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Biomedical subjects

S Okabe

Publications and source records attributed to S Okabe.

At least 235 records · Page 13Linked to original sources

A histamine H2 receptor antagonist, roxatidine, stimulates mucus secretion and synthesis by cultured rabbit gastric mucosal cells.

We examined the effects of the known antisecretory and mucosal protective drug, roxatidine, on the secretion and synthesis of mucus by cultured rabbit gastric mucosal cells. The amounts of secreted and synthesized mucus were determined by the [3H] glucosamine labelling method. Exposure of the cells to roxatidine for 8 hr caused increases in the secretion and synthesis of mucus in a dose-related manner. The increase in mucus synthesis was maximally induced 4 hr after the addition of roxatidine, while mucus secretion was maximally enhanced a further 4 hr later. However, other H2 antagonists such as cimetidine, rantidine and famotidine failed to stimulate the secretion and synthesis of gastric mucus. In addition, neither indomethacin nor NG-nitro-L-arginine methyl ester affected the roxatidine-induced increases in mucus secretion and synthesis. We conclude that roxatidine directly acts on gastric mucosal cells, inducing increases in both the secretion and synthesis of mucus, and that an unknown regulatory pathway might be involved in these stimulatory actions of roxatidine.

Animals↗

Role of GABAB receptors in the control of hypoglossal motoneurons in vivo.

There is little information on GABAB receptor-mediated effects on orofacial motoneurons. We recorded the inspiratory activity from both hypoglossal (XII) nerves in urethane-anesthetized, paralyzed, vagotomized and artificially ventilated rats. A GABAB receptor agonist, baclofen, or antagonist, CGP-35348, was microinjected into one XII nucleus. Baclofen rapidly reduced the XII nerve activity in a dose-dependent manner by over 50%. The antagonist caused a delayed suppression of activity by 40%. We conclude that: (1) GABAB receptors within the XII nucleus may suppress the activity of inspiratory XII motoneurons, but they are not tonically active under the conditions of our experiment; (2) there is a net endogenous excitatory effect in XII motoneurons that is mediated by GABAB receptors located in the reticular formation surrounding the XII nucleus.

Animals↗

In vivo release of glutamate in nucleus tractus solitarii of the rat during hypoxia.

1. An attempt has been made to test the hypothesis that, in the caudal part of nucleus tractus solitarii (NTS) where carotid sinus nerve (CSN) afferents project, L-glutamate (Glut) modulates the hypoxic ventilatory response. 2. Unanaesthetized, peripherally chemodenervated (carotid body denervated; CBD) and sham-operated, freely moving rats were used. During peripheral chemoreceptor stimulation by hypoxia (10% O2 for 30 min) or doxapram (Dox) infusion (2 mg kg-1 (30 min)-1), ventilation was recorded and successively, under the same conditions, the extracellular Glut concentration ([Glut]o) in the caudal NTS was measured by in vivo microdialysis. [Glut]o was also measured during hyperoxic hypercapnia (10% CO2-30% O2 for 30 min). 3. Furthermore, the effects on ventilation of exogenous Glut, the NMDA (N-methyl-D-aspartate) receptor antagonist MK-801 or the ionotropic receptor antagonist kynurenate microinjected into the caudal NTS were investigated in sham-operated rats. 4. In sham-operated rats, both ventilation and [Glut]o in NTS were increased during peripheral chemoreceptor stimulation. On the other hand, no increases in either ventilation or Glut release were observed in CBD rats. In spite of ventilatory augmentation during hypercapnia, no response of [Glut]o to hypercapnia was observed in either group. 5. Local Glut application into NTS increased ventilation. Pretreatment with MK-801 or kynurenate reduced the hypoxic ventilatory response. This reduction in ventilation was mainly due to the decrease in tidal volume. 6. These results suggest that hypoxia induced the release of Glut in NTS and that this effect was mediated by arterial chemosensory input.

Animals↗

Altered microtubule organization in small-calibre axons of mice lacking tau protein.

The tau gene encodes a protein (Tau) that is a major neuronal microtubule-associated protein localized mostly in axons. It has microtubule-binding and tubulin-polymerizing activity in vitro and is thought to make short crossbridges between axonal microtubules. Further, tau-transfected non-neuronal cells extend long axon-like processes in which microtubule bundles resembling those in axons are formed. In contrast, tau antisense oligonucleotides selectively suppress axonal elongation in cultured neurons. Thus tau is thought to be essential for neuronal cell morphogenesis, especially axonal elongation and maintenance. To test this hypothesis, we used gene targeting to produce mice lacking the tau gene. We show that the nervous system of tau-deficient mice appears to be normal immunohistologically. Furthermore, axonal elongation is not affected in cultured neurons. But in some small-calibre axons, microtubule stability is decreased and microtubule organization is significantly changed. We observed an increase in microtubule-associated protein 1A which may compensate for the functions of tau in large-calibre axons. Our results argue against the suggested role of tau in axonal elongation but confirm that it is crucial in the stabilization and organization of axonal microtubules in a certain type of axon.

Animals↗

Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma.

BACKGROUND: Many deaths from attacks of asthma may be preventable. However, the difficulty in preventing fatal attacks is that not all the pathophysiologic risk factors have been identified. METHODS: To examine whether dyspnea and chemosensitivity to hypoxia and hypercapnia are factors in fatal asthma attacks, we studied 11 patients with asthma who had had near-fatal attacks, 11 patients with asthma who had not had near-fatal attacks, and 16 normal subjects. Their respiratory responses to hypoxia and hypercapnia, determined by the standard rebreathing technique while the patients were in remission, were assessed in terms of the slopes of ventilation and airway occlusion pressure as a function of the percentage of arterial oxygen saturation and end-tidal carbon dioxide tension, respectively. The perception of dyspnea was scored on the Borg scale during breathing through inspiratory resistances ranging from 0 to 30.9 cm of water per liter per second. RESULTS: The mean (+/- SD) hypoxic ventilatory response (0.14 +/- 0.12 liter per minute per percent of arterial oxygen saturation) and airway occlusion pressure (0.05 +/- 0.05 cm of water per percent of arterial oxygen saturation) were significantly lower in the patients with near-fatal asthma than in the normal subjects (0.60 +/- 0.35, P < 0.001, and 0.16 +/- 0.08, P < 0.001, respectively) and the patients with asthma who had not had near-fatal attacks (0.46 +/- 0.29, P = 0.003, and 0.15 +/- 0.09, P = 0.004). The Borg score was also significantly lower in the patients with near-fatal asthma than in the normal subjects, and their lower hypoxic response was coupled with a blunted perception of dyspnea. CONCLUSIONS: Reduced chemosensitivity to hypoxia and blunted perception of dyspnea may predispose patients to fatal asthma attacks.

Adult↗

Effect of intraduodenally administered histamine on gastric acid secretion in rats and guinea pigs.

We examined the effect of histamine administered intraduodenally as well as subcutaneously or intravenously on the gastric acid secretion in rats and guinea pigs, using a newly devised cannula. Intraduodenally administered histamine dihydrochloride caused a significant dose-dependent increase in the gastric acid secretion in rats. The maximal acid secretion, which corresponded to that after subcutaneous (20 mg/kg) or intravenous (10 mg/kg/hr) administration of histamine, was observed within 30 min after intraduodenal administration (40 mg/kg). The plasma concentrations of histamine determined 30 min after intraduodenal, subcutaneous, and intravenous administration of histamine were nearly the same. Pretreatment with aminoguanidine sulfate (diamine oxidase inhibitor) at 30 mg/kg significantly increased the gastric acid secretion caused by intraduodenal histamine. The gastric acid secretion stimulated by intraduodenal histamine was significantly inhibited by cimetidine, pirenzepine, and omeprazole, but remained unchanged with tripelennamine. Intraduodenal histamine (20 mg/kg) also maximally stimulated the gastric acid secretion in guinea pigs. The response was comparable to that with subcutaneous histamine (1 mg/kg). We conclude that intraduodenal histamine has the ability to stimulate gastric acid secretion in both rats and guinea pigs.

Amine Oxidase (Copper-Containing)↗

Influences of urethane anesthesia on indomethacin-induced gastric mucosal lesions in rats. Relation to blood glucose levels.

Effects of urethane on gastric motility and mucosal ulcerogenic responses induced by indomethacin were investigated in the rat in relation to blood glucose levels (BGL) and compared with those of pentobarbital Na. Urethane (1.25 g/kg) given intraperitoneally, caused a progressive and significant rise in BGL, while pentobarbital (30 mg/kg) given intraperitoneally did not affect BGL. Subcutaneous administration of indomethacin (25 mg/kg) caused high-amplitude gastric contractions and induced hemorrhagic lesions in the stomachs of conscious rats. These lesions were significantly inhibited by urethane but not pentobarbital. Administration of urethane abolished basal gastric motility and almost completely suppressed the motility responses induced by indomethacin, while pentobarbital did not have much effect on gastric motility under basal and indomethacin-stimulated conditions. Acid secretion was significantly decreased by urethane and increased by pentobarbital. Pretreatment of the animals with yohimbine (5 mg/kg, subcutaneously) but not prazosin (0.5 mg/kg) inhibited the elevation in BGL seen after administration of urethane and allowed resumption both gastric motility and ulcerogenic responses induced by indomethacin, with less change in acid secretion. These results suggest that intraperitoneal administration of urethane prevented indomethacin-induced gastric lesions, probably by inhibiting the enhanced gastric motility response, and this effect may relate to its hyperglycemic action mediated by alpha 2-adrenoceptors. These findings also provide further evidence to support the importance of gastric motility in the pathogenesis of these lesions.

Anesthesia, General↗

Capsaicin-sensitive sensory neurons in healing gastric lesions induced by HCl in rats.

The role of capsaicin-sensitive sensory neurons in the healing of HCl-induced gastric lesions was investigated in rats. Rats fasted for 18 hr were given 0.6 N HCl orally for induction of gastric lesions, and they were fed normally from 1 hr later. On various days after HCl treatment, area of lesions, acid secretion, mucosal H+ permeability, and blood flow responses were measured. Functional ablation of capsaicin-sensitive sensory neurons was performed two weeks before the experiment by subcutaneous injections of high-dose capsaicin. Sensory deafferentation did not affect the development of gastric damage in response to HCl but significantly delayed the healing of these lesions. The mucosa damaged by HCl secreted less acid but showed significant rise in H+ permeability, resulting in acid back-diffusion accompanied by an increase of mucosal blood flow. Sensory deafferentation had no effect on acid secretion and mucosal permeability changes in the damaged stomach but completely blocked the hyperemic response caused by acid back-diffusion. Capsaicin-sensitive sensory neurons may contribute to healing of gastric lesions, probably by mediating the mucosal hyperemic responses associated with acid back-diffusion and by facilitating acid disposal in the mucosa.

Animals↗

Acid secretory and duodenal ulcerogenic responses induced by mepirizole in anesthetized rats. Relation to body temperature.

The role of body temperature in the acid stimulatory mechanism by mepirizole, a duodenal ulcerogen, was investigated in urethane-anesthetized rats. Subcutaneous administration of mepirizole (60 and 200 mg/kg) increased acid secretion in a dose-dependent manner and resulted in duodenal lesions within 8 hr. The acid secretory and ulcerogenic responses induced by mepirizole were inhibited completely by vagotomy and significantly reduced by subcutaneous pretreatment with atropine (1 mg/kg), hexamethonium (10 mg/kg), or clonidine (1 mg/kg). During anesthesia, body temperature was decreased to 34 degrees C in control rats but further reduced to 31 degrees C after administration of mepirizole. When body temperature was maintained at 36 degrees C during a test period, mepirizole caused significantly less effect on acid secretion and produced less damage in the duodenum. In addition, intracisternal administration of antiserum of thyrotropin-releasing hormone (TRH: 5 mu1/rat) also significantly inhibited acid hypersecretion and development of duodenal lesions in response to mepirizole. When acid output induced by mepirizole was plotted against duodenal lesion score from one group to another, a significant linear relationship was found between these two values (r = 0.814, P < 0.05). We conclude that mepirizole induced vagally mediated acid secretion and duodenal lesions in anesthetized rats. These responses may occur centrally in association with lowering of body temperature, which potentiates the acid stimulatory effect of mepirizole, probably through a TRH-dependent mechanism.

Animals↗

Induction of gastric lesions and hypoglycemic response by food deprivation in streptozotocin-diabetic rats.

Overnight fasting causes hemorrhagic lesions in the stomach of streptozotocin (STZ)-induced diabetic rats, but the pathogenetic mechanism remains unknown. The present study was performed to investigate the pathogenesis of such lesions developed in STZ-diabetic rats after starvation, mainly in relation to blood glucose changes. A single injection of STZ (70 mg/kg, intraperitoneally) induced hyperglycemic conditions one week after the administration, and high blood glucose levels (BGL: > 350 mg%) remained up to three weeks later. The STZ-diabetic rats developed gastric lesions with the marked reduction of BGL after 18 hr of fasting, depending upon the duration of diabetes; the lesion score and delta BGL reduction in the 3-week-old STZ rats were 32.0 +/- 7.8 mm and > 250 mg/100 ml, respectively. Acid secretion in the pylorus-ligated rats was not significantly changed in the STZ-induced diabetic conditions for the initial two weeks but slightly decreased at three weeks when compared with normal rats. Fasting of normal rats for 18 hr did not cause either BGL reduction or any lesion in the stomach. In the 3-week-old STZ animals, the severity of gastric lesions increased with the duration of fasting (4-18 hr) and was again closely associated with the degree of delta BGL reduction. These lesions induced by 18 hr of starvation in 3-week-old STZ rats were significantly inhibited by pretreatment with insulin (4 units/rat/day) for the last one week to maintain BGL within normal ranges or by intravenous infusion of 25% glucose during fasting period. Both of these treatments significantly prevented BGL reduction in response to fasting.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

The role of capsaicin-sensitive sensory neurons in healing of HCl-induced gastric mucosal lesions in rats.

BACKGROUND/AIMS: Capsaicin-sensitive sensory neurons are important in protecting the stomach against damage. This study investigated the role of these sensory neurons in the healing of gastric lesions. METHODS: Rats fasted for 18 hours were given 1 mL of 0.6N HCl orally for induction of gastric lesions; they were then fed normally from 1 hour later. On various days after HCl treatment, the area of lesion, acid secretion, mucosal DNA synthesis, mucosal H+ permeability, and blood flow responses were measured. RESULTS: Ablation of sensory neurons by capsaicin pretreatment did not affect the development of gastric lesions in response to HCl but significantly delayed the healing of these lesions. The damaged mucosa secreted less acid and had minimal changes in DNA synthesis but showed a marked increase in H+ permeability, resulting in luminal acid loss accompanied by an increase of mucosal blood flow. Sensory deafferentation did not have any influence on such changes in the damaged stomach, except the mucosal hyperemic response to acid. CONCLUSIONS: Capsaicin-sensitive sensory neurons may contribute to the healing of gastric lesions by mediating the mucosal hyperemic responses associated with acid back-diffusion and by facilitating acid disposal in the mucosa.

Animals↗

Endogenous nitric oxide in gastric alkaline response in the rat stomach after damage.

BACKGROUND/AIMS: The gastric mucosa responds to hypertonic NaCl by significantly decreasing acid secretion. This study examined the role of nitric oxide in this phenomenon. METHODS: A rat stomach was mounted in an ex vivo chamber and perfused with saline; then the potential difference (PD), pH, and acid and/or alkaline responses were measured before and after the application of 1 mol/L NaCl with or without pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO biosynthesis. RESULTS: A dose of 1 mol/L NaCl caused a reduction in PD, a decrease in basal and histamine-stimulated acid secretion, and an increase in luminal HCO3-. Prior administration of L-NAME did not affect either the PD or the HCO3- response but significantly attenuated the inhibitory effect of 1 mol/L NaCl on acid secretion. This effect of L-NAME was antagonized by the simultaneous administration with L-arginine but not D-arginine. Histamine-stimulated acid secretion in the normal stomach was significantly reduced by the exogenous NO donor nitroprusside but not by L-NAME. CONCLUSIONS: NO is involved in the mechanism of the gastric alkaline response after damage with 1 mol/L NaCl. Irritation of the gastric mucosa by hypertonic NaCl may release endogenous NO, which in turn inhibits acid secretion and unmasks luminal alkalinization caused by HCO3- flux in the damaged portion.

Animals↗

Risk factors for the postoperative local recurrence of tongue carcinoma.

Clinical and histologic studies on the risk factors for the postoperative local recurrence of tongue carcinoma were analyzed in 51 patients. Postoperative local recurrence occurred in 12 (23.5%), with almost all developing within the first 12 months after surgery. A comparison of patients with and without recurrence indicated that the risk factors for recurrence were 1) endophytic tumor growth, 2) grade 4 pattern of histologic invasion, and 3) tumor within 5 mm of the surgical margin (especially the deep margin). All T1 tumors were less than 5 mm deep, indicating that it is reasonable for partial glossectomy to be performed in patients with T1 carcinoma. However, for T2 through T4 carcinoma it seems that more extensive surgery should be performed because of the variability in depth of tumor invasion. The 5-year survival rate of the patients with recurrence was 45% and that of patients without recurrence was 73.7% (P < .01). The overall prognosis of tongue carcinoma should improve when surgeons take a more prudent attitude to the treatment of patients with these risk factors.

Adult↗

Differential dynamics of neurofilament-H protein and neurofilament-L protein in neurons.

Neurofilaments (NFs) are composed of triplet proteins, NF-H, NF-M, and NF-L. To understand the dynamics of NFs in vivo, we studied the dynamics of NF-H and compared them to those of NF-L, using the combination of microinjection technique and fluorescence recovery after photobleaching. In the case of NF-L protein, the bleached zone gradually restored its fluorescence intensity with a recovery half time of approximately 35 min. On the other hand, recovery of the bleached zone of NF-H was considerably faster, taking place in approximately 19 min. However, in both cases the bleached zone was stationary. Thus, it was suggested that NF-H is the dynamic component of the NF array and is interchangeable, but that it assembles with the other neurofilament triplet proteins in a more exchangeable way, implying that the location of NF-H is in the periphery of the core NF array mainly composed of NF-L subunits. Immunoelectron microscopy investigations of the incorporation sites of NF-H labeled with biotin compounds also revealed the lateral insertion of NF-H subunits into the preexisting NF array, taking after the pattern seen in the case of NF-L. In summary, our results demonstrate that the dynamics of the L and H subunit proteins in situ are quite different from each other, suggesting different and separated mechanisms or structural specialization underlying the behavior of the two proteins.

Animals↗

The mechanism underlying stimulation of gastric HCO3- secretion by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester in rats.

We investigated the mechanism underlying stimulation of gastric HCO3- secretion by the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in anaesthetized rats. A rat stomach was mounted in an ex vivo chamber, superfused with saline, and HCO3- secretion was measured in the absence of acid secretion (omeprazole pretreatment). Intravenous administration of L-NAME (1-5 mg/kg) increased gastric HCO3- secretion dose dependently with concomitant rise in arterial blood pressure and decrease in heart rate, and these effects were all antagonized by simultaneous administration of L-arginine (200 mg/kg). Vagotomy did not affect the increased blood pressure response but significantly inhibited the decrease in heart rate and increase of HCO3- secretion caused by L-NAME. The HCO3- stimulatory action of L-NAME was also inhibited by pretreatment with either yohimbine (5 mg/kg s.c.) or prazosin (0.5 mg/kg s.c.). These agents alone caused a decrease in blood pressure, and reduced the magnitude of blood pressure response caused by L-NAME, leading to inhibition of heart rate changes. When the change in HCO3- output induced by L-NAME was plotted against the change in blood pressure (from basal values) under various conditions, a significant relationship was found between these two parameters. These results suggest that L-NAME stimulates gastric HCO3- secretion in association with the inhibition of endogenous NO production, and this mechanism may be in part mediated by a neural reflex through vagal efferent nerves, resulting from the pressor response to L-NAME.

Amino Acid Oxidoreductases↗

Validity of kissing gastric ulcers induced in rats for screening of antiulcer drugs.

We examined the validity of kissing gastric ulcers induced in rats by determining the effects of conventional antiulcer drugs. Gastric ulcers were produced by luminal application of 60% acetic acid (0.2 mL, 45 s) to an area clamped with a pair of forceps. The ulcers were evaluated as to either the ulcerated area (mm2) or ulcer index (ulcerated area x depth). The healing of kissing ulcers was significantly enhanced by 2 week treatment with oral omeprazole (10, 30 mg/kg per day), leminoprazole (30, 60 mg/kg per day) or cimetidine (300, 450 mg/kg per day). The rate of healing was > 50% to both the ulcerated area and ulcer index. Aluminium hydroxide (up to 1800 mg/kg per day) had no effect on ulcer healing on the ulcerated area, but it caused a significant reduction in the ulcer index. Gastric acid secretion was significantly inhibited by repeated administration of omeprazole, leminoprazole and cimetidine in a dose-dependent manner. Aluminium hydroxide significantly increased the pH of the gastric contents. The mechanism of action of these drugs appears to involve partly the inhibition of gastric acid secretion and neutralization of secreted acid. We conclude that kissing gastric ulcers are a sensitive ulcer model for the screening of antiulcer drugs.

Acetates↗

Effects of submental stimulation for several consecutive nights in patients with obstructive sleep apnoea.

BACKGROUND: It has previously been reported that short term submental stimulation can reduce the frequency of apnoea and improve sleep architecture in patients with obstructive sleep apnoea. The effects of submental stimulation during consecutive nights on apnoea or on daytime sleepiness have not, however, been studied. METHODS: Patients with obstructive sleep apnoea were studied by polysomnography on a control night, for five consecutive nights of submental stimulation, and on three following nights (n = 8). A multiple sleep latency test (MSLT) (n = 8) and measurement of the upper airway resistance (n = 5) were performed during the day after the polysomnographic study, on the control night, and on the fifth stimulation night. In an additional five patients with obstructive sleep apnoea, matched for age, sex, and weight, the effects of two nights of stimulation were examined for comparison. Submental stimulation began when an apnoea lasted for five seconds and stopped with the resumption of breathing as detected by oronasal flow. RESULTS: The apnoea index, the number of times per hour that SaO2 dropped below 85% (SaO2 < 85%/hour), and the total apnoea duration expressed as a percentage of total sleep time during stimulation nights decreased to approximately 50% of the corresponding values on the control night. This improvement persisted for at least two nights after the five consecutive stimulation nights, but not after the two consecutive stimulation nights. Sleep architecture and MSLT following the stimulation nights improved but upper airway resistance did not change. CONCLUSIONS: Submental stimulation for five consecutive nights in patients with obstructive sleep apnoea improved the breathing disturbance, sleep quality, and daytime sleepiness. The effect lasted for the following two nights, but did not completely abolish the sleep disordered breathing.

Adult↗

Effects of prostaglandin E2 inhalation on hypercapnic response in normal subjects.

It is known that the ventilatory response to carbon dioxide (CO2) is increased in asthmatics with airway obstruction. Increased vagal afferent activity as well as increased airway resistance have been postulated as the causative mechanisms. However, whether increased vagal afferent activity without bronchoconstriction increases the ventilatory response to CO2 has not been investigated in humans. We examined the effects of prostaglandin E2 (PGE2) inhalation, which is known to stimulate vagal afferent receptors in the lung without an increase in airway resistance, on the respiratory response to CO2 in seven healthy male subjects. Either physiologic saline or PGE2 (100 micrograms/ml) was inhaled through a Bird nebulizer for 3 min. Twenty minutes after each inhalation, the responses of minute ventilation (VE) and occlusion pressure (P0.1) to hyperoxic hypercapnia were measured. Both the relationships between VE and P0.1 to an increase in tension of end-tidal CO2 (PETCO2) were analyzed by linear regression. Although the mean value of respiratory resistance after PGE2 (3.0 cm H2O/L/s +/- 0.4) did not differ significantly from that after saline (3.1 cm H2O/L/s +/- 0.4), inhaled PGE2 significantly increased the hypercapnic response. This result suggests that the increased vagal afferent activity per se plays an important role in increasing the hypercapnic ventilatory response in humans.

Administration, Inhalation↗