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Biomedical subjects

K Kitani

Publications and source records attributed to K Kitani.

At least 181 records · Page 10Linked to original sources
PubMed1986

Effect of tauroursodeoxycholate on the biliary transport maximum of sulfobromophthalein in the rat.

The effect of tauroursodeoxycholate (TU) infusion on the plasma level and biliary transport maximum (Tm) of sulfobromophthalein (BSP) was examined in male rats during a continuous intravenous infusion of BSP with different TU infusion rates. The infusion rate of 0.6 mumol/min/100 gm body weight of TU caused significantly higher bile flow and BSP Tm values compared with the respective control values in rats with only a BSP infusion. These values, however, were significantly lower than values obtained by an equimolar infusion of taurocholate (TC). The higher infusion rates of TU (1.2 and 1.8 mumol/min/100 gm) tended to cause higher bile flow rates, but the BSP Tm value did not increase beyond the value obtained at the lower infusion rate (0.6 mumol/min/100 gm). In the highest TU infusion rate study (1.8 mumol/min/100 gm), plasma BSP concentrations were significantly higher than corresponding control values or values at a lower TU or TC infusion rate. It was concluded that in rats TU can significantly increase the BSP Tm, but to a lesser extent than TC. Furthermore, it was suggested that TU infusion at a higher rate significantly interferes with the hepatic uptake (or storage) of BSP.

Animals↗
PubMed1985

Age-associated alterations in hepatic glutathione-S-transferase activities.

Age-associated alterations of hepatic cytosolic glutathione-S-transferase (GST) activities towards sulfobromophthalein sodium tetrahydrate (BSP), styrene oxide (STOX), trans-4-phenyl-3-butene-2-one (PBO), 1,2-dichloro-4-nitrobenzene (DCNB), and 1-chloro-2,4-dinitrobenzene (CDNB) were investigated in Fischer-344 rats of both sexes with ages ranging from 1.5 to 28 months. The GST activities towards PBO and DCNB in male rats increased with age till 6-12 months when maximum values were attained, and then gradually decreased till 28 months when the values became the lowest. The GST activities towards STOX and BSP did not show any significant increase after 1.5 months and stayed at this level till 12 months, followed by a gradual decrease till 28 months when the values were the lowest. In contrast, the GST activity towards CDNB in male rats did not show much of an age-associated alteration. Age-associated alterations in GST activities in females were much smaller than those observed in males. Sex differences in GST activities (significantly higher male values than female values) were observed with all the substrates examined at least at some time of the animal life. The kinetic studies of GST activities indicated that alterations in the relative abundance as well as the total quantity of GST isozymes caused the substrate selective alterations of GST activities with age.

Age Factors↗
PubMed1985

Increased anticonvulsant effect of phenobarbital with age in mice--a possible pharmacological index for brain aging.

We have recently reported that the anticonvulsant effect of phenytoin increases with age in mice (1). Since some of the mechanisms of anticonvulsant action of phenytoin and phenobarbital may be different, the present study sought to determine whether a similar increase with age in the anticonvulsant effect of phenobarbital could also be observed. The anticonvulsant effect of phenobarbital was examined in BDF1 female mice of different ages (6, 12, 24 and 30 months old) using the abolition of the tonic hindlimb extensor component of maximal electro-shock seizure as the index. The minimal effective concentration (MEC) values of phenobarbital in plasma and brain were significantly lower in aged (24 and 30 month old) mice compared with the respective values in the youngest animal group (6 month old). Series using nearly two-fold different intensities of electroshock (30 and 55 mA) showed almost identical MEC values in 24 month-old mice. It was concluded that the brain of aged mice is more sensitive to phenobarbital, as it is to phenytoin.

Aging↗
PubMed1985

Age related increased threshold for electroshock seizure in BDF1 mice.

The thresholds for inducing the minimal and maximal electroshock seizures were examined in relation to age in BDF1 mice of both sexes. The 50 percent effective intensities for the maximal electroshock seizure (tonic hindlimb extensor component) were lowest in the youngest age groups (6-month-old) for both male (10.68 mA) and female (9.18 mA) animals. The threshold increased with age and became significantly higher at 24 months (14.00 mA, 12.70 mA for male and female mice respectively). There was also a further increase in threshold at 30 months for both sexes. Similarly, the threshold for inducing the minimal seizure also increased with age but the differences in mean threshold levels between the youngest and oldest groups were much smaller in comparison to the maximal seizure. It was concluded that the threshold for inducing electroshock seizures significantly increases with age in mice of both sexes.

Age Factors↗
PubMed1985

Age associated alteration of lidocaine metabolism is position selective.

Patterns of associated alterations in N-deethylation, 3-hydroxylation, and aromatic methylhydroxylation of a single substrate, lidocaine in liver microsomes from 0.7 - 28 months old Fischer 344 rats were examined. These three patterns were all different from one another. In addition to this position selectiveness, a clear sex difference was observed in the pattern of alteration in N-deethylation. These results are consistent with the hypothesis that age associated alterations in drug metabolism are caused by age associated alterations in relative abundance of multiple species of cytochrome P-450.

Aging↗
PubMed1985

Sex difference in the biliary excretion of digoxin and its metabolites in aging Wistar rats.

The biliary excretion of digoxin (Dg3) and its metabolites was studied in both young (3-month-old) and old (25- and 30-month-old) Wistar rats of both sexes. The 2 h biliary recovery (% of the dose) of intravenously injected [3H]Dg3 (0.01 mg/100 g) radioactivity was similar between young male and female rats, while the first 10 min excretion was significantly higher in females. In old (25-month-old) male rats, the 2 h biliary recovery of radioactivity was significantly lower than the corresponding young value. This was primarily due to the drastic decrease with age in excretion of bis-digitoxoside. On the other hand, in old female rats (25- and 30-month-old) the 2 h recovery value was not significantly different from the corresponding young (3-month-old) value. This was due to the much higher percentage (more than 80% of the total) of Dg3 in the female bile radioactivity which did not significantly decrease with age. The results suggest that the rate of stepwise cleavages of the sugar chain of Dg3 decreases with age more rapidly in male than in female rats as has been previously shown by the authors for digitoxin. Large sex differences observed in the age-dependent alteration in Dg3 metabolism and its biliary excretion raise a caution against a generalization of the data obtained from a single sex in this animal species with regard to the effect of aging.

Aging↗
PubMed1985

The hepatic handling of sulfobromphthalein in aging Fischer-344 rats: in vivo and in vitro studies.

Biliary transport maximum (Tm) and relative storage capacity (S) for sulfobromphthalein (BSP) were compared in male and female Fischer-344 rats of different ages ranging from 3 to 30 mth. When expressed per unit liver weight, the male Tm value decreased rapidly with age reaching 40% of the 3-mth-old value at 30 mth. Female values, which were significantly lower than corresponding male values during the first year also decreased steadily with age but the rate of decrease was much lower than in male values. Consequently, at 30 mth there was no longer any difference between male and female rats. S values expressed per gram liver stayed essentially unchanged with age in both male and female rats, although female values were always lower than male values. The liver's in vitro conjugation capacity for BSP with glutathione also decreased significantly with age in male rats, while in female rats it remained unchanged between 3 and 28 mth of age. Thus, the decrease in BSP Tm value with age could not be fully explained by the decrease in liver's conjugation capacity with glutathione. The results of the present study, coupled with our previous observations on other rat strains suggest that, at least in rats, BSP Tm decreases with age but S does not, despite contrary reports made by other authors on man and rats.

Aging↗
PubMed1985

Absence of age effect on plasma haloperidol neuroleptic levels in psychiatric patients.

Plasma neuroleptic levels in 41 patients (21 men, 20 women, aged 18 to 74) on haloperidol therapy were examined in relation to their age by means of radioreceptor assay. There was no significant difference among three age groups (below 45 years, 46 to 60 years, over 60 years) in the ratio of the plasma neuroleptic level to daily dose (nM/mg/kg), but a significant difference in the plasma neuroleptic level was found between the average values in parkinsonian (19.1 +/- 8.5 nM, M +/- SD) and nonparkinsonian (5.5 +/- 3.0 nM, M +/- SD) patients. There was, however, no significant difference in the incidence of parkinsonian symptoms between the young (below 60 years) and the old (over 60 years) age groups. These results suggest that in contrast to the previously reported study with chlorpromazine, the plasma neuroleptic level of haloperidol is not altered with aging and that parkinsonian symptoms induced by haloperidol occur simply in a plasma-neuroleptic-level-dependent manner.

Administration, Oral↗
PubMed1985

Tauroursodeoxycholate prevents biliary protein excretion induced by other bile salts in the rat.

Biliary excretion of various proteins (5'-nucleotidase, alkaline phosphatase, lactate dehydrogenase, and albumin) was investigated in pentobarbital sodium-anesthetized rats infused with different bile salts [taurocholate (TC), taurochenodeoxycholate (TCDC), and tauroursodeoxycholate (TUDC)]. A TCDC infusion at 0.4 mumol . min-1 . 100 g body wt-1 caused much higher increases in the biliary excretion of these proteins compared with the respective values in rats that received an infusion of TC at a threefold higher rate (1.2 mumol . min-1 . 100 g body wt-1). In contrast, a TUDC infusion at 1.8 mumol . min-1 . 100 g body wt-1 showed the minimum effect on these protein leakages. A combined infusion of TCDC (0.4 mumol . min-1 . 100 g-1) and TUDC (0.6 mumol . min-1 . 100 g-1) resulted in drastic (8- to 20-fold) decreases in excretion of these enzymes and albumin compared with respective values in rats infused with TCDC alone. Similar preventive effects were observed with the addition of TUDC to the infusion of TC (1.2 mumol . min-1 . 100 g-1). These results suggest that the hepatic cytotoxic effects of TC and TCDC can be prevented by the simultaneous infusion of TUDC in rats.

5'-Nucleotidase↗
PubMed1985

Ursodeoxycholate-induced choleresis in taurine-deprived and taurine-supplemented rats.

The effect of i.v. infused ursodeoxycholate (1.2 micromol/(min . 100 g body weight)) was compared in control rats and in taurine supplemented (i.p. administration of a taurine solution) and taurine deprived (oral administration of beta-alanine) rats. In the control rats, the bile water output during the first hr was significantly lower than that of the second hr, while the bile salt output was significantly lower in the second hr. In beta-alanine pretreated rats, the increase in the bile flow in the first hr was more rapid compared to control rats, and the bile flow rate reached a peak earlier. The first hr and total 2 hr bile water outputs were significantly higher in the beta-alanine pretreated rats compared to the corresponding bile flow values of the control rats, while the bile salt outputs were significantly lower than respective control values. In taurine supplemented rats, the increase in bile flow in the second hr was less than in control rats, while the bile salt excretion rate was the highest among the three rat groups. Thus, among these three groups, the bile flow and bile salt excretion rate during the first hr and 2 hr total infusion periods were negatively correlated. On the other hand, a significant positive correlation was observed between the bile flow rate for 1 or 2 hr and bile salt concentration in the liver examined after a 1 or 2 hr bile salt infusion. These results seem most easily explained by our previous thesis that at least part of the bile is produced not by the excretion of bile salt into the bile canaliculus but by its presence inside the hepatocyte (secretory mechanism).

Animals↗
PubMed1985

Age-related alteration in the activities of drug-metabolizing enzymes and contents of sex-specific forms of cytochrome P-450 in liver microsomes from male and female rats.

Age-related changes in the amounts of sex-specific forms of cytochrome P-450 as well as the activities of drug-metabolizing enzymes in liver microsomes of Fischer-344 rats of different ages ranging from 3 to 30 months were studied. Activities of 7-propoxycoumarin O-depropylase and benzo(a)pyrene hydroxylase in male rats, which were higher than those in female rats in younger adults (3-12 months), decreased with increasing age, resulting in the loss of sex differences after 25 months. The male-specific form of cytochrome P-450, namely P-450-male, present in younger adults, was not detectable in older ages. In old male rats, the female-specific form of cytochrome P-450, namely P-450-female, appeared instead of P-450 male. In liver microsomes of young and old female rats, rather constant levels of P-450-female were observed, whereas P-450-male was not detectable. Serum concentrations of testosterone and estradiol were also quantitated. The ratio of testosterone to estradiol concentrations decreased with age in male rats whereas the ratio was not changed in female rats. Based on these results, we propose that the age-related decrease in the activities of drug-metabolizing enzymes in male rats is attributable to the change in the population of cytochrome P-450, especially P-450-male and P-450-female, probably owing to the alteration of the levels of gonadal hormones.

Aging↗
PubMed1984

The digitoxin metabolism in isolated hepatocytes from young and old male Wistar rats.

The metabolism of digitoxin (Dt3) in isolated hepatocyte preparations was studied in young (3-mth-old) male and female rats, young castrated (3-mth-old) male rats and old (22- to 28-mth-old) male rats. When hepatocytes were incubated with [3H]Dt3, the predominant metabolite of Dt3 was digitoxigenin-bis-digitoxoside (Dt2) which was 70-90% of the total metabolites in the three male rat groups. Only in the young female rat group was the proportion of Dt2 (40%) slightly exceeded by that of digoxigenin-bis-digitoxoside (Dg2) (50%). A kinetic analysis for Dt3 degradation velocity obtained from studies using different Dt3 concentrations in old male rats yielded a Vmax of only 21% of the young value. In young castrated males, the Vmax also decreased to 13% of the young non-castrated males, which is approaching the young female value. The changes were primarily due to the decline of Dt2 formation velocity in these groups. Apparent Km values also decreased with both castration and aging. The plasma testosterone levels which were much higher in young male rats than in female rats became significantly lower in young castrated rats as well as in old male rats. The results suggest that apparent decreases in Vmax and Km values observed in old male rats for Dt3 metabolic degradation may be at least partly through the steroidal hormone control, presumably, the decline of androgenic induction during aging.

Aging↗
PubMed1984

Increased anticonvulsant effect of phenytoin in aging BDF1 mice.

The anticonvulsant effect of phenytoin was examined in BDF1 mice of both sexes and various ages (6, 12, 24 and 30 months old) using the abolition of the tonic hindlimb extensor component of maximal electroshock seizure as the index. The minimal effective plasma concentration of phenytoin was significantly lower in 24- and 30-month-old mice compared with young adult (6 month old) mice. Similarly, all older groups (24 and 30 month old, both sexes) showed significantly lower minimal effective brain concentrations compared with respective younger (6 and 12 month old) animal groups. Studies using nearly 2-fold different intensities of electroshock (30 and 55 mA) showed almost identical results. The results provide evidence that, in adult mice, the brain becomes more sensitive with age to phenytoin with regard to its anticonvulsant effect.

Aging↗
PubMed1983

The bile flow and biliary excretion of ursocholate in the rat.

Several studies reported that ursodeoxycholate (but not its conjugates), when administered intravenously, increased the biliary bicarbonate concentration in the rat (1-3). At the same time, a complete dissociation between bile flow and the bile salt excretion rate was produced in the second hr of infusion (2). In order to examine whether this property was due to the 7 beta-hydroxy group in its molecular structure, the choleretic property of ursocholate (3 alpha, 7 beta, 12 alpha-trihydroxy-5 beta-cholanoic acid) was investigated in male Wistar rats. Immediately after the start of iv infusion of ursocholate at a rate of 1.2 mumole/min/100 g b. wt., both the bile flow and bile salt excretion rate began to increase. However, unlike with ursodeoxycholate, the bile salt excretion rate continued to be high in the second and third hr of infusion, while the bile flow rate gradually increased. Furthermore, the bicarbonate concentration in the bile fell slightly 10 min after the start of ursocholate infusion. Although the concentration tended to return to the baseline value before the bile salt infusion in the later period of observation, no significant increase in bicarbonate concentration was observed during the whole observation period. These properties were quite similar to those of cholate rather than those of ursodeoxycholate. However, a cholate infusion at the same rate of 1.2 mumole/min/100 g b.wt. caused a cholestasis as early as 20 to 30 min after the start of an infusion. These results suggest that the previously reported properties of ursodeoxycholate (that it causes a complete dissociation between the bile flow and bile salt excretion rate in the second hr and that it increases the biliary bicarbonate concentration) were not due to the 7 beta-hydroxy group in its steroidal structure, and that the choleretic property of ursocholate is similar to its 7 alpha-hydroxy epimer, cholate. However, the much lower cytotoxicity of ursocholate compared to cholate appears to be due to the 7 beta-hydroxy group that ursocholate has.

Animals↗