Biomedical subjects

H Nakane

Publications and source records attributed to H Nakane.

At least 19 recordsLinked to original sources

PubMed2004

Histamine: its novel role as an endogenous regulator of Con A-dependent T cell proliferation.

OBJECTIVE AND DESIGN: The roles of histamine formed by the macrophage - T lymphocyte system were evaluated in the regulation of lymphocyte proliferation using mice lacking histamine receptors. METHODS: Mice deficient in histamine type 1 (H1R), type 2 (H2R) or both receptors were employed to estimate possible intervention of the receptors in the histamine-dependent lymphocyte proliferation. RESULTS: Histamine was produced de novo by spleen cells. Con A-dependent T cell proliferation decreased when histamine produced in the culture was degraded by the addition of histaminase. The H2R-deficient mice also showed a significant decrease in the Con A-dependent T cell proliferation, whereas it was not modulated in the H1R-deleted mice. Consistent with the reduction in T cell proliferation, there was a significant down-regulation of the production of IL-2, a T cell growth factor, in the H2R-deficient mice. Con A-dependent IL-2 synthesis was abrogated by the addition of histaminase. CONCLUSION: Con A-dependent T cell proliferation is (up)regulated by histamine produced de novo through the H2R, suggesting that histamine is a newly found regulator of T cell proliferation.

Amine Oxidase (Copper-Containing)↗

PubMed2004

Regulation of Con A-dependent cytokine production from CD4+ and CD8+ T lymphocytes by autosecretion of histamine.

OBJECTIVES: Previously we have shown that both CD4+ T cells and CD8+ T cells produce histamine when activated with Con A. The aim of this study was to examine whether cytokine production by these cells is regulated by autosecretion of histamine. MATERIALS: CD4+ and CD8+ T cells were separated from spleen cells of C57BL/6 mice and mice lacking the H1 receptor (H1R) or H2R, using anti-CD4+- and anti-CD8+-coupled magnetic beads, respectively. RESULTS: Depletion of the H1R resulted in decreases in the release of IL-2 and IL-10 from both CD4+ and CD8+ cells and increases in the release of IL-4 from CD4+ T cells and IFN-gamma from CD8+ cells. Mice lacking the H2R showed up-regulation of IFN-gamma secretion from CD8+ cells and of IL-4 from CD4+ and CD8+ T cells. Release of IL-2 and IL-10 from CD4+ as well as CD8+ cells was down-regulated in these mice. Both CD4+ and CD8+ T cell fractions synthesized histamine, which was enhanced in the H1R-deficient CD8+ T cells. Treatment of the cells with alpha-fluoromethyl-histidine, a specific inhibitor of HDC, or histaminase increased IFN-gamma from CD8+ cells, whereas it had no appreciable effect on IL-4 secretion from CD4+ cells. CONCLUSION: These results suggest that cytokine production by CD4+ and CD8+ T lymphocytes is regulated by autosecretion of histamine.

Amine Oxidase (Copper-Containing)↗

PubMed2004

Epidermolysis bullosa acquisita sera react with distinct epitopes on the NC1 and NC2 domains of type VII collagen: study using immunoblotting of domain-specific recombinant proteins and postembedding immunoelectron microscopy.

BACKGROUND: The sera of epidermolysis bullosa acquisita (EBA) react with type VII collagen, a major component of anchoring fibrils, in which the major epitopes have been considered to be present in the N-terminal noncollagenous (NC) 1 domain. OBJECTIVES: To determine whether there are also epitopes in the C-terminal NC2 domain, and to determine their ultrastructural localization. METHODS: Immunoblotting using recombinant proteins of the NC1 and NC2 domains of type VII collagen, and postembedding immunoelectron microscopy. RESULTS: Twenty of 28 EBA sera tested reacted with the NC1 domain and eight sera reacted with the NC2 domain. The sera that reacted with the NC1 domain showed immunoreactivity within the lamina densa and the sera that reacted with the NC2 domain showed immunoreactivity in the dermis 300-360 nm below the lamina densa. CONCLUSIONS: This study clearly identified the presence of epitopes in the NC2 domain, and showed that the epitope in the NC1 domain is present in the lamina densa and that the epitope in the NC2 domain is in the dermis below the lamina densa.

Collagen Type VII↗

PubMed2001

Mice containing a human chromosome 21 model behavioral impairment and cardiac anomalies of Down's syndrome.

Trisomy 21 (Ts21) is the most common live-born human aneuploidy; it results in a constellation of features known as Down's syndrome (DS). Ts21 is the most frequent cause of congenital heart defects and the leading genetic cause of mental retardation. To investigate the gene dosage effects of an extra copy of human chromosome 21 (Chr 21) on various phenotypes, we used microcell-mediated chromosome transfer to create embryonic stem (ES) cells containing Chr 21. ES cell lines retaining Chr 21 as an independent chromosome were used to produce chimeric mice with a substantial contribution from Chr 21-containing cells. Fluorescence in situ hybridization and PCR-based DNA analysis revealed that Chr 21 was substationally intact but had sustained a small deletion. The freely segregating Chr 21 was lost during development in some tissues, resulting in a panel of chimeric mice with various mosaicism as regards retention of the Chr 21. These chimeric mice showed a high correlation between retention of Chr 21 in the brain and impairment in learning or emotional behavior by open-field, contextual fear conditioning and forced swim tests. Hypoplastic thymus and cardiac defects, i.e. double outlet right ventricle and riding aorta, were observed in a considerable number of chimeric mouse fetuses with a high contribution of Chr 21. These chimeric mice mimic a wide variety of phenotypic traits of DS, revealing the utility of mice containing Chr 21 as unique models for DS and for the identification of genes responsible for DS.

Animals↗

PubMed2001

Depressed cerebral oxygen metabolism in patients with chronic renal failure: a positron emission tomography study.

To elucidate brain oxygen metabolism in uremic patients, regional cerebral blood flow (rCBF), oxygen extraction (rOEF), and oxygen metabolism (rCMRO(2)) were measured by positron emission tomography (PET) in 10 hemodialysis (HD) patients and 13 predialysis patients with chronic renal failure (CRF). Data were compared with 20 nonuremic patients (controls) without neurological abnormalities, congestive heart failure, history of cerebrovascular accident, diabetes mellitus, or symptomatic brain lesion on magnetic resonance imaging. In the hemisphere, rCMRO(2) in both HD (1.82 +/- 0.10 mL/min/100 g) and CRF patients (1.95 +/- 0.09 mL/min/100 g) showed significantly lower values compared with controls (2.23 +/- 0.05 mL/min/100 g; P < 0.01). Hemispheric rCBF in HD (35.6 +/- 2.1 mL/100 g/min) and CRF patients (36.1 +/- 2.1 mL/100 g/min) was not different from controls (31.8 +/- 1.4 mL/100 g/min). Hemispheric rOEF in CRF patients (45.7% +/- 1.6%) was significantly greater than that in controls (40.5% +/- 1.2%; P < 0.02), but rOEF in HD patients (43.7% +/- 1.9%) did not increase significantly. These tendencies were similar in all regions of interest, especially cerebral cortices. All PET parameters in frontal cortices tended to show the lowest values in patients with renal failure. For all HD patients, rCBF in both the frontal cortex and white matter correlated inversely with HD therapy duration (P < 0.05). In conclusion, brain oxygen metabolism is depressed in patients with renal failure on or before the start of HD therapy. The cause for depressed brain oxygen metabolism is considered to be either dysregulation of cerebral circulation or lower brain cell activity.

Brain↗

PubMed2001

Cationic polymer and lipids augment adenovirus-mediated gene transfer to cerebral arteries in vivo.

Adenovirus-mediated gene transfer to blood vessels is relatively inefficient because binding of adenovirus to vessels is limited. The authors have reported that incorporation of cationic polymer and lipids with adenovirus augments gene transfer to blood vessels ex vivo. In this study, the authors determined whether complexes of adenovirus and cations improve efficiency of gene transfer in vivo. Poly-L-lysine, lipofectamine, or lipofectin was complexed with adenovirus encoding beta-galactosidase. Optimum ratios of the cations per adenovirus were determined by gene transfer to fibroblasts. After injection of the adenovirus into the cisterna magna of anesthetized rabbits, transgene activity was greater in the adventitia of intracranial arteries and meninges after injection of the complexes than adenovirus alone. Thirty minutes after application of adenovirus with the cations, binding of adenovirus to fibroblast cells in vitro or the basilar artery in vivo (by Southern blot analysis) was augmented, which suggests that enhanced binding of virus contributes to augmentation of transgene expression. Thus, cationic polymer and lipids improve transgene expression in intracranial arteries, primarily in the adventitia, after adenovirus-mediated gene transfer in vivo. This strategy may be applicable to studies of gene transfer and eventually for gene therapy.

3T3 Cells↗

PubMed2001

Gene transfer of extracellular superoxide dismutase increases superoxide dismutase activity in cerebrospinal fluid.

BACKGROUND AND PURPOSE: Copper-zinc superoxide dismutase (CuZnSOD) is expressed intracellularly, while extracellular SOD (EC-SOD) is released from cells. The purpose of this study was to determine whether gene transfer of CuZnSOD increases SOD activity predominantly in tissues, and gene transfer of EC-SOD increases SOD activity in cerebrospinal fluid (CSF). We also determined whether heparin or dextran sulfate releases EC-SOD into CSF. METHODS: We injected recombinant adenoviruses expressing EC-SOD (AdEC-SOD), CuZnSOD (AdCuZnSOD), or beta-galactosidase (Adbeta-gal) into the cisterna magna of rabbits. RESULTS: Total SOD activity in CSF was 39+/-11 U/mL (mean+/-SE) before virus injection. Three days later, total SOD activity in CSF increased to 148+/-22 U/mL after AdEC-SOD and 92+/-10 U/mL after AdCuZnSOD (P:<0.05 versus AdEC-SOD), with no change after Adbeta-gal (49+/-5 U/mL). EC-SOD protein was detected in CSF after AdEC-SOD but not AdCuZnSOD or Adbeta-gal. Injection of heparin or dextran sulfate into the cisterna magna increased total SOD activity 27-fold and 32-fold over basal values, respectively, in CSF of rabbits that received AdEC-SOD. In contrast to effects in CSF, total SOD activity in basilar artery and meninges was significantly higher after AdCuZnSOD and tended to be higher after AdEC-SOD than after Adbeta-gal. CONCLUSIONS: -We have developed a method for intracranial gene transfer of CuZnSOD and EC-SOD. After gene transfer, CuZnSOD was expressed mainly in tissues, and EC-SOD was released into the CSF, especially after injection of heparin or dextran sulfate. Gene transfer of different isoforms of SOD may be useful in studies of cerebral vascular physiology and pathophysiology.

Adenoviridae↗

PubMed2001

[The concept of mood disorder in ICD-10].

The classification of 'Manic-depressive illness(MDI)' has been changing in this several years greatly. MDI is recently named as a 'mood(affective) disorder' according to the ICD and DSM diagnostic system. Since 1990, with ICD-10(WHO), and 1994, with DSM-IV(APA), practitioners have had at their disposal two(practically compatible) classifications of mental disorders containing operational criteria for diagnosis, and helpful in guiding clinical and therapeutic approach. In ICD-10, mood disorder belongs to the F3 category, and there are seven subcategories which were divided in to subclasses. The two other subclasses of 'F06.3 organic mood disorder' 'F41.2 mixed anxiety and depressive disorders' were set up additionally.

Humans↗

PubMed2000

Decreased UV sensitivity, mismatch repair activity and abnormal cell cycle checkpoints in skin cancer cell lines derived from UVB-irradiated XPA-deficient mice.

Xeroderma pigmentosum group A gene (XPA)-deficient mice are defective in nucleotide excision repair (NER) and are therefore highly sensitive to ultraviolet (UV)-induced skin carcinogenesis. We established cell lines from skin cancers of UVB-irradiated XPA-deficient mice to investigate the phenotypic changes occurring during skin carcinogenesis. As anticipated, the skin cancer cell lines were devoid of NER activity but were less sensitive to killing by UV-irradiation than the XPA(-/-) fibroblast cell line. The lines were also more resistant to 6-thioguanine (6-TG) than XPA(-/-) and XPA(+/+) fibroblasts, which was suggestive of a mismatch repair (MMR) defect. Indeed, in vitro mismatch binding and MMR activity were impaired in several of these cell lines. Moreover, these cell lines displayed cell cycle checkpoint derangements following UV-irradiation and 6-TG exposure. The above findings suggest that MMR downregulation may help cells escape killing by UVB, as was seen previously for methylating agents and cisplatin, and thus that MMR deficient clones are selected for during the tumorigenic transformation of XPA(-/-) cells.

Animals↗

PubMed2000

Gene transfer of endothelial nitric oxide synthase reduces angiotensin II-induced endothelial dysfunction.

Angiotensin II stimulates vascular NADPH oxidase to produce superoxide, which can react with nitric oxide and impair vasomotor function. We tested the hypothesis that the overexpression of endothelial nitric oxide synthase (eNOS) or superoxide dismutase (SOD) would correct angiotensin II-induced endothelial dysfunction. We examined the effects of the gene transfer of eNOS or 2 isoforms of SOD to the aorta in angiotensin II-treated rabbits on vasomotor function. New Zealand White rabbits were treated for 1 week with angiotensin II (100 ng. kg(-1). min(-1)) or saline by osmotic minipumps. In angiotensin II-treated rabbits, mean blood pressure was 107+/-8 mm Hg; it was 67+/-5 mm Hg in saline-infused rabbits (P<0.05). In aortas from angiotensin II-treated rabbits, lucigenin-enhanced chemiluminescence demonstrated a 2.5-fold increase in superoxide levels, and the oxidative fluorescent probe hydroethidine indicated increased superoxide levels throughout the vascular wall, especially in the endothelium and adventitia. Maximal relaxation to acetylcholine was less in aortas from rabbits treated with angiotensin II (72+/-5% versus 87+/-4% in saline-treated rabbits; P<0.01), but responses to sodium nitroprusside were similar. Segments of the thoracic aorta were incubated in vitro with an adenoviral vector that expressed eNOS, copper zinc SOD (CuZnSOD), extracellular SOD (ECSOD), or beta-galactosidase. beta-Gal treatment with adenovirus containing the gene for eNOS (AdeNOS) but not adenovirus containing the gene for beta-gal (Adbeta-gal) (control virus) restored responses to acetylcholine (82+/-3% after AdeNOS and 67+/-4% after Adbeta-gal). Gene transfer of CuZnSOD or ECSOD did not improve the endothelium-dependent relaxation of the aorta in rabbits that received angiotensin II. Thus, gene transfer of eNOS, but not SOD, effectively restores vasomotor function in angiotensin II-infused rabbits.

Angiotensin II↗

PubMed2000

[A case of synchronous cervical lymph node metastases from testicular and thyroid cancers showing mixed response to chemotherapy].

We report a case of synchronous presentation of thyroid cancer and testicular seminoma with lymph node metastasis. A 37-year-old man presented with right scrotal swelling and multiple lymph node swelling. We performed right radical orchiectomy, and histological examination revealed a seminoma of the testis. After systemic work-up for staging, we diagnosed the patient with multiple lymph node metastasis of the seminoma, and administered three cycles of bleomycin, etoposide, and cisplatin (BEP) therapy. Although the chemotherapy was very effective for the retroperitoneal and left cervical lymph node metastases, the right cervical tumor did not change. Retroperitoneal lymphadenectomy combined with right cervical lymph node dissection and hemi-thyroidectomy were performed on September 8, 1998. Pathological examination of the thyroid revealed papillary thyroid cancer and its right cervical lymph node metastasis. There was no evidence of viable cancer cells from either of the primary cancers in the retroperitoneal lymph node. Unresponsiveness to chemotherapy for metastatic lesions from testicular cancer might be a useful clue to detect primary tumors of other origins.

Adult↗

PubMed1999

A thermophilic cyanobacterium Synechococcus elongatus has three different Class I prenyltransferase genes.

Prenyltransferases (prenyl diphosphate synthases), which are a broad group of enzymes that catalyze the consecutive condensation of homoallylic diphosphate of isopentenyl diphosphates (IPP, C5) with allylic diphosphates to synthesize prenyl diphosphates of various chain lengths, have highly conserved regions in their amino acid sequences. Based on the above information, three prenyltransferase homologue genes were cloned from a thermophilic cyanobacterium, Synechococcus elongatus. Through analyses of the reaction products of the enzymes encoded by these genes, it was revealed that one encodes a thermolabile geranylgeranyl (C20) diphosphate synthase, another encodes a farnesyl (C15) diphosphate synthase whose optimal reaction temperature is 60 degrees C, and the third one encodes a prenyltransferase whose optimal reaction temperature is 75 degrees C. The last enzyme could catalyze the synthesis of five prenyl diphosphates of farnesyl, geranylgeranyl, geranylfarnesyl (C25), hexaprenyl (C30), and heptaprenyl (C35) diphosphates from dimethylallyl (C5) diphosphate, geranyl (C10) diphosphate, or farnesyl diphosphate as the allylic substrates. The product specificity of this novel kind of enzyme varied according to the ratio of the allylic and homoallylic substrates. The situations of these three S. elongatus enzymes in a phylogenetic tree of prenyltransferases are discussed in comparison with a mesophilic cyanobacterium of Synechocystis PCC6803, whose complete genome has been reported by Kaneko et al. (1996).

Amino Acid Sequence↗

PubMed1999

Cerebral blood flow threshold and regional heterogeneity of heat shock protein 72 induction following transient forebrain ischemia in rats.

Heat shock proteins (HSPs) induced by brain ischemia may play an important role in neuroprotection from neuronal degeneration. In this study, we examined the cerebral blood flow (CBF) threshold to produce regional differences in HSP72 induction after transient forebrain ischemia in spontaneously hypertensive rats (SHRs). Female SHRs were subjected to 20 min of cerebral ischemia induced by bilateral carotid artery occlusion. The CBF was measured by laser Doppler flowmetry. At forty-eight hours after cerebral ischemia and reperfusion, the rats were decapitated and the brains were removed. Specific areas (hippocampal CA1, CA2-3, dentate gyrus, dorsolateral and ventromedial striatum, and parietal cortex) were thereafter dissected from the brain. The amounts of HSP72 in these samples were determined using Western blot analysis. In the hippocampus, HSP72 was induced when the CBF decreased to less than 18-25% of the resting level. The mean values of HSP72 produced in the CA1 area, CA2-3 area, and the dentate gyrus following ischemia and reperfusion treatment were 4.44 +/- 1.43 (+/-SD) ng/microg protein, 3.51 +/- 0.72 ng/microg protein and 3.77 +/- 1.05 ng/microg protein, respectively. In the parietal cortex, the amount of HSP72 induction was less pronounced (2.55 +/- 0.40 ng/microg protein), while HSP72 was hardly detected at all in the striatum, even under conditions of very severe CBF reduction and reperfusion. We demonstrated the existence of both a CBF threshold (i.e., approximately 20% of the resting level) for HSP72 induction and regional heterogeneity for the induction of HSP72 protein.

Animals↗

PubMed1999

Programmed cell death in normal epidermis and loricrin keratoderma. Multiple functions of profilaggrin in keratinization.

The terminal differentiation of epidermal keratinocytes has been regarded as an example of programmed cell death. Among the proteins specifically expressed in this process is profilaggrin, which consists offilaggrin repeats and N- and C-terminal domains. Profilaggrin is proteolytically processed into individual domains during the terminal differentiation. Filaggrin released from profilaggrin aggregates keratin filaments to form compacted cornified cells with a keratin pattern. A recent transfection experiment has indicated initiation of cell death by filaggrin expression constructs. The transitional cells between the granular and cornified cells show morphologic characteristics of apoptotic cells, and their nuclei contain fragmented DNA and profilaggrin N-terminal domains. This suggests that the N-terminus of profilaggrin may participate in nuclear events accompanying programmed cell death. Among inherited skin disorders with abnormal keratinization, progressive symmetric erythrokeratoderma is caused by loricrin mutation (loricrin keratoderma). In this disease, profilaggrin N-terminal domains are aggregated with mutant loricrin within condensed nuclei. These nuclei persist in the cornified layer as parakeratosis. Loricrin keratoderma could therefore be regarded as a representative form of disrupted cell death.

Animals↗

PubMed1999

Antigen retrieval of loricrin epitopes at desmosomal areas of cornified cell envelopes: an immunoelectron microscopic analysis.

Cell envelopes (CEs) are insoluble, chemically and mechanically tough structures formed during terminal differentiation of keratinocytes, providing skin with a protective barrier against the environment. They are 15 to 20 nm thick structures beneath the plasma membrane and continuous with desmosomal attachment plaques. Sequential deposition of several proteins including involucrin and loricrin leads to a gradual increase in envelope thickness and rigidity. Cross-linking of desmosomal components to other CE-proteins has been demonstrated and desmosomes in the cornified cells have been regarded as a part of CEs. Our previous immunoelectron microscopy studies showed that desmosomal areas of granular cells were loricrin-positive, but those in cornified cells were negative. We asked whether this is due to epitope masking and applied trypsin digestion of the electron microscopy sections to retrieve the possibly masked epitopes. Since this treatment made desmosomal structures obscure, one side of the sections was stained with anti-desmoglein antibody as an indicator of desmosomes. Trypsin was applied on the other side followed by immunolabeling with anti-loricrin antibody. Trypsin digestion indeed unmasked the loricrin epitopes in the desmoglein-positive desmosomal areas of CEs. It seems therefore that loricrin is first accumulated at the desmosomes before the CE-assembly and cross-linking of loricrin occurs at the desmosomal areas of CEs as well as at the non-desmosomal areas.

Cytoskeletal Proteins↗

PubMed1999

Electron microscopic in situ DNA nick end-labeling in combination with immunoelectron microscopy.

We describe an in situ DNA nick end-labeling method that can be performed at the electron microscopic level and can also be combined with immunoelectron microscopy. As the materials, we used skin tissues from normal skin and from Bowen's disease that had been cryofixed, freeze-substituted, and embedded in Lowicryl K11M resin. Ultrathin sections were cut and incubated with a reaction buffer containing digoxigenin-dUTP and terminal deoxynucleotidyl transferase. Digoxigenin nucleotides were labeled with anti-digoxigenin antibodies conjugated with colloidal gold. Specific signals were detected in the condensed chromatin of differentiated epidermal cells and hair follicles in normal skin and of dyskeratotic cells in Bowen's disease. The labeling density over chromosomal areas of apoptotic cells was significantly higher than that over chromosomal areas of mitotic cells or cytoplasmic areas. Ultrastructure was well preserved and double staining with an anti-keratin antibody was also successfully performed. This simple method has a wide range of applications to identify the nature of apoptotic cells and explore the mechanisms of apoptosis.

Adult↗

PubMed1998

A pathway where polyprenyl diphosphate elongates in prenyltransferase. Insight into a common mechanism of chain length determination of prenyltransferases.

Prenyltransferases catalyze the consecutive condensations of isopentenyl diphosphate to produce linear polyprenyl diphosphates. Each enzyme forms the final product with a specific chain length. The product specificity of an enzyme is thought to be determined by the structure around the unknown path through which the product elongates in the enzyme. To explore the path, we introduced a few mutations at the 5th, the 8th, and/or the 11th positions before the first aspartate-rich motif of geranylgeranyl-diphosphate synthase or farnesyl-diphosphate synthase. The side chains of these amino acids are situated on the same side of an alpha-helix. In geranylgeranyl-diphosphate synthase, a single mutated enzyme (F77S) mainly produces a C25 product (Ohnuma, S.-I., Hirooka, K., Hemmi, H., Ishida, C., Ohto, C., and Nishino, T. (1996) J. Biol. Chem. 271, 18831-18837). A double mutated enzyme (L74G and F77G) mainly produces a C35 compound with significant amounts of C30 and C40. A triple mutated enzyme (I71G, L74G, and F77G) mainly produces a C40 compound with C35 and C45. Mutated farnesyl-diphosphate synthases also show similar patterns. These findings indicate that the elongating product passages on a surface of the side chains of the mutated amino acids, the original bulky amino acids had blocked the elongation, and the path is conserved in prenyltransferases. Moreover, the fact that some double and triple mutated enzymes can also form small amounts of products longer than C50 indicates that the paths in these mutated enzymes can partially access the outer surface of the enzymes.

Alkyl and Aryl Transferases↗

PubMed1998

Modulation of ischemia-evoked release of excitatory and inhibitory amino acids by adenosine A1 receptor agonist.

Adenosine has been reported to have beneficial effects against ischemic brain damage, although the mechanisms are not fully clarified. To examine the role of adenosine on the ischemia-evoked release of neurotransmitters, we applied a highly selective agonist for adenosine A1 receptor, 2-chloro-N6-cyclopentyladenosine (CCPA), into the ischemic brain using in vivo brain dialysis, which directly delivered the agonist to the local brain area. Concentrations of extracellular amino acids (glutamate, aspartate, gamma-aminobutyric acid (GABA) and taurine) and regional blood flow in the striatum of spontaneously hypertensive rats (SHRs) were monitored during cerebral ischemia elicited by bilateral carotid artery occlusion for 40 min and recirculation. Striatal blood flow and basal levels of amino acids were not affected by direct perfusion of CCPA (10 microM or 100 microM). During ischemia, concentrations of glutamate, aspartate, GABA and taurine increased up to 37-, 30-, 96- and 31-fold, respectively, when vehicle alone was administered. Administration of CCPA did not affect the changes in regional blood flow during ischemia and reperfusion. Perfusion of CCPA (100 microM), however, significantly attenuated the ischemia-evoked release of aspartate (by 70%) and glutamate (by 73%). The ischemia-induced increase of GABA tended to be decreased by CCPA, although it was not statistically significant. In contrast, both low and high concentrations of CCPA had little effect on the release of taurine during ischemia. These results suggest that stimulation of adenosine A1 receptors selectively attenuated the ischemia-evoked release of excitatory amino acids, but not of inhibitory amino acids without affecting blood flow. This modulation of the release of amino acids by adenosine A1 receptor agonists may play a protective role against ischemic neuronal damage.

Adenosine↗