Spinal reflex and neuromuscular functions were investigated in the beagles ingesting clioquinol over a long period. The twitch tension, the refractory period, the summation of contraction and the discharge of the muscle spindles of the gastrocnemius muscle were not significantly damaged in the treated beagles, whereas the response with long latency of the spinal reflex disappeared completely during the administration not in the control but in the treated dogs. The meanings of disappearance of the spinal reflex in the treated dogs are discussed in relation to the degenerative change in the fasciculus gracilis at the cervical level of the spinal cord.
Effects of NKK-105 against lipid peroxidation of microsomes by CCl4 are investigated, in vitro. NKK-105 had no effect on microsomal lipid peroxidation. When the microsomal fraction was preincubated with NKK-105 before adding CCl4, the lipid peroxidation induced with CCl4 was almost prevented by NKK-105. Effects of NKK-105 administration on aminopyrine N-demethylase, cyt.b5, cyt.p-45O and lipid peroxidation in CCl4-induced liver damage were investigated, in vivo. NKK-105 had no effect on the activity of aminopyrine N-demethylase and the content of cyt.b5, cyt.p-450 and peroxide. The content of cyt.b5, cyt.p-450 and the activity of demethylase remarkably decreased with CCl4 administration, but the content of cyt. p-450 and the demethylase activity were restored about 75% of the control values and cyt.b5 content was completely restored with previous administration of NKK-105. The amount of peroxide in the microsomal fraction increased with CCl4 administration was restored to the control level with previous administration of NKK-105.
Visual system was examined in 3 beagles given clioquinol for a long period and in 2 control beagles. Ophthalmoscopic examination revealed the decreased diameter of the optic disks of the treated dogs except for one dog. There were degenerative changes of the optic nerves in all of the treated dogs. The changes included disruption of the axons and the myelin sheaths. It was difficult to observe the morphological change of the retinae of the treated dogs. The findings demonstrate that the changes in the visual system after clioquinol administration are severe in the optic nerves rather than in the retinae.
The present study was undertaken to elucidate the potentiation by furosemide of toxicity and positive inotropic effect of ouabain in guinea pigs. Arrhythmogenic responses to ouabain as well as the lowering of its lethal dose were potentiated by pretreatment with furosemide in guinea pigs. The potentiation of ouabain toxicity after furosemide administration was inhibited by pretreatment with potassium sparing diuretic, prorenoate. Furosemide-induced potentiations of contractile force and arrhythmogenic effect of ouabain were also observed in isolated guinea pig papillary muscle. However after pretreatment with furosemide, ouabain produced arrhythmias without any significant changes in either left ventricular or subcellular fractions binding of 3H-ouabain in guinea pigs. These findings suggest that furosemide-induced potentiation of ouabain toxicity is at least in part associated with the decreased intracellular potassium content of guinea pig heart. It was also demonstrated that the positive inotropic action induced by subtoxic dose of ouabain was potentiated by furosemide in guinea pig papillary muscle preparation.
The effects of fenitrothion and methylparathion on the activities of cholinesterase and hepatic microsomal monooxygenases were investigated and Compared following a single or repeated oral administration of an equimolar and low dose of the insecticides. The activities of cholinesterase in brain and plasma were inhibited equally by the repetitive administration of both insecticides. Aminopyrine N-demethylase activity and cyt. P-450 content were not affected under the same experimental conditions. However, methylparathion, when given repeatedly, inhibited the dearylation and desulfuration of its own. The results may indicate that low dose continuous exposure to methylparathion could cause the depression of its own metabolism in rat.
To observe the chronic toxicity of Sumithion (o, o-dimethyl, o-(3-methyl-4-nitrophenyl) phosphorothionate), 8 groups of male and female rats were fed for one year with control food and food containing 1, 5 and 25 ppm of the compound. Acute toxicity was also done. We obtained the following results ; 1. Oral and intraperitoneal <50> of male rats were 250 and 500 mg/kg and those of female rats were 310 and 500 mg/kg respectively. All rats showed neurotropic symptoms according to dose. 2. There was no significant difference in body weights, food and water intakes for one year experiment at those dose levels. Some pneumonitis was observed by histological findings in experimental groups at the end of the experiment. 4. Acetylcholinesterase activity of brain, liver and red blood cells were slightly decreased in the first month after feeding, but it recovered and kept normal level until the end of experiment.
A possible mechanism for the pressor effect of cadmium was investigated in isolated rat thoracic aorta. Cadmium produced contractions at low concentrations, but relaxations at high concentrations. Phentolamine, a sympathetic alpha blocking agent did not inhibit the cadmium-induced contractions. These contractions were reduced in accordance with the decrease in Ca content in medium and were abolished in Ca-free medium, rather inducing a small degree of relaxation. When low concentrations of cadmium were applied repeatedly for a short period of time, the contractions were remarkably reduced and finally abolished. Noradrenaline-induced contractions were not affected after the completion of cadmium-tachyphylaxis. Low concentrations of cadmium potentiated K-, Ba- and noradrenaline-induced contractions, while high concentrations suppressed them. These results suggest that cadmium-induced contractions are dependent on external Ca and that they are produced by direct stimulation on the cell membrane. In addition, low concentrations of cadmium accelerate Ca availability, while high concentrations inhibit it.
The effects of microsomal enzyme inhibitors (7, 8-BF and SKF 525-A) on the S-9-mediated mutagenicity of o-, m- and p-phenylenediamine were investigated using Salmottella typhimurium TA98. SKF 525-A did not affect the enzyme-mediated mutagenicity of m- and p-phenylenediamine, while 7, 8-BF reduced significantly the mutagenicity of all three isomers of pheny-enediamine. When the enzyme reactions in the agar overlayer were stopped successively by adding 7, 8-BF directly onto the plate, the number of revertants increased linearly with time at least for 6 hours. These data suggest that cytochrome P-448 takes a main role in the activation of phenylenediamines and that in the agar layer this microsomal enzyme remain active for a period as long as 6 hours at 37°C.
10 mg/kg of etretinate was administered orally for 4 weeks to a Sprague-Dawley rat (male, approx. 140 g in weight) and its toxity was checked at 2 and 4 weeks after the start of administration. Recovery was checked 2 and 4 weeks after end of administration. Three weeks after administration of etretinate, a decline in the increase of body weight and a decline in movement due to abnormality in the lower half of the body was seen. Two weeks after administration, the thigh bone was observed to thin and to have fragility; 4 weeks after administration the changes in the thigh bone became more eminent and the forearm was seen to thin 4 weeks after administration of etretinate, the hematological test showed an increase of leukocytes and the biochemical test showed an increase of triglycerides and phospholipides. The calcium in the thigh bone showed a notable decrease 2 and 4 weeks after administration. The decline in the increase of body weight; the increase of leukocytes, triglycerides and phospholipids; and the decrease of calcium in the thigh bone recovered to normal 2 weeks after the end of administration. Blood retinol decreased and a decrease in retinyl palmitate and retinol in the liver was induced by the administration of etretinate. the toxicity of etretinate was seen to be comparatively lower than that of retinoid. A more detailed study is thought to be needed concerning the changes in bone.