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Toru Kobayashi

Publications and source records attributed to Toru Kobayashi.

At least 19 recordsLinked to original sources
PubMed2006

Inhibition of G protein-activated inwardly rectifying K+ channels by the antidepressant paroxetine.

Paroxetine is commonly used as a selective serotonin reuptake inhibitor for the treatment of depression and other psychiatric disorders. However, the molecular mechanisms of the paroxetine effects have not yet been sufficiently clarified. Using Xenopus oocyte expression assays, we investigated the effects of paroxetine on G protein-activated inwardly rectifying K+ (GIRK) channels, which play an important role in reducing neuronal excitability in most brain regions and the heart rate. In oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, paroxetine reversibly reduced inward currents through the expressed GIRK channels. The inhibition was concentration-dependent, but voltage-independent and time-independent during each voltage pulse. However, two structurally different antidepressants: milnacipran and trazodone, caused only a small inhibition of basal GIRK currents. Additionally, Kir1.1 and Kir2.1 channels were insensitive to all of the antidepressants. Furthermore, the GIRK currents induced by activation of A1 adenosine receptors or by ethanol were inhibited by extracellularly applied paroxetine in a concentration-dependent manner, but not affected by intracellularly applied paroxetine. Our results suggest that inhibition of GIRK channels by paroxetine may contribute partly to some of its therapeutic effects and adverse side effects.

Adrenergic Uptake Inhibitors↗
PubMed2006

Inhibition of G protein-activated inwardly rectifying K+ channels by ifenprodil.

G protein-activated inwardly rectifying K+ channels (GIRK, also known as Kir3) are regulated by various G-protein-coupled receptors. Activation of GIRK channels plays an important role in reducing neuronal excitability in most brain regions and the heart rate. Ifenprodil, which is a clinically used cerebral vasodilator, interacts with several receptors, such as alpha1 adrenergic, N-methyl-D-aspartate, serotonin and sigma receptors. However, the molecular mechanisms underlying the various clinically related effects of ifenprodil remain to be clarified. Here, we examined the effects of ifenprodil on GIRK channels by using Xenopus oocyte expression assays. In oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2 or GIRK1/GIRK4 subunits, ifenprodil reversibly reduced inward currents through the basal GIRK activity. The inhibition was concentration-dependent, but voltage- and time-independent, suggesting that ifenprodil may not act as an open channel blocker of the channels. In contrast, Kir1.1 and Kir2.1 channels in other Kir channel subfamilies were insensitive to ifenprodil. Furthermore, GIRK current responses activated by the cloned kappa-opioid receptor were similarly inhibited by ifenprodil. The inhibitory effects of ifenprodil were not observed when ifenprodil was applied intracellularly, and were not affected by extracellular pH, which changed the proportion of the uncharged to protonated ifenprodil, suggesting its action from the extracellular side. The GIRK currents induced by ethanol were also attenuated in the presence of ifenprodil. Our results suggest that direct inhibition of GIRK channels by ifenprodil, at submicromolar concentrations or more, may contribute to some of its therapeutic effects and adverse side effects.

Adrenergic alpha-Antagonists↗
PubMed2006

Gene expression in the brain from fluoxetine-injected mouse using DNA microarray.

Previously we have examined the effects of phencyclidine and clozapine upon the gene expression in the mouse brain. Recently, fluoxetine (Prozac) has been introduced for the therapeutic purpose as an antidepressant drug. Miledi et al. reported blockage of mouse muscle and neuronal nicotinic acetylcholine receptor by various concentrations of fluoxetine. Furthermore, Kobayashi et al. discovered that fluoxetine inhibits G protein activated inwardly rectifying G protein activated K(+) (GIRK) channels using Xenopus oocyte expression assay. From these experiments, we considered that it might be interesting to study the effects of fluoxetine on the gene expression in the mouse brain. After we have injected fluoxetine once a day into mouse for 20 days, we sacrificed mouse by decapitation and extracted RNA from mouse cerebral cortex. We used DNA microarray method for examining the gene expression in the brain. We found the downregulation of many spot signals in the fluoxetine-treated mouse, for example cholecystockinin and prostaglandin D2 synthase.

Animals↗
PubMed2006

G protein-activated inwardly rectifying potassium channels as potential therapeutic targets.

G protein-activated inwardly rectifying K(+) (GIRK; Kir3) channels regulate the neuronal activity and heart rate. Molecular cloning of the GIRK channel genes has led to remarkable progress in our understanding of the molecular structure, distribution and functional modulation of these channels. Furthermore, the roles of GIRK channels in vivo have been shown by studies using GIRK knockout mice and weaver mutant mice, which have a missense mutation in the GIRK2 gene. We also review the possible roles of GIRK channels in the pathophysiology of various disorders, and discuss the therapeutic potential of GIRK channel modulation.

Analgesics↗
PubMed2005

G protein-activated inwardly rectifying K+ channel inhibition and rescue of weaver mouse motor functions by antidepressants.

Antidepressants, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), have been widely used for the treatment of not only depression but also other psychiatric disorders, although the molecular mechanisms of the drug effects have not yet been sufficiently revealed. Here, we investigated the in vivo effects of these antidepressants on G protein-activated inwardly rectifying K+ (GIRK) channels, which are important for regulating the excitability of various cells, by using weaver (wv) mice, which have mutant GIRK channels and show abnormal neuronal cell death and motor disturbances. First, we found that a widely used SSRI fluoxetine (also known as Prozac) effectively inhibited wv GIRK2 channels like wild-type GIRK channels, expressed in Xenopus oocytes. Next, we found that weaver motor disturbances were remarkably alleviated by chronic treatment with fluoxetine or desipramine. Furthermore, the chronic fluoxetine treatment substantially suppressed the abnormal neuronal cell death in the weaver mouse cerebellum and pontine nuclei. These results suggest that continuous inhibition of wv GIRK2 channels by a group of antidepressants caused substantial suppression of the neuronal cell death and resulted in improvement of motor abilities in weaver mice. These results provide evidence for in vivo GIRK channel inhibition by a group of antidepressants.

Animals↗
PubMed2004

Effects of interferon-alpha on cloned opioid receptors expressed in Xenopus oocytes.

Interferon-alpha (IFNalpha) affects the opioid system. However, the direct action of IFNalpha on cloned opioid receptors remains unknown. Taking advantage of the functional coupling of cloned opioid receptors to G protein-activated inwardly rectifying K+ (GIRK) channels in a Xenopus oocyte expression system, we investigated the effects of recombinant IFNalpha on cloned mu-, delta- and kappa-opioid receptors. In oocytes co-injected with mRNAs for either the delta- or kappa-opioid receptor and for GIRK channel subunits, IFNalpha at high concentrations induced small GIRK currents that were abolished by naloxone, an opioid-receptor antagonist, compared with the control responses to each selective opioid agonist. Additionally, IFNalpha induced no significant current response in oocytes injected with mRNA(s) for either opioid receptor alone or GIRK channels. In oocytes expressing the mu-opioid receptor and GIRK channels, IFNalpha had little or no effect. Moreover, in oocytes expressing each opioid receptor and GIRK channels, GIRK current responses to each selective opioid agonist were not affected by the presence of IFNalpha, indicating no significant antagonism of IFNalpha toward the opioid receptors. Furthermore, IFNalpha had little or no effect on the mu/delta-, delta/kappa- or mu/kappa-opioid receptors expressed together with GIRK channels in oocytes. Our results suggest that IFNalpha weakly activates the delta and kappa-opioid receptors. The direct activation of the delta- and kappa-opioid receptors by IFNalpha may partly contribute to some of the IFNalpha effects under its high-dose medication.

Animals↗
PubMed2004

Successful resection of a ruptured hepatoblastoma prior to chemotherapy: report of a case.

A 12-year-old boy was referred to our hospital suffering from severe anemia and liver dysfunction. The laboratory data on admission confirmed severe anemia and an elevated alpha-fetoprotein level. Abdominal ultrasonography revealed a mass measuring 51 x 49 mm in size, and abdominal computed tomography showed a low-density mass in S8 of Couinaud's segment and a low-density area in S7, thus suggesting bleeding in the tumor. Right subphrenic fluid collection and perirectal fluid collection were also observed. Celiac arteriography showed a faint tumor stain fed by A5-8 but no evidence of any extravasation. A diagnosis of pediatric liver carcinoma was made, and the case was classified as T2 C3 V0 N0 M0 Stage IIIA. Although there was no evidence of bleeding during angiography, because of the high risk of rebleeding, a laparotomy was performed before chemotherapy. At operation, the tumor rupture site and hematoma appeared to be in S7, and a right lobectomy was thus performed. Ascitic fluid cytology was class V. The cut surface of the resected specimen showed a tumor measuring 51 x 49 mm located in S8 and a hematoma located in S7. Histologically, the tumor was a well-differentiated hepatoblastoma. The patient was transferred to the pediatric department and treated with six courses of intravenous chemotherapy followed by peripheral blood stem cell transplantation. The outcome has been favorable, with no recurrence as of 25 months after the operation.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Frequency and time course of reocclusion and restenosis in coronary artery occlusions after balloon angioplasty versus Wiktor stent implantation: results from the Mayo-Japan Investigation for Chronic Total Occlusion (MAJIC) trial.

BACKGROUND: Compared with balloon angioplasty, stent implantation has been shown to reduce restenosis and reocclusion after treatment of chronic total coronary artery occlusions (CTOs). However, little is known about the time course of restenosis and reocclusion after the 2 procedures. The purpose of this study was to examine the frequency and time course of restenosis and reocclusion after treatment of CTOs with balloon angioplasty and Wiktor stent implantation. METHODS AND RESULTS: A total of 221 patients with successfully recanalized CTOs were randomly assigned to either treatment with a coil stent implantation (Wiktor stent, n = 110) or standard balloon angioplasty (n = 111). Repeat angiography was performed the day after treatment and at 6 months. Patients undergoing balloon angioplasty showed 29.8% restenosis and 1.1% reocclusion the following day versus 2% restenosis and no reocclusion in stent patients the following day. The cumulative reocclusion rate was significantly lower in the stent group than in the balloon group at 6 months (2.1% versus 9.3%, P <.05). As a result of the more frequent need of target vessel revascularization (49.5% in the balloon group and 30.6% in the stent group, P <.005) and earlier final follow-up angiography in the balloon group, the frequency of angiographic restenosis at 6 months was similar in both groups (57.3% in the stent group and 54.5% in the balloon group). CONCLUSIONS: The frequency and time course of reocclusion and restenosis after balloon angioplasty and stent placement differ within 24 hours of the procedure and remain different on angiography at 6 months.

Aged↗
PubMed2004

Inhibition of G protein-activated inwardly rectifying K+ channels by various antidepressant drugs.

G protein-activated inwardly rectifying K+ channels (GIRK, also known as Kir3) are activated by various G protein-coupled receptors. GIRK channels play an important role in the inhibitory regulation of neuronal excitability in most brain regions and the heart rate. Modulation of GIRK channel activity may affect many brain functions. Here, we report the inhibitory effects of various antidepressants: imipramine, desipramine, amitriptyline, nortriptyline, clomipramine, maprotiline, and citalopram, on GIRK channels. In Xenopus oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2 or GIRK1/GIRK4 subunits, the various antidepressants tested, except fluvoxamine, zimelidine, and bupropion, reversibly reduced inward currents through the basal GIRK activity at micromolar concentrations. The inhibitions were concentration-dependent with various degrees of potency and effectiveness, but voltage- and time-independent. In contrast, Kir1.1 and Kir2.1 channels in other Kir channel subfamilies were insensitive to all of the drugs. Furthermore, GIRK current responses activated by the cloned A1 adenosine receptor were similarly inhibited by the tricyclic antidepressant desipramine. The inhibitory effects of desipramine were not observed when desipramine was applied intracellularly, and were not affected by extracellular pH, which changed the proportion of the uncharged to protonated desipramine, suggesting its action from the extracellular side. The GIRK currents induced by ethanol were also attenuated in the presence of desipramine. Our results suggest that inhibition of GIRK channels by the tricyclic antidepressants and maprotiline may contribute to some of the therapeutic effects and adverse side effects, especially seizures and atrial arrhythmias in overdose, observed in clinical practice.

Animals↗
PubMed2004

Long-term exercise maintenance, physical activity, and health-related quality of life after cardiac rehabilitation.

OBJECTIVE: The purpose of this study was to determine exercise maintenance rate, leisure-time objective physical activity level, and health-related quality of life in relation to exercise maintenance over the 6-mo period after a supervised 5-mo recovery-phase cardiac rehabilitation program in acute myocardial infarction patients. The study also investigated whether exercise maintenance resulted in reproducible health-related quality-of-life outcomes comparable with those of the Japanese normal population. DESIGN: This observational study comprised 109 acute myocardial infarction patients (89 men, 20 women; mean age, 63.5 +/- 10.1 yrs). Physiologic outcomes (peak oxygen uptake, handgrip, and knee-extension strength) measured at 1 and 6 mos after acute myocardial infarction onset were compared. Completed exercise maintenance and health-related quality-of-life questionnaires and results of electronic pedometer recordings to evaluate leisure-time objective physical activity level were assessed 6 mos after cardiac rehabilitation. RESULTS: The mean period from acute myocardial infarction to evaluation of outcomes was 18.8 +/- 3.4 mos. Ninety of 109 patients (82.6%) continued exercise for >6 mos after cardiac rehabilitation (exercise group); 19 patients (17.4%) quit exercise after cardiac rehabilitation (nonexercise group). Improvement in physiologic outcomes was noted at 6 mos vs. those at 1 mo, but outcomes were not significantly different between groups. The exercise group performed significantly better than the nonexercise group for leisure-time objective physical activity level and scored significantly higher than the nonexercise group for seven of eight health-related quality of life measures, attaining scores similar to those of the Japanese normal population. CONCLUSIONS: At >18 mos after acute myocardial infarction, the exercise maintenance rate in our patients remains high, and exercise maintenance may be one of the factors contributing to improvement of health-related quality of life and leisure-time objective physical activity level.

Aged↗
PubMed2004

Modulators of G protein-activated inwardly rectifying K+ channels: potentially therapeutic agents for addictive drug users.

G protein-activated inwardly rectifying K+ (GIRK, Kir3) channels play an important role in the inhibitory regulation of neuronal excitability in most brain regions and heart rate through activation of various G protein-coupled receptors, such as opioid, cannabinoid, and D2 dopamine receptors. Therefore, modulators of GIRK channels may affect many brain functions. We have shown using Xenopus oocyte expression assays that ethanol directly activates GIRK channels, whereas various antipsychotics (thioridazine, clozapine, pimozide, and haloperidol) inhibit the channels. Here we investigated not only the effects of various selective serotonin reuptake inhibitor (SSRI) antidepressants (fluoxetine, citalopram, fluvoxamine, and zimelidine) and risperidone, an atypical antipsychotic, on GIRK channels, but also those of the various drugs tested on other Kir channels using the Xenopus oocyte system. Fluoxetine inhibited GIRK channels, whereas the other SSRIs and risperidone had a small or no effect on the channels. In contrast, Kir1.1 and Kir2.1 channels were insensitive to ethanol and various SSRIs and antipsychotics, although thioridazine weakly inhibited Kir1.1 channels. It has been shown that the function of GIRK channels is involved in seizure susceptibility, antinociception by opioids, cannabinoids, or ethanol, and cocaine reinforcement in studies using GIRK knockout mice and weaver mutant mice that have mutant GIRK2 channels insensitive to G proteins and ethanol. Activation of GIRK channels by opioids, cannabinoids, or ethanol may be one of these key effects. Therefore, GIRK channel modulators might be potential agents for the treatment of users of addictive drugs, such as cocaine, opioids, cannabinoids, and ethanol, as well as for the treatment of epilepsy and pain.

Animals↗
PubMed2004

PCR detection of Bacillus and Staphylococcus in various foods.

A broad-range PCR assay for the detection of bacteria belonging to Bacillus and Staphylococcus genera was developed. Primers targeting the bacterial 16S rRNA gene were newly designed and used in a PCR assay. To determine the specificity of the assay, 81 different bacterial strains (of 50 genera), 2 fungi, 3 animals, and 4 plants were tested. Results were positive for every tested Bacillus, Staphylococcus, or Aerococcus strain. In addition, the result for Listeria grayi was positive with lower PCR product. For all other bacterial strains and eukaryotes tested, results were negative. Bacterial DNA was prepared with the use of achromopeptidase and Chelex 100 resin from culture after growth in brain heart infusion medium. To test the sensitivity of this PCR assay for Bacillus or Staphylococcus genus, either Bacillus cereus or Staphylococcus aureus was inoculated into various foods with undetectable levels of endogenous microbial contamination as an indicator. Inoculation of bacteria at 10 to 30 CFU/g of food was followed by a 5-h enrichment culture step after which the PCR assay allowed the detection of bacterial cells. When the inoculation (B. cereus or S. aureus) of 10 to 90 CFU/g into noodle foods containing endogenous microflora (10(3) to 10(5) CFU/g) was followed by a 6-h enrichment culture step, the PCR assay detected the bacteria. Including the enrichment culture step, the entire PCR detection process can be completed within 8.5 h.

Bacillus↗
PubMed2004

Relations between strength and endurance of leg skeletal muscle and cardiopulmonary exercise testing parameters in patients with chronic heart failure.

OBJECTIVES: The relations between muscle strength, muscle endurance, and cardiopulmonary parameters were investigated in patients with chronic heart failure. METHODS: The subjects comprised 33 outpatients with stable chronic heart failure (27 men, 6 women, mean age 60.3 +/- 12.7 years). A pedal-type isokinetic device was used throughout the study. The safety of the study protocol was examined first. Maximum muscle power (peak power), an index of muscle strength, was measured for 6 consecutive revolutions(3 revolutions of each leg). The strength decrement index (SDI) was measured for 20 consecutive maximal revolutions (10 revolutions in each leg). The SDI is an index of muscle endurance and compares the mean power for revolutions 9 and 10 with that for revolutions 2 and 3. Each subjects underwent symptom-limited cardiopulmonary exercise testing with a cycle ergometer on another day. RESULTS: No subject experienced continuous abnormal heart rate or blood pressure response, chest pain, ischemic ST-T change, or severe arrhythmia. The peak power and the SDI were correlated with the anaerobic threshold (r = 0.42, 0.52, respectively), with peak oxygen uptake (r = 0.66, 0.61), and with the increase in oxygen uptake per unit increase in work rate (r = 0.43, 0.63). However, the slope of the ventilation equivalent to carbon dioxide output was correlated only with the SDI (r = -0.54) and the time constant for the oxygen uptake decrease was correlated only with the peak power (r = -0.46). CONCLUSIONS: Peak functional capacity depends on both muscle strength and endurance, and subjective symptoms in daily activity, especially dyspnea on exertion, depend mainly on muscle endurance in patients with chronic heart failure.

Aged↗
PubMed2004

[A case of pseudothrombocytopenia during antibiotic administration].

A 70 year-old woman was prescribed of levofloxacin and ceftriaxone for acute bronchitis. On the seventh day of administration she was hospitalized with a dry cough and a decreased platelet count(2.1 x 10(4)/microliter). However, bleeding tendency was not seen. So, we changed anticoagulants with citric acid and heparin from EDTA, and measured platelet count because we suspected pseudothrombocytopenia(PTCP), then platelet count became elevated (respectively, 12.5 x 10(4)/microliter and 15.0 x 10(4)/microliter). In addition, platelet associated IgG increased to 309.3 ng/10(7) cells. Based on drug lymphocyte stimulation test, she was diagnosed as having antibiotic-induced PTCP, especially as she had no history of thrombocytopenia. PTCP should be considered when thrombocytopenia occurs during antibiotic treatment.

Aged↗
PubMed2003

Mesenteric pseudocyst of the sigmoid colon.

A 31-year-old woman with right lower abdominal pain was hospitalized. Palpation revealed both tenderness and rebound tenderness in the right lower quadrant of her abdomen. Abdominal ultrasonography (US) indicated a multilocular cystic mass on the right side of the pelvic area, and a computed tomography (CT) scan showed a low-density mass measuring 7 cm in diameter. Torsion of the pedicle of a right ovarian cyst was suspected, and emergency laparotomy was performed. At operation, however, the uterus and both ovaries appeared normal, and exploration revealed a yellow-reddish cystic mass, approximately 10 cm in size, in the subserosa of the sigmoid colon. The mass was excised together with a 10-cm segment of the sigmoid colon. Macroscopically, it was a multilocular cyst, measuring 10 x 10 cm in size, and it contained white gelatinous fluid. Histological examination showed the cyst wall to be composed of neutrophils, lymphocytes, fibrin, and fibroblasts, but neither a specific endothelial lining nor proliferating lining was detected. The final pathological diagnosis was a mesenteric pseudocyst. Mesenteric pseudocysts are rare, and only 14 cases have been reported previously in the Japanese literature. Emergency operation was performed in 3 patients, including our own. The etiology of these three pseudocysts (manifested by acute abdomen) was unknown. We suspect that inflammation spread and injured lymph vessels, causing lymph to leak out and pool under the subserosal layer.

Adult↗
PubMed2003

Successful management of endodermal sinus tumor of the ovary associated with pregnancy.

BACKGROUND: Pregnancy complicated by endodermal sinus tumor of the ovary has rarely been reported. CASE: A 32-year-old pregnant woman was found to have an ovarian tumor. At 19 weeks of gestation, tumorectomy was performed and a diagnosis of primary endodermal sinus tumor of the ovary (stage Ic) was made. Pregnancy was continued without postoperative chemotherapy. At 36 weeks of gestation, she underwent cesarean section combined with second-look laparotomy. A normal infant was delivered and there were no signs of recurrence. Subsequently, three courses of combination chemotherapy with bleomycin, etoposide, and cisplatin were administered. There was no evidence of recurrence at 27 months after initial treatment. CONCLUSIONS: Successful management of endodermal sinus tumor of the ovary in a pregnant woman is reported.

Adult↗
PubMed2003

Inhibition of G protein-activated inwardly rectifying K+ channels by fluoxetine (Prozac).

1. The effects of fluoxetine, a commonly used antidepressant drug, on G protein-activated inwardly rectifying K(+) channels (GIRK, Kir3) were investigated using Xenopus oocyte expression assays. 2. In oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2 or GIRK1/GIRK4 subunits, fluoxetine reversibly reduced inward currents through the basal GIRK activity. The inhibition by fluoxetine showed a concentration-dependence, a weak voltage-dependence and a slight time-dependence with a predominant effect on the instantaneous current elicited by voltage pulses and followed by slight further inhibition. Furthermore, in oocytes expressing GIRK1/2 channels and the cloned Xenopus A(1) adenosine receptor, GIRK current responses activated by the receptor were inhibited by fluoxetine. In contrast, ROMK1 and IRK1 channels in other Kir channel subfamilies were insensitive to fluoxetine. 3. The inhibitory effect on GIRK channels was not obtained by intracellularly applied fluoxetine, and not affected by extracellular pH, which changed the proportion of the uncharged to protonated fluoxetine, suggesting that fluoxetine inhibits GIRK channels from the extracellular side. 4. The GIRK currents induced by ethanol were also attenuated in the presence of fluoxetine. 5. We demonstrate that fluoxetine, at low micromolar concentrations, inhibits GIRK channels that play an important role in the inhibitory regulation of neuronal excitability in most brain regions and the heart rate through activation of various G-protein-coupled receptors. The present results suggest that inhibition of GIRK channels by fluoxetine may contribute to some of its therapeutic effects and adverse side effects, particularly seizures in overdose, observed in clinical practice.

Animals↗