. It is considered from above observation that the retardation in chondrogenesis and osteogenesis caused during the repair and/or recovery process of cell death brought about the limb deformity; shortening, thinning and bending of hind limbs.

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The present study was carried out to investigate the effects of vitamin E-deficiency and supplementation of α-tocopheryl acetate (TOCA) on renin release from renin granules. Male Wistar rats were fed either a control or a vitamin E-deficient diet for 4 weeks. Subsequently, the vitamin E-deficient rats received dietary supplementation of TOCA (40mg/100g diet) for 5 d. The renin granule fraction was prepared from the kidney cortex homogenate by a discontinuous sucrose density gradient centrifugation. The intake of vitamin E-deficient diet for 4 weeks resulted in an increased level of endogenous lipid peroxides in the renin granule fraction, accompanied by a marked decrease in α-tocopherol content, and led to a significant increase in the rate of renin release form the granules during incubation at 37°C. These changes in α-tocopherol content, lipid peroxide level and renin release in the renin granule fraction were restored to the control values by dietary TOCA supplementation. Similarly, dietary supplementation of N, N'-diphenyl-p-phenylenediamine (80 mg/100 g diet), which has an antioxidative ability, suppressed the increases in lipid peroxidation and renin release due to vitamin E-deficiency, although this compound was ineffective in restoring α-tocopherol levels. These results suggest that vitamin E functions in maintenance of membrane integrity of renin granules by inhibiting the lipid peroxidation.

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The p-nitrophenol (PNP) sulfate conjugation rate in rat liver cytosol at pH 7.4 under 10-30 μM 3'-phosphoadenosine-5'-phosphosulfate (PAPS) was decreased at 10-200 μM PNP and increased again at more than 200 μM PNP. The higher the PAPS concentration, the more remarkable such substrate inhibition. These results indicate that the substrate inhibition was due to the direct interaction of PNP with the aryl sulfotransferase (phenol sulfotransferase, PST), The PST reaction was thermolabile at less than 20 μM PNP but thermostable at more than 200 μM PNP. The K_m values for PAPS obtained in the PST reactions where the inhibition was not observed was about 23 μM at 2.5-5 μH PNP and 11-14 μM at more than 200 μM PNP. And the K_m values for PNP at more than 500 μM PNP was 2.2 -2.6 mM. On the other hand, the inhibition in the PST reaction at pH 5.6 was observed at much higher PNP concentration, approximately 200 μM, than that at pH 7.4. Based on these characteristic results, the correspondence of the PST catalyzing the PNP sulfate conjugation (pH 7.4) at the low and high concentrations of PNP in the liver cytosol with the multiplicity obtained in the purified preparation of the liver previously reported by another researchers was compared and discussed. Finaly the selection of an endogeneous substrate for estimating such complexed sulfate conjugation in advance in each individual man was also proposed.

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Not only cytochrome P-450 and cytochrome P-450 reductase, but considerable amount of cytochrome b₅ and cytochrome b₅ reductase were also contained in the adrenal microsomes of guinea pig. Addition of nicotineamide adenine dinucleotide (NADH) stimulates the activities of cytochrome P-450 monooxygenases such as 21-hydroxylase, 17α-hydroxylase and C_{17, 20} lyase supported with nicotineamide adenine dinucleotide phosphate (NADPH) as a cofactor. In addition, substrate for Δ⁵-3β-hydroxysteroid dehydrogenase plus NAD⁺ also stimulate the same cytochrome P-450 monooxygenase activities. These observations were suggesting the participation of cytochrome b₅ electron transport system on cytochrome P-450, monooxygenase (21 -hydroxylase, 17 α-hydroxylase and C_{17, 20} lyase) reactions associated with the biosynthesis of corticoids and adrenal androgens. Furthermore, it is also suggesting that cytochrome b₅ electron transport system involves the reaction of Δ⁵-3β-hydroxysteroid dehydrogenase.

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Platelet activating factor (PAF) showed profound and long-lasting hypotensive effects in normotensive and spontaneously hypertensive rats, guinea pigs, rabbits and dogs. Sensitivity to PAF was different among the animal species. The magnitude and duration of the hypotensive effect was dose-dependent. Pharmacological studies suggested that the hypotensive action was unlikely to be caused by the actions on the central or autonomic nervous systems but seemed to be mainly due to some direct action(s) on the peripheral blood vessels.

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The antagonistic effect of 2, 4'-dimethyl-3-piperidino propiophenone hydrochloride (Mydocalm) and its 15 derivatives against the activity of slow reacing substance of anaphylaxis (SRS-A) were examined in vitro. Mydocalm, 2-methyl-3-piperidino-β-propionaphtone hydrochloride (As-5) and 2, 3', 4'-trimethyl-3 piperidinopropiophenone hydrochloride (As-14) were found to be potent antagonists to SRS-A. The above three compounds inhibited homologous passive cutaneous anaphylaxis (PCA) in rats and guinea pigs but not heterologous PCA in guinea pigs. As-5 inhibited the release of histamine from and the degranulation of rat mesenterium mast cells. As-14 also showed the inhibition of the degranulation. Mydocalm, however, showed no inhibition of these reactions. Experimental asthma in guinea pigs which were passively sensitized with guinea pig immunoglobulin E antibody was significantly inhibited by p.o. adminstration of Mydocalm, As-5 or As-14 respectively.

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Plasma concentrations of clioquinol and its metabolites after single or repeated oral administration of clioquinol, absorption region of clioquinol in gastrointestinal tract, and intestinal metabolism were studied in rats. Plasma concentrations of clioquinol after oral administration of four different doses (20, 100, 200 and 400 mg/kg) were lower than those of the two metabolites, clioquinol glucuronide and sulfate. Mean maximal plasma concentration of unchanged drug was in the range of 1-8 nmol/ml. Clioquinol was absorbed poorly from the stomach and fairly from the small intestine. Bile was an important route for excretion of clioquinol in rats. The mesenteric venous plasma from the closed intestinal loops of both jejunal and ileac regions was analyzed for clioquinol and the metabolites and it was found that clioquinol glucuronide was formed predominantly in both regions. From the results of the present studies, intestinal metabolism of clioquinol can be pointed out as a major factor for difficulty to cause clioquinol intoxication.

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Brush border membrane vesicles of rat small intestinal mucosa were prepared by the modified calcium precipitation method in order to investigate the intestinal secretion mechanism of p-acetamidobenzoic acid (Ac-PABA). The release rate of [¹⁴C]-Ac-PABA from preloaded vesicles was much faster than that of p-aminobenzoic acid (PABA) and was enhanced by the addition of unlabelled Ac-PABA in the outer medium. In contrast, the membrane transfer rate of Ac-PABA across the egg lecithin liposomes was slower than that of PABA. The contribution of a carrier-mediated transport mechanism in the brush border membrane to the intestinal secretion of Ac-PABA was suggested.

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Effect of vitamin E-deficiency on renin release was examined with rat kidney cortical slices. Male Wistar rats were fed either a control or a vitamin E-deficient diet for 4 weeks. When kidney cortical slices were incubated in a Krebs-Ringers' bicarbonate solution (pH7.4) at 37°C, the rate of renin release into the incubation medium in vitamin E-deficient group was significantly higher than that in the control group. However, dietary supplementation of α-tocophery1 acetate (TOCA) or N, N'-diphenyl- p-phenylenediamine (DPPD) to the vitamin E-deficient rats for 5 d suppressed the stimulation of renin release from kidney cortical slices by vitamin E-deficiency. On the other hand, the release of protein, acid phosphatase and alkaline phosphatase during incubation of kidney cortical slices was not affected by vitamin E-deficiency or supplementations of TOCA and DPPD. These findings indicate that vitamin E-deficiency specifically stimulates renin release from kidney cortical slices and this effect is attenuated by the dietary supplementation of TOCA or DPPD.

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