The influences of immobilization and footshock stress on pharmacokinetics of theophylline (20 mg kg-1) and caffeine (30 mg kg-1) administered orally were examined in rats. The immobilization stress for 30 min or 1 h immediately after oral administration caused marked immobilization period-related decreases in plasma theophylline concentrations during the absorption phase, but did not affect plasma caffeine concentrations. The ka and Cmax values for theophylline were significantly decreased, and the tmax was significantly increased. On the other hand, when the immobilization stress was loaded for 1 or 3 h before the oral administration, the plasma theophylline or caffeine concentrations were not affected. The footshock stress for 30 min immediately after oral administration did not significantly decrease plasma theophylline concentrations during the absorption phase. These results suggest that the pharmacokinetics of theophylline are influenced by strong stress, possibly due to the inhibition of its absorption from the gastrointestinal tract, but the pharmacokinetics of caffeine are not influenced by stress, probably due to its central action.

Animals↗

PubMed1995

Biosynthesis and processing of lysosomal cathepsin D in primary cultures of rat hepatocytes.

To investigate the intracellular transport and maturation of lysosomal cathepsin D, we carried out an in vivo pulse-chase analysis with [35S]methionine in the primary cultures of rat hepatocytes. Cathepsin D was initially synthesized as a proenzyme of 45 kDa. The proenzyme was subsequently processed, becoming a mature enzyme of 43 kDa. The proenzyme and mature enzyme showed complete susceptibility to endoglycosidase H treatment, suggesting the presence of high-mannose type oligosaccharide chains. The effects of tunicamycin and chloroquine were also investigated. In the presence of tunicamycin, the 42.5-kDa unglycosylated precursor polypeptide appeared in the cell, and this protein was exclusively secreted from the cells without undergoing proteolytic processing. These results support the notion that the oligosaccharide moieties are of importance in addressing the lysosomal hydrolases to the lysosomes. However, in the presence of chloroquine, proteolytic processing of the proenzyme was prevented, and the enhanced release of proenzyme from the cells was observed. These results indicate that the processing of proenzyme to mature enzyme would take place in the lysosomes.

Animals↗

PubMed1995

Inhibitory effect of leupeptin on the intracellular maturation of lysosomal cathepsin L in primary cultures of rat hepatocytes.

To investigate the intracellular processing event for lysosomal cathespin L, we examined the effect of leupeptin, a non-covalent cysteine proteinase inhibitor, on the intracellular processing kinetics of cathepsin L as analyzed by pulse-chase experiments in vivo with [35S]methionine in primary cultures of rat hepatocytes. This revealed that cathepsin L was initially synthesized as proenzyme of molecular weight 39 kDa and the proenzyme was subsequently processed to the mature form of the enzyme, 30 and 25 kDa. In the leupeptin-treated cells, the proteolytic conversion of cellular procathepsin L, of molecular weight 39 kDa, to the mature enzyme was significantly inhibited and considerable amounts of proenzyme were found in the cell after 8 h chase periods. Furthermore, the subcellular fractionation experiment demonstrated that the intracellular processing of procathepsin L in the high density lysosomal fraction was significantly inhibited and that considerable amounts of the procathepsin L form were still observed in the dense lysosomal fraction after a 2 h chase period. These results suggest that leupeptin treatment caused significant inhibition of the intracellular maturation of cathepsin L. These findings show that cysteine proteinase plays an important role in the intracellular proteolytic processing and activation of lysosomal cathepsin L in vivo and that this processing event occurs within the lysosomes.

Animals↗

PubMed1995

Effects of exposure to cigarette smoke on intestinal propulsion in rats.

The effects of acute exposure to cigarette smoke and systemic administration of nicotine on intestinal propulsion were investigated in rats. The propulsive activity was measured as migration of charcoal powder in the intestine. This activity was suppressed by acute exposure (10 min) to cigarette smoke and by nicotine (0.5 mg/kg x 2, s.c.) administration. This intestinal suppression was more marked in the rats given nicotine than in those exposed to cigarette smoke, whereas the plasma concentrations of nicotine in both rats were similar. These results suggest that acute exposure to cigarette smoke and nicotine administration delay gastric emptying and/or suppress intestinal propulsion, and that some components other than nicotine contained in cigarette smoke may attenuate the suppression of intestinal propulsion induced by nicotine.

Animals↗

PubMed1995

Effect of pregnancy on plasma phenobarbital concentrations in rats.

We examined the pharmacokinetics of phenobarbital before and during pregnancy in rats. Animals were divided into four groups: (a) control, (b) pregnant, (c) phenobarbital-treated, and (d) phenobarbital-treated pregnant groups. The increase in body weight of nonpregnant or pregnant rats was not influenced by long-term phenobarbital treatment. Plasma phenobarbital concentrations during the period of long-term phenobarbital treatment with a fixed dosage by body weight were not significantly affected by pregnancy. Furthermore, pregnancy did not affect pharmacokinetic parameters of phenobarbital between 0.25 and 24h after administration. These results suggest that pregnancy does not influence on the pharmacokinetics of long-term phenobarbital treatment at a fixed dosage by body weight.

Animals↗

PubMed1995

Effect of cigarette smoke on lipid peroxidation and liver function tests in rats.

The effect of cigarette smoke on organ weights, lipid peroxidation and plasma biochemical parameters was investigated in male Wistar rats. Daily exposure (for 20 min twice a day) to cigarette smoke for 27 days caused a significant decrease in liver weight and a significant increase in lung weight. The smoke-exposure group showed increased lipid peroxidation in the liver, but not in the lung. In the smoke-exposure group, the GOT, gamma-GTP, total bilirubin and LDH values were significantly higher than those in the control group, while the plasma glucose value was significantly lower. These results suggest that cigarette smoking might induce liver injury by enhancing lipid peroxidation.

Animals↗

PubMed1995

High susceptibility to paraquat-driven lipid peroxidation of cultured hepatocytes loaded with linolenic acid.

Rat hepatocytes cultured without (normal cells) and with 1 mM alpha-linolenic acid-bovine serum albumin complex (alpha-linolenic acid [LNA]-loaded cells) for 12 hr were challenged with paraquat at concentrations ranging from 0.01 to 5 mM. The addition of paraquat to normal hepatocytes induced a relatively low level of lipid peroxidation as measured by the accumulation of malondialdehyde in the medium, even at a high paraquat concentration that caused severe cell injury. LNA-loaded hepatocytes markedly underwent lipid peroxidation on addition of paraquat, with a rise in the malondialdehyde accumulation beginning at the lowest concentration used (0.01 mM). The enhanced lipid peroxidation induced in LNA-loaded hepatocytes by the addition of paraquat was accompanied by the occurrence of cell injury at noncytotoxic paraquat concentrations for normal cells. Of further importance was that in LNA-loaded cells, lipid peroxidation promptly occurred after the addition of paraquat and was followed by the loss of cell viability. Addition of antioxidants such as N,N'-diphenyl-p-phenylenediamine and alpha-tocopherol with paraquat prevented lipid peroxidation in both normal and LNA-loaded hepatocytes but protected only the latter cells from cell injury. Neither lipid peroxidation nor cell injury in either group of hepatocytes was prevented by the presence of .OH scavengers such as mannitol and dimethyl sulfoxide. In addition, paraquat-driven lipid peroxidation in LNA-loaded hepatocytes was promoted by the addition of ascorbate but was rather suppressed by the addition of H2O2. In conclusion, it is likely that the addition of paraquat induced Fe(++)-lipid hydroperoxide-dependent lipid peroxidation that led to lethal cell injury in LNA-loaded hepatocytes.

Animals↗

PubMed1995

[Cephalad movement of the carina due to CD (Cotrel-Dubousset) instrumentation for idiopathic scoliosis].

Recently we experienced a case of tracheal tube obstruction due to the upward displacement of carina during CD (Cotrel-Dubousset) instrumentation for idiopathic scoliosis. Therefore, we hypothesized that CD instrumentation may affect the position of the carina as a result of correction of chest deformity, and studied the displacement of carina before and after CD instrumentation on chest X-ray in 12 patients with scoliosis. The length between the bottom of the 6th cervical vertebral body and the carina was measured by using chest X-ray before and after the correction. In all patients studied, cephalad movement of the carina was observed, and it was more than 1.00 cm in 5 patients. The maximal movement of the carina was 1.59 cm. The tracheal length after the correction was significantly shorter than before (P < 0.01). These results suggest that the carina may be displaced upwards due to the correction by the CD instrumentation, and that such induced displacement may affect the tracheal tube position and obstruct the tube during the operation.

Adolescent↗

PubMed1995