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H Kita

Publications and source records attributed to H Kita.

At least 37 records · Page 2Linked to original sources
PubMed2002

Effects of dynorphin on rat entopeduncular nucleus neurons in vitro.

The entopeduncular nucleus (EP) receives dense neostriatal afferent axons that contain dynorphin (DYN, an endogenous kappa-receptor agonist), in addition to GABA and substance P. To examine the role of DYN in the EP, whole-cell recordings were performed in rat brain slice preparations. Based on the physiological and morphological characteristics, all the neurons recorded were similar to the Type-I EP neuron described in a previous study. The kappa-receptor agonist dynorphin A (1-13) (DYN13) hyperpolarized and decreased the input resistance of approximately one-quarter of the EP neurons examined. The hyperpolarization was due to an increase in potassium conductance since current-voltage relationship curves obtained before and after DYN13 application crossed at the potassium equilibrium potential. In the presence of the glutamate blocker 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide and 3-(2-carboxypiperzin-4-yl)-propyl-1-phosphonic acid in artificial cerebrospinal fluid, stimulation of the globus pallidus evoked bicuculline-sensitive multi-component GABAergic responses in EP neurons. Application of DYN13 equally reduced the amplitudes of the short-latency response, conceivably evoked by pallido-EP axons, and the medium-latency response, conceivably evoked by striato-EP axons. These effects were reversed by bath application of a non-selective opioid antagonist naloxone or by a kappa-opioid receptor-selective antagonist nor-binaltorphimine dihydrochloride (nor-BNI), but not by the partial differential -antagonist naltrindole or the mu-antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2). DYN13 also reduced the frequency of tetrodotoxin-insensitive miniature-inhibitory postsynaptic potential (mIPSPs) without changing their amplitude distributions. The decrease of the frequency of mIPSPs was reversible upon washing and was also completely blocked by nor-BNI. The results of the present study on the EP indicated that DYN released from striatal axons might exert at least three different effects on these target nuclei. Firstly, DYN might provide negative feedback regulation of striatal GABAergic outputs at their termination sites. Secondly, DYN released from the striatal terminals might diffuse to the pallidal terminals, regulating their GABA release. Thirdly, DYN might exert a direct inhibition of EP neurons. Thus, DYN released from striatal axons might control the activity of EP neurons by reducing the GABAergic transmission and also by hyperpolarizing postsynaptic membrane.

Anesthetics, Local↗
PubMed2002

Removal of bronchoalveolar cells augments the late eosinophilic response to segmental allergen challenge.

BACKGROUND: In patients with quiescent asthma, macrophages are the most prevalent cells recovered by bronchoalveolar lavage (BAL). Through activation via their FcepsilonRII receptors or by acting as antigen-presenting cells, macrophages could, in theory, promote the late airway response to allergen. OBJECTIVE: In order to investigate the importance of macrophages and other airway luminal cells in inducing the late airway response, a novel washout experiment was designed. METHODS: Five patients with ragweed-allergic asthma underwent bronchoscopy and segmental bronchial challenge with either normal saline or short ragweed extract in two segments of one lung. In a third segment of the opposite lung, 12 successive BALs (25 mL each) were performed, followed by challenge with an identical dose of short ragweed (washed-challenged segment). After 24 h, all three challenged segments underwent BAL. RESULTS: Initially, in the washed-challenged segment, over 80% (mean 80.4%, range 68-88%) of the recoverable airway dwelling cells were removed. Unexpectedly, 24 h later these same washed-challenged segments contained more eosinophils in the BAL than the challenged segments from the opposite lung (P = 0.033). CONCLUSIONS: Removing the majority of airway luminal cells followed by allergen bronchoprovocation increased the number of eosinophils recovered 24 h after challenge. Our results suggest that in quiescent allergic asthma, the airway luminal cells are protective and attenuate the late eosinophilic response to allergen challenge.

Adult↗
PubMed2001

Trypsin induces activation and inflammatory mediator release from human eosinophils through protease-activated receptor-2.

Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors, which are activated by proteolytic cleavage of the amino terminus of the receptor itself. PARs are most likely involved in various biological responses, such as hemostasis and regulation of muscle tone; however, the roles of PARs in the functions of inflammatory and immune cells are poorly understood. Because eosinophils are most likely involved in allergic inflammation and are exposed to a variety of proteases derived from allergens and other inflammatory cells, we investigated whether PARs regulate effector functions of eosinophils. Human eosinophils constitutively transcribe mRNA for PAR2 and PAR3, but not those for PAR1 and PAR4. The expression of PAR2 protein was confirmed by flow cytometry. When trypsin, an agonist for PAR2, was incubated with eosinophils, it potently induced superoxide anion production and degranulation; 5 nM trypsin induced responses that were 50-70% of those induced by 100 nM platelet-activating factor, a positive control. In contrast, thrombin, an activator for PAR1, PAR3, and PAR4, showed minimal effects. The stimulatory effect of trypsin was dependent on its serine protease activity and was blocked 59% by anti-PAR2 Ab. Furthermore, a specific tethered peptide ligand for PAR2 potently induced superoxide production and degranulation; the effects of peptide ligands for PAR1, PAR3, and PAR4 were negligible. These findings suggest that human eosinophils express functional PAR2, and serine proteases at the inflammation site may play important roles in regulating effector functions of human eosinophils. The expression and functional relevance of other PARs still need to be determined.

Amino Acid Sequence↗
PubMed2001

Number, origins, and chemical types of rat pallidostriatal projection neurons.

The dorsal globus pallidus (GP) receives major inputs from the dorsal neostriatum (Str), the subthalamic nucleus (STN) and the dorsal thalamus. The GP projects to multiple basal ganglia nuclei. One of the GP projection sites is the Str. The pallidostriatal projection has been considered minor. However, several recent studies have suggested that this projection is heavier than previously thought and that it might play a significant role in controlling the activity of the Str. To reveal more details of this projection, we examined the number of GP neurons that participated in the projection, their origins in the GP and their immunoreactivity for the calcium binding protein parvalbumin (PV), by using a combination of Fluoro-Gold (FG) retrograde labeling and immunohistochemical methods. Immunostaining for the calcium binding protein calbindin-28K (CaBP) was used to identify the CaBP-poor sensorimotor and CaBP-rich associative Str regions and the corresponding CaBP-poor middle, CaBP-rich border, and the caudomedial GP regions. The CaBP-poor dorsolateral Str region occupies a small portion of the Str, whereas the CaBP-poor middle GP region occupies a large portion of the GP. The immunostaining for neuron-specific nuclear protein (NeuN) was used to visualize neurons that were immunonegative for FG or PV. Cell counts revealed that the middle GP region contained a higher density of neurons and also a higher percentage of PV-positive neurons than the border and caudomedial regions of the GP. These observations suggested that the GP is involved more in sensorimotor function than associative function. Approximately 40% of neurons in the CaBP-poor middle GP region project to the CaBP-poor part of the dorsolateral Str. Approximately 30% of the neurons in both the CaBP-rich border and the caudomedial GP regions project to the CaBP-rich Str region. More than 40% of the pallidostriatal neurons in CaBP-poor middle GP region are PV-positive, whereas most of those in CaBP-rich GP regions are PV-negative. It was estimated from the cell count data that most of the PV-negative neurons in all three regions of the GP project to the Str. The results indicate that the sensorimotor and associative territories of the Str have reciprocal projections between corresponding territories of the GP. The involvement of a large number of GP neurons suggested that the pallidostriatal projection should be taken into account in the analysis of functional roles of the basal ganglia.

Animals↗
PubMed2001

Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington's disease.

Huntington's disease (HD) is one of 10 known diseases caused by a (CAG)(n) trinucleotide repeat expansion that is translated into an abnormally long polyglutamine tract. We have developed stable inducible neuronal (PC12) cell lines that express huntingtin exon 1 with varying CAG repeat lengths under doxycycline (dox) control. The expression of expanded repeats is associated with aggregate formation, caspase-dependent cell death and decreased neurite outgrowth. Post-mitotic cells expressing mutant alleles were more prone to cell death compared with identical cycling cells. To determine early metabolic changes induced by this mutation in cell models, we studied changes in gene expression after 18 h dox induction, using Affymetrix arrays, cDNA filters and adapter-tagged competitive PCR (ATAC-PCR). At this time point there were low rates of inclusion formation, no evidence of mitochondrial compromise and no excess cell death in the lines expressing expanded compared with wild-type repeats. The expression profiles suggest novel targets for the HD mutation and were compatible with impaired cAMP response element (CRE)-mediated transcription, which we confirmed using CRE-luciferase reporter assays. Reduced CRE-mediated transcription may contribute to the loss of neurite outgrowth and cell death in polyglutamine diseases, as these phenotypes were partially rescued by treating cells with cAMP or forskolin.

Animals↗
PubMed2001

Acute effect of nasal continuous positive airway pressure therapy on the systemic immunity of patients with obstructive sleep apnea syndrome.

OBJECTIVES: To investigate whether in patients with obstructive sleep apnea syndrome (OSAS) the systemic immunity is disturbed and whether it changes with nasal continuous positive airway pressure (NCPAP) therapy. DESIGN: Polysomnography was performed on 18 OSAS patients (Group A) before NCPAP was started and again on the first night of NCPAP. Blood samples were collected at 8:00PM, 1:00AM and 6:00AM during each polysomnography. Lymphocyte subsets, lymphocyte blastformation, and natural killer (NK) cell activity were determined. Six normal subjects were also studied. A different six OSAS patients were studied over 6 days of NCPAP. SETTING: N/A. PATIENTS OR PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The only immunological parameter that significantly differed between the Group A OSAS patients either before or on the first night of NCPAP, and the normal subjects was the epinephrine level. Among the Group A OSAS patients, the following immunological parameters were significantly lower at 6:00AM on the first night of NCPAP than before NCPAP was started: percentage (49.4+/-1.9% before NCPAP vs 45.7+/-2.0% with NCPAP, mean+/-SEM, p<0.005) and absolute count of CD4+ cells (944.1+/-63.8 vs 829.6+/-71.3/mm3, p<0.05); absolute count of CD4+HLA-DR+ cells (91.9+/-13.3 vs 75.1+/-8.9/mm3, p<0.05); CD4+/CD8+ ratio (2.13+/-0.21 vs 1.91+/-0.18, p<0.05). The reduction in the percentage of CD4+ cells at 6:00AM was significantly correlated with the change in apnea-hypopnea index (AHI) (r=0.729, p<0.01). The CD4+ cell count recovered after 6 days of NCPAP. The lymphocyte blasfformation and NK cell activity levels did not change with NCPAP. CONCLUSIONS: First-night NCPAP therapy reduced the CD4+ cell count after sleep, which recovered after one week of NCPAP. OSAS patients do not have immunological abnormalities.

Adult↗
PubMed2001

Regulation of human eosinophil NADPH oxidase activity: a central role for PKCdelta.

Eosinophils play a primary role in the pathophysiology of asthma. In the lung, the activation state of the infiltrating eosinophils determines the extent of tissue damage. Interleukin-5 (IL-5) and leukotriene B4 (LTB4) are important signaling molecules involved in eosinophil recruitment and activation. However, the physiological processes that regulate these activation events are largely unknown. In this study we have examined the mechanisms of human eosinophil NADPH oxidase regulation by IL-5, LTB4, and phorbol ester (PMA). These stimuli activate a Zn2+-sensitive plasma membrane proton channel, and treatment of eosinophils with Zn2+ blocks superoxide production. We have demonstrated that eosinophil intracellular pH is not altered by IL-5 activation of NADPH oxidase. Additionally, PKCdelta inhibitors block PMA, IL-5 and LTB4 mediated superoxide formation. Interestingly, the PKCdelta-selective inhibitor, rottlerin, does not block proton channel activation by PMA indicating that the oxidase and the proton conductance are regulated at distinct phosphorylation sites. IL-5 and LTB4, but not PMA, stimulated superoxide production is also blocked by inhibitors of PI 3-kinase indicating that activation of this enzyme is an upstream event common to both receptor signaling pathways. Our results indicate that the G-protein-coupled LTB4 receptor and the IL-5 cytokine receptor converge on a common signaling pathway involving PI 3-kinase and PKCdelta to regulate NADPH oxidase activity in human eosinophils.

Acetophenones↗
PubMed2001

Neostriatal and globus pallidus stimulation induced inhibitory postsynaptic potentials in entopeduncular neurons in rat brain slice preparations.

Recent anatomical studies revealed that the entopeduncular nucleus of the rat receives GABAergic inputs from both the neostriatum and the globus pallidus. The present study was undertaken to reveal the physiological features of these inputs using the intracellular recording method in rat brain slice preparations. Most of the entopeduncular nucleus neurons generated repetitive firing without spike accommodation with intracellular current stimulation and thus were classified as Type-I. A small number of neurons were classified as Type-II since they generated spikes with pronounced accommodation. Most of the Type-I, but none of Type-II, entopeduncular nucleus neurons exhibited monosynaptic GABAergic inhibitory postsynaptic potentials (IPSPs) after stimulation of the neostriatum and the globus pallidus. Neostriatal stimulation induced long latency IPSPs while pallidal stimulation induced long latency IPSPs compounded with short latency IPSPs. The IPSPs were mediated by GABA(A) receptors. The unitary IPSPs to striatal stimulation were small while those to pallidal stimulation were large in amplitude and able to reset ongoing rhythmic firing. The short latency IPSPs induced by pallidal stimulation reversed at a somatic membrane potential that was a few millivolts more depolarized than the long latency IPSPs, suggesting that the striatal inputs were evoked in more distal portions of the neurons than the pallidal inputs. Repetitive activation of these inputs resulted in a poor amplitude summation but a prolongation of the duration of the IPSPs. The results of the present study indicate that the pallidal projection to the entopeduncular nucleus is physiologically significant and that the neostriatum and the globus pallidus play important roles in controlling the activity of the entopeduncular nucleus, although in different ways.

Animals↗
PubMed2001

Relationship between regional cerebral blood flow and verbal fluency in Alzheimer's disease.

Category and letter verbal fluency tests are widely used for dementia detection and severity measure. Performances of these tasks have been regarded to be mainly associated with the left frontal lobe function. However, some recent studies suggest that there are different neuropsychological bases between these two tasks, and the brain region which contributes to these performances still remains unclear in Alzheimer's disease (AD). To clarify the neural basis of verbal fluency in AD, we examined the relationship between performances of these tasks and regional cerebral blood flow (rCBF). Twenty-five AD patients were administered verbal fluency tasks and single photon emission computed tomography (SPECT) scans. Thirteen cortical regions of interest were symmetrically defined in each hemisphere. Letter fluency scores were correlated significantly only with the left prefrontal (Brodmann's area (BA) 10-46) regional cerebral blood flow (rCBF). In contrast, category fluency scores were correlated most strongly with the left temporal rCBF and also with the left prefrontal (BA 10-46) rCBF. In conclusion, the present study suggests that left prefrontal (BA 10-46) dysfunction contributes to decline in both letter and category fluency scores in AD, while typical posterior dysfunction of AD has a closer relationship with decline in category fluency scores.

Aged↗
PubMed2001

Qualitative analyses of clock drawings in Alzheimer's disease and vascular dementia.

Although quantitative analyses of clock drawings (CD) have achieved widespread clinical use as a cognitive screening, little is known about the qualitative profiles of CD in Alzheimer's disease (AD) and vascular dementia (VD). To address this issue, the present study examined the significance of qualitative analyses of CD in AD and VD. Sixty-seven AD patients, 44 VD patients and eight controls underwent a clock drawing test and took the Mini-Mental State Examinations (MMSE). In the dementia groups, quantitative scores significantly decreased compared with controls and were significantly correlated with MMSE scores. Qualitative analysis demonstrated that in AD patients qualitative error patterns were stable and independent of severity. In contrast, in VD patients the frequency of graphic difficulties and conceptual deficit increased, while the frequency of spatial and/or planning deficit decreased, as severity worsened. In mild dementia groups the frequency of spatial and/or planning deficit was significantly higher in VD. In moderate dementia groups, the frequency of graphic difficulties was significantly higher in VD and the difference in the frequency of spatial and/or planning deficit seen in mild dementia disappeared. The present study suggests that qualitative analyses of clock drawings could demonstrate the neuropsychological profiles of AD and VD and their differences between these dementias.

Aged↗
PubMed2001

The lymphoid liver: considerations on pathways to autoimmune injury.

Immunologic injury in the liver involves immigrant T and B lymphocytes and a resident lymphoid population that comprises distinct lymphocytic cells and accessory cells. The forerunner to autoimmunity is breaching of natural self-tolerance and hence the disruption of a fundamental property of the immune system. Such breaching occurs by processes that include inflammatory activation of immunocytes and macrophages, spillage of intracellular constituents, and epitope mimicry by constituents of microorganisms, with these acting on a genetically conditional phenotype; compounding factors include aberrations of apoptosis, whether insufficient or excess. The downstream end requires specifically directed inflammatory leukocyte traffic as an essential component of autoimmune expressions in the liver. The culmination is an orchestrated attack on hepatocytes or biliary epithelial cells by multiple effector pathways. Progress in type 1 autoimmune hepatitis still requires knowledge of a disease-specific autoantigen(s) involved in T-cell reactivity, although such knowledge in type 2 autoimmune hepatitis, in which the known autoantigen is cytochrome P4502D6, has not yet been integrated into a clearly defined scheme of pathogenesis. For PBC there has been a very promising amalgamation of molecular knowledge of the mitochondrial autoantigens. Future insights require deeper analysis of molecular, genetic, macroenvironmental, and microenvironmental elements in predisposition.

Animals↗
PubMed2001

Bile acids induce eosinophil degranulation by two different mechanisms.

Eosinophil infiltration and activation occur in the vicinity of the bile ducts in immune cholangiopathies. When cholangiocytes are injured, bile acids may cross the damaged biliary epithelia and affect periductal immune cells. Although immunomodulatory actions of bile acids have been well explored, their effects on eosinophils have never been examined. In this study, we tested the hypothesis that bile acids directly activate eosinophils and induce their effector functions. We found that a hydrophobic bile acid, taurine-con- jugated chenodeoxycholic acid (TCDCA), induces eosinophil degranulation in vitro via 2 different mechanisms depending on its concentration. Degranulation induced by 100 to 500 micromol/L TCDCA was an active and regulated release because it was completely abolished by a tyrosine kinase inhibitor (genistein), by a microfilament inhibitor (cytochalasin B), and by incubation at 4 degrees C. Furthermore, eosinophils stimulated with 10 to 250 micromol/L TCDCA vigorously produced superoxide and interleukin-8 (IL-8). In contrast, at higher concentrations (e.g., > or = 1,000 micromol/L), TCDCA induced granule protein release without concomitant superoxide production and IL-8 production. Further genistein and cytochalasin B failed to inhibit eosinophil degranulation induced by 2,500 micromol/L TCDCA, suggesting that TCDCA at this concentration induced passive degranulation via cytolysis. The analyses of cell morphology and functional viability also supported the presence of 2 mechanisms for TCDCA-induced eosinophil degranulation. Taurine-conjugated ursodeoxycholic acid, a hydrophilic bile acid, similarly activated human eosinophils at relatively low concentrations, although the potency was always lower compared with that of TCDCA. In conclusion, we have shown that bile acids are capable of directly activating eosinophils.

Cell Degranulation↗
PubMed2001

Colonisation and transmission of Clostridium difficile in healthy individuals examined by PCR ribotyping and pulsed-field gel electrophoresis.

Healthy adults who had not been exposed to antimicrobial agents for the preceding 4 weeks were examined for intestinal carriage of Clostridium difficile. The 1234 individuals examined were composed of seven groups: three classes of university students, hospital workers at two hospitals, employees of a company and self-defence force personnel at a local station. Overall, 94 (7.6%) individuals were positive for C. difficile by faecal culture but carriage rates among the study groups ranged from 4.2% to 15.3%. Typing by PCR ribotyping and pulsed-field gel electrophoresis demonstrated clusters of carriers colonised by a single type in each of three groups, indicating that cross-transmission of C. difficile can occur in community settings. Follow-up culture was performed on 38 C. difficile-positive individuals and C. difficile was isolated again from 12 (32%) of them 5-7 months after the initial culture; six (50%) of these 12 individuals had a new strain on repeat culture. Two or more family members were C. difficile-positive in five of 22 families examined. C. difficile with an identical type was isolated from persons within a family in only one family. These results suggest that intestinal carriage by healthy adults may play a role as a reservoir for community-acquired C. difficile-associated diarrhoea, but that cross-transmission of C. difficile does not occur frequently among family members at home.

Adolescent↗
PubMed2001

Cysteine protease secreted by Paragonimus westermani attenuates effector functions of human eosinophils stimulated with immunoglobulin G.

An immunoglobulin G (IgG)-coated surface, such as that found on helminth parasites, is one of the most effective physiologic stimuli for eosinophil activation. The cysteine proteases secreted by tissue-invasive helminth larvae play an important role in evasion of the immune response by degrading the host immunoglobulins. In this study, we investigated whether cysteine proteases in the excretory-secretory product (ESP) produced by Paragonimus westermani newly excysted metacercariae (PwNEM), which cause pulmonary or extrapulmonary paragonimiasis in human beings, could modify effector functions of human eosinophils stimulated with IgG. We coated 96-well plates with human IgG in the absence or presence of the ESP produced by PwNEM. When eosinophils were incubated in the wells coated with IgG in the presence of the ESP, eosinophil degranulation and superoxide production were significantly reduced compared with results for cells incubated in wells coated with IgG alone. This inhibitory effect of the ESP on IgG-induced superoxide production was dose dependent and was significantly abolished by pretreatment of the ESP with heat. These findings suggest that the cysteine proteases secreted by PwNEM attenuate both activation and degranulation of eosinophils stimulated with IgG. Thus, the cysteine proteases produced by tissue-invasive helminth larvae play crucial roles in evasion of IgG-dependent eosinophil helminthotoxicity and in reduction of eosinophil-associated tissue inflammation during the migratory period.

Animals↗
PubMed2001

A comparison study of self-adaptation in evolution strategies and real-coded genetic algorithms.

This paper discusses the self-adaptive mechanisms of evolution strategies (ES) and real-coded genetic algorithms (RCGA) for optimization in continuous search spaces. For multi-membered evolution strategies, a self-adaptive mechanism of mutation parameters has been proposed by Schwefel. It introduces parameters such as standard deviations of the normal distribution for mutation into the genetic code and lets them evolve by selection as well as the decision variables. In the RCGA, crossover or recombination is used mainly for search. It utilizes information on several individuals to generate novel search points, and therefore, it can generate offspring adaptively according to the distribution of parents without any adaptive parameters. The present paper discusses characteristics of these two self-adaptive mechanisms through numerical experiments. The self-adaptive characteristics such as translation, enlargement, focusing, and directing of the distribution of children generated by the ES and the RCGA are examined through experiments.

Algorithms↗
PubMed2001

Eosinophil-associated inflammation and elaboration of eosinophil-derived proteins in 2 children with raccoon roundworm (Baylisascaris procyonis) encephalitis.

OBJECTIVE: Eosinophil-associated proteins, especially eosinophil-derived neurotoxin, may be important contributors to the neurologic pathology and symptoms caused by Baylisascaris procyonis infection. METHODS: Two cases of severe B procyonis encephalitis with evidence of marked eosinophil degranulation in the central nervous system are presented. Serial cerebrospinal fluid (CSF) specimens were collected from each patient during the course of their illness. Antibodies against B procyonis were measured in the patients' serum and CSF. Levels of the eosinophilopoietin interleukin-5 (IL-5) and 2 important eosinophil proteins, eosinophil-derived neurotoxin and major basic protein, were assayed in the CSF. RESULTS: Both patients had rapidly progressive central nervous system disease with evidence of eosinophilic meningoencephalitis. Both tested positive for antibodies to B procyonis in serum and CSF and had progressively worsening deep white matter changes on magnetic resonance images of the brain. CSF levels of IL-5, eosinophil-derived neurotoxin, and major basic protein were markedly elevated over controls. CONCLUSIONS: This is the first report of the measurement of IL-5, eosinophil-derived neurotoxin, and major basic protein in human CSF. In addition to traumatic damage and necrosis caused by migrating larvae, eosinophil-derived neurotoxin from associated eosinophilic inflammation may be an important contributory factor in the pathogenesis of B procyonis encephalitis. parasite, eosinophil-derived-neurotoxin, major basic protein, eosinophilia, hypereosinophilia, interleukin-5, encephalitis, child.

Animals↗
PubMed2000

Roles of mitochondrial ATP-sensitive K channels and PKC in anti-infarct tolerance afforded by adenosine A1 receptor activation.

OBJECTIVES: This study intended to assess the role of mitochondrial ATP-sensitive potassium (mitoK ATP) channels and the sequence of signal transduction with protein kinase C (PKC) and adenosine A1 receptors in rabbits. BACKGROUND: To our knowledge, the link between trigger receptors of preconditioning, PKC and mitoK ATP channels has not been examined in a whole heart model of infarction. METHODS: In the first series of experiments, myocardial infarction was induced in isolated buffer-perfused rabbit hearts by 30-min global ischemia and 2-h reperfusion. Infarct size in the left ventricle was determined by tetrazolium staining and expressed as a percentage of area at risk (i.e., the whole left ventricle) (%IS/AR). In the second series of experiments, mitochondria were isolated from the heart, and their respiratory function was examined using glutamate as a substrate. RESULTS: Pretreatment with R-phenylisopropyladenosine (R-PIA, 1 micromol/liter), an A1-receptor agonist, reduced %IS/AR from 49.8 +/- 6.5% to 13.4 +/- 2.9%. This protection was abolished by calphostin C, a PKC inhibitor, and by 5-hydroxydecanoate (5-HD), a selective inhibitor of mitoK ATP channels. A selective mitoK ATP channel opener, diazoxide (100 micromol/liter), mimicked the effect of R-PIA on infarct size (%IS/AR = 11.6 +/- 4.0%), and this protective effect was also abolished by 5-HD. However, calphostin C failed to block the infarct size-limiting effect of diazoxide. Neither calphostin C nor 5-HD alone modified %IS/AR. State III respiration (QO2) and respiratory control index (RCI) were reduced after 30 min of ischemia (QO2 = 147.3 +/- 5.3 vs. 108.5 +/- 12.3, RCI = 22.3 +/- 1.1 vs. 12.1 +/- 1.8, p < 0.05). This mitochondrial dysfunction was persistent after 10 min of reperfusion (QO2 = 96.1 +/- 15.5, RCI = 9.5 +/- 1.9). Diazoxide significantly attenuated the respiratory dysfunction after 30 min of ischemia (QO2 = 142.8 +/- 9.7, RCI = 16.2 +/- 0.8) and subsequent 10-min reperfusion (QO2 = 135.3 +/- 7.2, RCI = 19.1 +/- 0.8). CONCLUSIONS: These results suggest that mitoK ATP channels are downstream of PKC in the mechanism of infarct-size limitation by A1-receptor activation and that the anti-infarct tolerance afforded by opening of mitoK ATP channels is associated with preservation of mitochondrial function during ischemia/reperfusion.

Adenosine Triphosphate↗