Hideyo Shindo

Relationship between inhibition of pressor response to angiotensin I and blood concentration of captopril following a single oral administration to dogs

The time courses for the inhibition of the pressor response to AI and for the blood concentration of captopril and its metabolites were determined following a single oral administration of captopril at a dose of 0.8 or 2.5 mg/kg to normal dogs. Captopril was rapidly absorbed from the gastro-intestinal tract attaining a maximum blood concentration 1-1.5h after its administration. The inhibition of the pressor response to AI was closely related with the blood concentration of unchanged captopril but not of total captopril. The blood concentrations of captopril which produced 50 and 100% inhibition were estimated to be 0.1 and 0.4 millimicron/ml respectively. At 2.5 mh/kg the maximum blood concentration attained was 4 times higher than the concentration required to completely inhibit the pressor response to AI, suggesting that a fraction of the absorbed captopril was in excess of the therapeutic requirement.

Whole-body Autoradiography of Bumetanide-14C in Dogs by Round Saw Method

The distribution of a new potent diuretic, Bumetanide, in dogs was studied by means of a combined method of whole-body autoradiography and tissue radioassay, after oral administration of Bumetanide-14C to five young beagle dogs (ca. 1.2 kg). A round saw method developed by Kalberer was applied to obtain frozen slices of dog whole-body with a thickness of 3 mm. After exposure to X-ray films from both sides of the slices at -60 degrees C, frozen samples of the main tissues as well as the blood, urine, bile and intestinal contents were obtained to be assayed for radioactivity and to be analyzed for metabolites by TLC. The advantages of the round saw method (thick slices) in larger animals as dogs and monkeys as compared to the conventional microtome method (thin sections) were pointed out and discussed.

Transport of Organic Compounds through Biological Membranes. II. Red Cell Permeability to O-Acyl-S-benzoylthiamines

The cell permeability was compared for a series of O-acyl-S-benzoylthiamine in human red cell suspensions. On varying the length of straight chain alkyl group in the acyl part, it was found that i) at the earliest stage of the transport, the red cells showed a rapid and high uptake of the molecules due to the adsorption at the cell membranes, and ii) an equilibrium state was reached within 120 minutes of incubation and the intracellular concentration of total thiamine was in the following order : acetate valerate>caproate>capryrate, showing a maximum intracellular accumulation (the cell to medium concentration ratio of 2.9) with 4 carbon acyl group. In order to elucidate the mechanism, the followings were compared for the series of compounds : i) the partition coefficient from aqueous to organic phases, ii) the rate of debenzoylation in the cells and at the membrane site, and iii) the rate of conversion of the corresponding O-acylthiamine to thiamine in the cells and at the membrane site. The results indicated that the hydrolytic enzyme systems associated with the cell membrane (acetylcholinesterase) and the cytoplasm (carboxylesterase) play the most important role in determining the intracellular accumulation rather than the lipid solubility of the compound and that the butyrate with the highest rate of conversion to thiamine in the cells results in the highest intracellular accumulation.