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R Doi

Publications and source records attributed to R Doi.

At least 73 records · Page 4Linked to original sources
PubMed1995

Structural and functional changes of rat exocrine pancreas exposed to nicotine.

Nicotine, an addictive agent in cigarette smoking, has been implicated in the etiology of pancreatitis and pancreatic carcinoma. Very little experimental data are, however, available regarding the effects of nicotine on the structural and functional changes in the exocrine pancreas. Two groups of rats divided into control and nicotine exposed were used. The animals in the nicotine group were maintained for 28 d with ad libitum water containing 0.77 mM of nicotine. At term, the animals were sacrificed, and pancreas was examined for pathological and functional changes. Nicotine induced cytoplasmic vacuolation and cellular edema in the exocrine pancreas. Plasma levels of glucose and insulin and CCK-8-stimulated amylase release in isolated acini were significantly decreased by nicotine, whereas the total cellular amylase content was significantly increased. Analysis of competitive ligand binding data on membranes from isolated acini showed that the Bmax and Kd values for CCK receptors were not significantly changed by nicotine, p > 0.05. These data indicate that a postreceptor mechanism is involved in the inhibition in stimulus-secretion coupling of enzyme secretion by nicotine. The increase in total cellular amylase content and decreased enzyme secretion by nicotine may be implicated in the induction of pancreatic pathology.

Amylases↗
PubMed1995

Carbachol and cholecystokinin enhance accumulation of nicotine in rat pancreatic acinar cells.

Nicotine is a possible risk factor for chronic pancreatitis and pancreatic cancer. To study the loci where nicotine might exert its effect, we examined interactions between nicotine and rat pancreatic acini. When pancreatic acini were incubated with [3H]nicotine, [3H]nicotine levels in pancreatic acini were increased in time-and dose-dependent manners, and the t1/2 for dissociation of [3H]nicotine was 63.8 min. At 4 degrees C, the association of [3H]nicotine was 33% of the association at 37 degrees C. Unlabeled nicotine had no significant effect on the accumulation of [3H]nicotine. In addition, surface-bound [3H]nicotine was not detected when acini were washed in a low-pH solution or when they were trypsinized. These results suggest that the accumulation of nicotine may be a biological phenomenon and that [3H]nicotine does not bind to surface receptors of acinar cells, but accumulates intracellularly. The addition of verapamil (0.1 mM) or 12-O-tetradecanoylphorbol-13-acetate (1 microM) had no effect on [3H]nicotine association, while 4-bromo-A23187 (2 microM) or EGTA (10 mM) significantly increased the accumulation of [3H]nicotine. Carbachol and cholecystokinin significantly enhanced the accumulation of [3H]nicotine in a dose-dependent manner. Taken together, the increasing effects of carbachol and cholecystokinin on the accumulation of nicotine may explain, at least in part, the mechanisms involved in the multiplicative effects of the combination of two risk factors, smoking habit and high-fat or high-protein diets, on human pancreatic diseases.

Animals↗
PubMed1995

Effect of a new bombesin receptor antagonist, (E)-alkene bombesin isostere, on amylase release from rat pancreatic acini.

The short-chain pseudopeptide, [D-Phe6, Leu13 psi (CH2NH)Leu14]bombesin(6-14) (RDI), is reported to be a potent antagonist of bombesin, and development of this type of compound has greatly contributed to the investigation of biological actions of bombesin and its related peptides. We recently synthesized (E)-alkene bombesin isostere by replacing the peptide bond with an (E)-double bond: [D-Phe6, Leu13 psi [(E)CH = CH]Leu14] bombesin(6-14) (EABI). The present study examined the effect of EABI on amylase release from rat pancreatic acini. EABI showed no agonistic activity at concentrations up to 1 microM, and RBI showed slight agonistic activity at concentrations > 10 nM. EABI caused a dose-dependent inhibition of amylase release stimulated by 0.1 nM bombesin, with an IC50 of 6.7 +/- 1.7 nM, and induced almost-complete inhibition at 0.3 microM. RDI caused a dose-dependent inhibition of amylase release, with an IC50 of 68.7 +/- 16 nM. EABI caused a parallel and rightward shift of the entire dose-response curve of bombesin-stimulated amylase release, and the degree of the shift was dependent on the concentrations of EABI. EABI (100 nM) and RDI (100 nM) inhibited amylase releases stimulated by gastrin-releasing peptide (1 nM) and neuromedin-C (1 nM). In contrast, amylase release stimulated by cholecystokinin octapeptide (0.1 nM), carbachol (10 microM), vasoactive intestinal peptide (1 nM), and gastrin-17 (10 nM) was not inhibited by EABI and RDI. The results indicate that EABI is a potent and specific bombesin receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

Residual neurobehavioural effects associated with chronic exposure to mercury vapour.

To find the residual effects of long term exposure to mercury vapour, neurobehavioural tests were given to ex-mercury miners about 18 years after the end of mercury exposure. Seventy six male ex-mercury miners who had been exposed to high concentrations of mercury vapour (over 1.0 mg/m3) and with a history of mercury intoxication were compared with controls matched for age (within 3 years), sex, and education. Although the extent of the workers' symptoms caused by mercury poisoning, termed erethismus merculialis, decreased considerably after the end of exposure, matched paired comparison showed that performances of motor coordination, simple reaction time, and short term memory had deteriorated significantly in the exposed group. Multiple linear regression analysis of exposure variables with neurological examination measures showed positive correlations between poorer neurological performance and variables related to mercury exposure. Thus the duration of exposure correlated with poorer performance of hand-eye coordination, tapping, and a colour card reading test. Job categories classified by exposure to mercury also had a significant negative correlation with these performances. The period of years after the end of exposure had a significant correlation with better performance of reaction time and digit span. On the other hand, the history of intoxication itself had no significant correlation with any of the current neurobehavioural performances. These results suggest that there are slight but persistent effects on neurobehavioural function, especially on motor coordination, among mercury miners even more than 10 years after the end of exposure.

Aged↗
PubMed1993

Agonist-regulated alteration of the affinity of pancreatic muscarinic cholinergic receptors.

Heterologous desensitization is a term that indicates that exposure of a cell to an agonist attenuates the response of that cell to other agonists. We examined heterologous desensitization of muscarinic cholinergic receptors of pancreatic acini and characterized mechanisms that might be responsible for desensitization. Muscarinic cholinergic receptor binding was measured by using N-[3H]methscopolamine bromide ([3H]NMS). N-Methscopolamine bromide (NMS), a receptor antagonist, bound to a single class of receptors with an affinity of 0.22 +/- 0.04 nM and a capacity of 61.5 +/- 5.1 fmol/mg of protein. These parameters of NMS binding sites were not altered by an addition of cholecystokinin (CCK) octapeptide, CCK-JMV-180, vasoactive intestinal peptide, 8-bromo-cAMP, 4-bromo-A23187, thapsigargin, or 12-O-tetradecanoylphorbol-13-acetate (TPA). Analysis of competitive inhibition curve of [3H] NMS binding by carbachol showed apparently two classes of carbachol binding sites with high affinity (38.6%) and low affinity (61.4%). Simultaneous incubation of carbachol with CCK or TPA increased the relative affinity of [3H]NMS binding, and the competitive inhibition curves showed a single class of carbachol binding site. L-364,718 blocked the effect of CCK, and staurosporine blocked the effects of TPA and partially blocked the effect of CCK. CCK-JMV-180, vasoactive intestinal peptide, 8-bromo-cAMP, 4-bromo-A23187, and thapsigargin had no effects on the competitive binding. Second, the carbachol-induced sequestration of the receptors was examined. Incubation of acini with carbachol resulted in a decrease of [3H] NMS binding sites, and the addition of CCK or TPA caused an inhibition of the carbachol-induced disappearance of [3H]NMS binding sites. Finally, studies that examined the biological response of the acinar cells showed that biphasic amylase release in response to carbachol was completely suppressed by 10 nM CCK for entire range of carbachol. Taken together, these results suggest that the effect of CCK on carbachol-induced sequestration is important for the alteration of the apparent affinity of carbachol binding sites and the biological response of acinar cells to carbachol. Further, the results suggest that another factor that induces uncoupling of receptor from effector might be involved in agonist-regulated desensitization. The results, that CCK-JMV-180 or other agonists that activate the adenylate cyclase pathway did not exert these effects of CCK, suggest that protein kinase C may be one of the key factors involved in heterologous desensitization by CCK on the carbachol binding sites and the suppression of carbachol-induced amylase release.

Amylases↗
PubMed1993

Significance of subclinical entrapment of nerves in lead neuropathy.

We examined a left-handed 25-year-old man engaged for 2 years at a vinyl chloride resin factory where he had been exposed to lead stearate, a stabilizer of resin. Neurological examination revealed atrophy of small hand muscles, especially in the left dorsal interossei. Sensation of all modalities was intact. A nerve conduction study showed conduction block at the elbow, indicating possible cubital tunnel syndrome. Following CaEDTA therapy, continued recovery of conduction velocities, amplitude of compound muscle action potential, and diminution of conduction block at elbow were observed within a few months. In lead intoxication, nerves may incur mechanical damage. Subclinical entrapment may thus be an important factor leading to vulnerability of nerves in lead neuropathy.

Action Potentials↗
PubMed1993

Subjective symptoms and neurobehavioral performances of ex-mercury miners at an average of 18 years after the cessation of chronic exposure to mercury vapor. Mercury Workers Study Group.

In order to determine if there are any residual effects of long-term exposure to mercury vapor, neurobehavioral tests were given to ex-mercury miners about 18 years after the cessation of mercury exposure. Seventy-six male ex-mercury miners who had been exposed to relatively high concentrations of mercury vapor (over 1.0 mg/m3) and with a past history of mercury intoxication were compared to age (+/- 3 years)-, sex-, and years of education-matched controls. Although the extent of the workers' symptoms caused by mercury poisoning, termed erethismus merculialis, markedly decreased after the cessation of exposure, the prevalence of neurological symptoms (such as hand tremors, headaches, and slurred speech) and symptoms of senility (such as low-back pain, loss of sexual desire) in the ex-miners was significantly higher than those in the controls. Matched-pair analysis showed that performances of motor coordination, Simple reaction time, and Short-term memory in the ex-miners were significantly deteriorated compared to those of controls. There are slight but persistent effects on neurobehavioral function, especially on motor coordination function, among mercury miners more than 10 years after the cessation of exposure.

Aged↗
PubMed1993

The effect of intravenous cadmium on exocrine and endocrine pancreatic functions in conscious dogs.

This study was conducted in conscious dogs to investigate the effect of cadmium on exocrine pancreatic secretion and plasma levels of pancreatic polypeptide (PP). Mongrel dogs weighing 20-25 kg were prepared with chronic gastric and pancreatic fistulas, and were acclimated for 3 wk prior to studies. The dogs were given iv infusion of saline, secretin at 25 U/kg/h, cadmium at 0.15 mg/kg/h, or various combinations of these compounds. During the infusion, pancreatic juice and blood samples were collected at regular intervals. Secretin infusion stimulated pancreatic secretions. Infusion of cadmium alone had no effect on pancreatic secretions and plasma levels of PP. When cadmium infusion was stopped with the background infusion of secretin, pancreatic secretions and plasma levels of PP were significantly increased. This latent effect of cadmium on pancreatic secretions and plasma levels of PP was abolished by an iv injection of 100 mg/kg atropine. These results indicate that cholinergic signaling may be involved in the effect of cadmium on pancreatic exocrine secretions and PP release. The current study suggests that cadmium may have diverse physiological functions in both exocrine and endocrine pancreatic cells.

Animals↗
PubMed1993

The role of gastrointestinal peptides on pancreatic secretion in response to different stimulants in conscious rats.

Effects of intragastric food, intraduodenal amino acids, and intravenously administered bombesin and gastrin-releasing peptide (GRP) were examined in conscious rats with pancreatic fistula in terms of responses of exocrine pancreatic secretion, plasma levels gastrin, and cholecystokinin (CCK). Pancreatic juice and blood samples were collected at regular intervals before and after the stimuli. Intragastric food increased pancreatic secretion and plasma levels of gastrin and CCK. Intraduodenal infusion of amino acids had no effect on pancreatic secretion and plasma levels of gastrin and CCK. Intravenous infusion of bombesin at 1 microgram/kg/h induced significant increases in pancreatic volume and protein outputs, but had no effect on plasma levels of gastrin and CCK. Bombesin infusion at 10 micrograms/kg/h resulted in significant increases in pancreatic volume and protein outputs as well as plasma gastrin levels, but had no effect on plasma CCK levels. Intravenous infusion of GRP induced increases in pancreatic volume and protein outputs and plasma gastrin levels, but had no effect on CCK levels. Antrectomy resulted in significant decreases in basal levels of plasma gastrin. GRP-stimulated pancreatic volume and protein outputs were not significantly changed by antrectomy. In rats that underwent antrectomy, GRP infusion significantly increased pancreatic volume and protein outputs, but had no effect on plasma levels of gastrin and CCK. Food-stimulated pancreatic secretion and plasma levels of gastrointestinal peptides of rats were similar to other species, but amino acids, bombesin, or GRP may not be the stimulants for CCK release in rats. The stimuli that release CCK from duodenal mucosa probably varies among species.

Amino Acids↗
PubMed1993

Exogenous administration of estradiol and cholecystokinin alters exocrine pancreatic function in rats.

This study was conducted in rats to investigate the influence of exogenously administered estradiol (ESD) and/or cholecystokinin (CCK) on components and secretions of the pancreatic acini. Intact male rats were treated for 14 d with exogenous administration of ESD, CCK, or ESD+CCK. After 14 d CCK treatment induced significant increases in DNA and RNA contents, and DNA/RNA ratio in the pancreas, indicating hyperplasia and hypertrophy of the pancreas, however, ESD treatment did not have these effects. Both ESD treatment and CCK treatment induced significant increases in amylase and trypsinogen contents in pancreatic acini and each decreased secretion from acini in response to CCK. Combined treatment with ESD plus CCK augmented these effects on enzyme contents and secretion. The results indicate that exogenous administration of CCK has trophic effects on the exocrine pancreas, increasing effects on enzyme contents and inhibitory effects on amylase secretion. In contrast, exogenous administration of ESD had no trophic effects on pancreas, but had increasing effects on enzyme contents and inhibitory effects on amylase secretion. The results suggest that the effects of exogenous ESD and CCK on pancreas are not similar to each other, but both ESD and CCK may be involved in regulating pancreatic exocrine functions.

Amylases↗
PubMed1993

Structural and functional changes of exocrine pancreas induced by FK506 in rats.

BACKGROUND: The pancreas has been reported as a possible target for FK506 toxicity. This study was conducted to examine the effects of FK506 on the structure and function of pancreatic acinar cells. METHODS: Male Sprague-Dawley rats received an intramuscular injection of saline or FK506, and pancreatic acini were isolated on the day of sacrifice. RESULTS: FK506 caused a time-dependent suppression in amylase secretory response to cholecystokinin or carbachol at days 3-14, and increases in amylase and trypsinogen content at days 7-14. The properties of cholecystokinin and scopolamine binding sites in acini were not altered by FK506. Amylase release by A23187 and secretin were decreased by FK506, but those by phorbol ester 12-O-tetradecanoylphorbol-13-acetate, forskolin, 5'-cyclic adenosine monophosphate and vasoactive intestinal peptide were not changed. Increases in cytosolic free calcium concentration induced by cholecystokinin were not changed by FK506. Histologically, a significant increase in cytoplasmic zymogen granules was observed in pancreas from FK506-treated rats. CONCLUSION: These data suggest that FK506 induced changes in function and metabolism in pancreatic acinar cells, and these changes might be caused by altering postreceptor loci in stimulus-secretion coupling.

Amylases↗