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Biomedical subjects

T Manabe

Publications and source records attributed to T Manabe.

At least 325 records · Page 18Linked to original sources
PubMed1992

Protective effects of combined therapy with a protease inhibitor, ONO 3307, and a xanthine oxidase inhibitor, allopurinol on temporary ischaemic model of pancreatitis in rats.

The protective effect of a new potent protease inhibitor, ONO 3307, in combination with a xanthine oxidase inhibitor, allopurinol, was tested in pancreatico-biliary duct obstruction (PBDO) with temporary pancreatic ischemia in rats. After PBDO with ischemia, we observed hyperamylasemia, pancreatic edema, congestion of amylase and lysosomal enzyme cathepsin B as well as impaired output of amylase and cathepsin B into the pancreatic juice and a redistribution of lysosomal enzyme from the lysosomal fraction to the zymogen fraction. The administration of ONO 3307 plus allopurinol almost completely prevented the pancreatic injuries induced by PBDO with ischemia. These results indicate the important roles of temporary pancreatic ischemia in the pathogenesis of pancreatic damage and the usefulness of combination therapy with a new potent protease inhibitor and xanthine oxidase inhibitor in the protection against clinical acute pancreatitis.

Acute Disease↗
PubMed1992

[Protective effect of prostaglandin E2 on cerulein-induced rat pancreatitis].

In order to clarify the effect of prostaglandin E2 (PGE2) on cerulein-induced rat pancreatitis, we investigated the interaction of PGE2 with cerulein or secretin. Intravenous infusion of 10 micrograms/kg.h cerulein inhibited external secretion of the pancreas from one hour and caused macroscopic edema at 3 hours. Administration of PGE2 relieved the inhibitory effect of supramaximal dose of cerulein and decreased the pancreatic edema. The 100 micrograms/kg.hr PGE2 had no significant effect on the pancreatic juice volume and amylase secretion stimulated with 0.2 micrograms/kg.hr of cerulein. Intravenous injection of 100 micrograms/kg PGE2 inhibited both the volume and amylase secretion of pancreatic juice stimulated with 1 U/kg.h of secretin. The protective effect of PGE2 on cerulein-induced pancreatitis was not the stimulation on secretion but caused the cytoprotective effect of PG such as stabilization of cytoplasmic and lysosomal membrane.

Acute Disease↗
PubMed1992

Secretion of lysosomal and digestive enzymes into pancreatic juice under physiological and pathological conditions in rabbits.

To investigate the possible secretion of lysosomal enzymes into pancreatic juice during stimulation with a pancreatic secretagogue under both physiological and pathological conditions, we measured the amount of cathepsin B, a lysosomal enzyme, in the pancreatic juice during the infusion of 6 different concentrations of caerulein (0.02, 0.05, 0.2, 0.5, 1.0, and 2.0 micrograms/kg. hr). In one group of rabbits the pancreatic duct was only cannulated (free-flow group); in others the pancreatic duct was obstructed for 7 hours and secretin was infused at 0.2 CU/kg. hr (obstructed group). In addition, we evaluated the effect of the intraduodenal instillation of a liquid meal (2 g/kg) on the secretion of lysosomal enzymes into pancreatic juice. Caerulein stimulated the secretion of cathepsin B into pancreatic juice in a dose-dependent manner, as it did that of amylase, and at higher concentrations of caerulein (1.0 and 2.0 micrograms/kg. hr), both cathepsin B output and amylase output were decreased. There was a significant positive correlation between cathepsin B output and amylase output into pancreatic juice during stimulation with caerulein. Blockage of the pancreatic duct for 7 hours caused a significant rise in serum amylase levels and a redistribution of cathepsin B activity in the pancreatic subcellular fractions, as a result of which an increased amount of cathepsin B was recovered in the pellet obtained by 1000 x g centrifugation for 15 min, which contained many zymogen granules. These changes noted after short-term pancreatic duct obstruction are very similar to those previously noted in the early stage of diet-and caerulein-induced experimental pancreatitis, suggesting the colocalization of lysosomal enzyme and digestive enzymes. In the duct-obstructed animals, the secretion of cathepsin B stimulated by caerulein was significantly greater than in the free-flow group. Furthermore, the intraduodenal instillation of a liquid meal caused the secretion of cathepsin B into the pancreatic juice along with amylase. These results indicate that under physiological conditions, such as food intake, lysosomal enzymes are secreted into the pancreatic juice in response to stimulation by gut hormones in the same manner as classical pancreatic digestive enzymes. Moreover, zymogen colocalized with lysosomal enzymes in duct-obstructed animals is secreted into pancreatic juice in increased amounts together with digestive enzymes; this finding suggests that lysosomal enzymes play important pathophysiological roles in pancreatic juice and that acinar cells are altered to maintain cellular organization by secreting the potentially dangerous lysosomal enzymes. This pancreatic duct-obstructed rabbit model should be useful in clarifying the early events of acute pancreatitis.

Amylases↗
PubMed1992

Effect of 3-hour pancreatic duct obstruction on pancreatic lysosomal and digestive enzymes in rabbits.

We studied the effect of short-term (3 hours) pancreatic duct obstruction (PDO) on the exocrine pancreas and on the secretion of lysosomal enzymes into the pancreatic juice of rabbits during stimulation by pancreatic secretagogues. The following evaluations were made: serum amylase levels, pancreatic water content, pancreatic amylase, trypsinogen and cathepsin B content, and output of pancreatic enzymes and lysosomal hydrolases when stimulated by secretin and caerulein as well as the distribution of cathepsin B in subcellular fraction. PDO for 3 hours plus secretin infusion caused a significant rise in serum amylase levels, pancreatic water content, and pancreatic amylase and trypsinogen content due to congestion of digestive enzymes during PDO. There was also a redistribution of cathepsin B from the lysosomal fraction to the zymogen fraction. In normal rabbits and in those with only secretin infusion, caerulein stimulated the secretion of cathepsin B, into pancreatic juice. Just after PDO, the secretion of cathepsin B, amylase and trypsinogen significantly decreased. By 24 hours after PDO, the output of cathepsin B stimulated by caerulein and secretin had increased significantly. Amylase and trypsinogen output were also significantly increased at this stage, in both the secretin and caerulein fractions. These results indicate that the secretion of lysosomal enzymes into pancreatic juice is stimulated by gut hormones, such as caerulein, in the normal physiological state and in pathological states, such as PDO. These results also show augmented secretion of both lysosomal enzymes and pancreatic digestive enzymes in the recovery stage after PDO and their important roles at this stage.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed1992

Postsynaptic contribution to long-term potentiation revealed by the analysis of miniature synaptic currents.

Miniature excitatory synaptic currents were recorded from CA1 pyramidal cells in hippocampal slices to study the site of the persistent change in synaptic efficacy during long-term potentiation. Induction of long-term potentiation produced a large increase in the amplitude of these currents. Such a change in amplitude suggests an increase in postsynaptic transmitter sensitivity.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1992

Direct surface cooling of the exocrine pancreas in the rat.

A study was carried out to evaluate the effects of direct cooling on the exocrine pancreas. Changes in amylase and cathepsin B release, and in the subcellular distribution of amylase and cathepsin B were measured after 1, 2 and 3 h of direct pancreatic cooling in rats. Cooling for 2 and 3 h caused significant hyperamylasaemia and increased pancreatic amylase content, but minimal histological change. Furthermore, 3 h of cooling caused marked redistribution of cathepsin B activity from the lysosomal fraction to the heavier zymogen fraction, and co-localization of lysosomal and digestive enzymes; amylase and cathepsin B output into pancreatic juice after caerulein stimulation were also reduced. These results show that direct pancreatic cooling impairs exocrine function and implicate lysosomal enzymes in the pathogenesis of pancreatic injury, in agreement with results from other models of experimental pancreatitis.

Amylases↗
PubMed1992

Role of ischemia in acute pancreatitis. Hemorrhagic shock converts edematous pancreatitis to hemorrhagic pancreatitis in rats.

Ischemia has been considered to play a role in the development of acute pancreatitis. The aim of this study was to investigate the effect of ischemia, caused by hemorrhagic shock, on cerulein-induced acute pancreatitis in rats. Acute pancreatitis was induced by the intravenous infusion of a supramaximally stimulating dose of cerulein (10 micrograms/kg/hr) for 6 hr. Hemorrhagic shock was induced by the removal of blood until the mean arterial blood pressure reached 35 mm Hg. This level was maintained for 30 min, after which time all the blood was reinfused. Hemorrhagic shock alone induced no morphological change in the pancreas. However, after the induction of hemorrhagic shock in animals treated with cerulein, hemorrhage and parenchymal necrosis were frequently observed in the pancreas. Seven of 20 rats (35%) receiving cerulein plus hemorrhagic shock had died by 48 hr after the start of cerulein infusion, whereas none of the rats in the cerulein or shock group died during this experiment. Cathepsin B activity in the pancreas of the cerulein plus shock group was significantly higher than in the other groups at 48 hr. These results suggest that ischemia may be a contributing factor in the pathogenesis of acute pancreatitis.

Acute Disease↗
PubMed1992

Evidence for a role of free radicals by synthesized scavenger, 2-octadecylascorbic acid, in cerulein-induced mouse acute pancreatitis.

To define the role of free radicals and of lipid peroxide involvement during the progress of cerulein-induced acute pancreatitis in mice, we evaluated the effect of a novel free radical scavenger, 2-octadecylascorbic acid (CV-3611), on pancreatic edema formation, and the levels of serum enzymes (amylase, lipase) and of lipid peroxide in pancreatic tissue. Mice were divided into three groups: control group, intraperitoneal injection of saline only; pancreatitis group, cerulein 50 micrograms/kg injected intraperitoneally six times at 1-hr intervals; treatment groups, CV-3611 10 mg/kg subcutaneously just after intraperitoneal cerulein injection. After the cerulein injection, the degree of pancreatic edema formation, serum amylase and lipase levels, and the amount of lipid peroxide in pancreatic tissue increased significantly during the observation period of 12 hr. Treatment with CV-3611 resulted in significant reduction in pancreatic edema formation at 3.5 hr (P less than 0.05) and 9 hr (P less than 0.05), serum amylase and lipase levels at 3.5 hr (P less than 0.05) and 12 hr (P less than 0.05), and lipid peroxide levels at 3.5 hr (P less than 0.05), 6 hr (P less than 0.05) and 12 hr (P less than 0.05). These results indicate that a novel free radical scavenger, CV-3611, has a strong therapeutic effect during the development of acute pancreatitis and suggest that oxygen-derived free radicals play an important role in the pathogenesis of acute pancreatitis.

Acute Disease↗
PubMed1992

Impaired hepatic energy metabolism in rat acute pancreatitis: protective effects of prostaglandin E2 and synthetic protease inhibitor ONO 3307.

To evaluate the effects of acute pancreatitis on the energy metabolism of the liver and on the fragility of hepatic cells and subcellular organelles, we studies (1) the arterial blood ketone body ratio (BKBR) (aceto acetate/beta-hydroxy butyrate), which is in equilibrium with the free NAD+/NADH ratio in liver mitochondria; (2) the hepatic energy charge (EC) = (ATP + 1/2 ADP)/(ATP + ADP + AMP); (3) the cathepsin B leakage from hepatic lysosomes and the malate dehydrogenase leakage from hepatic mitochondria in vitro; and (4) the protective effects of prostaglandin E2 (PGE2) and a new synthetic protease inhibitor ONO 3307 on hepatic injury in acute pancreatitis induced in rats by a supramaximal dose of caerulein. Decreased BKBR and hepatic EC as well as increased hepatic lysosomal and mitochondrial fragility were observed in rats with this type of acute pancreatitis, and both PGE2 and ONO 3307 had a significant protective effect against hepatic injury in these rats, especially ONO 3307. These results suggest that impaired hepatic energy metabolism is closely related to increased hepatic lysosomal and mitochondrial fragility and that some proteases, which are derived from pancreatitis and are susceptible to inhibition by ONO 3307, seem to play an important pathological role in this liver injury induced by pancreatitis. Therefore, it is important to take care of the liver in patients with acute pancreatitis.

3-Hydroxybutyric Acid↗
PubMed1992

Pharmacokinetics of intratumoral RK-28, a new hypoxic radiosensitizer.

RK-28 is one of the new hypoxic cell radiosensitizers being developed in Japan and has been tested clinically. To reduce its toxicity and increase its sensitizing activity, intratumoral injection of RK-28 was performed during intraoperative radiation therapy for pancreatic cancer. This report presents the results of pharmacokinetic studies performed in 10 of the 17 patients who were administrated intravenous or intratumoral RK-28 during intraoperative radiation therapy. No adverse effects were noted following intravenous or intratumoral injection of the drug. Pharmacokinetic studies demonstrated several metabolites of RK-28 in both serum and tumor tissues. After intratumoral injection, the tumor drug concentration ranged from 123 micrograms/g to 9,292 micrograms/g just after intraoperative radiation therapy (30-50 min after injection of the compound), while the serum concentration ranged from 4.1 to 9.8 micrograms/ml. The tumor drug concentration was 23.3 micrograms/g at 45 min after intravenous injection of RK-28. Thus, intratumoral injection of RK-28 was superior to intravenous administration in this pharmacokinetic study. The combination of intraoperative radiation therapy and intratumoral injection of RK-28 appears to be a feasible treatment method.

Adult↗
PubMed1992

Ca2+ entry via postsynaptic voltage-sensitive Ca2+ channels can transiently potentiate excitatory synaptic transmission in the hippocampus.

We have studied the role of Ca2+ entry via voltage-sensitive Ca2+ channels in long-term potentiation (LTP) in the CA1 region of the hippocampus. Repeated depolarizing pulses, in the presence of the NMDA receptor antagonist D-APV and without synaptic stimulation, resulted in a potentiation of excitatory postsynaptic potentials (EPSPs) or currents (EPSCs). This depolarization-induced potentiation was augmented in raised extracellular Ca2+ and was blocked by intracellular BAPTA, a Ca2+ chelator, or by nifedipine, a Ca2+ channel antagonist, indicating that the effect was mediated by Ca2+ entry via voltage-sensitive Ca2+ channels. Although the peak potentiation could be as large as 3-fold, the EPSP(C)s decayed back to baseline values within approximately 30 min. However, synaptic activation paired with depolarizing pulses in the presence of D-APV converted the transient potentiation into a sustained form. These results indicate that a rise in postsynaptic Ca2+ via voltage-sensitive Ca2+ channels can transiently potentiate synaptic transmission, but that another factor associated with synaptic transmission may be required for LTP.

2-Amino-5-phosphonovalerate↗
PubMed1992

Pancreatic secretion of lysosomal enzymes stimulated by intraduodenal instillation of a liquid meal in rabbits.

1. Studies have been performed to determine the effect of intraduodenal food on pancreatic secretion of lysosomal enzymes. 2. Intraduodenal instillation of a liquid meal (3 g/kg body weight; 15.3% protein, 19.7% fat, 59.7% carbohydrate) caused significant increases in pancreatic juice volume and pancreatic secretion of amylase and protein compared with basal values for 2h after instillation in anaesthetized rabbits. 3. Intraduodenal instillation of a liquid meal also caused significant increases in pancreatic secretion of three lysosomal enzymes (cathepsin B, N-beta-acetyl-galactosaminidase and N-acetyl-beta-glucosaminidase) compared with basal values for 2h after instillation. 4. In addition, there were significant correlations between cathepsin B secretion and amylase secretion (r = 0.7764, P < 0.001) and between cathepsin B secretion and protein secretion (r = 0.6216, P < 0.001), both in basal conditions and in response to the liquid meal. 5. These results are evidence for the localization of lysosomal enzymes in the secretory granules-zymogen granules in normal acinar cells, and also indicate that the pancreatic secretion of lysosomal enzymes is gut-hormone-regulated.

Acetylglucosaminidase↗
PubMed1992

Cytoprotective effects of prostaglandins and a new potent protease inhibitor in acute pancreatitis.

The redistribution of cathepsin B, a lysosomal enzyme, from the lysosomal pellet to the zymogen pellet in the subcellular fractionation, the colocalization of cathepsin B with digestive enzyme, and increased cellular, lysosomal, and mitochondrial fragility within acinar cells have been found during the early stages of caerulein-induced acute pancreatitis in rats. In the present study, the authors investigated the protective effects of prostaglandin E1 and E2, a combined therapy of these prostaglandins, and a new, synthetic, low molecular weight protease inhibitor, ONO3307, on the exocrine pancreas in this noninvasive model of experimental pancreatitis in vivo and in vitro. Prostaglandin E2, but not E1, prevented hyperamylasemia, congestion of amylase and trypsinogen in the acinar cells, redistribution of cathepsin B, and amylase and lactate dehydrogenase discharge from the dispersed acini. It also prevented cathepsin B leakage from the lysosomes and malate dehydrogenase leakage from the mitochondria in an almost dose-dependent manner, particularly at the dose of 100 micrograms/kg/hr continuous infusion. Furthermore, the combined therapy of prostaglandin E2 with ONO3307 strongly inhibited all the parameters tested in this study. This combination therapy seems to be the most effective against secretagogue-induced pancreatic injuries. These results indicate that cellular and subcellular organellar fragility seem to be closely involved in the pathogenesis of acute pancreatitis. Prostaglandin E2 seems to have important cytoprotective effects on the biologic membranes, such as a stabilizer of lysosomal or mitochondrial membranes. In addition, these findings also suggest the crucial roles of some unknown proteases in the etiology of acute pancreatitis, and indicate the clinical effectiveness of prostaglandins and this type of low molecular weight protease inhibitor for acute pancreatitis.

Acute Disease↗
PubMed1992

Pulmonary mucormycosis with fatal massive hemoptysis.

A case of pulmonary mucormycosis in a 57-year-old woman with acute promyelocytic leukemia (APL) who died of massive hemoptysis is reported. Chest radiography revealed changes that began with a small focal infiltration and progressed to a large round nodule with cavity formation. Postmortem examination showed the nodule to be composed mainly of infarcted lung tissue with saprophytic growth of Mucor. An adjacent proximal branch of the left pulmonary artery was thrombosed with mucoraceous hyphae, and it had ruptured into the cavitary space around the necrotic tissue and then into a conducting bronchus. In general, both fatal massive hemoptysis and cavity formation are rare in pulmonary mucormycosis. In our present case, the histological findings suggested that both phenomena were closely related to the pulmonary infarction caused by Mucor invasion of the pulmonary artery.

Female↗
PubMed1992

Protection by a new synthetic protease inhibitor, ONO3307, of the rat exocrine pancreas during acute edematous pancreatitis induced by a supramaximal dose of caerulein in comparison with FOY007.

The present study investigated the protective effects of the new potent synthetic protease inhibitors, ONO3307 (4-sulfamoyl phenyl-4-guanidinobenzoate methanesulfonate) and FOY007 (gabexate misilate), on the exocrine pancreas in rat caerulein-induced acute pancreatitis in both in vitro and in vivo experiments. These protease inhibitors prevented hyperamylasemia, pancreatic edema, congestion of amylase, redistribution of lysosomal enzyme in acinar cells, and lactic dehydrogenase (LDH) discharge from dispersed acini. They also inhibited the cathepsin B leakage from the lysosomes in a dose-dependent manner in doses of 2-10 mg/kg.h of ONO3307 and 20-50 mg/kg.h of FOY007. These results indicate that both ONO3307 and FOY007 exert protective effects against pancreatitis at subcellular levels in lysosomes and cellular or organelle membranes. Proteases appear to be important in the pathogenesis and development of acute pancreatitis, and low-molecular-weight protease inhibitors may be of clinical use in the treatment of acute pancreatitis.

Acute Disease↗
PubMed1992

Functional changes of the exocrine perfused rat pancreas in cerulein-induced pancreatitis.

Functional changes of the exocrine pancreas in cerulein-induced pancreatitis were evaluated with the isolated perfused rat pancreas. In control specimens (n = 7), baseline pancreatic juice volume was 0.23 +/- 0.06 microliter/min and after stimulation with CCK-8 (10(-10) M) and secretin (10(-10) M), it was 2.26 +/- 0.45 microliter/min, and in cerulein-induced pancreatitis specimens (n = 8), the corresponding values were 0.11 +/- 0.03 and 0.23 +/- 0.08 microliter/min. The amylase content in the pancreatic juice (IU/min) was 0.73 +/- 0.15 (baseline) and 7.03 +/- 1.66 (stimulated) in the control specimens, and 0.012 +/- 0.002 (baseline) 0.018 +/- 0.004 (stimulated), in the cerulein-induced pancreatitis specimens. Amylase and lipase concentrations in the portal effluents were significantly higher in the cerulein-induced pancreatitis (481.3 +/- 79.4 IU/ml, 283.7 +/- 47.2 BALB U/ml) than in the control specimens (10.7 +/- 1.8 IU/ml, 8.9 +/- 2.9 BALB U/ml). Using the electron microscope fusion of large vacuoles with lateral plasma membrane was observed in cerulein-induced pancreatitis. In cerulein-induced pancreatitis, normal secretion was markedly decreased, and the lateral secretion was suggested to result in the elevation of pancreatic enzyme levels in portal effluents.

Amylases↗