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Biomedical subjects

K Hatanaka

Publications and source records attributed to K Hatanaka.

At least 91 records · Page 5Linked to original sources
PubMed1996

Biochemical profile of YM992, a novel selective serotonin reuptake inhibitor with 5-HT2A receptor antagonistic activity.

YM992, (S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride, exhibited the biochemical profile of a selective serotonin (5-HT) reuptake inhibitor (SSRI) with 5-HT2A receptor antagonistic activity. YM922 showed the same high affinity as fluoxetine against the 5-HT reuptake site (Ki = 21 nM) and a similar affinity to that of crazodone against the 5-HT2A receptor (Ki = 86 nM). In other receptor binding studies, an affinity for the adrenergic alpha 1 receptor (Ki = 200 nM) and 5-HT2C receptor (Ki = 680 nM) was observed. In a monoamine uptake study, YM992 showed a selective 5-HT uptake inhibition (IC50 = 0.15 microM), but only very weakly inhibited both noradrenaline (NA) and dopamine (DA) uptake (IC50 = 3.1 microM (NA), > 10 microM (DA)). YM992 was also found to potently inhibit the aggregation of human platelets (IC50 = 1.9 microM), revealing antagonistic activity for the 5-HT2A receptor in vitro. Enhanced serotonergic neurotransmission, in particular that mediated by the 5-HT1A receptor, has recently been reported to be important in the long-term treatment of depressive disorders with antidepressants. In addition, some 5-HT1A receptor-mediated responses are known to be potentiated by co-administration of 5-HT2A receptor antagonists. Thus, YM992, having both selective 5-HT reuptake inhibition and 5-HT2A antagonistic activity, might show potent therapeutic activity as a novel antidepressant in comparison with conventional SSRIs.

Animals↗
PubMed1996

YM90K: pharmacological characterization as a selective and potent alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor antagonist.

We investigated the pharmacological properties and neuroprotective actions of a novel alpha-amino-3-hydroxy-5-methylisoxazole-y-propionate (AMPA)/kainate receptor antagonist, [6-(1H-imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxalinedione hydrochloride (YM90K); formerly YM900], in comparison with those of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX). YM90K selectively displaced [3H]-AMPA binding (Ki = 0.084 microM) and was less potent in inhibiting [3H]-kainate (Ki = 2.2 microM), [3H]-L-glutamate (N-methyl-D-aspartate-sensitive site; Ki > 100 microM) and [3H]-glycine (strychnine-insensitive site; Ki = 37 microM) binding to rat brain membranes. YM90K co-injected with AMPA or kainate into the rat striatum protected cholinergic neurons against AMPA- or kainate-induced neurotoxicity. YM90K showed potent suppressive activity against audiogenic seizure in DBA/2 mice; ED50 values of YM90K and NBQX against tonic seizure were 2.54 and 7.17 mg/kg (i.p.), respectively. The duration of the anticonvulsant effects of YM90K and NBQX was 30 min, indicating that both compounds possess short action. In a global ischemia model, YM90K (15 mg/kg i.p. x 3), NBQX (30 mg/kg i.p. x 3) and CNQX (60 mg/kg i.p. x 3) significantly prevented the delayed neuronal death in the hippocampal CA1 region in Mongolian gerbils when administered 1 h after 5-min ischemia. In addition, the therapeutic time window for the neuroprotective effect of YM90K (30 mg/kg i.p. x 3) was 6 h. In a focal ischemia model, YM90K (30 mg/kg i.v. bolus+10 mg/kg/h for 4 h) reduced the volume of ischemic damage in the cerebral cortex in F344 rats. Thus, YM90K was shown to be a potent and selective antagonist for AMPA/kainate receptors in vitro and in vivo. This compound may provide a therapeutic effect in various neurodegenerative disorders such as ischemic stroke in which glutamate neurotoxicity is thought to play a critical role in neuronal damage.

Animals↗
PubMed1996

Neuromagnetic evidence that the P100 component of the pattern reversal visual evoked response originates in the bottom of the calcarine fissure.

Visual evoked magnetic fields due to pattern reversal stimuli were measured in 5 normal subjects using a helmet-shaped 66 channel magnetoencephalography system linked to MRI. The magnetic topography of the prominent 100 ms response (P100m) evoked by fullfield visual showed a double-dipole pattern in the occipital areas of all subjects. Right or left half-field stimuli and upper or lower quadrant-field stimuli evoked a single-dipole pattern in the contralateral occipital area. The P100m sources were then localized using a current dipole model and superimposed on MRI images of each subject. The visual cortex was morphologically variable among the subjects, but the P100m dipoles were all localized at the lateral bottom of the calcarine fissure. Moreover, these P100m dipoles had similar orientations for both half-or quadrant-field stimuli. These results suggest that the P100m is located in a smaller part of the striate cortex than previously reported.

Adult↗
PubMed1996

Clinical application of visual evoked fields using an MRI-linked whole head MEG system.

We have demonstrated anatomo-functional correlation of the brain visual function using an MRI-linked whole-head magnetoencephalography system. Visual evoked magnetic fields (VEFs) due to pattern reversal stimuli were measured in seven healthy subjects and 13 patients with intracranial structural lesions. Full-field stimuli evoked the most prominent peak around 100 ms latency (P100m) as a two-dipole pattern over the occipital area in all of the normal subjects and four patients with mild and partial hemianopsia. In five patients with homonymous hemianopsia due to unilateral occipital lesion, a single-dipole pattern of the P100m appeared over the normal occipital area only. In four patients with bitemporal hemianopsia due to pituitary tumors, a single-dipole pattern of the P100m appeared only over the ipsilateral occipital area to the stimulated eye. Using current dipole models, P100m sources were localized at the lateral bottom of the calcarine fissures. Although human occipital lobes are known to be morphologically variable, our results indicate excellent correlation of the cortical anatomy and human visual function. Full-field stimuli, requiring no strict visual fixation, are especially useful for clinical application. A clear two-dipole pattern in the normal VEFs enables us to compare two hemispheric activities.

Adult↗
PubMed1995

Role of free protein S and C4b binding protein in regulating the coagulant response to Escherichia coli.

Previous studies showed that infusion of C4b-binding protein with sublethal Escherichia coli (E. coli) in the primate produced a consumptive coagulopathy followed by microvascular thrombosis and renal failure. The first objective of this study was to characterize the pathophysiology and mechanism of this phenomena following infusion of both these agents with emphasis on defining the role of free protein S. The second objective was to examine the relevance of this model to the hemolytic uremic syndrome. Infusion of C4b-binding protein alone reduced free protein S and decreased platelet concentration to 20% of baseline, whereas infusion of the C4b-binding protein/protein S complex did not. There was no activation of other inflammatory or coagulant factors. Infusion of sublethal E coli alone produced a transient inflammatory response with no reduction of free protein S. However, coinfusion of C4b-binding protein with sublethal E coli reduced free protein S and produced a thrombocytopenia, anemia, and a microvascular thrombotic response, whereas infusion of the C4b-binding protein/protein S complex with sublethal E coli did not. Studies comparing the effects of neutralizing (S-163) and nonneutralizing (S-145) antibodies with protein S coinfused with sublethal E coli produced similar contrasting results. Therefore, we concluded that neutralization of free protein S, and not some other property of C4b-binding protein influenced by protein S, accounted for this microvascular thrombotic response. This response is similar to the hemolytic uremic syndrome characterized by thrombocytopenia, anemia, shistocytosis, and renal glomerular thrombosis with uremia. Comparison of the respective renal histopathologic appearance supports this conclusion. This raises the possibility that inhibition of protein S activity (possibly by one of the forms of C4b-binding proteins) might be one of the factors contributing to microvascular thrombotic disorder, such as the hemolytic uremic syndrome.

Animals↗
PubMed1995

Ischemic time-dependent microvascular changes and reperfusion injury in the rat small intestine.

The significance of the reperfusion period in the pathophysiology of complete occlusion of the intestinal circulation is controversial. Our study was designed to evaluate the exact magnitude of reperfusion-induced intestinal mucosal damage in a standardized rat model of complete segmental arterial ischemia as a function of the occlusion time. Intestinal ischemia was maintained for 15, 30, or 60 min, or ischemia was followed by a 30-min reperfusion period. Intraarterial India ink perfusion was applied to visualize the mucosal vascularity changes induced by ischemia or ischemia-reperfusion. The height of the distributing arterioles of the villi and the average mucosal thickness were recorded by an image analysis system, and the degree of mucosal damage was established on a semiquantitative 0 to 5 grade scale. Ischemia induced erythrocyte obstructions at the villus tip, a progressive decrease in carbon-filled arteriole height, and a concomitant 7, 23, or 35% reduction of the mucosal thickness. The percentage decrease in perfused arteriole height/percentage mucosal thickness reduction ratio was 2.2, 1.5, or 1 during the 15-, 30-, or 60-min ischemia, respectively. Extravasation of the carbon tracer was observed in the 60-min ischemia group. During reperfusion, the mucosal layer was reduced by 27, 38, or 57%, respectively, compared with the baseline values. The arteriole height reduction/mucosal thickness reduction ratio was 1:1 in all ischemic-reperfused groups. The degree of mucosal damage was significantly increased during reperfusion after the 15-min ischemia. Microvessel obstruction is initiated at the villus tip following the onset of arterial occlusion, with subsequent destruction of the surrounding tissues during reperfusion. The reperfusion component of the net mucosal damage may be very significant in early forms of complete occlusion of the mesenteric circulation.

Animals↗
PubMed1995

Phosphatidylserine-specific transbilayer lipid translocation in synaptosomal plasma membranes from Narke japonica.

We measured the translocation of exogenous radiolabeled phospholipid probes from the outer to the inner leaflet in the synaptosomal plasma membranes from the electric organs of Narke japonica, a Japanese marine ray. These radioactive probes can provide a convenient and highly sensitive means of measuring the translocation kinetics of phospholipids between outer and inner leaflets of biomembranes that are available only with low yield [Anzai et al. (1993) Biochim. Biophys. Acta 1151, 69-75]. Translocation kinetics revealed that the behavior of phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidylcholine (PC) differed. PS quickly disappeared from the outer leaflet of the bilayer. The translocation of PE and PC was slow and about 80% of the PE- and PC-probes remained in the outer leaflet at 3 h. These results differ from those of translocation in erythrocyte membranes measured using the same probes, where aminophospholipid translocase translocated both PS and PE from the outer to the inner leaflet of the bilayer, although the rate was faster for PS than for PE. In this study, the translocation was apparently PS-specific, and it was inhibited by SH reagent or intrasynaptosomal ATP-depletion. These findings clearly demonstrate that the translocation is driven by an ATP-dependent protein, which has apparent PS-specificity. We suggest that there is a translocase other than erythrocyte-type aminophospholipid translocase in synaptosomal plasma membranes from N. japonica.

Adenosine Triphosphate↗
PubMed1995

Immunohistochemical localization of C-reactive protein-binding sites in human atherosclerotic aortic lesions by a modified streptavidin-biotin-staining method.

One-step fluorescein-conjugated polyclonal antibody technique has shown that C-reactive protein (CRP) was located only extracellularly in human atherosclerotic lesions. In this report a more sensitive streptavidin-biotin technique was applied to detect the localization of CRP in human atherosclerotic lesions. Immunohistochemical staining with polyclonal and monoclonal anti-human CRP antibodies both produced a brown color extracellularly in the necrotic lesions, and intracellularly in CD68+ foam cells. The latter suggests an uptake of CRP-lipid complexes by macrophages. The staining is human CRP-specific because it was eliminated by preabsorption of the monoclonal antibody with pure human CRP, or by substitution of the primary antibody with non-immune rabbit serum. By overlaid CRP-binding study, a positive stain was observed on intimal smooth muscle cells and foam cells, suggesting that they have CRP-binding sites unless the CRP-binding activity was generated de novo through the fixation procedure. Accordingly, it is hypothesized that CRP may facilitate the uptake of lipids by macrophages accumulating in atherosclerotic lesions. Further, CRP might participate in cytolysis, which enlarges the necrotic area, and/or in phagocytosis that scavenges the necrotic tissue.

Actins↗
PubMed1995

Characterization of serum amyloid P component from human aortic atherosclerotic lesions.

Serum amyloid P component (SAP) is a glycoprotein in human plasma. We recently showed the localization of SAP in human atherosclerotic lesions by immunohistochemical staining. In this study, the presence of SAP in atherosclerotic lesions was confirmed, and the biochemical character of SAP in atherosclerotic intima was investigated and compared with that of native SAP. Atherosclerotic intima was sequentially extracted with 2 mmol/L CaCl2-Tris-buffered saline (TBS), 10 mmol/L EDTA-TBS, 3 mol/L guanidine-TBS, and collagenase digestion. The character of SAP in each extract was studied with double immunodiffusion, electroimmunoassay, crossed immunoelectrophoresis, and Western immunoblotting. The total amount of SAP in atherosclerotic intima was 190 +/- 64 micrograms/g wet tissue with an SAP-albumin ratio of 1:22.7, which is 44 times higher than the relative plasma ratio of 1:1000. This suggests that SAP is specifically localized in atherosclerotic lesions. SAP from the intima was indistinguishable from plasma or purified SAP with respect to immunological character and molecular weight. However, electrophoretic mobility and the binding of SAP to atherosclerotic intima appeared heterogeneous. Of total extractable SAP, about 43% appeared in the CaCl2-TBS fraction, 25% in the EDTA-TBS fraction, and 32% in the collagenase digestion fraction. SAP is one of the two pentraxins in human plasma; the other is C-reactive protein, which has also been reported to locate in atherosclerotic lesions. Our findings suggest a role for SAP in atherogenesis and encourage efforts to determine more precisely the physiological contributions of the pentraxin family to the development of atherosclerosis.

Aged↗
PubMed1995

Induction of cyclooxygenase type-2 (COX-2) in rat endometrium at the peak of serum estradiol during the estrus cycle.

We investigated the induction of cyclooxygenase (COX) in rat endometrium during the estrus cycle. The estrus cycle was divided into five stages (proestrus, estrus, diestrus-1, diestrus-2, diestrus-3) by cytological observation of vaginal smears. COX-1 was detected in the endometrium during all five stages of the estrus cycle. In contrast, COX-2 in the endometrium was detectable only in three stages (diestrus-3, proestrus, estrus) and showed a peak at diestrus-3, coinciding with the peak in serum estradiol level, suggesting the estradiol-dependent induction of COX-2.

Animals↗
PubMed1995

Response of mucosal mast cells to intestinal ischemia-reperfusion injury in the rat.

The goals of this study were to investigate the in vivo effects of intestinal ischemia-reperfusion on mucosal mast cells, and to evaluate the morphological changes induced by standardized arterial occlusion in anesthetized rats. Complete segmental ileal ischemia was maintained for 15, 30, or 60 min, and was followed by a 30 min reperfusion period. Intestinal biopsies taken at the end of ischemia and in the 30th min of reperfusion were evaluated by image analysis, and the rate of release of type II rat mast cell protease, a marker of mast cell exocytosis, was determined from the venous effluent of the segment. Electron microscopy revealed cytoplasmic vacuolization of the mast cells of the villi after the 15 min ischemia. Ischemia induced a continuous diminution of the mucosal thickness and a significant fall in the number of mast cells in the villi; with immunoperoxidase staining with a monoclonal antibody that recognizes the AD1 mast cell surface antigen, the decrease was 57, 49, and 66% in the 15, 30, and 60 min ischemia groups, respectively. In these groups, the mucosal type II mast cell protease concentration increased to 2.4-, 2.5-, and 3.6-fold, respectively, and a significant increase in plasma protease levels was observed on reperfusion. These results lead us to conclude that mucosal mast cells are very sensitive to intestinal ischemia, with the majority of mast cells in the ileal villi already involved in the response to ischemia after a short period of arterial occlusion.

Animals↗