| Co-Investigator(Kenkyū-buntansha) |
SAWADA Yasufumi Faculty of Pharmaceutical Science University of Tokyo, 薬学部, 助手 (80114502)
SUGIYAMA Yuichi Faculty of Pharmaceutical Science University of Tokyo, 薬学部, 助教授 (80090471)
IGA Tatsuji Department of Pharmacy University of Tokyo Hospital Faculty of Medicine Universi, 医学部, 助教授 (60012663)
FUKUDA Hideomi Faculty of Pharmaceutical Science University of Tokyo, 薬学部, 教授 (50080172)
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| Research Abstract |
1) At the molecular level, cardiac glycosides inhibit Na^+,K^+-ATPase, a membrane bound enzyme associated with the sodium pump. Since the sodium pump is necessary for maintenance of normal resting potential in most excitable cells, it is generally believed that at least a portion of the toxicity of digitals is caused by this enzyme-inhibiting action. It has been controversial whether this pump inhibition is the cause of positive inotropic action (PIA) of cardiac glycosides or just a parallel phenomenon. We then performed the kinetic analysis of the appearance process of PIA of ouabain in the rabbits by changing infusion rate. We also examined the specific binding of ouabain to Na^+,K^+-ATPase in the cardiac tissue homogenate, using rapid filtration method. In in vivo experiments, we measured the plasma concentration (Cp) and PIA of ouabain simultaneously, using 3H-ouabain and dp/dt, max as an index of PIA. Remarkable infusion rate dependency was found in th relationship between Cp and
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PIA. In addition the appearance process of PIA was kinetically the same as that of ouabain transfer from plasma compartment to peripheral compartment. This process could not be explained by the assumption that PIA is related to the single receptor and its occupation process is the rate limiting step of the appearance of PIA. It was made clear from in vitro binding experiments that the binding of ouabain to cardiac Na^+,K^+-ATPase is slow and classified into two types (high and low affinity). Then it is suggested that infusion rate rate dependet relationship between Cp and PIA may be explained by the model based on the two-receptors.
2) Local cerebral glucose (G) utilization was measured, using the double-label glucose analogue method, based on the brain disposition of 3H-3-0-methyl-glucose (M) and 14C-2-deoxy-glucose (D) in the brain region of awake mouse, at 1 hr after i.v. administration of clonazepam (0.01-1.0 mg/kg). After bolus i.v. injection of two compounds (M,D), time activity data of tracers in plasma (C^M,C^D) and regional brain were obtained. For cortex, the apparent volume of distribution (V^D for D, V^M for M), at 10 min after i.v. administration of D and M, were 0.64 0.07 (ml/g brain) and 0.33 0.03 (ml/g brain), respectively. The phosphorylation clearance (CL^D=(V^D-V^M)/theta) significangly decreased (30%) in the presence of clonazepam, whereas the lumped constant (LC;LC=LC , isotope-effect) did not change. The glucose metabolic rate (rCMRglc=CL^DXC^G/LC), in the presence of clonazepam, decreased (15%) in the regional brain. Thus, it should be possible to clearly visualize the sedative effects of benzodiazepine on regional brain function in vivo, using the double-label glucose analogue method. Less
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