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Biomedical subjects

K Tsurumi

Publications and source records attributed to K Tsurumi.

At least 19 recordsLinked to original sources

Effect of opioids on delayed neuronal death in the gerbil hippocampus.

The effect of opioids on delayed neuronal death was evaluated in the gerbil hippocampus. Male Mongolian gerbils were subjected to transient forebrain ischemia and neuronal density was evaluated in the hippocampus 7 days following ischemia. When hypothermia during and after ischemia was prevented, treatment with morphine, U-50488H, or naloxone provided no significant protection. In contrast, a spontaneous drop in rectal temperature to 32 degrees C at the end of ischemia produced near-complete protection of CA1 pyramidal neurons. No opioids modulate the protective effect of hypothermia.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh

[Affinity of Z-105 to the 1,4-dihydropyridine type calcium channel and several other receptor bindings in the central nervous system].

The affinity of a 1,4-dihydropyridine (DHP) type calcium channel blocker, NZ-105 ((+/-)-2-[benzyl (phenyl) amino] ethyl 1,4-dihydro-2, 6-dimethyl-5- (5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan- 2-yl)-4-(3-nitrophenyl)-3-pyridinecarboxylate hydrochloride ethanol), on the DHP-binding site in the central nervous system and various receptor sites were compared with nicardipine and diltiazem by the use of a receptor binding assay technique. NZ-105 exhibited a displacement effect against [3H]nimodipine in the rat brain DHP-binding site with a potency similar to that of nicardipine. Nicardipine also inhibited the specific binding of several other [3H]-labelled ligands to their receptor such as adrenergic alpha 1, alpha 2, beta, dopamine D1, D2, opioid mu, delta, and kappa-type receptors. Diltiazem also showed a similar inhibitory property. However, NZ-105 showed only weak inhibition against the binding to these receptors. These results suggest that Z-105 has strong affinity to the DHP-binding site in voltage-dependent calcium channels with higher specificity.

Animals

Dopaminergic unique affinity of tetrahydroberberine and l-tetrahydroberberine-d-camphor sulfonate.

l-Tetrahydroberberine-d-camphor sulfonate (THB-CS) possessed an inhibitory effect on apomorphine-induced chewing movement in a similar manner to that of tetrahydroberberine (THB). Both compounds enhanced barbiturate-induced hypnosis. They did not have an anticonvulsant effect on convulsive seizures induced by bicuculline, pentetrazole or strychnine. THB and THB-CS blocked dopamine-stimulated adenylate cyclase activity. These compounds showed almost equipotent affinities to dopamine D1 (3H-SCH-23390) and D2 (3H-spiperone) receptors but did not have significant affinity to mu-opioid, muscarinic and alpha 2-adrenergic receptors, and benzodiazepine binding sites. Furthermore, both compounds did not elicit cataleptogenic behavior, even at very high doses. These data suggest that THB and THB-CS have a central depressant effect through both D1 and D2 dopaminergic receptors and may have different modes of action from that of standard neuroleptics.

Animals

A human skeleton from the Ohguruwa remains.

In 1941, the Ohguruwa remains were discovered at the Mizuho sports ground site in Nagoya. They date from about 3000 B.C., which is the early Jomon era. When the stadium was reconstructed in 1980, four human skeletons were found. Three of them, however, were in poor condition and moreover, were incomplete. However, the second skeleton was in good condition and could almost be reconstructed, and this skeleton (No. 2) was used for our study. It was found in the classic posture with arms and legs folded. Some pieces of a dog's skeleton were also discovered near the No. 2 skeleton's chest. This particular skeleton generally showed characteristics typical of the Jomon era. It had a stout structure and was judged to be a middle aged male because of the following features. There was considerable attrition of the occlusal surfaces on the remaining teeth. The teeth were worn flat, probably owing to the hard food and to their use as a tool. Both canines and first premolars of the upper and lower arches had been extracted in accordance with the custom of the time. Typical caries and localized periodontal breakdown were not observed, although there was horizontal alveolar bone loss, especially in the anterior regions. The mastoid process was extremely large and prominent. The lateral prominence of the mandible was developed. Analysis of lateral cephalogram revealed that the mandible was in the anterior position. The angles of SNA, SNB and ANB were 89.6 degrees, 89.2 degrees and 0.4 degrees, respectively. The skeletal pattern was definitive Class III. The adaptive changes in the teeth, their supporting tissues, temporomandibular joints and the related muscles--the harmonious masticatory system--were all estimated.

Cephalometry

[Effects of opioids on Ca2+ flux of polymorphonuclear leukocytes].

The effects of opioids on Ca2+ influx were evaluated using rat polymorphonuclear leukocytes, comparing with those of nicardipine and TMB-8, 8-(N, N diethyl amino) 3, 4, 5 trimethoxybenzoate. Selective opioid kappa-agonist, U-50488H, inhibited Ca2+ influx caused by f-Met-Leu-Phe (fMLP). U-50488H also strongly inhibited the elevation of intracellular free Ca2+ concentration in Ca2+ free medium. In contrast, mu-agonist, morphine showed no effects. The purified enantiomers of U-50488H exerted no difference in their effects on Ca2+ mobilization of PMNs, and naloxone did not antagonize the effects of U-50488H. Both nicardipine and TMB-8 inhibited the Ca2+ flux. The inhibitory effects of TMB-8 were potentiated by lowering extracellular free Ca2+. These results suggest that U-50488H may interfere with the Ca2+ regulatory system of PMNs via opioid receptor non-mediated pathway. The effect was suspected to be caused by selective inhibition of Ca2+ release from intracellular Ca2+ store sites by affecting post-receptor mechanisms of f-MLP.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh

Platelet prostaglandin E1 hyposensitivity in schizophrenia: decrease in cyclic AMP formation and in inhibitory effects on aggregation.

Cyclic adenosine monophosphate (cAMP) formation via prostaglandin E1 (PGE1) or forskolin stimulation was determined in washed platelets from 35 schizophrenic patients and 34 normal controls. The inhibitory effects of PGE1 and forskolin on platelet aggregation response (PAR) elicited by adenosine diphosphate (ADP) were also examined simultaneously. Both PGE1- and forskolin-stimulated cAMP formation decreased in platelets from schizophrenic patients, as compared with those from normal controls. PGE1 inhibition of PAR was significantly lowered in schizophrenic patients compared to normal controls, but forskolin inhibition was not. No correlations between PGE1- or forskolin-stimulated cAMP formation and inhibitory effects of PGE1 or forskolin on PAR, respectively, were explained by the complex factors involved in PAR. In conclusion, platelet hyposensitivity to PGE1 in schizophrenic patients is partially based on aberrant adenylate cyclase (AC) activity and includes other variables related to PAR.

Adult

Pathological studies on nephrotoxic serum nephritis accelerated with rabbit gamma-globulin in mice.

In order to characterize nephrotoxic serum nephritis accelerated with rabbit gamma-globulin in mice, histopathological studies were carried out 15 days after NTS injection, the time when increases in urinary protein and serum cholesterol and a decrease in serum albumin were apparent. Characteristic changes were widespread thickening of glomerular capillary walls and widening of mesangial areas, owing to deposits of mesangial matrixlike substances. The mesangial interposition into subendothelial areas and the resultant narrowing of the capillary lumen were shown ultrastructurally. In severely affected glomeruli, a hyaline nodular lesion was observed. Visceral epithelial cells demonstrated fusion of the foot processes, microvilli formation, occasional proliferation, and enlargement. Parietal epithelial cells proliferated, forming a cellular crescent. Based on these characteristics, it appears this nephritic model shares a common pathology with human membranoproliferative glomerulonephritis type 1 and crescentic glomerulonephritis and can be considered an appropriate model for producing severe nephritis for short periods.

Animals

Platelet prostaglandin E1 hyposensitivity in schizophrenia: reduction of prostaglandin E1- or forskolin-stimulated cyclic AMP response in platelets.

Cyclic 3',5'-adenosine monophosphate (cAMP) formation via prostaglandin E1 (PGE1)-or forskolin-stimulation were determined in washed intact platelets from 32 schizophrenic patients and 30 normal controls. Regarding basal cAMP levels in the platelets, there were no differences between schizophrenic patients and normal controls. Both PGE1-and forskolin-stimulated cAMP response reduced in platelets from schizophrenics compared with normal controls. These results suggested that platelets in schizophrenics were impaired not only in the adenylate cyclase unit per se but also extensively in the cAMP generating system coupled to a PGE1 receptor.

Adenylyl Cyclases

[Kappa-type opioid receptor in human placental membrane].

Since many opioid receptor preparations are heterogeneous systems containing multiple types of receptor, characterization of each type of the receptor is influenced by contamination with other types of receptor. Demonstrating kappa receptor proved more difficult owing to the ability of kappa ligands to interact with a number of receptor classes and to the lack of the homogeneous preparation. It has been reported that kappa ligands selectively bind to human placental membrane. To establish homogeneous kappa receptor preparation, the kappa binding to human placenta was characterized. The portion which was predominantly villus tissue was removed from freshly collected placenta, and the P3-membrane fraction was prepared. Kappa opioid agonist, such as 3H-Dynorphin A, 3H-ethylketocyclazocine and 3H-U-69593, bound to the human placental membrane fraction in a manner of single class of binding site (Bmax: approximately 40 fmol.mg-1 protein). In contrast, 3H-dihydromorphine, 3H-DAGO (mu agonist), 3H-DADLE (delta agonist) or 3H-SKF-10047 (sigma agonist) showed no binding activity. The specific binding of 3H-diprenorphine was displaced only by kappa-selective ligand (U-50488H, dynorphin, butorphanol). These results suggest that opioid binding in human placental membrane is specific for kappa opioid.

Humans

[Characterization of adrenal medullary opioid receptors. I. Binding of opioids to adrenal medullary opioid receptors].

We studied the binding of [3H]D-Ala2-D-Leu5-enkephalin ([3H]DADLE) and [3H] diprenorphine to crude plasma membrane fraction obtained from the bovine adrenal medulla (bovine adrenal medullary membranes) in order to characterize adrenal medullary opioid receptors. The [3H] diprenorphine binding was the highest in crude plasma membrane-mitochondrial fraction among all subcellular fractions studied. The amount of [3H] diprenorphine bound to bovine adrenal medullary membranes was proportional to the protein concentration. Association kinetics of the [3H] diprenorphine binding to bovine adrenal medullary membranes showed that the maximal binding was achieved following 8 min incubation and that the binding conformed the second-order kinetics. [3H] DADLE and [3H] diprenorphine bound to bovine adrenal medullary membranes with high affinities. The Kd and Bmax for the [3H] DADLE binding were found to be 2.9 nM and 57.5 fmole/mg protein, respectively, while those for the [3H] diprenorphine binding were 0.31 nM and 250 fmole/mg protein, respectively. Displacement studies showed that the [3H] diprenorphine binding was inhibited dose-dependently by levorphanol, dynorphin (1-13), beta-endorphin and DADLE. Levorphanol was at least 1000-fold more potent to inhibit the [3H] diprenorphine binding than dextrorphan, indicating stereospecificity of the [3H] diprenorphine binding. Na+, Li+ and K+ (100 mM) diminished the [3H] DADLE binding and enhanced [3H] diprenorphine binding. Na+ (100 mM) increased the Kd value for the [3H] DADLE binding from 2.9 nM to 14.1 nM. Mn++, Ca++ and Mg++ diminished the [3H] diprenorphine binding. Mn++ (1 mM) increased the Bmax value for the [3H] DADLE binding from 95 fmole/mg protein to 450 fmole/mg protein. These effects of Na+ and Mn++ on the [3H] diprenorphine binding were found to be dose-dependent. [3H] Diprenorphine binding to the digitonin-solubilized opioid receptor was also inhibited dose-dependently by Mn++. These results suggest that bovine adrenal medullary membranes contain high affinity and stereospecific opioid receptors and that the binding of opioids to the bovine adrenal medullary opioid receptors is influenced by cations. Binding study also revealed the presence of opioid receptors in human malignant pheochromocytoma. The Kd and Bmax of the [3H] diprenorphine binding to crude membrane fraction obtained from malignant pheochromocytoma were found to be 0.14 nM and 10.4 fmole/mg protein, respectively.

Adrenal Medulla

[Characterization of adrenal medullary opioid receptors. II. Coupling of adrenal medullary opioid receptors to GTP binding proteins].

We studied possible coupling of opioid receptors to GTP-binding proteins to clarify the mechanism(s) of opioid action in bovine adrenal medullary membranes. Guanylyl imidodiphosphate (Gpp(NH)p) reduced the binding of [3H] D-Ala2-D-Leu5-enkephalin ([3H] DADLE) to bovine adrenal medullary membranes dose-dependently, and enhanced the binding of [3H] diprenorphine to them. Gpp(NH)p (0.1 mM) enhanced the Kd value of the [3H] DADLE binding from 2.9 nM to 3.9 nM, but did not change its Bmax. Pretreatment of bovine adrenal medullary membranes with pertussis toxin (PT) reduced the [3H] DADLE binding. The Gpp(NH)p inhibition for [3H] DADLE binding was diminished by the PT-pretreatment. On the other hand, the [3H] diprenorphine binding to PT-pretreated membranes was higher than that to control membranes. Levorphanol inhibited the adenylate cyclase activity of the rat caudate nucleus crude synaptosomal fraction, but did not change that of bovine adrenal medullary membranes. These results suggest that opioid receptors in bovine adrenal medullary membranes are coupled to PT-sensitive GTP-binding protein which may not influence on adenylate cyclase.

Adenylate Cyclase Toxin

Coupling of adrenal medullary opioid receptors to islet-activating protein-sensitive GTP-binding proteins.

Possible coupling of bovine adrenal medullary opioid receptors to islet-activating protein (IAP, pertussis toxin)-sensitive GTP-binding proteins was investigated by studying effects of guanyl-5'-yl imidodiphosphate (Gpp(NH)p) and IAP treatment of membranes on opioid binding. Gpp(NH)p inhibited [3H]D-Ala2-D-Leu5-enkephalin ([3H]DADLE) binding by increasing the dissociation constant of [3H]DADLE and membranes, and enhanced slightly [3H]diprenorphine binding. IAP treatment of membranes reduced [3H]DADLE binding and abolished almost completely the Gpp(NH)p inhibition of [3H]DADLE binding. Treatment of membranes with IAP and [32P]NAD resulted in radio-labeling of membrane proteins of approximately 39,000 dalton. DADLE inhibited adenylate cyclase activity in rat brain caudate nucleus. However, DADLE, beta-endorphin, levorphanol and dynorphin A(1-13) did not show any significant inhibitory action on bovine adrenal medullary adenylate cyclase activity. These results suggest that bovine adrenal medullary opioid (DADLE) receptors are linked to IAP-sensitive GTP-binding proteins which are not directly coupled to adenylate cyclase.

Adenylate Cyclase Toxin

Opioid and non-opioid binding of beta-endorphin to bovine adrenal medullary membranes.

Binding of human beta-endorphin (beta h-EP) to bovine adrenal medullary membranes was characterized using [125I]Tyr27-beta h-EP [( 125I]beta h-EP) as a primary ligand. The specific binding of [125I]beta h-EP was time-dependent, saturable and stereospecific. Analysis of a saturation isotherm revealed two apparent classes of specific binding sites with dissociation constants of 2.4 and 34 nM. The extent of maximum inhibition of specific [125I]beta h-EP binding by either levorphanol, morphine, naloxone, dynorphin A (1-13) or D-Ala2-D-Leu5-enkephalin was similar to each other and remained partial (60-70%). Levorphanol eliminated the high affinity component but showed no effect on the low affinity component of [125I]beta h-EP binding. beta h-EP(1-31) displaced completely the [125I]beta h-EP binding. However, beta h-EP(1-23) only partially (approximately 80%) inhibited the [125I]beta h-EP binding. beta h-EP(6-31) showed inhibitory activity on [125I]beta h-EP binding. These results suggest that [125I]beta h-EP binding to bovine adrenal medullary membranes consists of a high affinity opioid-sensitive component and a low affinity non-opioid component. The non-opioid component of [125I]beta h-EP binding may be related to COOH-terminal of the beta h-EP molecule.

Adrenal Medulla

Adrenal medullary opioid receptors are linked to GTP-binding proteins, pertussis toxin substrates.

Effects of Gpp(NH)p and pretreatment of membranes with pertussis toxin (PT) were studied on opioid binding to bovine adrenal medullary opioid receptors. Gpp(NH)p inhibited [3H]DADLE binding by increasing the dissociation constant. PT treatment reduced [3H]DADLE binding and almost abolished the Gpp(NH)p inhibition of [3H]DADLE binding. Levorphanol did not show any significant effect on bovine adrenal medullary adenylate cyclase activity. These results suggest that bovine adrenal medullary opioid receptors are linked to PT-sensitive GTP-binding proteins which are not directly coupled to adenylate cyclase.

Adenylate Cyclase Toxin

Pharmacological investigations of the new antiinflammatory agent 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid. 2nd communication: inhibitory effects on acute inflammation and prostaglandin-related reactions.

Since a newly synthesized nonsteroidal antiinflammatory drug (NSAID) having weaker effects on gastrointestinal tract, 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid (CN-100), was found to markedly inhibit rat paw edema induced by carrageenin and other phlogists, the effects of the drug on other acute inflammatory reactions and prostaglandins (PGs)-related reactions were compared with those of known NSAID in this study. At even a large dose of CN-100, 20 mg/kg, the drug did not significantly inhibit the increased vascular permeability induced by histamine in rat skin, but CN-100 could dose-dependently inhibit the increased vascular permeability induced by acetic acid in mouse peritoneum. The inhibitory activity of CN-100 in the latter was equivalent to that of pranoprofen and indometacin. CN-100 exerted a potent inhibitory action on erythema induced by UV irradiation, which was equal to and 3 times stronger than pranoprofen and indometacin in activity, respectively. Since PGs participate in these acute inflammatory reactions, the effects of CN-100 on reactions relevant to PGs were examined. The drug at dose levels lower than antiinflammatory doses could prevent acute death and diarrhea induced by i.v. injection of arachidonic acid in rabbits and endotoxin in mice, respectively, suggesting that the drug had a potent inhibitory action on biosynthesis of PGs. The adverse effects of CN-100 on gastric and small intestinal mucosa was very weak, the activity being about one-tenth of that of pranoprofen and indometacin.

Animals