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Biomedical subjects

S Kanai

Publications and source records attributed to S Kanai.

At least 127 records · Page 7Linked to original sources
PubMed1989

Morphological, physiological and biochemical alterations in livers of rodents induced by protease inhibitors: a comparison with old livers.

A "Protease inhibitor model of aging" has been proposed primarily based on observations on brain tissues exposed to a thiol protease inhibitor, leupeptin (Ivy et al., 1984a). In order to validate this model in terms of a mechanism of cellular aging, as well as of lipofuscin formation in particular, attempts have been made to induce lipofuscin in hepatocytes in young rodent (rat and mouse) livers by continuous i.p. infusion of two different thiol protease inhibitors, leupeptin and E-64C. With doses of leupeptin higher than 1.0 mg/100g/day for 2 wks, a fine granular lipofuscin-like deposition with distinct yellowish-green fluorescence was induced in young rat hepatocytes. The deposition became greater in degree with increasing leupeptin doses. In Kupffer cells and other endothelial cells, fluorescent granules were also induced. In contrast to rat livers, lipofuscin-like pigments induced in hepatocytes in mice were much less, even with a higher dose (20 mg/100 g/day). E-64C also induced the accumulation of lipofuscin-like pigments at a dose of 5 mg/100 g/day, their characteristics being very similar to those induced by leupeptin, but the accumulation being smaller in degree. The fluorescence of leupeptin induced lipopigments was yellowish-green having a peak around 520 nm in emission profile, closely resembling that observed in old rat livers. The hepatobiliary transport functions such as biliary transport maximum (Tm) for sulfobromophthalain and the biliary recovery of iv injected ouabain which are known to decline with age tended to decline in young (6-wk-old) rats administered with leupeptin at a dose of 5 mg/100 g/day for 2 wks. On the other hand, dolichol concentration in leupeptin treated livers was not increased in comparison to control livers, whereas in old rat livers, the dolichol concentration was more than 2 times greater than in young livers. A clear-dose-dependent deposition of ceroid-lipofuscin induced in young rodent livers by protease inhibitors strongly suggests that the "Protease inhibitor model" is generally valid not only for the brain but for other tissues such as the liver, and for two different thiol protease inhibitors.

Aging↗
PubMed1989

Hepatic biotransformation and choleretic effect of 7-ketolithocholic acid in the rat.

Hepatic biotransformation and the effect on bile flow of 7-ketolithocholic acid (7-oxo-3 alpha-hydroxy-5 beta-cholan-24-oic acid), in comparison to ursodeoxycholic acid, were examined in rats under conditions of continuous infusion of solutions of sodium salts of these bile acids (1.2 mumol/min/100 g body wt) for 2 hr. Both bile salts elevated the bile flow rate as well as the bile bicarbonate concentration to a similar degree. The minor difference observed was a transient (10-20 min) and subtle drop of bile flow during the first hour in rats given 7-ketolithocholate. In ursodeoxycholate infused rats, the major bile salt in the bile was its taurine conjugate, although excretion of tauroursodeoxycholate dropped considerably during the second hour. In 7-ketolithocholate infused rats, the major bile salt in the bile was again its taurine conjugate, but ursodeoxycholate and chenodeoxycholate and their conjugates were also excreted. In contrast to ursodeoxycholate infused rats, the drop in excretion of taurine conjugates and the increase of glycine conjugates in rats infused with 7-ketolithocholate were more rapid. In rats infused with 7-ketolithocholate, excretion of ursodeoxycholate and its conjugates was significantly higher than the corresponding values for chenodeoxycholate, suggesting that 7-ketolithocholate is reduced predominantly to the 7 beta-epimer in this species. However, the concentration of ursodeoxycholate and its conjugates excreted into the bile in rats infused with 7-ketolithocholate was only 10% of that of rats infused with ursodeoxycholate, yet the magnitude of choleresis and the rise in bile bicarbonate concentration were similar in both experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Redistribution of haloperidol after electroshock: experimental evidence.

We have previously reported that plasma and red blood cell levels of haloperidol, a neuroleptic agent, significantly increased immediately after electroconvulsive shock therapy (ECT) in schizophrenic patients on long term haloperidol treatment. To elucidate the mechanism of this increase, we attempted to reproduce this phenomenon in female Wistar rats. After 4 successive days of ip administration of haloperidol (10 mg/kg body weight, once daily), rats were given ECT through corneal electrodes on the fifth day (a.c. 50 Herz, 55 mA, 2.0 sec). Haloperidol levels were determined in plasma and other major tissues using a radioreceptor assay for haloperidol distribution before and after ECT at appropriate time intervals. Plasma haloperidol level was significantly increased 1 min after ECT but tended to return to the control level (without ECT) after 5 min. A significant decrease in haloperidol concentration in tissues was not observed in any of the tissues examined including frontal cerebrum, striatum, and muscle tissues (gluteal muscles). However, the relatively high haloperidol level and the large volume of muscle tissues suggested that the muscle could be the source of the transient increase in haloperidol levels in plasma. This conclusion was also supported by the data showing no significant rise of plasma haloperidol level after ETC in rats previously given a muscle relaxant, succamethonium chloride.

Animals↗
PubMed1989

Differences in the influence of diet on hepatic glutathione S-transferase activity and glutathione content between young and old C57 black female mice.

The effect of a protein-free diet (PFD) on hepatic activity of glutathione S-transferase (GST) and hepatic content of total glutathione (GSH) was examined in young (9-month-old), middle-aged (17-month-old) and old (27-month-old) C57BL/6CrS1c female mice. There were no significant differences in the control values of GSH or of enzyme activity for four of five substrates among young, middle-aged, and old animals fed normal diet (ND) only. Both GSH and GST activity were significantly decreased by the 7-day PFD in both young and old groups but the decrement was generally greater in old mice. After a 2-3-day refeeding of ND, young mouse enzyme activities were significantly higher than control (basal) values for all five substrates, whereas old mouse values were still significantly lower than corresponding control values. There was no overshooting of GSH levels after refeeding of ND in either young or old animals. This study indicates that an age difference in this detoxification system can be clearly demonstrated in the hepatic response to PFD feeding and especially to ND refeeding, despite the enzymes' stable basal activities with aging.

Aging↗
PubMed1989

Age-related differences in the coordination disturbance and anticonvulsant effect of oxazepam in mice.

The effects of oxazepam on coordination and maximal seizure were compared between young (6-month-old) and old (24-month-old) BDF1 mice by using a rotorod test and a pentylenetetrazole (PTZ)-induced seizure test, respectively. The apparent sensitivity to oxazepam's anticonvulsant effect, as examined by its effect on PTZ-induced maximal seizure, was increased in old animals of both sexes in comparison to young ones. The effect of oxazepam on coordination was also significantly greater in old male mice as compared with the young. The results of the present study, together with our past observations on other anticonvulsants such as phenytoin and phenobarbital, strongly suggest that the anticonvulsant effect, as well as the effect on coordination, in mice generally increases with age.

Age Factors↗
PubMed1989

The nature of choleresis induced by deoxycholate and its conjugates in the rabbit.

A hypothesis for the mechanism of bile salt-induced choleresis with increased bile bicarbonate concentration (cholehepatic recycling; CHR), requires a relatively high pK'a value of a bile salt to be easily protonated in bile canaliculi. If the choleresis induced by taurodeoxycholate and glycodeoxycholate (which increase bile bicarbonate concentration in rabbits) is to be explained by this thesis, these bile salts must be extensively deconjugated in the liver, enabling a bile salt having a higher pK'a value, free deoxycholate, to undergo CHR. With a stepwise increase in the infusion rate, the increments of bicarbonate concentration, as well as the bile flow rate induced by taurodeoxycholate and glycodeoxycholate, were as efficient as those caused by an equimolar infusion of deoxycholate. With infusion of conjugated deoxycholates, the major bile salts excreted in the bile were those which had been infused. In studies with conjugated deoxycholates, unconjugated deoxycholate was not detectable in the bile. Furthermore, deoxycholate concentration in the liver significantly increased after a 2-h infusion of deoxycholate but did not increase after infusion of either glycodeoxycholate or taurodeoxycholate. The present results suggest that the choleresis induced by conjugated deoxycholates in rabbits requires an explanation other than CHR of deoxycholate.

Animals↗
PubMed1989

Biliary albumin excretion induced by bile salts in rats is a pathological phenomenon.

The bile to plasma 125I-albumin concentration ratio (B/P ratio) was examined before and during various bile salt infusions in male Wistar rats that had previously received iv injection of 125I-albumin. Endogenous rat albumin and IgG concentrations in the bile were also determined by a single radial immunodiffusion method. Taurocholate (TC) infusion (1.0 mumol/min/100 g body wt) significantly increased the bile flow rate in the first hr but the flow began to decline in the second hr. The B/P ratio as well as rat albumin (and IgG) excretion into the bile significantly increased as early as 15 min after the start of TC infusion, and the increase became more pronounced in the second hr, when the bile flow began to decrease. Infusion of taurochenodeoxycholate (TCDC, 0.4 mumol/min/100 g) caused a reduction in bile flow 15 min after the start of infusion but the B/P ratio increased 40 times at its peak compared with the basal value before the bile salt infusion. Simultaneous infusion of tauroursodeoxycholate (TUDC, 0.6 mumol/min/100 g) and TCDC not only abolished the cholestasis induced by TCDC but maintained stable choleresis as long as for 2 hr. During this choleretic period, the B/P ration never exceeded the basal value. The choleresis induced by either taurodehydrocholate (TDHC) or bucolome was not accompanied by enhanced albumin excretion. In rats given TDHC infusion, albumin excretion started to increase only after the bile flow began to decline following the initial choleretic period. The enhanced excretion of albumin induced by TC and TCDC is therefore suggested to be caused not by the choleresis per se but by a possible concomitant increase in the communication between sinusoids and bile canaliculi, which eventually leads to cholestasis. Our results suggest that the biliary excretion of albumin enhanced by bile salt infusion in rats is primarily the result of hepatocyte damage closely related to cholestasis rather than to choleresis, and that the rate of such excretion can be used as a convenient and reliable marker for hepatocyte damage.

Albumins↗
PubMed1989

[A case of renal cell carcinoma on chronic hemodialysis].

We report a case of renal cell carcinoma on maintenance dialysis for chronic renal failure. A 61-year-old male, treated for diabetes mellitus for 20 years, developed diabetic nephropathy and has been put on maintained hemodialysis during the past 2 years. He complained of asymptomatic hematuria. Computed tomographic scan and renal angiography suggested the presence of a malignant neoplasm in his right kidney. He underwent right nephrectomy, and hemodialysis was resumed on the 4th day post operation. Pathologic examination revealed renal cell carcinoma, clear cell type, together with hyalinized glomeruli, where an acquired cystic change was not detected.

Carcinoma, Renal Cell↗
PubMed1988

Age-dependent decrease in the hepatic uptake and biliary excretion of ouabain in rats.

The biliary excretion of i.v. injected ouabain was examined in male and female Wistar-derived rats in relation to age. The hepatic uptake velocity for ouabain was also determined in isolated hepatocyte preparations obtained from male rats of various ages. Biliary recovery values of ouabain (percent of the dose) were fairly comparable for young male and female rats (3-4 month old). Recovery progressively decreased with age, the first 10-min recoveries at 24 months being about one-third those of respective young values in both sexes. A significant linear relation was demonstrated between the first 10-min recovery (Y, percent of the dose) and rat age (X, month), yielding the relations of Y = 17.75-0.43X for males and Y = 18.99-0.43X for females respectively. Similarly, the initial uptake velocity (Y, nmol/mg/min) for ouabain decreased in a linear fashion with age (X, month), yielding a significant negative correlation (Y = 0.704-0.0021X, r = -0.839, P less than 0.005, N = 21) at an ouabain concentration of 8 microM. Kinetic studies using non-linear regression analysis revealed a significantly lower Vmax value (0.533 +/- 0.041 nmol/mg/min) in old (24-29 months) rats compared to the young (4-4.5 months) value (1.193 +/- 0.105 nmol per mg/min, P less than 0.05), while the affinity constant (Km, microM) did not differ significantly between young and old animals (203.12 +/- 25.42 microM in young rats vs 283.68 +/- 28.90 microM in old rats, mean +/- SE, 0.05 less than P less than 0.1). The results of the present study suggest that the age-dependent decrease in the biliary recovery of i.v. injected ouabain in rats can be largely explained by the decrease with age in the hepatic uptake of ouabain. Furthermore, the results provide further support for our previous thesis that the decrease in the lateral mobility of hepatocyte plasma membrane proteins, as revealed by the fluorescence recovery after photobleaching technique, may play a significant role in the age-dependent decrease in the physiological function(s) of the hepatocyte plasma membrane, such as the hepatobiliary transport of ouabain.

Aging↗
PubMed1988

The neurotoxicity of phenobarbital and its effect in preventing pentylenetetrazole-induced maximal seizure in aging mice.

The effects of age on the neurotoxicity of phenobarbital and its anticonvulsant effect were examined in female BDF1 mice of different ages by means of a rotorod test and the pentylenetetrazole (PTZ)-induced maximal seizure, respectively. The minimal neurotoxic concentrations (MTCs) of phenobarbital in both plasma and brain evaluated by a rotorod test were 50% lower (p less than 0.05) in old (24-months-old) mice compared with the respective values in young (6-months-old) mice, while 12-months values were the highest of the three groups. Mice given some dosages of phenobarbital, particularly old (24-months-old) mice, died within the 15-min observation period after an i.p. injection of PTZ (150 mg/kg) without demonstrating a hindlimb extensor component (HLE) of maximal seizure. When these animals were classified as responders with regard to the anticonvulsant effect of phenobarbital, the minimal effective concentrations (MECs) in plasma and brain required for abolishing the PTZ-induced maximal seizure in old mice were only 10-20% those of young mice. Present results coupled with our past studies using electroshock seizure suggest that both the neurotoxicity and the efficacy of phenobarbital increase with age in mice.

Administration, Oral↗
PubMed1988

The age-dependent decline in the biliary transport maximum of conjugated sulfobromophthalein in the rat.

In order to elucidate the effect of aging on the biliary transport of organic anions, we examined the biliary transport maximum (Tm) for sulfobromophthalein (BSP) conjugated with glutathione in male and female Fischer-344 rats of various ages (3, 6, 24 and 30 months) during the constant intravenous infusion of conjugated BSP. For young rats the Tm values for conjugated BSP were higher in females than in males in contrast to the reported higher Tm value in males infused with free (unconjugated) BSP. In both sexes, Tm values progressively decreased with age up to 30 months. The results suggest that the previously reported higher Tm value for young male rats compared to young females during free BSP infusion is due to the lower conjugation capacity in females, and that the biliary transport process per se is more efficient in females at least for organic anions like conjugated BSP. Furthermore, the results support the previously proposed hypothesis that the biliary transport mechanism per se is steadily affected by aging in rats of both sexes.

Aging↗
PubMed1988

[Female urethral carcinoma: results of irradiation in 2 patients].

Urethral carcinoma in 2 females has been treated with irradiation together with adjunct chemotherapy. In case 1, a 73-year-old female with squamous cell carcinoma was successfully treated with irradiation of 4,000 rad and peplomycin of 60 mg intravenously given. She has been free from the disease for the past 43 months. In case 2, a 61-year-old female with transitional cell carcinoma was initially treated with irradiation of 5,000 rad together with peplomycin 90 mg, which was followed by another 5,000 rad irradiation. The tumor recurred and the patient was operated on for cystourethrectomy and partial resection of the vagina. A further chemotherapy of cisplatin, peplomycin, and mitomycin C was instituted. She died of the tumor recurrence 23 months after the first visit to our clinic. Diagnosis and treatment modalities on the female urethral carcinoma are briefly discussed.

Aged↗
PubMed1988

Enhancing effect of bucolome on biliary excretion of ouabain and digoxin in the rat.

The effect of bucolome (1-cyclohexyl-5-n-butyl-2,4,6-trioxoperhydropyrimidine) on the biliary excretion of intravenously administered ouabain and digoxin was examined in rats. The intravenously administered [3H] ouabain (0.1 mg/100 g b wt) was more rapidly excreted in the bile in female rats than in males. Intraperitoneal administration of bucolome induced a two fold increase in bile flow rate, accompanied by a significant increase in biliary recovery of ouabain during first 10 min (by 100% in males and 50% in females) resulting in significantly higher 60-min total biliary recoveries in both sexes. In female rats 80% of radioactivity was recovered in the bile as an unmetabolized form after 10 min of intravenous administration of [3H] digoxin. Biliary excretion of the parent drug, digoxin, was also enhanced by intraperitoneal administration of bucolome. Although the underlying mechanism(s) remains unknown, it was shown that biliary excretion of both ouabain and digoxin was enhanced by bucolome, as was previously shown for ouabain in male rats.

Animals↗
PubMed1987

Increasing anticonvulsant effect of AD-810 (zonisamide) in aging BDF1 mice.

The anticonvulsant efficacy of a newly developed anticonvulsant, AD-810 (zonisamide, 3-sulfamoylmethyl-1,2-benzisoxazole) was examined in relation to mouse age in three different age groups of female BDF1 mice (7-, 25- and 29-month-old). The minimal effective concentration (MEC) of AD-810 in both plasma and brain for abolishing the electroshock-induced maximal seizure steadily decreased with age, the 25- and 29-month values being 50 and 30% of respective 7-month values. The observation in the present study was almost identical to previous observations by the authors on phenytoin, phenobarbital and oxazepam. The present results support our previous contention that the dose and plasma concentration of anticonvulsants can (and probably should) be reduced in the elderly regardless of the drug. Since the anticonvulsant mechanism of AD-810 has been reported to differ from those of previously examined drugs (phenobarbital and oxazepam), the results also suggest that the apparent increase in the pharmacological effect of these anticonvulsants may be due to old animals' lowered response capability for seizures rather than a specific age effect on the pharmacological reaction sites for individual anticonvulsants.

Aging↗
PubMed1987

Biliary excretion of ouabain in aging male and female F-344 rats.

The biliary excretion of ouabain was examined in Fischer-344 rats of both sexes and of different ages. The biliary recoveries for the first 10-min period after the intravenous injection of ouabain (0.1 mg/100 g body weight) were nearly 2-fold higher in female than in male rats for all age groups compared (4, 6, 12, 24, 28 months). In both sexes, the biliary recovery showed a gradual decrease with age, and the first 10-min value in 24-months old rats was about one third of those in the youngest rats. The 60-min total recovery values also significantly decreased with age. Some very old (males, 28 months; females, 31 months) rats, however, showed higher 60-min total recovery values than younger rats comparable to the youngest animal values. It was concluded that the biliary excretion of ouabain in rats decreases with age in both sexes which suggests that this is a general phenomenon in this animal species.

Aging↗
PubMed1987

Molecular cloning of complementary DNA for human medullasin: an inflammatory serine protease in bone marrow cells.

Medullasin, an inflammatory serine protease in bone marrow cells, modifies the functions of natural killer cells, monocytes, and granulocytes. We have cloned a medullasin cDNA from a human acute promyelocytic cell (ML3) cDNA library using oligonucleotide probes synthesized from the information of N-terminal amino acid sequence of natural medullasin. The cDNA contained a long open reading frame encoding 237 amino acid residues beginning from the second amino acid of natural meduallasin. The deduced amino acid sequence of medullasin shows a typical serine protease structure, with 41% homology with pig elastase 1.

Amino Acid Sequence↗