Biomedical subjects
Publications and source records attributed to N Terao.
In vitro activities of Ca2+-ATPase and 45Ca2+ uptake in microsomes, which were prepared from vitamin D-deficient rat parotid glands, were decreased in parallel by the oral administration of vitamin D3 as compared with those of control animals (r = 0.83). In vivo 45Ca2+ uptake in the parotid glands of vitamin D-deficient rats was also decreased by the oral administration of vitamin D3.
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The effect of uranyl nitrate-induced renal failure on the pharmacokinetics of the levo-isomer of propranolol in rats was investigated. The serum clearance of an i.v. dose of propranolol (1.5 mg/kg) in normal animals approached hepatic blood flow, suggesting that the systemic clearance of the drug is rate-limited by blood flow to the liver. Extensive first-pass metabolism was observed after oral administration of l-propranolol was only 7%. Renal failure had no apparent effect on the distribution and elimination of i.v. administered l-propranolol. In contrast, the area under the serum drug concentration time curve after oral administration was increased from 6.95 to 19.3 micrograms X min/ml, which corresponded to a 2.5-fold increase in the systemic availability of l-propranolol (from 7 to 18%). The gastrointestinal absorption of l-propranolol, as assessed by comparing the urinary recovery of radioactivity after i.v. and oral administration of l-[3H]propranolol, was complete in normal animals. Hence, an increase in the extent of absorption of l-propranolol in renal failure cannot be offered as a cause of increased systemic availability. Neither the in vitro nor the in vivo serum protein binding of l-propranolol differed between renal failure and control animals. The intrinsic metabolic clearance of unbound l-propranolol in renal failure rats is estimated to be about 60% lower than that in control rats. These results suggest that the previously reported increase in propranolol serum concentration after oral administration of the drug to uremic patients is due to decreased presystemic biotransformation of the drug.
Preliminary investigations in the rat revealed some unexpected alterations in the pharmacokinetics of l-propranolol when single dose studies were performed on two separate occasions 7 days apart. The apparent volume of distribution of l-propranolol was found to be consistently lower on the second study day. Also, the systemic availability of orally administered propranolol (6 mg/kg) increased from 4.1 to 7.8% from the 1st to the 2nd study day, indicating a decrease in the presystemic clearance of the drug. These changes were associated with a 50 to 60% decrease in the serum unbound fraction of l-propranolol between the 2 study days. Further investigations revealed that the time-dependent increase in the serum protein binding of l-propranolol was elicited by the presence of an indwelling venous catheter which was surgically implanted for the purpose of blood sampling. In contrast, a slight decrease in the serum protein binding of an acidic drug, phenytoin, was observed after catheter implantation. These changes in serum drug protein binding were readily reversed when the indwelling catheter was removed. The total serum protein concentration was not affected by catheter implantation. Fractionation of serum proteins by electrophoresis revealed an increase in alpha 1- and gamma-globulin fractions, a slight decrease in serum albumin and no change in beta- and alpha 2-globulin fractions. Competitive protein binding studies with tris(2-butoxyethyl)phosphate, a specific ligand to alpha 1-acid glycoprotein (AAG), indicate that the increase in serum l-propranolol binding was largely due to an elevation in serum AAG. These observations also explain the opposite effect of catheterization on the serum protein binding of phenytoin, which is bound largely to serum albumin.(ABSTRACT TRUNCATED AT 250 WORDS)
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1. The activation of K+-NPPase by both Na+ and ATP was inhibited by indomethacin in vitro. 2. Indomethacin concentration required for 50% inhibition was 6.25 X 10(-4) M. 3. Inhibition manners of indomethacin for Na+ and ATP were competitive type and noncompetitive type, respectively. 4. The Ki values for indomethacin for Na+ and ATP were 1.4 X 10(-4) M and 8.8 X 10(-4) M, respectively. 5. The inhibitory effect of indomethacin was reversible.
1. The activity of the overall Na+-K+-ATPase reaction was inhibited by indomethacin in vitro. 2. The K+-NPPase activity was also inhibited by indomethacin. 3. The activity of Na+-dependent phosphorylation of Na+-K+-ATPase was activated by indomethacin. 4. Indomethacin required for 50% inhibition of K+-NPPase activity was 0.4 mM. 5. Inhibition mode of indomethacin for both the substrate and K+ in K+-NPPase reaction was competitive type. 6. The Ki values for indomethacin for the substrate and K+ in K+-NPPase reaction were 0.4 and 0.24 mM, respectively. 7. Inhibitory effect of indomethacin on K+-NPPase was reversible.
The question of the nasotemporal overlap of ganglion cells in the central retina, which project to the ipsilateral and contralateral lateral geniculate nucleus, was reexamined in the cat by means of a retrograde fluorescent double-labeling technique. The horizontal separation between the ipsilateral and contralateral decussation lines, which corresponded to the width of the median strip of overlap, was approximately 0.2 mm. This is the first direct confirmation of the extent of such overlap in the cat retinal ganglion cells, which had been previously studied by indirect methods.
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To characterize acidification by the distal nephron of the intact kidney independent of alterations in buffer availability, we subjected isolated rat kidneys perfused with glucose as the sole substrate to stepwise acidification of the perfusate. In response to progressive perfusate acidification with hydrochloric acid, a maximal pH gradient between urine and perfusate, which averaged 1.71 +/- 0.12, was achieved at a mean perfusate pH of 6.89 +/- 0.04. The maximum pH gradient was increased when sulfuric acid rather than hydrochloric acid was used to acidify the perfusate, and it was decreased by 0.67 when amiloride (10(-5) M) was added to the perfusate. Thus, hydrogen ion transport by the distal nephron of the intact rat kidney appears to be amenable to study, and it responds similarly to the hydrogen ion pump of anuran urinary epithelia. Kidneys from animals subjected to a variety of dietary regimens were studied in a response to stepwise perfusate acidification with hydrochloric acid. Ammonium excretion averaged 0.49 +/- .03 mumoles/min and did not differ significantly between any of the dietary groups. Chronic acidosis and the ingestion of either a low or high salt diet had no influence on the maximal pH gradient. Neither a low nor a high potassium diet affected the pH gradient, suggesting that the difference in urine pH between these two conditions in vivo is the result of differences in ammonia production. Ingestion of a high bicarbonate diet significantly decreased the pH gradient to 1.20 +/- 0.09. Thus, an adaptive change in distal nephron hydrogen ion transport occurs in the rat kidney in response to chronic ingestion of alkali.
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To elucidate the factors mediating the response of renal ammoniagenesis to acute acidosis, the isolated perfused rat kidney was subjected to acute metabolic and respiratory acidosis with either standard collection or drainage of urine back into the perfusate. Midway during a 90-min perfusion with 0.4 mM glutamine and 5 mM glucose, perfusate pH was decreased to 6.8 by addition of HCl or alteration of the PCO2. Metabolic acidosis increased NH3 production, acidified the urine, and increased urinary NH4 excretion. Respiratory acidosis increased NH3 production to a comparable degree without urine acidification and with a minimal increase in NH4 excretion. When respiratory acidosis preceded perfusion at control PCO2 levels, NH3 production was increased but NH4 excretion was lower than control values. If urine drained back into the perfusate, NH3 production was not altered by either metabolic or respiratory acidosis. Accordingly, acute changes in perfusate pH stimulate renal ammoniagenesis by the isolated perfusate pH stimulate renal ammoniagenesis by the isolated perfused kidney independent of changes in urinary pH and NH4 excretion. This response is inhibited by an unidentified factor excreted in the urine.
The interactions of sucralfate in various physical states, i.e., suspension, paste, and dissociated sucrose sulfate ion, with the enzyme pepsin were studied. The suspended form of sucralfate strongly adsorbs pepsin. The paste form also adsorbs pepsin but to a limited extent due to the reduced effective surface area. In view of other studies indicating selective coating of the ulcer lesion with sucralfate, this property supports the concept that it provides a potential protective barrier against the peptic attack of the lesion. By contrast, the interaction of sucrose sulfate ions with pepsin was found almost nil, giving additional evidence to the previous conclusion that the inhibition of peptic hydrolysis by sucrose sulfate is due to the interaction with the substrate rather than pepsin.
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As an extension from a previous study with serum albumins, the interaction of sucrose sulfate with bovine plasma fibrinogen was studied with respect to peptic inhibition, complexation and pH-dependence. While such features unique to this protein were found as a small degree of dependences on substrate concentration in peptic inhibition and in compositional ratios of insoluble complexes, the interaction of sucrose sulfate with fibrinogen at acid pH proved essentially similar to that with serum albumin. Both interactions are electrostatic in nature and show extensive binding that results in the formation of soluble as well as insoluble complexes resistant to peptic hydrolysis. The concentration ratio is more important than the absolute concentrations of the substrate and the inhibitor determining the degree of peptic inhibition. A sucrose sulfate to fibrinogen molar ratio of 50 represented the saturation point and was almost identical to the ratio found in the interaction with serum albumin expressed in mol of sucrose sulfate bound by a unit weight of protein. The principles found with serum albumin and fibrinogen will also apply in the interaction with other proteins at acid pH.
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