Tissues responses for durgs are often altered by chronic administration of drugs and this alteration is one kind of functional abnormality of the tissues. One mechanism under this functional abnormalities is considered to be in changes in receptors for drugs. In this study, we examined amounts and properties of receptors in sub- and supersensitive states caused by pre-exposure of tissues to drugs and the results obtained were summarized as follows. I. Long term exposure of tissue to agonists or to conditions which elevate concentration of agonist around the receptor caused reduction in amount of receptor without change in its property. II. Short term exposure to agonists altered the configuration of the receptor accompanying reduction in sensitivity of the tissue to drugs. But amount of receptor in the tissue was not changed. III. Heterologous desensitization was observed in some cases by exposure to durgs and no significant change was observed in the receptor of the tissue, qualitatively and quantitatively, indicating dysfunction in the process (es) after activation of the receptor. IV. Denervation and chronic treatments with antagonist and ganglion blocker caused supersensitive state accompanying increase in amount of receptor. But in some cases, qualitative change of receptor, increase in affinity of receptor for agonist, seemed to relate with supersensitive state of tissues.
Methylazoxymethanol (MAM) injection to pregnant rats on day 15 of gestation caused a significant rise in monoamine concentrations accompanying a decrease in the brain weight and DNA content in the cerebral hemispheres of the offspring at 3 months of age ; in the brain stem, these changes were much smaller. Similar change of monoamine concentrations was observed in cytosine arabinoside (ara-C)-induced microencephaly. The decrease of DNA content and elevation of monoamine levels were lower with MAM-injection on day 15, 13 or 17 of gestation (in that order). Serotonin content of the MAM-treated cerebral hemispheres was already 50% higher than the control immediately after birth. The activity of tryptophan hydroxylase in the MAM-treated cerebrum was 1.6 times the control value, with no change in the brain stem, while the concentration of tryptophan in the brain and plasma was equal to the control value. That the remaining neurons, axons, and oligodendroglia were intact was suggested by the normal activity of 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) [EC 220.127.116.11] and levels of brain specific proteins. When neonatal rats were injected with ara-C, a decrease of DNA content per cerebellum and an elevation of monoamine concentrations in the cerebellum were found. The neonatal administration of ara-C caused an elevation of CNPase activity and myelin protein content in the cerebellum, suggesting a relative increase in myelin concentration as a result of hypoplasia of granule cells.
The purpose of this paper is to present experimental data illustrating the importance of a toxicopathological basis necessary for understanding the role of nutrition on drug toxicity. Nutritional status constitutes an important factor capable of modulating the results of animal experiments in toxicology. Therefore, it is necessary in any toxicity testing to consider the effects of nutrition on drug toxicity and, at the same time, the effect of drug toxicity on the nutritional state of animals.
The present experiment was undertaken to study the relationship between hemodynamic changes and intracranial hemorrhage induced by intraperitoneal injection of large doses of hypertonic glucose solution in rats. A fifty per cent glucose solution was intraperitoneally injected at a volume of 3.5 ml/100 g b. w. into Wistar rats anesthetized with urethanechloralose. The time span from the start of injection to death was expressed in terms of 100% corrected death time (100% DT) for each rat. Saline that was added to the cerebrospinal fluid in the brain ventricle disappeared gradually from 30% DT up to death. Blood colloid osmotic pressure was slightly elevated temporally 5 minutes (7% DT) after intraperitoneal injection of the glucose solution and returned to the former level 5 minutes later. With regard to hemodynamic changes, a decrease in blood pressure and heart rate began to occur between 5-10% DT. Thereafter, blood pressure and heart rate decreased significantly as compared with the pretreatment period, and the plasma levels of both epinephrine and norepinephrine showed sharply increasing curves as time elapsed after the intraperitoneal injection of the hypertonic glucose solution. It was suggested that the decrease in cerebrospinal fluid and the fall in blood pressure were related to the movement of water from the brain and the flow of body fluid into the hypertonic blood plasma which caused an enlargement of the ventricles due to brain reduction and a change in circulating blood volume. However, guestions still remain concerning the mechanisms of the marked increase in plasma catecholamines and bleedings which occurred only in the subarachnoideal space and ventricles.
The possible protective effect of cysteine on chemical-induced liver injury was studied in rats in vivo and in vitro. There was no increase in the activity of serum glutamic oxaloacetic transaminase (GOT) of rats pretreated with cysteine (1.2 g/kg, p, o.) followed by 0.25 ml/kg carbon tetra-chloride (CCl4), d-galactosamine (GalN) or α-naphthylisothiocyanate (ANIT). However, rats pretreated with cysteine followed by 0.5 ml/kg CCl4 were not protected. The content of cytochrome P-450, activity of aminopyrine N-demethylase or serum ratio of 5, 5-dimethyl-2, 4-oxazolidinedione (DMO) to trimethadione (TMO) (DMO/TMO ratio) after CCl4, GalN or ANIT were not altered by pretreatment with cysteine. However, pretreatment with cysteine prevented changes in the content of cytochrome P-450, activity of aminopyrine N-demethylase and DMO/TMO ratio in serum as well as the activities of serum GOT and GPT when the rats were treated with bromobenzene (BZ). The degree of lipid peroxidation from CCl4 was markedly reduced by the presence of 10-4M cysteine. These results suggest that cysteine has a protective effect on chemical-induced liver injury produced via epoxies metabolites.
An active glucoside that enhanced release of histamine from rat peritoneal mast cells was isolated from a toxic fraction of bracken fern, Pteridium aquilinum, by partition column chromatography on Sephadex G-25. It was a yellowish amorphous powder on freeze-drying, readily soluble in water or ethanol, and insoluble in ether. It was hydrolysed with β-glucosidase to release D-glucose. It was assumed to be a kind of β-glucopyranoside with a carbocyclic structure in the aglycone moiety.
Flive kinds of plastics (3 polyvinyl chlorides, 1 polyhydroxyethyl metacrylate and 1 dimethyl polysiloxane) were implanted into subcutaneous tissues of Wistar rats of both sexes. Subcutaneous tumors developed in all experimental groups. The incidences of the tumors, however, differed from each other, although these materials were tested on the same experimental condition. This result indicates that chemical characters of the materials may influence the incidence of subcutaneous tumors. Histologically, most of these subcutaneous tumors were mesenchymal tumors with spindle cells arranged in a storiform pattern, with sheets of histiocyte-like cells or pleomorphic giant cells. Electron microscopy showed mixture of fibroblastic cells, histiocytic cells and undifferentiated cells in these tumors. From these histological and electron microscopical findings, many of the tumors were diagnosed as malignant fibrous histiocytomas.