Continuous anti-dsDNA antibody apheresis in systemic lupus erythematosus.
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Adult↗
Biomedical subjects
K Kitani
Publications and source records attributed to K Kitani.
The importance of the C-terminal amide structure of rat pancreastatin to inhibit pancreatic exocrine secretion.
A C-terminal fragment of rat pancreatatin, a 26 residue peptide amide and a fragment without a C-terminal amide were synthesized by Fmoc-based solid phase methods and their biological activities were compared. The rat C-terminal fragment inhibited pancreatic exocrine secretions produced by the intravenous injection of 2-deoxy-D-glucose (a central vagal nerve stimulation), whereas the fragment without a C-terminal amide showed no effect on pancreas. These results indicate that the C-terminal amide of this peptide is necessary to reveal its biological activity.
Animals↗
Rat pancreastatin inhibits both pancreatic exocrine and endocrine secretions in rats.
Effects of synthetic rat pancreastatin C-terminal fragment on both exocrine and endocrine pancreatic functions were examined in rats, in vivo and in vitro. Pancreastatin (20, 100 pmol, 1 nmol/kg/h) significantly inhibited CCK-8-stimulated pancreatic juice flow and protein output in a dose-related manner, in vivo. The inhibitory effect on bicarbonate output was not statistically significant. Pancreastatin did not significantly inhibit basal pancreatic secretions in vivo, and did not inhibit amylase release from the dispersed acini, in vitro. Insulin release stimulated by intragastric administration of glucose (5 g/kg) was significantly inhibited by pancreastatin (1 nmol/kg/h), in vivo. Plasma glucose concentrations were increased by pancreastatin infusion, but the increase was not statistically significant. Furthermore, pancreastatin inhibited insulin release from isolated islets, in vitro. Synthetic rat C-terminal pancreastatin fragment has bioactivities on both exocrine and endocrine pancreatic functions in rats.
Amylases↗
Age-dependent decrease in the hepatic uptake of taurocholic acid resembles that for ouabain. A possible role of surface membrane protein mobility.
Isolated hepatocytes were prepared from Wistar-derived male rats of different ages (4, 12 and 27-29 months) by the collagenase perfusion method. The hepatic uptake rate of taurocholate (TC) for the saturable fraction was calculated by subtracting the non-saturable fraction from the total hepatic uptake. The Vmax and the apparent affinity constant Km were computed for the saturable fraction by means of non-linear regression. The Vmax (nmol/mg protein/min, mean +/- SE) for young rats (N = 6) was 2.15 +/- 0.11, whereas in old rats (N = 4) the value was 50% lower (1.16 +/- 0.11, P less than 0.005). In contrast, Km (microM) values were not significantly different between young (25.88 +/- 1.90) and old (30.34 +/- 4.96) rats. There was a significant inverse linear relationship (r = 0.79; P less than 0.01) between the age of rats and the uptake velocity (nmol/mg/mg protein/min) at 1 microM of TC, suggesting a steady and almost linear decrease of TC uptake velocity with age. The rate of decrease per month (2.1%) was quite close to the value for ouabain uptake (2.8%) previously found by the authors. Furthermore, a marked linearity was observed between the average values for TC uptake rates for three age groups and corresponding lateral diffusion constants of hepatocyte plasma membrane proteins previously obtained by the authors using the fluorescence recovery after photobleaching method. The results support our previous proposal that protein mobility within the hepatocyte surface membrane may play at least a partial role in regulation of carrier-mediated hepatocyte uptake functions for various materials.
Age Factors↗
Comparative effects of simvastatin (MK-733) and pravastatin (CS-514) on hypercholesterolemia induced by cholesterol feeding in rabbits.
The preventive effects of simvastatin (MK-733) and pravastatin (CS-514), 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors, on hypercholesterolemia induced by 0.25% cholesterol feeding were compared in rabbits. MK-733 (6, 2 and 0.7 mg/kg) was found to prevent the increase in serum total cholesterol levels dose-dependently. High dose CS-514 (18 mg/kg) also limited the increase in the cholesterol levels, but medium (6 mg/kg) and low doses (2 mg/kg) of CS-514 were ineffective in preventing it. MK-733 inhibited the increase in VLDL and LDL cholesterol levels dose-dependently. MK-733 suppressed the increase in serum phospholipid levels. MK-733 inhibited the accumulation of cholesterol in the liver. The high dose of CS-514 also limited it. High dose MK-733 (6 mg/kg) reduced the cholesterol concentration in gallbladder bile. Neither MK-733 nor CS-514 affected bile acid excretion in the gallbladder bile. High dose MK-733 decreased the lithogenic index. MK-733 increased the number of LDL receptors, and high dose CS-514 also increased it. The suppressive effect of CS-514 on serum cholesterol levels at 18 mg/kg was found to be less than that of MK-733 at 0.7 mg/kg.
Animals↗
Hepatic injury induced by bile salts: correlation between biochemical and morphological events.
Continuous intravenous infusion of taurochenodeoxycholate at a rate of 0.4 mumol.min-1.100 gm-1 for only 30 min in rats caused threefold to tenfold greater release of proteins (alkaline phosphatase, lactate dehydrogenase and albumin) into bile in comparison with animals infused with tauroursodeoxycholate at much higher rates (1.8 mumol.min-1.100 gm-1) for 2 hr. The simultaneous infusion of tauroursodeoxycholate and taurochenodeoxycholate (0.6 and 0.4 mumol.min-1.100 gm-1, respectively) for 2 hr prevented the marked biochemical changes in the bile induced by taurochenodeoxycholate for 15 to 60 min exhibited significantly more necrotic hepatocytes, especially in zone 1, in comparison with animals infused with tauroursodeoxycholate or a combination of taurochenodeoxycholate and tauroursodeoxycholate. A good correlation was observed between biochemical and morphological indices of bile acid-induced hepatocyte injury. These data suggest that (a) primary events induced by the acute infusion of toxic bile salts responsible for cholestasis include zone 1 hepatocellular necrosis and (b) this can be prevented by the simultaneous infusion of tauroursodeoxycholate.
Animals↗
Hydrolysis and acyl migration of a catechol monoester of L-dopa: L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine.
Hydrolysis and acyl migration studies on L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine (1, NB-355), which produced long-lasting plasma L-dopa levels after oral dosing, have been conducted. Compound 1 exists as pure 4-O-pivaloyl-L-dopa in the solid state, but it converts rapidly to a mixture of the 3- and 4-O-isomers in solution. The rate of acyl migration increased with increases in pH and temperature, and the content of the 4-O-isomer in the equilibrium state was 53-59%. The hydrolysis rate of 1 to L-dopa (6) also increased with increases in pH and temperature, and accelerated steeply at neutral and alkaline pH. The rapid hydrolysis at neutral pH was not observed with O-pivaloyl-L-tyrosine (3), di-O-pivaloyl-L-dopa (4), or L-dopa methyl ester (5). Because of this chemical lability, 1 was hydrolyzed in rat plasma far faster than the other tested catechol esters. However, in rat intestinal homogenate at pH 6.0, 1 was hydrolyzed at the slowest rate among the tested esters, predominantly by a diisofluorophosphate (DFP)-sensitive esterase. Thus, 1 showed a unique in vitro profile on hydrolysis and acyl migration due to the existence of a neighboring hydroxyl group. The stability of 1 in the intestine might be essential for the long-lasting plasma L-dopa profile after oral dosing of 1.
Acylation↗
Luminal bile regulates cholecystokinin release in conscious rats.
The effects of intraluminal bile on cholecystokinin release and pancreatic exocrine secretion were studied in conscious rats. Since it has been suggested that bile acid may influence pancreatic secretion indirectly by interacting with luminal protease activities, intraduodenal protease activities were eliminated by pancreatic juice diversion accompanied with simultaneous intraduodenal infusion of aprotinin. This treatment resulted in gradual increases in pancreatic juice flow, bicarbonate and protein outputs, and an increase in plasma cholecystokinin levels, reaching plateau levels 2 hr after the start of the treatment. When endogenous bile was excluded from the intestine, the pancreatic secretion and plasma cholecystokinin concentrations further increased. The intraduodenal infusion of sodium taurocholate during bile pancreatic juice diversion inhibited cholecystokinin release, while pancreatic protein output was only transiently decreased. The results indicate that bile in the duodenum directly regulates cholecystokinin release, probably through its major components, bile salts.
Animals↗
Inhibitory effect of pancreastatin on pancreatic exocrine secretions. Pancreastatin inhibits central vagal nerve stimulation.
The effects of the C-terminal fragment of rat pancreastatin on exocrine pancreatic secretions induced by several neural stimulations [IV injection of 75 or 15 mg/kg of 2-deoxy-D-glucose (central vagal nerve stimulation), injection of 2 mg of cisapride (proposed to elicit acetylcholine release from cholinergic nerve ending), and infusion of 1 or 3 mg.kg-1.h-1 of bethanechol (direct stimulation of acinar cells)] were examined in conscious rats. Rats with external bile and pancreatic fistulae were used. All the stimulations caused significant increases in pancreatic exocrine secretions. Pancreastatin at 100 pmol.kg-1.h-1 inhibited pancreatic secretions stimulated by IV injection of 2-deoxy-D-glucose but not those induced by the infusion of bethanechol or the injection of cisapride. Because these findings showed that pancreastatin inhibited pancreatic secretions induced by central vagal nerve stimulation, the effect of pancreastatin on cholecystokinin-stimulated pancreatic secretions in vagotomized rats was examined. Pancreastatin at 100 pmol.kg-1.h-1 did not inhibit pancreatic secretions stimulated by cholecystokinin octapeptide at 100 pmol.kg-1.h-1 in conscious rats after bilateral truncal vagotomy. These results suggest that pancreastatin inhibits pancreatic exocrine secretions by inhibiting vagal efferent nerve activity.
Animals↗
The order of hepatic cytotoxicity of bile salts in vitro does not agree with that examined in vivo in rats.
Using an enzyme release from isolated rat hepatocytes incubated with a bile salt as a marker, the cytotoxic order of bile salts was found to be taurochenodeoxycholate, glycochenodeoxycholate greater than tauroursodeoxycholate, glycoursodeoxycholate, cholate greater than taurocholate, glycocholate. Thus, the cytotoxicity of conjugates of ursodeoxycholate was greater than that of conjugates of cholate. However, these data do not agree with the order of cytotoxicity of these bile salts previously studied in vivo by the authors which demonstrated the least cytotoxic nature of conjugates of ursodeoxycholate.
5'-Nucleotidase↗
Tauro beta-muricholate is as effective as tauroursodeoxycholate in preventing taurochenodeoxycholate-induced liver damage in the rat.
Cholestasis and enhanced biliary leakage of proteins such as lactate dehydrogenase (LDH) and albumin are known to be induced by infusions of relatively toxic bile salts such as taurocholate (TC) and taurochenodeoxycholate (TCDC). Tauroursodeoxycholate (TUDC) was previously shown to prevent these bile abnormalities when simultaneously infused (1-5). In the present study, we examined whether tauro beta-muricholate (T beta-MC) has a similar effect. The enhanced biliary excretion of LDH and albumin induced by the infusion of TCDC at a rate of 0.4 mumol/min/100 g was markedly prevented by the simultaneous infusion of T beta-MC or TUDC at a rate one-fourth that of TCDC. Increased LDH level in plasma and hemolysis caused by the infusion of TCDC were also reduced by either T beta-MC or TUDC. These results indicate that T beta-MC has a preventive effect on TCDC-induced hepatobiliary changes, which is as efficient as that of TUDC as shown previously, suggesting that the 7 beta-hydroxy group is important for this hepatoprotective effect. Furthermore, our results suggest that beta-muricholic acid may also have clinical value since current reports demonstrate a beneficial effect of ursodeoxycholic acid on a variety of cholestatic conditions, including primary biliary cirrhosis.
Animals↗
Effect of protein-free diet on activities and subunits of glutathione S-transferase in livers of young and aged female rats.
Female Fischer-344 rats of different ages (8 and 25 months old) were fed a protein-free diet (PFD) for 7 days and refed a normal diet (ND) (23% protein) thereafter. Rats were killed immediately after the PFD was stopped (day 0) and at different time intervals during refeeding of a ND. Four subunits (1,2,3 and 4) and activities of glutathione S-transferases (GSTs) toward five different substrates, [styrene oxide (STOX), 1,2-dichloro-4-nitrobenzene (DCNB), 1-chloro-2,4-dinitro benzene (CDNB), sulfobromophthalein (BSP) and benzalacetone (PBO)] were determined. There were no significant differences between young and old rats in the liver enzyme activities before the PFD. The PFD caused significant decreases in activities for three substrates (DCNB, BSP and STOX) in both age groups, with no significant differences between young and old rats a day 0. During recovery from the PFD, activities for the three substrates exceeded basal levels in young rats but at different time intervals (STOX, day 2; BSP, day 5; DCNB, day 9), while enzyme values in old rats tended to return slowly to basal values with no "overshoot." Concentrations of subunits 3 and 4 in young rat livers that were depressed by the PFD did not recover until day 9 of the ND, while subunits 2 and especially 1 increased during the ND refeeding, overshooting the basal levels. In contrast, in old rat livers the only change was a reduction of subunit 1 by the PFD and its gradual recovery during ND refeeding. These results demonstrate that our previous observation of overshooting of enzyme activities in mice is reproducible in rats but with certain substrate specificities. Furthermore, changes in subunit concentrations caused by aging and a PFD are more complex than what was predicted from changes in enzyme activities of GSTs.
Aging↗
Difference in the effects of ursodeoxycholate and its taurine conjugate on the biliary excretion of sulfobromophthalein in the rat.
A simultaneous intravenous infusion of sulfobromophthalein (BSP) (0.3 mg.min-1.100 g-1) and ursodeoxycholate (UDC) or tauroursodeoxycholate (TUDC) (1.2 mumol.min-1.100 g-1) caused a significantly higher excretion rate of BSP than in the control value without bile salt infusion. In UDC-infused rats, however, the BSP excretion rate began to fall rapidly within the first 30 min of infusion, while the bile flow rate remained high, or even continued to increase. In contrast, the BSP excretion rate in TUDC-infused rats was stable up to 60 min and then began to decline in parallel with the fall of bile flow rate. A significant increase in the BSP transport maximum (Tm) induced by UDC and TUDC in rats does not agree with a previous observation in hamsters where neither of these bile salts enhanced BSP Tm. The discrepancy between these two studies can best be explained by the poor biliary excretion of either TUDC or UDC in hamsters as was previously reported. It was concluded that in rats both TUDC and UDC can significantly increase BSP Tm, which paralleled the excretion rate of bile salts and not the bile flow rate.
Animals↗
Necessity of hyperglycemia for effects of endogenous cholecystokinin on insulin and pancreatic exocrine secretion in conscious rats.
The effects of endogenous cholecystokinin (CCK) on insulin and pancreatic exocrine secretion were examined in conscious rats. Rats with bile and pancreatic fistulae, one duodenal cannula, and two jugular vein cannulae were divided into four groups, with and without glucose infusion (0.2 g/(ml.h)), and with bile and pancreatic juice (BPJ) diversion and return. Without glucose infusion, BPJ diversion did not have any significant effect on the plasma level of insulin or glucose; but with glucose infusion, it caused a significant increase in plasma insulin concentration 1 h after the diversion. The plasma glucose concentrations in the groups with BPJ diversion and return were not significantly different, and the response of pancreatic exocrine secretion to BPJ diversion was suppressed slightly, but not significantly, by glucose infusion. The plasma CCK concentration was increased significantly by BPJ diversion, but not affected by glucose infusion. These results indicate that, as observed in in vitro experiments with exogenous CCK, in conscious rats, endogenous CCK stimulates both exocrine and endocrine secretion of the pancreas, and that hyperglycemia is necessary for these effects to become apparent.
Animals↗
[The digestive system and aging].
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Aging↗
Alteration of plasma sex hormone levels associated with old age and its effect on hepatic drug metabolism in rats.
A mechanism of age-associated alterations in plasma sex hormone levels as well as their effect on drug metabolizing enzyme activities were studied using male and female Fischer 344 rats of ages ranging between 3 and 30 months. Plasma testosterone levels as well as the activity of the rate limiting enzyme required for testosterone production in testes, androstenedione 17 beta-oxido-reductase, decreased with senescence in parallel with the alteration of drug metabolism whereas activity of hepatic microsomal androstenedione 5 alpha-reductase, the testosterone metabolizing enzyme, increased with age. The profile of drug metabolizing activities with imipramine, diazepam, hexobarbital, lidocaine, p-nitroanisole and androstenedione as substrates in old (27-month-old) male rats was almost identical to that in young or old female rats, indicating that neonatal androgenic imprinting of drug metabolism in male rats was erased in senescence. Castration of adult (9-month-old) male rats caused a decrease in drug metabolism, but did not result in complete feminization of the profiles of drug metabolism as was observed in old male rats, indicating that neonatally imprinted male pattern of drug metabolism was still retained in the absence of testosterone in adult male rats. Testosterone administration restored completely male-level activities in castrated adult rats, but caused only a partial recovery in old male rats. It is proposed that senescence associated feminization of the drug-metabolizing ability of the male rat liver may be in part due to the decrease in testosterone levels in old age and in part to the loss of neonatal imprinting.
Aging↗
Evaluation of the involvement of a male specific cytochrome P-450 isozyme in senescence-associated decline of hepatic drug metabolism in male rats.
The major "male specific" species of cytochrome P-450 (P-450ml) was purified and an antibody against it used to evaluate the involvement of this isozyme in alterations of drug metabolism in senescence. P-450ml exhibited strikingly high imipramine (IM) N-demethylase activity while it showed no IM 2-hydroxylation, which is an alternate pathway of IM metabolism in rat liver microsomes. The antibody to P-450ml inhibited 80% of imipramine N-demethylation in young male rats. In old male rats, which have been shown to have lower IM N-demethylase activity, a 60% inhibition was observed. The inhibitable portion of this activity in old male rats is about one third of that in young rats, but the remaining portion not inhibited by this antibody is almost identical in young and old rats. IM 2-hydroxylation on the other hand was not inhibited by this antibody at all. It also inhibited about 30% of diazepam(DZ) N-demethylation in young rats but showed no inhibition in old rats, resulting in the loss of the age difference in the remaining portion. DZ 3-hydroxylation was not inhibited by this antibody, in spite of the fact that it showed a markedly higher activity in young male than in young female rats with a subsequent reduction in old age in male rats. This study provides the first direct evidence that differences in the amount of the major male specific P-450 isozyme (P-450ml) are responsible for the age- and sex-associated differences in some of the drug metabolizing activities. It also became apparent that P-450ml may not be the only isozyme responsible for these differences.
Aging↗