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Yukio Hirata

Publications and source records attributed to Yukio Hirata.

72 records · Page 4Linked to original sources
PubMed2003

Relationships of circulating nitrite/nitrate levels to severity and multiple organ dysfunction syndrome in systemic inflammatory response syndrome.

Excessive nitric oxide (NO) production has been implicated to be responsible for the development of septic shock. To determine whether plasma nitrite/nitrate (NOx) levels are related to the severity of systemic inflammatory response syndrome (SIRS) and the degree of multiple organ dysfunction, we studied plasma NOx levels in 70 patients with SIRS consisting of noninfectious SIRS (n = 32), sepsis (n = 23), and septic shock (n = 15). Infection is a microbial phenomenon characterized by an inflammatory response to the presence of microorganism. Positive culture for microorganism is regarded as infectious SIRS (sepsis and septic shock) and negative culture is regarded as noninfectious SIRS. Plasma samples collected from each patient within 24 h from admission to the intensive care unit were subjected for measurement of NOx levels, the stable end products of NO, by the high performance liquid chromatography-Greiss system. Mean plasma NOx levels in patients with SIRS were 52.8 +/- 44 microM/L, ranging from 8.1 to 186.2 microM/L. Plasma NOx levels were positively correlated with Acute Physiology, Age, and Chronic Health Evaluation (APACHE) III score (r = 0.414, P < 0.01) and sequential organ failure assessment (SOFA) score (r = 0.433, P < 0.01). Plasma NOx levels in patients with sepsis (51.0 +/- 38.5 microM/L) and septic shock (94.5 +/- 53.7 microM/L) were significantly (P < 0.01) higher than those in patients with noninfectious SIRS (25.8 +/- 16.9 microM/L) and healthy subjects (29.6 +/- 8.9 microM/L). Our study shows that plasma NOx levels are increased in patients with infectious, but not noninfectious SIRS, which increase as the severity of SIRS and the development of multiple organ dysfunction syndrome, suggesting its possible pathogenic role in SIRS.

APACHE↗
PubMed2003

Atrial natriuretic peptide infusion improves ischemic renal failure after suprarenal abdominal aortic cross-clamping in dogs.

OBJECTIVE: The suprarenal abdominal aortic cross-clamping during aortic aneurysm repair causes renal dysfunction after surgery. Atrial natriuretic peptide (ANP), a hormone synthesized by the cardiac atria, induces diuresis-natriuresis and increases glomerular filtration rate. Therefore, we tested the hypothesis that prophylactic ANP infusion could limit the development of acute renal failure after aortic cross-clamping. DESIGN: Prospective, comparative, experimental study. SETTING: Laboratory at a university hospital. SUBJECTS: Twelve male beagle dogs (10-13 kg) with mechanical ventilation under pentobarbital anesthesia. INTERVENTIONS: A catheter was inserted into the femoral vein, and lactated Ringer solution (10 mL/kg/hr) was administered throughout the study period. Two groups of animals were studied: the control group (n = 6), which received saline vehicle before and after suprarenal abdominal aortic cross-clamping for 1.5 hrs; and the ANP group (n = 6), which received ANP (1 microg/kg/min) for 5 hrs, starting from 10 mins before suprarenal abdominal aortic cross-clamping until the end of procedure. MEASUREMENTS AND MAIN RESULTS: Changes in systemic and renal hemodynamics, blood gases, and renal function were measured at baseline and 1, 2, 3, 4, and 5 hrs after aortic cross-clamping. After aortic cross-clamping, urine volume, renal blood flow, and creatinine clearance significantly (p <.01) decreased, and serum creatinine concentrations significantly (p <.01) increased, but these effects were limited by continuous ANP infusion. CONCLUSIONS: The present study shows that ANP infusion preserved renal function after suprarenal abdominal aortic cross-clamping in dogs. These results justify a trial of ANP infusion in humans during aortic aneurysm repair.

Acute Kidney Injury↗
PubMed2003

Coexpression of calcitonin receptor-like receptor and receptor activity-modifying protein 2 or 3 mediates the antimigratory effect of adrenomedullin.

Three isoforms of the receptor activity-modifying protein (RAMP) are thought to transport the calcitonin receptor-like receptor (CRLR) to the plasma membrane to function as calcitonin gene-related peptide or adrenomedullin receptors, but their role remains largely unknown. We investigated whether coexpression of RAMP and CRLR are involved in the regulation of cell migration using a monolayer-wounding protocol. Quantification of gene transcripts revealed expression of all RAMP isoforms and CRLR in cultured rat vascular smooth muscle cells (VSMCs), RAMP2 and RAMP3 in rat endothelial cells, and RAMP1 in rat fibroblasts. CRLR expression was minimal in endothelial cells and fibroblasts. Adrenomedullin potently suppressed the migration of VSMCs, whereas calcitonin gene-related peptide did not suppress migration in any cell type. The antimigratory effect of adrenomedullin on VSMCs was potentiated by transfecting CRLR cDNA. Cotransfection of RAMP2 or RAMP3 with CRLR into VSMCs resulted in a slower migratory rate, and this effect was enhanced by adrenomedullin. Migration of fibroblasts was also suppressed after cotransfection of RAMP2 or RAMP3 with CRLR. cAMP agonists had no effect on VSMC migration, and a cAMP antagonist failed to abrogate the antimigratory effect of adrenomedullin. Thus, coexpression of CRLR and RAMP2 or RAMP3 mediates the inhibitory effect of adrenomedullin on cell migration, independent of cAMP-dependent signaling pathways.

Adrenomedullin↗
PubMed2003

Activation of cell adhesion kinase beta by mechanical stretch in vascular smooth muscle cells.

We have studied whether activation of cell adhesion kinase beta (CAKbeta) is involved in stretch-induced signaling pathway in cultured rat vascular smooth muscle cells. Cyclic stretch (1 Hz) induced a rapid (within 1 min) phosphorylation of CAKbeta, whose effect was time and strength dependent. Both Ca(2+) and Na(+) ionophores (A23187 and monensin) stimulated phosphorylation of CAKbeta in a similar fashion to mechanical stretch. The stretch-induced phosphorylation of CAKbeta was inhibited completely by an intracellular Ca(2+) chelator [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester)] and largely by gadolinium, but only partially by an extracellular Ca(2+) chelator (EGTA). An angiotensin type 1 receptor antagonist (CV11974) abolished the phosphorylation of CAKbeta stimulated by angiotensin II, but not by mechanical stretch. Mechanical stretch rapidly (within 1 min) increased the association of CAKbeta with c-Src, but not pp125(focal adhesion kinase). Stretch-induced phosphorylation of ERK1/2 was inhibited by EGTA and an inhibitor of the Src kinase family [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine], but not by cytochalasin D, to disrupt actin polymerization. 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine or cytochalasin D did not affect stretch-induced phosphorylation of CAKbeta. These data suggest that mechanical stretch stimulates activation of CAKbeta, followed by its association with c-Src, which requires ion influx mainly via stretch-activated nonselective ion channels, thereby leading to activation of the p21(Ras)/ERK1/2 cascade in vascular smooth muscle cells.

Actin Cytoskeleton↗
PubMed2003

Urotensin II is an autocrine/paracrine growth factor for the porcine renal epithelial cell line, LLCPK1.

Urotensin-II (UII), a cyclic dodecapeptide with potent cardiovascular effects, has recently been shown to be abundantly expressed in the human kidney and excreted in human urine. To investigate whether UII acts as an autocrine/paracrine growth factor for renal epithelial cells, we have studied the effects of human UII (hUII) on DNA synthesis, cytosolic free Ca(2+) concentration ([Ca(2+)](i)), ERK activation, and protooncogene (c-myc) expression in a porcine renal epithelial cell line (LLCPK1). hUII stimulated [(3)H]thymidine uptake into quiescent cells in a dose-dependent manner (10(-9) to 10(-7) M); this effect was inhibited by a protein kinase C inhibitor (GF109203X), a MAPK kinase inhibitor (PD98059), and a calcium channel blocker (nicardipine). Neither phosphatidyl inositol-3 kinase inhibitors (LY294002, wortmannin) nor p38 kinase inhibitor (SB203580) affected the hUII-induced DNA syntheses. hUII rapidly (within 5 min) and dose-dependently (10(-9) to 10(-7) M) increased [Ca(2+)](i) in fura-2-loaded cells. hUII also caused a rapid and transient activation of ERK1/2 and induction of c-myc. LLCPK1 cells expressed UII mRNA and its receptor GPR14 mRNA, as determined by RT-PCR, and released UII-like immunoreactivity into media. Neutralization of endogenous UII by anti-hUII antibody, but not nonimmune serum, significantly suppressed DNA synthesis. These data suggest that hUII is an autocrine/paracrine growth factor for renal epithelial cells via activation of both protein kinase C and ERK1/2 pathways as well as Ca(2+) influx via voltage-dependent Ca(2+) channels.

Animals↗
PubMed2003

Regulation of cell growth and apoptosis by adrenomedullin.

Adrenomedullin, originally discovered in human pheochromocytoma, has been shown to have potent vasodilatory activity. However, like other vasoactive peptide hormones, its physiological roles have been found to extend far beyond the regulation of vascular tonus, and to include such functions as the regulation of cell proliferation and differentiation. There is a growing body of evidence that adrenomedullin exerts a wide range of effects on cell growth and apoptotic death, and that these effects are dependent on cell type and experimental conditions. Signaling pathways independent of cyclic AMP, such as protein tyrosine kinase(s) and mitogen-activated protein kinases, may play key roles in the regulation of mitogenesis and apoptosis by adrenomedullin.

Adrenomedullin↗
PubMed2003

Octreotide-sensitive ectopic ACTH production by islet cell carcinoma with multiple liver metastases.

We report a 21-year-old woman with ectopic ACTH syndrome due to islet cell carcinoma with multiple liver metastases. On admission, she showed Cushingoid appearance (moon face, central obesity etc.) and had acute respiratory distress syndrome due to pneumocystis carinii pneumonia. Laboratory examination revealed marked elevations of plasma ACTH (735 pg/ml) and cortisol (145 microg/dl) with a profound hypokalemia (2.0 mEq/l). She was found to have multiple masses in the liver and a solid mass in the tail of pancreas by abdominal computerized tomography scanning. Treatment with octreotide successfully reduced elevated plasma ACTH and cortisol levels, and she received frequent transhepatic arterial embolization and chemotherapy. The primary pancreatic tumor was surgically removed, revealing islet cell carcinoma which contained high content of ACTH (100 microg/g wet weight) and abundantly expressed proopiomelanocortin and somatostatin receptor subtype-2 mRNAs as determined by Northern blot analysis. Postoperatively, she was free from symptoms for almost one year. However, progressive enlargement of multiple liver metastases refractory to chemotherapy led her to decide on total hepatectomy and liver transplantation from her father. After liver transplantation, she remained almost free from symptoms for almost one year. However, metastases developed to the mediastinal and paraaortic lymph nodes as detected by 111[In] pentetreotide scintigraphy. Eleven months after liver transplantation, she was again treated with octreotide and, 16 months after, with metyrapone, both of which were effective in reducing ACTH and cortisol levels, respectively, until she died of acute respiratory failure. This case of a young female patient with ectopic ACTH-producing islet cell carcinoma of the pancreas was quite unique in that she survived for 5 years despite the acute onset and rapid progression of the multiple liver metastases at least in part due to the long-lasting favorable response to octreotide and living-related liver transplantation.

ACTH Syndrome, Ectopic↗
PubMed2003

Serially coupled capillary columns supercritical fluid chromatography with a coupling restrictor.

A serially coupled column system for capillary supercritical fluid chromatography was constructed by connecting two capillary columns of different polarities using or without using a coupling restrictor. The influence of the column sequence, the size of the coupling restrictor and the column temperature on the polarity of the system were studied. The system without a coupling restrictor (the directly coupled system) provided an intermediate polarity between two columns, depending on the column geometry, such as the film thickness and column length, although it slightly shifted to that of the first column. In the system with a coupling restrictor, the contribution of the second column to the overall retention increased with its resistance. The use of a coupling restrictor allowed to control the polarity of the coupled system virtually over the whole range between two columns. The temperature was an additional effective parameter for tuning the polarity of the system.

Journal Article↗
PubMed2003

Ascorbic acid augments cytotoxicity induced by oxidized low-density lipoprotein.

Although ascorbic acid (ASA) is known as a water-soluble antioxidant, we found that it accelerated the cytotoxicity induced by oxidized low-density lipoprotein (OxLDL) in vitro. This suggests that ASA may enhance the oxidation of LDL to augment the atherogenic activities of OxLDL under certain conditions. Thus, this study was designed to investigate the underlying mechanism that ASA enhances OxLDL-induced cytotoxicity. ASA enhanced the cytotoxicity of macrophage cell line (J774) induced by OxLDL in a dose-dependent manner, whose effect was more apparent in high glucose concentration in the medium. The ASA-induced enhancement in cytotoxicity was inhibited by the presence of lipid-soluble antioxidants, such as alpha-tocopherol and probucol, suggesting that the pro-cytotoxic effect by ASA is likely due to its pro-oxidant property. We also investigated the effects of ASA at different time points on the Cu2+-mediated oxidation of LDL. ASA decreased the rate of conjugated dienes formation when added at the early phase of oxidation, whereas it increased when added at the late phase of oxidation. These data suggest that ASA may act as a pro-oxidant under the condition of extensive LDL oxidation. To prevent oxidation stress, ASA would be better used together with lipid-soluble antioxidants for antioxidant therapies.

Animals↗
PubMed2003

[Phase III additional clinical study of 111In-pentetreotide (MP-1727): diagnosis of gastrointestinal hormone producing tumors based on the presence of somatostatin receptors].

Additional phase III multicenter clinical study was performed to investigate the efficacy, safety, and usefulness of somatostatin receptor scintigraphy using 111In-pentetreotide (MP-1727), which binds to somatostatin receptors. Forty patients were included in the study; Group A: 18 patients, gastrointestinal hormone producing tumors had been detected with conventional imaging modalities, Group B: 22 patients, no tumors had been detected with conventional imaging modalities in spite of high serum hormone levels. By comparing the results of the octreotide suppression test, 12/16 cases (75.0%) of Group A and 11/19 cases (57.9%) of Group B were assessed as "effective." By comparing the results of immunohistological examination, 5/9 cases (55.6%) of Group A and 2/4 cases (50.0%) of Group B were assessed as "effective." Severe adverse events were not observed in any of the evaluable 35 cases. MP-1727 was judged as clinically useful in 11/16 cases (68.8%) of Group A and 5/19 cases (26.3%) of group B. These results suggest that MP-1727 scintigraphy is very useful for the diagnosis and decision of the therapeutic strategy of gastrointestinal hormone producing tumors.

Aged↗
PubMed2002

Genetic and epigenetic inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to survival.

Sequence alterations of mitotic checkpoint genes, hBUB1 and hBUBR1, were examined, and their gene transcripts were quantified using on-line, real-time quantitative reverse transcription-PCR in surgically resected human colorectal cancers and their neighboring normal tissues. Our results reveal a new hBUB1 missense mutation (Ala130Ser) but not any hBUBR1 coding sequence mutations. hBUB1 and hBUBR1 mRNA levels were reduced to < 10% of the neighboring normal tissues in 3 of 103 and 3 of 109 carcinomas, respectively, and to < 50% in 7 and 7 carcinomas, whereas the overall expression levels were markedly higher in cancers than in normal tissues. Carcinomas with reduced hBUB1 and/or hBUBR1 mRNA levels, as well as the colon carcinoma harboring the hBUB1 mutation, were associated with lymph node metastasis (P < 0.005) and shorter relapse-free survival after surgery (P = 0.006). Thus, hBUB1 and hBUBR1 may contribute to a specific driving force in tumor metastasis and progression as a result of nonmutational, as well as mutational, inactivation.

Carcinoma, Hepatocellular↗
PubMed2002

Cytokine-activated Jak-2 is involved in inducible nitric oxide synthase expression independent from NF-kappaB activation in vascular smooth muscle cells.

Inflammatory cytokines, such as interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, activate nuclear factor-kappa B (NF-kappaB) which transactivates inducible nitric oxide synthase (iNOS) gene in vascular smooth muscle cells (VSMCs). However, it remains obscure whether cytokine-mediated iNOS expression in VSMCs requires signaling pathway(s) other than NF-kappaB activation. The present study was designed to elucidate whether protein tyrosine kinases (PTKs) are involved in the cytokine-induced NF-kappaB activation and iNOS expression in cultured rat VSMCs. Both IL-1beta and TNF-alpha stimulated NF-kappaB activity, iNOS mRNA and protein expression with massive nitrite/nitrate (NOx) production in rat VSMCs. PTK inhibitors (genistein, herbimycin A) dose-dependently inhibited the cytokine-stimulated NOx production and iNOS mRNA expression. However, neither genistein nor herbimycin A affected the cytokine-stimulated phosphorylation and degradation of IkappaB-alpha, or NF-kappaB activation, whereas they completely blocked the cytokine-stimulated iNOS transcriptional activity. Tyrphostin B42 (AG490), a Jak-2 tyrosine kinase inhibitor, similarly blocked the cytokine-induced NOx production, iNOS expression and its promoter activity without affecting NF-kappaB-dependent transcription. Transfection of a dominant-negative Jak-2 mutant antagonized the cytokine-induced NOx production and iNOS expression, while wild-type Jak-2 expressing construct was without effect. These data indicate that the cytokine-induced iNOS expression involves activation of Jak-2 signaling pathway independent from NF-kappaB activation in rat VSMCs.

Animals↗
PubMed2002

Effects of endothelin receptor antagonists on endothelin-1 and inducible nitric oxide synthase genes in a rat endotoxic shock model.

Levels of the endothelium-derived vasoconstrictor endothelin (ET)-1 and the vasodilator nitric oxide (NO) are markedly increased in endotoxic shock, although the pathophysiological role of ET-1 and its relation to NO under septic conditions remains obscure. To delineate the roles of ET-1 and the ET receptors, and the NO/inducible NO synthase (iNOS) system in endotoxic shock, we examined the gene expression of ET-1, ET receptors A and B (ETA and ETB) and iNOS in the heart and the liver of a rat endotoxic shock model, and we studied the effects of ET receptor antagonists on haemodynamics, survival rate and expression of ET-1, ET receptors and iNOS. Administration of bacterial lipopolysaccharide (LPS) into rats caused a profound hypotension with resultant death. However, these effects were blocked by a non-selective ETA/ETB receptor antagonist (TAK044), but not by an ETA-selective antagonist (BQ123). Injection of LPS caused a marked elevation in the plasma levels of both ET-1 and NO, which were not affected by treatment with either ET receptor antagonist. Administration of LPS caused increases in levels of ET-1, ETB and iNOS mRNA in the heart and the liver, whereas ETA mRNA expression was markedly downregulated in these organs. These results suggest that ET receptor subtype genes are differentially regulated in major organs from endotoxic shock rats, and that non-selective ET receptor antagonists ameliorate endotoxin-induced hypotension and death irrespective of iNOS-derived NO.

Animals↗
PubMed2002

A novel six-nucleotide insertion in exon 4 of the MEN1 gene, 878insCTGCAG, in three patients with familial insulinoma and primary hyperparathyroidism.

Three Japanese patients (a man and his two sons) in a family with clinical diagnosis of familial multiple endocrine neoplasia type 1 (MEN1) suffered from insulinoma(s), primary hyperparathyroidism and pituitary microadenoma. Genomic DNA of the patients was analyzed by sequencing for the MEN1 gene and an insertion of six nucleotides, CTGCAG, in exon 4, resulting in insertion of two amino acids, Leu-Gln, after the 256th amino acid of the menin (256insLQ), was identified. CTGCAG is a palindromic sequence and repeated twice in the wild-type allele (nucleotides 879-890). It is speculated that mutations involving only exon 4 of the MEN1 gene might induce development of insulinoma(s).

Adult↗
PubMed2002

Atrial natriuretic peptide improves pulmonary gas exchange by reducing extravascular lung water in canine model with oleic acid-induced pulmonary edema.

OBJECTIVE: The purpose of this study was to examine and compare the effects of atrial natriuretic peptide and furosemide on pulmonary gas exchange, hemodynamics, extravascular lung water, and renal function in a dog model of oleic acid-induced pulmonary edema. DESIGN: Prospective, comparable, experimental study. SETTING: Laboratory at a university hospital. SUBJECTS: Eighteen male beagle dogs were studied under mechanical ventilation with pentobarbital anesthesia. INTERVENTIONS: Oleic acid (0.08 mL/kg) was injected and allowed for 1 hr to achieve pulmonary edema with hypoxemia at Fio2 of 0.3. After lung injury, dogs were divided into three groups; control group (n = 6) receiving saline (2.5 mL/hr for 5 hrs), atrial natriuretic peptide group (n = 6) receiving atrial natriuretic peptide (1 microg x kg(-1) x min(-1) for 5 hrs), and furosemide group (n = 6) receiving furosemide (1 mg x kg(-1) x hr(-1) for 5 hrs). MEASUREMENTS AND MAIN RESULTS: Hemodynamics, arterial blood gases, extravascular lung water, and renal function were measured hourly for 7 hrs after injury. Oleic acid increased extravascular lung water and induced hypoxemia. In the atrial natriuretic peptide group, extravascular lung water was significantly (p <.05) lower and Pao2 was significantly (p <.05) higher than in the control and furosemide groups, respectively. Pulmonary hypertension induced by oleic acid was attenuated by atrial natriuretic peptide infusion but not by saline or furosemide. Increased natriuresis/diuresis did not significantly differ between the atrial natriuretic peptide and the furosemide group, whereas creatinine clearance in the atrial natriuretic peptide group was significantly higher than that in the furosemide group. CONCLUSIONS: These findings suggest that atrial natriuretic peptide improves pulmonary gas exchange by reducing extravascular lung water and pulmonary arterial pressure, possibly independently from natriuresis/diuresis in oleic acid-induced pulmonary edema.

Animals↗