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T Yamamura

Publications and source records attributed to T Yamamura.

At least 37 records · Page 2Linked to original sources
PubMed2001

IGF-I differentially regulates Bcl-xL and Bax and confers myocardial protection in the rat heart.

Bcl-2 family proteins play a crucial role in the cytoprotective action of insulin-like growth factor-I (IGF-I) by regulating cell death signaling at the mitochondrial level. The present study examined the effect of IGF-I on the expression of Bcl-2 family proteins in the rat heart mitochondria in relation to myocardial protection against ischemia-reperfusion injury. Systemic IGF-I (1 mg) treatment in the rat increased Bcl-xL and attenuated Bax 12-24 h later in the heart mitochondria fraction. Permeability transition and cytochrome c release occurred in a Ca(2+) concentration-dependent manner in the vehicle-treated mitochondria. This was significantly inhibited by the IGF-I-pretreatment. Moreover, ATP synthesis was significantly greater in the IGF-I-pretreated mitochondria. IGF-I pretreatment 24 h before 25 min of global ischemia in the isolated rat heart model significantly improved recovery of isovolumic left ventricular function and inhibited creatine kinase release during reperfusion. This was associated with a significantly less number of terminal transferase labeling-positive myocytes and nonmyocytes 2 h after reperfusion. These results suggest that IGF-1 differentially regulates Bcl-xL and Bax in heart mitochondria, which may be causally related to myocardial protection against ischemia-reperfusion injury.

Adenosine Triphosphate↗
PubMed2001

NHE and ICAM-1 expression in hypoxic/reoxygenated coronary microvascular endothelial cells.

Although Na+/H+ exchange (NHE) has been implicated in myocardial reperfusion injury, participation of coronary microvascular endothelial cells (CMECs) in this pathogenesis has been poorly understood. NHE-induced intracellular Ca2+ concentration ([Ca2+]i) overload in CMECs may increase the synthesis of intercellular adhesion molecules (ICAM), which is potentially involved in myocardial reperfusion injury. The present study tested the hypothesis that NHE plays a crucial role in [Ca2+]i overload and ICAM-1 synthesis in CMECs. Primary cultures of CMECs isolated from adult rat hearts were subjected to acidic hypoxia for 30 min followed by reoxygenation. Two structurally distinct NHE inhibitors, cariporide and 5-(N-N-dimethyl)-amiloride (DMA), had no significant effect on the acidic hypoxia-induced decrease in intracellular pH (pH(i)) of CMECs but significantly retarded pH(i) recovery after reoxygenation. These NHE inhibitors abolished the hypoxia- and reoxygenation-induced increase in [Ca2+]i. Expression of ICAM-1 mRNA was markedly increased in the vehicle-treated CMECs 3 h after reoxygenation, and this was significantly inhibited by treatment with cariporide, DMA, or Ca2+-free buffer. In addition, enhanced ICAM-I protein expression on the cell surface of CMECs 8 h after reoxygenation was attenuated by treatment with cariporide, DMA, or Ca2+-free buffer. These results suggest that NHE plays a crucial role in the rise of [Ca2+]i and ICAM-1 expression during acidic hypoxia/reoxygenation in CMECs. We propose that inhibition of ICAM-1 expression in CMECs may represent a novel mechanism of action of NHE inhibitors against ischemia-reperfusion injury.

Amiloride↗
PubMed2001

Natural killer type 2 bias in remission of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease characterized by clinical relapse and remission. Because of the potential role of natural killer (NK) cells in the regulation of autoimmunity, we have examined cytokine profile and surface phenotype of NK cells in the peripheral blood of MS. Here we demonstrate that NK cells in the remission of MS are characterized by a remarkable elevation of IL-5 mRNA and a decreased expression of IL-12Rbeta2 mRNA, as well as a higher expression of CD95. Moreover, the NK cells from MS in remission produced much larger amounts of IL-5 than did those from controls after stimulation with phorbol myristate acetate (PMA) and ionomycin. These features are reminiscent of those of NK type 2 (NK2) cells that can be induced in a condition favoring functional deviation of T cells toward Th2. Remarkably, the NK cells lose the NK2-like property when relapse of MS occurs, but regain it after recovery. We also found that NK2 cells induced in vitro inhibit induction of Th1 cells, suggesting that the NK2-like cells in vivo may also prohibit autoimmune effector T cells. Taken together, it is possible that NK cells play an active role in maintaining the remission of MS.

Adult↗
PubMed2001

Characterization of T cell receptor beta chains of accumulating T cells in chronic ongoing myocarditis demonstrated by heterotopic cardiac transplantation in mice.

Autoimmne mechanisms have been implicated in the pathogenesis of chronic ongoing mycarditis. An earlier study of murine chronic ongoing myocarditis reported that infiltrating T cells and macrophages were prominent in the normal donor heart, in a heterotopic cardiac transplantation model. It was demonstrated that myocarditis was transferred to a normal heart transplanted into a mouse with chronic myocarditis. The present study investigated an autoimmune link to the pathogenesis of chronic ongoing myocarditis by analyzing the T cell clonalities in the model. To characterize the accumulating T cells in the donor heart, the T cell receptor beta genes (TCRBG) were amplified by reverse transcriptase-polymerase chain reaction (RT-PCR) from mRNA in the donor hearts and accumulating TCRBG clonotypes were contrasted with those from recipient hearts. Inbred 3-week-old A/J mice were inoculated intraperitoneally with Coxsackievirus B3 (Nancy strain), 2 x 10(4) PFU, and housed for more than 60 days. Normal A/J mouse hearts were transplanted into the same strain of mice without myocarditis, as well as into the mice with chronic ongoing myocarditis. Both recipient and donor hearts were evaluated histologically 2 weeks after the transplantation. TCRBG were amplified by RT-PCR from mRNA of recipient and donor hearts and spleens. The specific accumulating TCRBG clonotypes were identified by their single strand conformation polymorphism. Multiple clonotypic accumulations occurred in the donor heart after cardiac transplantation. Distinct oligoclonal accumulation of TCR Vbeta1, 10, and 13 T cells was found in both recipient and donor hearts in 3 of 4 mice. Moreover, these clonotypes were not observed in spleen cells of the recipient mice. T specific cells expanding clonotypes of TCRBG are responsible for transferring myocarditis to the donor heart. An autoimmune response may, therefore, play a key role in the progression of chronic ongoing myocarditis.

Animals↗
PubMed2001

Magnitude of sustained multiple risk factors for ischemic heart disease in Japanese employees: a case-control study.

A case-control study was performed to clarify the cause of ischemic heart disease (IHD), such as acute myocardial infarction and angina pectoris, in Japanese employees. Among 122,051 workers from 31 industries, 94 cases of IHD were the subjects of the study, and a total of 191 age-matched subjects from the same department, but who did not develop IHD, served as the controls. Compared with the control group, body mass index, blood pressure, fasting plasma glucose, serum total cholesterol and serum triglyceride were significantly higher, and cigarette consumption and serum uric acid also tended to be higher, in the patient group from at least 10 years prior to onset. The frequency of moderate-drinkers tended to be lower in the case group. Electrocardiograms showed that, compared with the control group, the frequency of myocardial ischemia was higher in the case group from 9 years prior to onset and further rapidly increased from 3 years prior. The frequency of subjects with arrhythmia was the same as the control group until 3 years before onset and increased rapidly from 2 years prior. The frequency of subjects with multiple risk factors, particularly obesity, hypertension, hyperlipidemia and hyperglycemia, was consistently higher in the case group compared with the control group from 10 years prior to onset. Conditional logistic regression analysis demonstrated that having more than one risk factor greatly increased the risk; in particular, the combination of 3 or more factors increased the relative risk to 10.56 (95% confidence interval: 3.30-33.78). These findings suggest that a long duration of multiple risks is involved in the onset of IHD in Japanese employees, and that annual ECG monitoring as part of the medical examination was important in the prognosis.

Adult↗
PubMed2001

[Long survival in a case of unresectable hepatic metastasis from rectal carcinoma treated with second-look hepatectomy plus pharmacokinetic modulating chemotherapy (PMC)].

A 67-year-old female with rectal cancer and multiple liver metastases underwent low anterior resection by total mesorectal excision (TME), cholecystectomy and hepatic arterial cannulation in June 1995. She was treated with hepatic arterial infusion chemotherapy (HAI) (5-FU 600 mg/m2/day x 2 days/w) and oral UFT (400 mg/body, 5 days/w) once a week for 6 months on an outpatient basis. As the metastatic foci of the liver significantly decreased (83.3%) and extrahepatic disease were not observed, partial resection of the liver (second-look hepatectomy) was performed in March 1996. She continued arterial infusion PMC and venous infusion PMC as an outpatient. During the follow-up period a lung metastasis appeared in November 1997. Her regimen was changed to modified PMC with MMC (mitomycin C) and CPT-11. She has been managed at our outpatient clinic while the lung metastasis remained but with no liver metastasis for 57 months after the first operation, until the present. Second-look hepatectomy and PMC with a two-way port system was a useful option for unresectable hepatic metastases from colorectal carcinoma.

Adenocarcinoma↗
PubMed2001

[Therapeutic strategy for multiple sclerosis targeting NK and NKT cells].

Recent works from our laboratory have demonstrated that natural killer (NK) cells and CD1d-restricted NKT cells are functionally biased toward producing type 2 cytokine in the remission phase of multiple sclerosis, an autoimmune disease putatively mediated by Th1 T cells. Indirect evidence would indicate that the type 2 bias of NK and NKT cells is not the cause of MS but an adaptive change to protect against activation of pathogenic Th1 cells. In fact, NK cells biased for producing IL-5 (NK2 cells) would inhibit induction of Th1 cells in vitro. Here I propose that it is a reasonable strategy for the control of MS to maximize and/or optimize the regulatory potentials of the innate regulatory cells. We have already found that experimental autoimmune encephalomyelitis (EAE), an animal model for MS, can be inhibited when NKT cells are partially stimulated by glycolipid ligands for NKT cells. Experiments proved that the suppression of disease is mediated by IL-4 produced by NKT cells. Future studies should be directed for identifying useful ligands for inducing regulatory cytokines from NK and NKT cells.

Animals↗
PubMed2000

Vacuolar H(+)-ATPase plays a crucial role in growth and phenotypic modulation of myofibroblasts in cultured human saphenous vein.

BACKGROUND: The molecular mechanism of neointimal hyperplasia after vein graft surgery remains elusive. Vacuolar H(+)-ATPase (V-ATPase) is involved in intracellular trafficking and may play a crucial role in neointimal cell growth. METHODS AND RESULTS: Cultured human saphenous vein segments developed neointimal formation within 10 days. Neointimal cells were positive for vimentin and alpha-smooth muscle actin but negative for desmin, which is indicative of myofibroblasts. Those myofibroblasts were found to have originated from periadventitial fibroblasts, which upregulated the expression of 16-kDa proteolipid of V-ATPase before proliferation and phenotypic modulation. Neointimal myofibroblast growth and survival were highly sensitive to inhibition of V-ATPase by bafilomycin A(1) (BA(1)), because the incorporation of [(3)H]thymidine into the myofibroblasts was significantly inhibited by nanomolar concentrations of BA(1) and apoptotic cell death was induced by a similar concentration range of BA(1). In contrast, endothelial cells and differentiated smooth muscle cells were resistant to apoptosis by BA(1). CONCLUSIONS: These results suggest that V-ATPase plays a crucial role in growth and phenotypic modulation of myofibroblasts that contributes to neointimal formation in cultured human saphenous vein.

Adult↗
PubMed2000

Effect of a novel bifunctional endothelin receptor antagonist, IRL 3630A, on guinea pig respiratory mechanics.

This study characterized the in vitro pharmacological properties of a newly developed endothelin receptor antagonist, N-butanesulfonyl-[N-(3, 5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-(D)- alanyl]-( L)-valineamide sodium salt (IRL 3630A), and its in vivo effects on respiratory mechanics were determined. IRL 3630A showed highly balanced affinities to human endothelin ET(A) and ET(B) receptors, giving apparent K(i) values of 1.5 and 1.2 nM, respectively. This compound also potently antagonized the endothelin-1-induced intracellular Ca(2+) increases in both embryonic bovine tracheal (EBTr) cells expressing endothelin ET(A) receptors and human Girardi heart (hGH) cells expressing endothelin ET(B) receptors. In guinea pig isolated tracheas having both endothelin ET(A) and ET(B) receptors, IRL 3630A greatly inhibited endothelin-1-induced contraction (pA(2)=7.1), which was partially or scarcely suppressed by the endothelin ET(A) receptor antagonist cyclo[-(D)-Trp-(D)-Asp-(L)-Pro-(D)-Val-(L)-Leu-] (BQ-123) or the endothelin ET(B) receptor antagonist N-(3, 5-dimethylbenzoyl)-N-methyl-3-(4-phenyl)-(D)-phenylalanyl-(L)-t ryptop han (IRL 2500), respectively. Bolus i.v. injections of IRL 3630A administered into anaesthetized guinea pigs at 10 and 30 microg/kg inhibited endothelin-1 (1.3 microg/kg)-induced changes in respiratory resistance and compliance in a dose dependent manner, whereas both sodium 2-benzo[1, 3]dioxol-5-yl-4-(4-methoxy-phenyl)-4-oxo-3-(3,4, 5-trimethoxy-benzyl)-but-2-enoate (an endothelin ET(A) receptor antagonist: PD 156707) and IRL 2500 at doses of up to 30 microg/kg did not affect endothelin-1-induced changes in respiratory mechanics, reflecting the in vitro results. IRL 3630A is thus an effective bifunctional endothelin receptor antagonist, and will be useful in clarifying the role of endothelin in pulmonary diseases such as bronchial asthma.

Airway Resistance↗
PubMed2000

Results of pharmacokinetic modulating chemotherapy in combination with hepatic arterial 5-fluorouracil infusion and oral UFT after resection of hepatic colorectal metastases.

BACKGROUND: Pharmacokinetic modulating chemotherapy (PMC) is a new therapeutic concept in combination with continuous 5-fluorouracil (5-FU) infusion and UFT. UFT enhanced plasma 5-FU concentration and antitumor effects during 5-FU infusion. The authors report on their experiences with arterial 5-FU infusion and UFT after resection of hepatic colorectal secondaries. METHODS: Fifty-eight patients were divided into two groups after hepatectomy. Group A, 30 patients, underwent hepatic arterial infusion (HAI) via implantable port system with perfusion 5-FU for 2 consecutive days per week at 600 mg/m(2)/day, and oral administration of UFT at 400 mg/day for 5-7 days per week, repeated 10 times, and Group B, 28 patients, underwent oral administration of UFT at 400 mg/day for 6 months. All the patients were managed at the outpatient clinic at Hyogo College of Medicine, and recurrence, survival, and toxicity were documented. Plasma 5-FU concentrations during chemotherapy were detected using high performance liquid chromatography. RESULTS: Maximum plasma concentrations of 5-FU in Group A reached 144.0 ng/mL and in Group B 58.7 ng/mL. Cumulative 5-year survival rate after hepatectomy in Group A was 59% and in Group B was 27%. (P = 0.00001) HAI-PMC drastically decreased hepatic recurrence (median hepatic recurrence free times were 34.2 months in Group A vs. 18.4 months in Group B; P = 0.00002). Grade 3 toxicity in Group A was found in 3 patients CONCLUSIONS: Pharmacokinetic modulating chemotherapy was designed as a uracil-related biochemical modulation. HAI-PMC significantly decreased hepatic recurrence after curative resection. This new chemotherapy concept significantly improved prognosis in patients with hepatic colorectal metastases.

Administration, Oral↗
PubMed2000

Differential expression of NK T cell V alpha 24J alpha Q invariant TCR chain in the lesions of multiple sclerosis and chronic inflammatory demyelinating polyneuropathy.

Human V alpha 24+ NK T cells are a unique subset of lymphocytes expressing the V alpha 24J alpha Q invariant TCR chain. Because they can rapidly produce large amounts of regulatory cytokines, a reduction of NK T cells may lead to the development of certain autoimmune diseases. Using a single-strand conformation polymorphism method, we demonstrate that a great reduction of V alpha 24J alpha Q NK T cells in the peripheral blood is an immunological hallmark of multiple sclerosis, whereas it is not appreciable in other autoimmune/inflammatory diseases such as chronic inflammatory demyelinating polyneuropathy. The chronic inflammatory demyelinating polyneuropathy lesions were often found to be infiltrated with V alpha 24J alpha Q NK T cells, but multiple sclerosis lesions only rarely expressed the V alpha 24J alpha Q TCR. It is therefore possible that the extent of NK T cell alteration may be a critical factor which would define the clinical and pathological features of autoimmune disease. Although the mechanism underlying the NK T cell deletion remains largely unclear, a remarkable contrast between the CNS and peripheral nervous system diseases allows us to speculate a role of tissue-specific elements such as the level of CD1d expression or differences in the CD1d-bound glycolipid.

Adult↗
PubMed2000

Effect of Ca(2+)-independent mechanisms on the hypoxic relaxation of guinea-pig tracheal rings.

Hypoxia induces bronchodilation in vivo and in vitro, but the mechanisms are still unclear. To evaluate whether an extra- or intracellular free Ca(2+) ion is involved in the mechanisms of hypoxic relaxation, we simultaneously measured cytosolic Ca(2+)levels and tensions in both intact and denuded guinea-pig tracheal strips precontracted with histamine (100 microM), and assessed the effect of hypoxia on guinea-pig tracheal rings precontracted with okadaic acid (10 microM) and calyculin-A (0.1 approximately 10 microM) under an extracellular Ca(2+)-free state. The exposure of tracheal rings to hypoxia induced an immediate decrease of tracheal tension without decrease in intracellular free Ca(2+)levels. In the presence of okadaic acid but not calyculin-A, hypoxic air exposure caused significant transient reductions in tracheal tone. Further, thapsigargin (5 microM or 10 microM) did not affect hypoxic bronchodilation, suggesting that the release of intracellular Ca(2+) does not take a role in hypoxic bronchodilation. Hypoxic dilation decreased ATP content in epithelium-intact rings but not epithelium-denuded rings, indicating a relationship between hypoxic dilation and change of adenine nucleotide in epithelium-intact rings. Our findings indicate that the epithelium dependent mechanisms of hypoxic relaxation of guinea pig tracheal rings preconstricted with histamine may not be related to the mobilization of extra and intra-cellular Ca(2+).

Adenosine Diphosphate↗
PubMed2000

Freehand cryopreserved mitral valve allograft with flexible ring in the pig.

OBJECTIVE: Cryopreserved valve allografts have proven satisfactory in aortic and pulmonary positions but not mitrally because of the difficulty in properly aligning the mitral valve allograft due to the complex subvalvular apparatus. To make the surgical procedure easier, we developed a freehand cryopreserved mitral valve allograft with a flexible ring. METHODS: Whole cryopreserved mitral valve allografts with the papillary muscle, chordae, and leaflets from donor pigs were implanted mitrally in recipient pigs under cardiopulmonary bypass divided into 2 experimental groups; control allografts without the ring (n = 6) (CA group) and allografts with a flexible ring (n = 7) (RA group). Postimplantation hemodynamics and valvular function were evaluated by measuring arterial pressure, left ventricular end diastolic pressure, and left atrial pressure and by evaluating 2-dimensional echocardiography. Allografts were evaluated pathohistologically after cryopreservation and surgery by light microscopy. RESULTS: Hemodynamics did not differ significantly between groups. Aortic cross-clamping and Cardiopulmonary bypass times were significantly shorter in the RA group than the CA group (p < 0.05). Pigs requiring optional procedures with sutured annuloplasty and valvuloplasty numbered more in the CA group than the RA group. Postoperative echocardiography showed satisfactory mitral valve opening in diastole and good leaflet coaptation in systole in both groups. Light microscopic examination of cryopreserved allografts after surgery showed almost normal structures. CONCLUSIONS: Acute hemodynamic function and morphology of freehand cryopreserved valve allografts implanted mitrally in pigs proved acceptable. Adaptation of the flexible ring to allografts might be useful for technical benefit to facilitate accurate positioning of mitral subvalvular apparatus at implantation.

Animals↗
PubMed2000

Long-term role of nitric oxide in the enteric nervous system of the transplanted rat intestine.

We investigated the long-term changes of the nitric oxide (NO)-related neural component after syngeneic total small bowel transplantation in rats. In the present study, the NO-related neural component was examined using the electrophysiological and NADPH-diaphorase histochemical technique. The rats were divided into four groups: an untreated young adult control group, an untreated 2-year-old control group, a group killed 1 month after transplantation, and a group killed 2 years after transplantation. A superfusion apparatus was used to evaluate the response of jejunal strips to electrical transmural stimulation. In the presence of adrenergic and cholinergic blockade, the inhibitory effect of L-N(G)-nitro arginine (L-NNA; a nitric oxide synthesis inhibitor) on nonadrenergic, noncholinergic (NANC) relaxation was expressed as a L-NNA-sensitive component. The L-NNA-sensitive component accounted for 41.6 +/- 4.6% (mean +/- SE), 43.1 +/- 3.5%,54.6 +/- 4.1%, and 55.8 +/- 3.5% in the young control group, 2-year control group, 1-month transplant group, and 2-year transplant group, respectively, being significantly higher in the transplant groups (p < 0.05). The actual strength of the L-NNA-sensitive component was 0.24 +/- 0.03 (mean +/- SE), 0.26 +/- 0.02, 0.44 +/- 0.04, and 0.46 +/- 0.04 mg of tension per mg of wet weight, respectively, also being significantly higher in the transplant groups (p < 0.001). In addition, the percentage of NADPH-diaphorase-positive fibers was 24.1 +/- 1.1% (mean +/- SE), 25.5 +/- 1.4%, 31.0 +/- 1.6%, and 30.9 +/- 2.0%, respectively, being significantly higher in the transplant groups (p < 0.05). These results suggest that NO neurons in the intrinsic jejunal nervous system have an adaptive role in maintaining intestinal graft motility.

Animals↗