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Biomedical subjects

J Matsumoto

Publications and source records attributed to J Matsumoto.

At least 19 recordsLinked to original sources
PubMed1992

A novel class of enkephalinase inhibitors containing a C-terminal sulfo group.

A new series of sulfonic acids were synthesized and tested for their enkephalinase inhibitory activity. Among them, the most potent was N-(2-benzyl-3-mercaptopropionyl)metanilic acid 10i with an IC50 value of 0.27 nM. Several other analogues (10a,b,j,n,o,gg,hh) showed the inhibitory activity comparable to or greater than thiorphan (IC50 = 2.6 nM), a C-terminal carboxyl-containing inhibitor of enkephalinase. Thus compounds containing a C-terminal sulfo group, instead of the C-terminal carboxyl group, were found to show a remarkably high level of inhibition of enkephalinase. The analgesic activity of 10b, (S)-10b, and (R)-10b was also evaluated by the phenylbenzoquinone writhing test.

Analgesics↗
PubMed1992

Physiological abnormalities in hereditary hyperekplexia.

Five patients from a kindred with hereditary hyperekplexia had physiological testing. The surface-recorded electromyographic pattern of audiogenic muscle jerks was identical to that of the normal acoustic startle reflex. Testing at graded stimulus intensities indicated an increase in the gain of the acoustic startle reflex. Nose-tap stimuli resulted in short-latency generalized electromyographic bursts that were similar to the R1 component of the blink reflex. Electrical stimulation of peripheral nerves elicited a pattern of generalized muscle jerks that was similar to that of the acoustic startle reflex. Somatosensory evoked potentials, brainstem auditory evoked potentials, and cortical auditory evoked potentials were normal. The primary physiological abnormality in hereditary hyperekplexia is widespread elevated gain of vestigial withdrawal reflexes in the brainstem and possibly the spinal cord, most likely resulting from increased excitability of reticular neurons.

Acoustic Stimulation↗
PubMed1992

Role of capsaicin-sensitive afferent neurons in mucosal blood flow response of rat stomach induced by mild irritants.

The role of capsaicin-sensitive sensory nerves in gastric mucosal blood flow (GMBF) responses to mild irritants was investigated in the rat stomach mounted on a lucite chamber using hypertonic NaCl and 0.2 N HCl. Exposure of the mucosa to hypertonic NaCl (0.5, 0.75, 1 M) for 10 min caused a reduction in the transmucosal potential difference (PD) in a concentration-related manner, followed by an increase of luminal pH and GMBF. In contrast, mucosal application of 0.2 N HCl caused no or little change in PD and pH, but increased GMBF significantly. Functional ablation of capsaicin-sensitive sensory nerves significantly inhibited the increase of GMBF after exposure to these irritants, although the PD and pH responses induced by 1 M NaCl remained unaltered by this treatment. Pretreatment with indomethacin (5 mg/kg, subcutaneously) significantly attenuated the GMBF responses to 1 M NaCl and 0.2 N HCl and inhibited the increase of pH caused by 1 M NaCl. Mucosal application of capsaicin (0.1 mg/ml for 10 min) produced an increase of GMBF without being accompanied by change in PD and pH, and this effect was significantly blocked by either indomethacin or chemical deafferentation. These results suggest that capsaicin-sensitive sensory nerves as well as endogenous prostaglandins may be involved in the mechanism of GMBF responses induced by mild irritants, and the latter might sensitize these nerves to mucosal irritation. PD reduction may be obligatory for pH but not GMBF responses.

Animals↗
PubMed1992

Role of capsaicin-sensitive sensory nerves in acid-induced bicarbonate secretion in rat stomach.

The effect of capsaicin-sensitive afferent nerves on the alkaline secretory response induced by mucosal acidification was investigated in the ex vivo stomachs of anesthetized rats. The stomach was mounted on a Lucite chamber and perfused with saline (pH 4.5) in the absence of acid secretion (omeprazole pretreatment: 60 mg/kg, intraperitoneal), and luminal pH and transmucosal potential difference (PD) were monitored simultaneously. Under these conditions the gastric mucosa responded to intravenous injection of prostaglandin E2 (PGE2: 300 micrograms/kg) and mucosal acidification (0.2 N HCl for 10 min) by a significant increase of pH with a slight decrease of PD; the HCO3- output was 9.2 +/- 0.7 mumol and 8.4 +/- 0.8 mumol, respectively. The increased pH and HCO3- responses were significantly inhibited by prior administration of indomethacin (5 mg/kg, subcutaneously) or chemical deafferentation following capsaicin injections (total dose: 100 mg/kg, subcutaneously), whereas those induced by PGE2 remained unchanged after either treatment. On the other hand, the mucosal application of capsaicin (0.3-6 mg/ml) increased the luminal pH and HCO3- output in a concentration-related manner, and this action was also significantly attenuated by either indomethacin or chemical deafferentation of capsaicin-sensitive sensory neurons. These results suggest that capsaicin-sensitive sensory nerves may be involved in the mechanism of acid-induced HCO3- secretion in the stomach, in addition to endogenous PGs, and these two pathways may interact somewhere in the stimulatory process.

Animals↗
PubMed1992

The predictive value of head ultrasound in the ECMO candidate.

Cranial ultrasound (US) examination is the screening technique of choice for assessing preexisting neurological damage in potential neonatal extracorporeal membrane oxygenation (ECMO) candidates. Currently, US evidence of intracranial hemorrhage greater than grade I in severity is a contraindication to ECMO at this ECMO center. In the current study, radiological findings were reviewed in 129 consecutive neonatal ECMO cases in an attempt to identify which pre-ECMO US findings were associated with the development of subsequent intracranial complications while on ECMO. Pre-ECMO head US, post-ECMO head US, and head computed tomography (CT) scans were reviewed retrospectively by one radiology team. Ventricular, parenchymal, and extraaxial fluid abnormalities were recorded for each case. Pre-ECMO US findings were then correlated with the subsequent development of significant intracranial radiological abnormalities noted on post-ECMO studies as well as with clinical data regarding ECMO course and outcome. Results showed that infants with evidence of severe edema or periventricular leukomalacia on pre-ECMO imaging had a 63% incidence of subsequent major intracranial complications. This represents a significantly higher risk than in candidates with a normal examination or evidence of grade I intracranial hemorrhage, subependymal cysts, or mild edema. These results suggest that infants with sonographic evidence of ischemic or anoxic damage on pre-ECMO US are at high risk for the development of significant intracranial complications if ECMO therapy is instituted.

Brain↗
PubMed1992

Expression and transmission of wild-type pigmentation in the skin of transgenic orange-colored variants of medaka (Oryzias latipes) bearing the gene for mouse tyrosinase.

Transgenic fish carrying a reconstructed mouse tyrosinase gene, mg-Tyrs-J, were produced by microinjecting the gene into the oocyte nucleus of an orange-colored variant of medaka (Oryzias latipes). Of 64 oocytes microinjected and subsequently inseminated, 13 embryos developed normally beyond hatching and three of them exhibited brown skin pigmentation in the adult as was commonly observed in the wild type of this species. Light and electron microscopic examination disclosed a ubiquitous distribution of typical melanophores in the skin of these transgenic fish. Judging from their population density and distribution pattern, it was presumed that melanogenesis in these fish was elicited in amelanotic melanophores that resided in the skin of the orange-colored fish of this variant. Immunofluorescence with use of the anti-mouse tyrosinase antiserum lacking reactivity to medaka tyrosinase clearly disclosed that the gene introduced was expressed in the melanophores of transgenic fish. Crosses of female transgenic fish and males from an orange-colored variant yielded offspring exhibiting wild-type or orange-colored pigmentation in a ratio of 1:1, thus implying that mg-Tyrs-J integrated into the medaka genome behaves like a dominant gene. Little melanogenesis was observed in xanthophores, leucophores and iridophores in transgenic fish, suggesting possible specificity in recognition of teleostean cell types (i.e., melanophores) by the regulatory region of the mouse tyrosinase gene.

Animals↗
PubMed1992

Induction of duodenal ulcers in sensory deafferented rats following histamine infusion.

We used capsaicin as a selective probe for sensory neuronal mechanisms and examined in rats whether defunctionalization of the sensory nerves caused duodenal ulcers in the presence of acid hypersecretion. Chemical deafferentation was performed by subcutaneous injection of capsaicin for 3 days (total dose: 100 mg/kg) 2 weeks before the experiment. This treatment did not cause by itself any damage in the duodenum. However, intravenous infusion of histamine (4, 8 and 16 mg/kg/h) in these animals caused hemorrhagic lesions in the proximal duodenum within 6 h in a dose-dependent manner with an incidence of 100%. Histamine alone in the control animals did not induce macroscopically visible lesions at lower doses and caused only slight damage at the highest dose (16 mg/kg/h), although acid secretion was stimulated to the maximal degree at 8 mg/kg/h. Ablation of capsaicin-sensitive sensory neurons did not have any effect on acid secretion induced by histamine (8 mg/kg/h), but significantly inhibited the increase in duodenal HCO3- secretion in response to mucosal acidification. We conclude that functional ablation of capsaicin-sensitive sensory nerves impairs duodenal HCO3- secretory response to acid and results in duodenal ulcers if acid hypersecretion is present. These sensory nerves may be important in the defense mechanism of the duodenum against luminal acid.

Animals↗
PubMed1992

Novel benzamides as selective and potent gastrokinetic agents. IV. Synthesis and structure-activity relationships of 2-substituted 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chlorobenzamides.

A new series of 2-substituted 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chlorobenzamides (4-39) including a few 4-fluorobenzyl analogues were prepared and evaluated for their gastrokinetic activity by determining their effects on the gastric emptying activity of phenol red semisolid meal in rats. The C-2 substituent comprises alkoxy and variously substituted alkoxy groups. Among the derivatives, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-2-(n-butoxy)-5-chlorobenza mide (5), its 4-fluorobenzyl (6), and 3-methyl-2-butenyloxy analogues (22) were superior to cisapride and essentially equipotent to the 2-ethoxy analogue (1b, AS-4370 as its citrate) in gastrokinetic activity. These compounds, like AS-4370, had no dopamine D2 receptor antagonistic activity.

Animals↗
PubMed1992

Novel benzamides as selective and potent gastrokinetic agents. III. Synthesis and structure-activity relationships of 4-amino-5-chloro-2-methoxy- and 2-ethoxy-N-[(4-substituted 2-morpholinyl)methyl]-benzamides.

A series of 4-amino-5-chloro-2-methoxy- and 2-ethoxy-N-[(4-substituted 2-morpholinyl)methyl]benzamides (11-64) were prepared and evaluated for gastrokinetic activity by determining their effects on the gastric emptying of phenol red semisolid meal in rats. The N-4 substituent includes alkyl, phenoxyalkyl, (4-fluorobenzoyl)alkyl, and heteroarylmethyl groups. The benzamide derivatives, having an isopropyl, isoamyl, neopentyl, 3-(4-chlorophenoxy)-propyl, or pyridylmethyl group at N-4, showed potent in vivo gastric emptying activity. In particular, 4-amino-5-chloro-2-ethoxy-N-[[4-(3-pyridylmethyl)-2- morpholinyl]methyl]benzamide (57b) was equipotent to the 4-fluorobenzyl analogue 1b (AS-4370 as its citrate) in the gastrokinetic activity on phenol red semisolid meal in rats and mice, and on resin pellet solid meal in rats. Moreover, compound 57b was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests. Structure-activity relationships of compounds with various substituents at N-4 are also discussed.

Animals↗
PubMed1992

Stimulation by capsaicin of gastric alkaline secretion in anesthetized rats.

Effects of mucosal application of capsaicin on alkaline secretion were examined in the stomachs of anesthetized rats and compared with those in the duodenum. The stomach (acid secretion was inhibited by omeprazole given i.p.) or the duodenum was perfused with saline (pH 4.5); both the pH of the perfusate and transmucosal potential difference (PD) were continuously monitored; and the HCO3- output was determined by the pH change. Under these conditions, the mucosal application of capsaicin (0.3-6 mg/ml for 30 min) caused significantly increased pH and HCO3- output in a concentration-related manner in both tissues, while PD increased in the duodenum and decreased in the stomach. The HCO3- stimulatory action of capsaicin was markedly attenuated by sensory deafferentation, significantly mitigated by prior administration of indomethacin, and exhibited a marked tachyphylaxis after the repeated exposure at a high concentration (6 mg/ml). None of these treatments had any effect on the pH, PD and HCO3- responses induced by prostaglandin E2 (300 micrograms/kg, i.v.) in these tissues. These results indicate that mucosal application of capsaicin increased the gastroduodenal HCO3- output by stimulation of capsaicin-sensitive sensory neurons. This action may be in part mediated by endogenous prostaglandins.

Afferent Pathways↗
PubMed1992

Induction of gastric lesions by 2-deoxy-D-glucose in rats following chemical ablation of capsaicin-sensitive sensory neurons.

Effects of chemical ablation of capsaicin-sensitive sensory nerves on functional and mucosal ulcerogenic responses to 2-deoxy-D-glucose (2DG) were investigated in the rat stomach, in comparison with those of indomethacin, a prostaglandin (PG) biosynthesis inhibitor. Intravenous injection of 2DG (200 mg/kg) followed by infusion of this agent (100 mg/kg/hr, i.v.) significantly increased gastric acid secretion and motility, but rarely induced macroscopic damage in the gastric mucosa of normal conscious rats. Chemical ablation of capsaicin-sensitive sensory nerves or pretreatment with indomethacin (5 mg/kg, s.c.) did not significantly affect the acid secretory and motility responses to 2DG, but induced severe hemorrhagic lesions in the stomach within 4 hr. Gastric mucosal blood flow (GMBF) determined by laser Doppler flowmetry under anesthetized conditions did not consistently change during 2DG treatment in any of these three groups, but the rise in GMBF in response to mucosal acidification (0.2 N HCl) was significantly inhibited in the animals pretreated with indomethacin or following chemical deafferentation. We conclude that functional ablation of capsaicin-sensitive sensory neurons, similar to the PG deficiency, increases the gastric mucosal vulnerability during 2DG infusion (acid hypersecretion and hypermotility due to vagal excitation), resulting in hemorrhagic lesions, and that the mechanism may be accounted for at least partly by the impairment of gastric mucosal blood flow response to mucosal acidification.

Animals↗
PubMed1992

[Prostaglandin E1 infusion fails to inhibit the increase of serum granulocyte elastase and myeloperoxidase and the decrease of plasma angiotensin converting enzyme in patients undergoing open-heart surgery].

We studied whether prostaglandin E1 (PGE1) could inhibit the increase of serum granulocyte elastase (GEL) and myeloperoxidase (MPO), and the decrease of plasma angiotensin converting enzyme (ACE) induced by oxygenator in 19 patients undergoing open-heart surgery. The patients were randomly allocated into 2 groups: one group (PGE1 group, n = 9) received a continuous infusion of PGE1 at a rate of 30 ng.kg-1.min-1 during cardiopulmonary bypass (CPB), and the other group (control group, n = 10) received saline infusion. GEL, MPO and ACE were measured serially at 8 points: before induction of anesthesia (as baseline), immediately before initiation of CPB, 10 min after initiation, 60 min after initiation, immediately after the end of CPB, 60 min after CPB, 120 min after CPB, and on the first postoperative day. Serum levels of GEL and MPO during 120 min after the end of CPB in both groups increased significantly compared with the baseline values. There was no significant difference between the two groups. Plasma levels of ACE in both groups decreased significantly immediately after the end of CPB compared with values taken 10 min after the initiation of CPB. There was no significant difference between the groups. We conclude that the infusion of PGE1 30 ng.kg-1.min-1 failed to inhibit the increase of GEL as well as MPO, and the decrease of ACE.

Aged↗
PubMed1992

[A clinical trial of arterial infusion chemotherapy combined with calcium antagonist for liver metastases].

Calcium antagonists enhance the effect of some anticancer agents, but only limited administration is feasible because of their cardiovascular action. We noticed their inactivation in liver and investigated the possibility of combined intra-arterial chemotherapy. Both verapamil (0.5 mg/kg) and adriamycin were infused into hepatic artery in 8 patients with liver metastases. The serum concentration of verapamil in hepatic vein was 182 +/- 178 ng/ml at maximum. Blood pressures, heart rates and electrocardiograms were quite stable. Tumors became nearly necrotic after the therapy in three hepatectomized cases. A more appropriate dose, infusion method and prognosis should be studied in future.

Adult↗
PubMed1992

[Activation of complement and serial changes of anaphylatoxin (C3a, C5a) in patients for open-heart surgery using a membrane oxygenator].

Activation of complement and serum changes in anaphylatoxin (C3a and C5a) were studied in 8 patients who underwent open-heart surgery using a membrane oxygenator. C1 esterase inhibitor (C1-EI), C3, C5, CH50, C3a and C5a were measured serially at 7 points. C1-EI, C3, and C5 were measured by single radial immunodiffusion, CH50 by Mayer's method, and C3a and C5a by radioimmunoassay. Levels of C1-EI, C3 and C5 decreased significantly from 10 min after initiation to 120 min after the end of CPB compared with base line values. Degree of activation of complement increased in proportion to duration of CPB. Significant decreases of C3 and C5 continued until first postoperative day. Level of C3a increased significantly 10 min after initiation of CPB, and gradually increased till immediately after the end of CPB, when the level was maximum (4625 +/- 560 ng.ml-1) among 7 points. Level of C3a decreased gradually till 120 min after end of CPB. C5a was not detected during whole course. No patient showed respiratory distress of pulmonary edema. In conclusion, membrane oxygenator activated classical pathway of complement at 10 min after initiation of CPB. C3a increased significantly from 10 min after initiation of CPB to 120 min after end of CPB, but C5a was not detected at all during the whole course. The significant activation of complement continued till first postoperative day.

Aged↗
PubMed1991

Role of capsaicin-sensitive afferent neurons in alkaline secretory response to luminal acid in the rat duodenum.

The role of capsaicin-sensitive afferent neurons in acid-induced HCO3- secretion was investigated in the duodenum of anesthetized rats. The proximal duodenum was perfused with saline (pH 4.5), the pH of perfusate and the transmucosal potential differences were continuously monitored, and HCO3- output was determined by pH change. Under these conditions, duodenal pH, potential difference, and HCO3- output were significantly increased in response to IV injection of prostaglandin E2 (300 micrograms/kg) and luminal acidification (10 mmol/L HCl, 10 minutes). These responses induced by luminal acid were significantly attenuated by SC pretreatment with indomethacin (5 mg/kg), preexposure of the mucosa to lidocaine (4%, 15 minutes), functional ablation of capsaicin-sensitive afferent neurons, or even prior application of capsaicin (6 mg/mL, 30 minutes) to the duodenum. Although capsaicin application by itself (0.3-6 mg/mL) produced a concentration-dependent increase of HCO3- output, this effect was significantly reduced by lidocaine, indomethacin, or chemical deafferentation and exhibited a tachyphylaxis after repeated application at a high concentration (6 mg/mL). Neither of these treatments significantly affected the HCO3- response induced by prostaglandin E2. It was concluded that stimulation of capsaicin-sensitive afferent neurons increased duodenal HCO3- secretion and that these neurons may be involved in the mechanism of HCO3- response induced by luminal acid in the duodenum.

Animals↗
PubMed1991

Novel benzamides as selective and potent gastrokinetic agents. 2. Synthesis and structure-activity relationships of 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2- morpholinyl]methyl] benzamide citrate (AS-4370) and related compounds.

The title compounds (19-55) with a 4-substituted 2-(aminomethyl)morpholine group were prepared and evaluated for the gastrokinetic activity by determining their effect on gastric emptying of phenol red semisolid meal in rats. Introduction of chloro, fluoro, and trifluoromethyl groups to the benzyl group of the parent compounds 1a and 1b enhanced the activity. Among compounds tested, 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl] methyl] benzamide (23b) showed the most potent gastric emptying activity (effects on phenol red semisolid meal in rats and mice, and on resin pellets solid meal in rats). The gastrokinetic activity of 23b citrate (AS-4370) compared very favorably with that of cisapride and was higher than that of metoclopramide. In contrast to metoclopramide and cisapride, AS-4370 was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests.

Animals↗
PubMed1991

Oxygen free radicals and lipid peroxidation in the pathogenesis of gastric mucosal lesions induced by indomethacin in rats. Relation to gastric hypermotility.

The relationship of gastric hypermotility to mucosal hemodynamics, lipid peroxidation and vascular permeability changes was investigated in the pathogenesis of indomethacin-induced gastric lesions in rats. Subcutaneous administration of indomethacin (25 mg/kg) produced an increase in both the amplitude and frequency of stomach contraction from 30 min after treatment, resulting in hemorrhagic damage 2 h later. Gastric mucosal blood flow measured by a Laser flowmetry showed oscillatory fluctuations under hypercontractile states: a decrease during contraction followed by an increase during relaxation. Mucosal lipid peroxidation and vascular permeability were significantly increased with time after indomethacin treatment, and these changes preceded the appearance of hemorrhagic damage. All these events were prevented when gastric hypermotility was inhibited by atropine or 16,16-dimethyl prostaglandin E2. Pretreatment of the animals with allopurinol and hydroxyurea or continuous infusion of superoxide dismutase and dimethyl sulfoxide during a test period also attenuated these functional changes and mucosal lesions induced by indomethacin, without affecting the motility response. We conclude that oxygen free radicals may play a role in the development of mucosal lesions associated with gastric hypermotility in indomethacin-treated rats.

16,16-Dimethylprostaglandin E2↗