Inhibitory effects on low Km cyclic AMP-phosphodiesterase (PDE) obtained from guinea-pig ileum and rat cardiac muscle were studied using papaverine (Pap) and its related moiety compounds which were classified into group I : isoquinoline derivatives, group II : 2-veratrylpyridine derivatives and group III : 1-veratryl-veratrylamine derivatives. 3, 4-Dimethyl-2-veratryl-pyridine (P-3, 4M) belonging to group II was more effective than 1-methyl-6, 7-dimethoxy-isoquinoline (IQ) belonging to group I, but not so as Pap. Compounds in group III were little effective inhibitors. Pap and P-3, 4M seemed to be a competitive type and IQ to be a non-competitive type of compound. In the steric configuration of Pap molecule, an aphorphine type compound was more effective than a berberine type compound. Barium chloride did not exert any antagonistic effect upon low Km cyclic AMP-PDE inhibited by Pap. Potentiation effects on dose-relaxation curve induced by cyclic AMP in guinea-pig taenia coli fell into the order of Pap>P-3, 4M>IQ, being parallel with the potency order of cyclic AMP-PDE inhibition.

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The significance of liver enlargement induced by various chemicals was studied. Biochemical changes of principal hepatic components and enzymes were compared under the short-term administratior, to male rats for 5 days that did not cause the retardation of growth of the treated animals. Polychlorinated biphenyls (PCB, administered dietary) was most potent in inducing liver enlargement, followed by 3-methylchlolanthrene (MC, i.p.), AF-2 (furylfuramide, dietary), phenobarbital (PB, i.p.), and di-2-ethylhexyl phthalate (DEHP, dietary). The biochemical parameters of the liver were affected in a different manner by these chemicals under the condition that caused the increase in the liver weight to the same level. The observed changes in the liver showed three patterns of response : drug-metabolisminducer type, AF-2 type and DEHP type. The differences of these three types were mainly observed in respect to the drug-metabolizing enzyme activity, glycogen and lipid contents and the appearance of hyperplasia or hypertrophy. The significance of these types of response is discussed in relation to toxicity, dysfunction, and adaptation of the liver.

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Gastrointestinal absorption characteristics of drugs in lipid-containing oral dosage forms were studied in rats. A new antiinflammatory agent 1-cyclopropyl-4-phenyl-6-chlor-2 (1H)-quinazolinone (SL-512) was selected as a model of hardly water soluble drugs. Medium chain triglyceride (MCT), medium chain monoglyceride (MCM), and corn oil were used as models of well-digestible lipids, and N-α-methylbenzyllinoleamide (MBLA) for that of hardlydigestible ones. Absorption of orally dosed SL-512 strongly depended on the dose volume of lipid vehicles. Larger volume of lipids (≤100 mcl/rat) delayed absorption of SL-512 due to larger remaining of SL-512 both in the stomach and in the intestine. The gastric retension was also affected by the fluidity of lipids employed. In smaller volume of lipids (5-20 mcl/rat), which has not been examined in previous papers in spite of its compatibility to human clinical dose volume, the amount of intestinal remaining was much less than that of gastric remaining of the preparation. In experiments designed to minimize intestinal remaining of SL-512, serum level of the drug calculated by using gastric emptying rate instead of absorption rate was found to be in good accordance with that of experimental value.

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Reaction of S-benzylthioisothiouronium hydrochloride with 6-mercaptopurine (1), 9-β-D-ribofuranosyl-6-mercaptopurine (2), 6-thioguanine (3) and 9-β-D-ribofuranosyl-6-thioguanine (4) afforded corresponding benzyl disulfide derivatives (5-8) in good yield. These compounds were converted easily to parent mercapto derivatives when they were treated with various reducing agents such as β-mercaptoethanol. Antitumor activity of compound 5 was higher than that of 1 both in ascites Sarcoma 180 and in Nakahara-Fukuoka sarcoma systems. However, toxicity and immunosuppressive activity of compound 5 and 6 were higher than those of 1 and 2, respectively.

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We studied gastric mucosal susceptibility (GMS) to erosive action of acid in stressed rats in response to surgical or pharmacological treatments. The optimal experimental conditions, which were less severe for animals but sensitive for detecting change in GMS to erosive action of acid, were determined ; after 60 min of restraint and water (25°) immersion stress, the pylorus was ligated, a test solution of isotonic saline or hydrogen ion of 50 meq/l was instilled into the stomach at a volume of 3 ml, and gastric lesions were examined after 60 min of exposure to the test solution. Change in GMS was estimated as a difference in erosion severity between saline- and acid-instilled groups. Acid instillation caused a significant increase in formation of gastric erosions only when rats were exposed to stress. Vagotomy, methylatropine (10 mg/kg, s.c.), chlorpromazine (10 mg/kg, s.c.), and aluminum hydroxide (2.0 g/kg, p.o.) which were performed or administered before stress inhibited a formation of gastric erosions in the saline-instilled group as compared with their own control treatment, but only vagotomy and methylatropine markedly protected the stressed rat against an increase in GMS to erosive action of acid. Adrenalectomy performed before stress rather intensified the severity of gastric erosions in the saline-instilled group but moderately inhibited an increase in GMS. The present results demonstrated an increase in GMS to erosive action of acid in stressed rats and strongly suggested that this change may be mediated chiefly by vagal activity although involvement of sympatho-adrenal activity was not ruled out. The role of acid in forming gastric erosions during stress was also discussed.

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In order to investigate the mode of contraction of smooth muscle cells in taenia coli of guinea-pig, single cells were isolated and contraction of the cells by acetylcholine and carbachol was examined. To isolate the single cells, enzymatic digestion of the tissue with collagenase and elastase was useful to preserve responsiveness to the cholinergic agents. When the single cells were exposed to acetylcholine, phasic contraction followed by tonic contraction occurred and the phasic contraction completed within 1 sec at 35°. Degree of contraction of the single cells was dependent on concentration of acetylcholine. The results suggested that contraction of individual cells in the tissue might reflect the contraction of the whole tissue directly. However, not all of the single cells is responsive to acetylcholine. Examination with a piece of enzymically digested mince resulted occasionally that contraction by acetylcholine did not occur in all the cells of the mince synchronously but contraction propagated gradually to the other cells. This result suggested that some cells in the tissue were originally not responsive to the cholinergic agents but there were contracted by stimuli propagated from the other cells.

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Metabolism of 3'-methyl-4-(dimethylamino) azobenzene (3'-Me-DAB) in the rat was examined by the ion cluster technique, using a mixture of non-labeled 3'-Me-DAB and its deuterated compound. Labeled 3'-Me-DAB in cotton seed oil was administered orally by a stomach tube. The bile collected during 24 hr was enzymically hydrolyzed. This sample was applied to an Amberlite XAD-2 column and the column was washed with water. The metabolites were eluted with methanol. The doublets of molecular ion in the mass spectra originating in the mixture of non-labeled and labeled dye were respectively recognized in the fractions separated by thin-layer chromatography. Twenty-four metabolites were identified for 3'-Me-DAB by this technique and the new metabolic pathway of the aminoazo dye at the site of ring methyl group was established. Effect of the ring methyl group on the carcinogenic action of aminoazo dyes is discussed.

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