2,2'-Dithiodibenzamides as inhibitors of blood platelet aggregation.
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Biomedical subjects
Publications and source records attributed to T Ono.
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The hypotensive effect of FR35447 was comparable to that of prazosin and was more potent than that of hydralazine, but its duration of action was shorter. Repeated administration of FR35447 or prazosin to hypertensive rats for 5 consecutive days induced no significant difference in the intensity or duration of the hypotensive effect. In contrast, marked tachyphylaxis to hydralazine or phentolamine was observed. FR35447 as well as prazosin induced only a transient increase in cardiac output in anesthetized dogs, whereas hydralazine induced a longlasting increase. This difference may contribute to no development of tolerance to FR35447 or prazosin. FR35447 decreased the pressor response to noradrenaline, but not that to angiotensin II or vasopressin in pithed rats, which indicates that FR35447 is an alpha-adrenoceptor antagonist. FR35447 has some selectivity for alpha 2-adrenoceptors, but the selectivity was far less than that of yohimbine. Since FR35447 induced only slight hypotension following intracerebroventricular injection in anesthetized cats, the hypotensive effect of the drug does not appear to be mediated through the central nervous system. Whereas prazosin induced a dose-dependent increase in blood glucose in rats, FR35447 showed no significant effect.
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The glycosidase activities in a rat liver microsome fraction were investigated in comparison with those in a submitochondrial fraction. The activities of beta-N-acetylglucosaminidase, beta-galactosidase and beta-glucosidase in the former were distinguished from those in the latter on the basis of solubilization pattern, pH optimum, thermal stability and elution pattern of concanavalin A-Sepharose chromatography. It is suggested that these activities are not due to the contamination of lysosomal enzymes but intrinsic to microsomes.
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For the purpose of characterizing the nature of the phorbol ester receptor on intact cells, the effects of acylglycerols and phospholipids, which are known as activators of protein kinase C, on the binding of 3H-phorbol dibutyrate to Friend erythroid leukemia cells (FLC) were examined. Even when intact cells were used, diolein inhibited the binding of phorbol ester, and the degrees of inhibition by several kinds of acylglycerols paralleled their abilities to activate protein kinase C. On the other hand, phosphatidylserine enhanced the binding. Among phospholipids tested, the order of activities for increasing the binding was almost the same as that for activating protein kinase C. These results provide support for the hypothesis that the phorbol ester receptor in intact cells is protein kinase C, and that the ability of intact cells to bind phorbol ester is affected by endogenous lipids.
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Antral ulcers develop spontaneously in (WB X C57BL/6)F1-W/Wv mice. Most W/Wv mice with severe ulcers die within 3 months after birth. When healthy-looking W/Wv mice were selected at 4 months of age, 80-90% of them were free from the ulcer. Even if the ulcer was present, it was small. The authors compared the susceptibility of such healthy-looking W/Wv mice to ulcerogenic treatments with that of the congenic +/+ mice. Stress caused development of fundic erosions in both W/Wv and +/+ mice. The susceptibility of the W/Wv mice to either cold or water-immersed stress was not higher than that of the +/+ mice. Topical administration of aspirin produced erosions in both fundus and antrum. The susceptibility of W/Wv mice to aspirin was comparable to that of the +/+ mice in either the starved or the fed condition. Subcutaneous injection of indomethacin produced both fundic erosions and antral ulcers in the starved condition, but it produced only antral ulcers in the conventionally fed condition. The susceptibility of the starved W/Wv mice to indomethacin was not higher than that of the starved +/+ mice. In contrast, the fed W/Wv mice were significantly more susceptible to indomethacin than the fed +/+ mice. A considerable proportion of the fed W/Wv mice died of blood loss from the ulcer within 24 hours. The size of the ulcer of the W/Wv mice was significantly larger than that of the +/+ mice. Both genetic and feeding conditions seem to determine the susceptibility to indomethacin.
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A neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces pathological changes similar to human idiopathic Parkinson's disease in animals, was injected in mice for biochemical and pharmacological studies. The dopamine concentration showed a marked decrease (-75%) in the striatum 1-2 weeks after the injection of MPTP (30 mg/kg i.p. twice a day for 5 days; a total dose, 300 mg/kg) but no changes or only slight decreases in other brain regions. The norepinephrine concentration also decreased to half the preadministration level in the striatum. These changes closely resembled those observed in the brain of parkinsonian patients. An examination for evaluating bradykinesia of MPTP-treated mice (pole test) devised by the author revealed that bradykinesia was alleviated dose-dependently by injection of L-DOPA. These results suggested that MPTP-treated mice are a useful experimental model for the study of parkinsonism, and that the pole test using these animals is of value in the screening of anti-parkinsonian agents.
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