Biomedical subjects

Y Hirata

Publications and source records attributed to Y Hirata.

At least 163 records · Page 9Linked to original sources

PubMed1999

Progression of cancer.

Carcinoma constitution originates in the hetero-duplication mitoses (4) which divide non-maturable stem cells into two different types of daughter cells: maturable and non-maturable cancerous stem cells. Throughout the progression of such mitoses, the organoid continuity of the cancer depends only on the non-maturable daughter stem cells, not on the maturable ones. This type of cancer can be considered non-progressive or to be in the incubation stage, as it only enables cancer tissue to preserve its organoid continuity without allowing progressive growth. However, when an occasional mitotic phase of the hetero-duplication mitotic progression undergoes genuine cell-phase duplication mitosis, this non-progressive or incubation stage of cancer is converted to a progressive type of cancer. This conversion is dependent on the reappearance of the complete mitotic condition of the mitotic maturation promoting system (MMPS) containing an abnormal supplement. Thus, a thorough investigation of the abnormal supplement and the reappearance of the complete mitotic condition is an essential part of research efforts to prevent and eradicate cancer.

Disease Progression↗

PubMed1999

Effects of the new potassium channel opener JTV-506 on coronary vessels in vitro and in vivo.

The vascular effects of JTV-506 ((-)-(3S,4R)-2.2-bis(methoxymethyl)- 4-[(1,6-dihydro-l-methyl-6-oxo-3-pyridazinyl)amino]-3-hydroxychroman+ ++-6- carbonitrile hemihydrate, CAS 170148-29-5), a new potassium channel opener, was evaluated in isolated coronary arteries and anesthetized dogs. JTV-506 (1 nmol/l-3 mumol/l) produced a concentration-dependent relaxation in porcine isolated epicardial large coronary arteries precontracted with KCl (30 mmol/l), phenylephrine (3 mumol/l), histamine (3 mumol/l), serotonin (5-HT; 300 nmol/l), prostaglandin F2 alpha (PGF2 alpha; 10 mumol/l), U-46619 (100 nmol/l), endothelin-1 (ET-1; 30 nmol/l) and Bay K-8644 (100 nmol/l). JTV-506 was 2.5-8.5 and 13.3-81.5 times more potent than levcromakalim (CAS 94535-50-9) and nicorandil (CAS 65141-46-0), respectively, but was less potent than nifedipine (CAS 21829-25-4). JTV-506 and levcromakalim produced almost a complete relaxation in arteries precontracted with various kinds of vasoconstrictor, except for KCl. In contrast, nifedipine produced about 80-90% relaxation in arteries, precontracted with PGF2 alpha, U-46619 and ET-1. Thus, this potassium channel opener can be characterized as an agonist-nonselective vasorelaxant. The relaxing effects of JTV-506 and levcromakalim on coronary arteries precontracted with 30 mmol/l KCl was competitively antagonized by 3 mumol/l glibenclamide, an ATP-sensitive potassium (KATP) channel blocker. In canine isolated epicardial large coronary arteries, 10 mumol/l JTV-506, 10 mumol/l levcromakalim, 100 mumol/l nicorandil and 0.1 mumol/l nifedipine eliminated 10 mmol/l 3,4-diaminopyridine-induced rhythmic contractions. In anesthetized dogs, when administered directly into the coronary artery, JTV-506 induced dose-dependent increases in coronary arterial diameter and coronary blood flow. These results suggest that JTV-506 elicits coronary vasorelaxation through activation of the KATP channel. It is expected that JTV-506 might be useful in the treatment of coronary vasospasm in angina pectoris.

Anesthesia↗

PubMed1999

Possible associations of rectal carcinoma with Schistosoma japonicum infection and membranous nephropathy: a case report with a review.

We report the first case of rectal carcinoma associated with S. japonicum and membranous nephropathy. A 57-year-old Japanese man noticed narrowing of his feces. He had lived in Yamanashi prefecture, an endemic area of S. japonicum. He had suffered from nephrotic syndrome for about 1 year. Barium enema study showed a severe stricture in the upper rectum and biopsy specimens from the tumor demonstrated well differentiated adenocarcinoma and many ova of S. japonicum. Sonography of the liver showed a network pattern and a linear high echoic area. Low anterior resection with incisional biopsy of the liver and the right kidney was performed. Histopathological findings showed well differentiated adenocarcinoma and schistosomal ova. The total number of ova in the resected colon amounted to 15,133, consisting of 2243 inside and 12,890 outside the carcinoma. The nearer to the carcinoma the area was, the higher was the density of ova. The findings of light microscopy and electron microscopy of the biopsy specimen from the kidney were compatible with membranous nephropathy (stage II). This case suggests that schistosomal ova have some effect on carcinogenesis and nephrotic syndrome. In patients with nephrotic syndrome of unknown cause, especially in inhabitants of endemic areas of S. japonicum, gastrointestinal malignancy should be ruled out as an etiological factor. Sigmoidoscopy would be useful for colorectal carcinoma surveillance in S. japonicum patients.

Adenocarcinoma↗

PubMed1999

Brain metastases in musculoskeletal sarcomas.

BACKGROUND: In musculoskeletal sarcomas, brain metastases are rare, but severely affect quality of life. METHODS: All patients with musculoskeletal sarcomas who were treated at our institutions from 1975 to 1997 were reviewed for examples of brain metastasis. RESULTS: Of 480 sarcoma patients, 179 had distant metastases, including 20 patients with brain metastases (4.2%). Alveolar soft part sarcoma (3/4), extraskeletal Ewing's sarcoma (2/8), rhabdomyosarcoma (2/13) and bone Ewing's sarcoma (2/18) tended to metastasize to the brain. All 20 patients had distant or local relapses and 16 of the 20 patients had pulmonary metastases. Three patients underwent surgical treatment and two of them survived over 1 year. Mean survival after diagnosis of brain metastasis was 5.1 months. CONCLUSIONS: Patients with alveolar soft part sarcoma, Ewing's sarcoma, rhabdomyosarcoma and pulmonary metastases have a high risk of brain metastasis.

Adolescent↗

PubMed1999

Osteosarcoma metastatic to the kidneys without lung involvement.

Symptomatic renal metastasis is very rare in osteosarcoma. A few reported cases had pulmonary metastases before renal involvement. We present a case of metastatic renal osteosarcoma without pulmonary involvement. The patient presented with hematuria 8 years after initial treatment of osteosarcoma of the left distal femur. Computed tomography revealed a bilateral calcified renal mass. The patient died of disease 4 months after detection of the metastases. At autopsy, metastatic osteosarcoma was discovered in the bilateral kidney, both renal veins, inferior vena cava and right atrium. There was no pulmonary involvement. We emphasize the need for renal evaluation for the follow-up of patients with osteosarcoma.

Adult↗

PubMed1999

Improvement of renal dysfunction in dogs with endotoxemia by a nonselective endothelin receptor antagonist.

OBJECTIVES: During endotoxemia, there is a marked and intractable decrease in systemic blood pressure, as well as profound vasoconstriction of the renal artery, thereby leading to septic shock and acute renal failure. The purpose of this study was to elucidate the effect of endothelin-1, a potent endothelium-derived vasoconstrictor peptide, on the hemodynamic and renal vascular changes seen in endotoxemia. DESIGN: Prospective, comparative, experimental study. SETTING: Laboratory at a university hospital. SUBJECTS: Thirty-two male mongrel dogs (12.1+/-0.4 kg) under pentobarbital anesthesia. INTERVENTIONS: Four groups of animals were studied: a) the lipopolysaccharide (LPS) group (n = 10), which received LPS (250 ng/kg/min for 2 hrs); b) the TAK-044 (a nonselective endothelinA/ endothelinB receptor antagonist) plus LPS group (n = 12), which received a bolus of TAK-044 (5 mg/kg) 0.5 hr before the start of LPS infusion; c) the TAK-044 plus vehicle group (n = 5), which received the same dose of TAK-044 0.5 hr before the start of vehicle infusion; and d) the control group (n = 5), which received only vehicle infusion. MEASUREMENTS AND MAIN RESULTS: Changes in systemic and renal hemodynamics, blood gas, and renal function were measured at baseline, and at 0.5, 1, 2, 3, and 4 hrs. Infusion of LPS resulted in significant decreases in mean arterial pressure, arterial pH, Pao2, base excess, urine volume, renal blood flow, creatinine clearance, and urine osmolality. The administration of TAK-044 before LPS infusion did not affect the LPS-induced hypotension. In contrast, the receptor antagonist prevented LPS-induced metabolic acidosis and hypoxemia, and improved LPS-induced decreases in urine volume, renal blood flow, creatinine clearance, and urine osmolality, whereas TAK-044 or vehicle administered alone resulted in no significant hemodynamic or blood gas changes. Plasma endothelin-1 concentrations significantly increased after LPS infusion, with or without TAK-044. CONCLUSIONS: The present study suggests that endothelin-1 plays an important role in the impaired renal hemodynamics and renal function associated with endotoxemia, and that endothelin receptor antagonists may be useful as therapeutic agents for acute renal failure during endotoxemia.

Acute Kidney Injury↗

PubMed1999

Pressor hyperreactivity to mental and hand-grip stresses in patients with hypercholesterolemia.

OBJECTIVE: To investigate the role of hypercholesterolemia in the regulation of blood pressure. SUBJECTS AND METHODS: We compared blood pressure responses to arithmetic stress and hand-grip tests in normotensive patients with hypercholesterolemia n = 15) and a mean (+/- SEM) age of 49 +/- 3 years, and normal cholesterolemic controls (n = 22) aged 48 +/- 1 years. Blood pressure and heart rate were measured throughout the tests. We examined the intracellular Ca2+ concentration in platelets with or without low-density-lipoprotein stimulation (2.9 nmol/l, 10 mg/ml). The plasma nitrite plus nitrate and cyclic GMP were determined before and at the end of each test to evaluate nitric oxide production and activity. RESULTS: Both tests showed that systolic/diastolic blood pressure was higher in the hypercholesterolemic patients than in the normal controls (stress test: 139 +/- 3/91 +/- 4 versus 127 +/- 2/80 +/- 3 mmHg, P < 0.01/P < 0.05; hand-grip test: 164 +/- 5/106 +/- 5 versus 144 +/- 3/88 +/- 3 mmHg, P < 0.01/P < 0.01). The intracellular Ca2+ concentration in platelets and the increase in response to low-density-lipoprotein stimulation were higher in the hypercholesterolemic patients (without stimulation: 72 +/- 3 versus 64 +/- 3 nmol/l, P < 0.01; with 2.9 nmol/l stimulation: 145 +/- 21 versus 89 +/- 6 nmol/l, P < 0.01). The increase in Ca2+ in response to 2.9 nmol/ml stimulation with low-density lipoprotein was positively related to the increase in mean blood pressure in response to the stress test (r = 0.56, P < 0.002). Nitric oxide production appeared to be increased in the hypercholesterolemic patients (65 +/- 5 versus 51 +/- 4 mmol/l, P < 0.05), and was not affected significantly by the tests. In contrast, cyclic GMP was lower in the patients and was increased significantly in the normal controls by the hand-grip test (P < 0.05). As a result, plasma cyclic GMP was lower in the patients (1.9 +/- 0.2 versus 2.5 +/- 0.1 nmol/l, P < 0.01). The ratio of plasma cyclic GMP to nitric oxide was also lower in the hypercholesterolemic patients at rest (P < 0.05), and at the end of the mental stress (P < 0.02) and hand-grip (P < 0.001) tests. CONCLUSIONS: Patients with hypercholesterolemia showed an exaggerated blood pressure response to both mental stress and exercise, even if resting blood pressure was normal. Increases in the intracellular Ca2+ concentration can contribute to these excessive responses. A disproportionately lower level of cyclic GMP to nitric oxide in plasma may also be involved in these abnormal responses.

Baroreflex↗

PubMed1999

Natriuretic peptides and nitric oxide induce endothelial apoptosis via a cGMP-dependent mechanism.

Apoptosis is a mode of cell death in which the cell participates in its own demise. We studied whether endothelium-derived relaxing factor, nitric oxide (NO), and natriuretic peptides affect apoptosis of rat vascular endothelial cells via a cGMP-dependent pathway and whether such effects are antagonized by an endothelium-derived vasoconstrictor, endothelin-1 (ET-1). Three natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide) induced endothelial apoptosis as demonstrated by nucleosomal laddering on agarose gel electrophoresis and by the terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling method. This dose-dependent relation was assessed by quantifying the fragmented and intact DNA contents by the diphenylamine method. The atrial natriuretic peptide-induced endothelial apoptosis was completely blocked by a guanylate cyclase-coupled receptor antagonist (HS-142-1) and an inhibitor of cGMP-dependent protein kinase (KT5823). An NO donor, NOR3 ((+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide; FK409) also induced endothelial apoptosis; the effect of this compound was abrogated by KT5823 and an inhibitor of soluble guanylate cyclase, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). A cGMP derivative, 8-bromo-cGMP, but not the cAMP derivative 8-bromo-cAMP, caused endothelial apoptosis; the effect of ODQ was also abrogated by KT5823. Endothelial apoptosis induced by ANP, NOR3, and 8-bromo-cGMP was similarly antagonized by ET-1. ANP, NOR3, and 8-bromo-cGMP caused marked accumulations of the tumor suppressor gene product p53 but not of bcl-2, as determined by Western blot analysis. These results demonstrate for the first time that endothelium-derived NO and natriuretic peptides are proapoptotic factors for endothelial cells, whereas the endothelium-derived vasoconstrictor ET-1 is an antiapoptotic factor, suggesting that the countervailing balance between these vasodilators and vasoconstrictors, in addition to regulation of vascular tonus, may contribute to endothelial cell integrity.

Animals↗

PubMed1999

Involvement of PYK2 in angiotensin II signaling of vascular smooth muscle cells.

-PYK2, a recently identified Ca2+-sensitive tyrosine kinase, has been implicated in extracellular signal-regulated kinase (ERK) activation via several G protein-coupled receptors. We have reported that angiotensin II (Ang II) induces Ca2+-dependent transactivation of the epidermal growth factor receptor (EGFR) which serves as a scaffold for preactivated c-Src and downstream adaptors (Shc/Grb2), leading to ERK activation in cultured rat vascular smooth muscle cells (VSMC). Herein we demonstrate the involvement of PYK2 in this cascade. Ang II rapidly induced tyrosine phosphorylation of PYK2, whose effect was completely inhibited by an AT1 receptor antagonist and an intracellular Ca2+ chelator. A Ca2+ ionophore also induced PYK2 tyrosine phosphorylation to a level comparable with that by Ang II, whereas phorbol ester-induced phosphorylation was less than that by Ang II. Moreover, PYK2 formed a complex coprecipitable with catalytically active c-Src after Ang II stimulation. Although a selective EGFR kinase inhibitor completely abolished Ang II-induced recruitment of Grb2 to EGFR and markedly attenuated Ang II-induced ERK activation, it had no effect on Ang II-induced PYK2 tyrosine phosphorylation or its association with c-Src and Grb2. These data suggest that the AT1 receptor uses Ca2+-dependent PYK2 to activate c-Src, thereby leading to EGFR transactivation, which preponderantly recruits Grb2 in rat VSMC.

Angiotensin II↗

PubMed1999

Effects of vasodilatory beta-adrenoceptor antagonists on endothelium-derived nitric oxide release in rat kidney.

The mechanisms for the vascular actions of vasodilatory beta-blockers remain undetermined. For some kinds of beta-blockers, the involvement of nitric oxide (NO) has been suggested. We studied the effects of vasodilatory beta-blockers on renal perfusion pressure (RPP) and NO release in the rat kidney. Infusion of bopindolol, celiprolol, and nebivolol caused a dose-dependent reduction in RPP and an increase in NO release (RPP: bopindolol 10(-6) mol/L, -23+/-2%; celiprolol 10(-4) mol/L, -27+/-2%; nebivolol 10(-5) mol/L, -35+/-3%; NO: bopindolol 10(-6) mol/L, +33+/-2; celiprolol 10(-4) mol/L, +41+/-2; nebivolol 10(-5) mol/L, +45+/-5 fmol. min-1. g kidney-1, mean+/-SEM). Metergoline (10(-6) mol/L), a 5-hydroxytryptamine (5-HT)1/2 antagonist, or NAN-190 (10(-6) mol/L), a 5-HT1A antagonist, almost completely abolished the vasorelaxation and NO release caused by bopindolol, celiprolol, and nebivolol. However, neither propranolol nor bisoprolol decreased RPP. Celiprolol and nebivolol caused vasodilation in the rat thoracic aorta, and it was markedly reduced by endothelial denudation, Nomega-nitro-L-arginine methyl ester (10(-4) mol/L), or NAN-190 (10(-6) mol/L). In deoxycorticosterone acetate-salt hypertensive rats, 4-week administration of celiprolol (50 mg. kg-1. d-1 IV) restored the responses regarding RPP and NO release to acetylcholine. These results suggest that several beta-blockers exert their vasodilatory action through the 5-HT1A receptor/NO pathway and that treatment with these beta-blockers may protect against endothelial injury in hypertension.

Adrenergic beta-Antagonists↗

PubMed1999

Role of nitric oxide-cGMP pathway in adrenomedullin-induced vasodilation in the rat.

We previously reported that adrenomedullin (AM), a potent vasodilator peptide discovered in pheochromocytoma cells, stimulates nitric oxide (NO) release in the rat kidney. To further investigate whether the NO-cGMP pathway is involved in the mechanisms of AM-induced vasodilation, we examined the effects of E-4021, a cGMP-specific phosphodiesterase inhibitor, on AM-induced vasorelaxation in aortic rings and perfused kidneys isolated from Wistar rats. We also measured NO release from the kidneys using a chemiluminescence assay. AM (10(-10) to 10(-7) mol/L) relaxed the aorta precontracted with phenylephrine in a dose-dependent manner. Denudation of endothelium (E) attenuated the vasodilatory action of AM (10(-7) mol/L AM: intact (E+) -25.7+/-5.2% versus denuded (E-) -7. 8+/-0.6%, P<0.05). On the other hand, pretreatment with 10(-8) mol/L E-4021 augmented AM-induced vasorelaxation in the intact aorta (-49. 0+/-7.9%, P<0.05) but not in the denuded one. E-4021 also enhanced acetylcholine (ACh)-induced vasorelaxation in the rat intact aorta (10(-7) mol/L ACh -36.6+/-8.4% versus 10(-8) mol/L E-4021+10(-7) mol/L ACh -62.7+/-3.1%, P<0.05). In perfused kidneys, AM-induced vasorelaxation was also augmented by preincubation with E-4021 (10(-9) mol/L AM -15.4+/-0.6% versus 10(-8) mol/L E-4021+10(-9) mol/L AM -23.6+/-1.2%, P<0.01). AM significantly increased NO release from rat kidneys (DeltaNO: +11.3+/-0.8 fmol. min-1. g-1 kidney at 10(-9) mol/L AM), which was not affected by E-4021. E-4021 enhanced ACh-induced vasorelaxation (10(-9) mol/L ACh -9.7+/-1.7% versus 10(-8) mol/L E-4021+10(-9) mol/L ACh -18.8+/-2.9%, P<0.01) but did not affect ACh-induced NO release from the kidneys. In the aorta and the kidney, 10(-4) mol/L of NG-nitro-L-arginine methyl ester, an NO synthase inhibitor, and 10(-5) mol/L of methylene blue, a guanylate cyclase inhibitor, reduced the vasodilatory effect of AM. These results suggest that the NO-cGMP pathway is involved in the mechanism of AM-induced vasorelaxation, at least in the rat aorta and kidney.

Adrenomedullin↗

PubMed1999

Endothelin-mediated vascular growth requires p42/p44 mitogen-activated protein kinase and p70 S6 kinase cascades via transactivation of epidermal growth factor receptor.

Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor peptide, exerts a growth-promoting effect on vascular smooth muscle cells, implicating its pathogenic role in vascular remodeling. To gain insight into the cellular and molecular mechanism whereby ET-1 induces vascular growth, we studied whether transactivation of receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor, are required for activation of p42/p44 mitogen-activated protein (MAP) kinase and p70 S6 kinase (p70S6K), and subsequent growth-promotion by ET-1 in cultured rat vascular smooth muscle cells. Immunoblotting with antiphosphotyrosine antibody revealed that ET-1 rapidly (within 2 min) and transiently induced tyrosine phosphorylation of several proteins, among which 180-kDa protein was shown to be EGFR. ET-1 rapidly increased association of EGFR and Shc with glutathione-S-transferase-Grb2 fusion protein. The ET-1-induced activation of MAP kinase was reduced by an EGFR kinase inhibitor (AG1478) but not by a platelet-derived growth factor receptor kinase inhibitor (AG1296). AG1478 dose-dependently decreased ET-1-stimulated MAP kinase activity as well as [3H]leucine and [3H]thymidine uptake. The ET-1-induced tyrosine phosphorylation of EGFR, as well as MAP kinase activation, was inhibited by an ETA receptor antagonist and intracellular Ca2+ antagonists but not by an ETB receptor antagonist, pertussis toxin, or protein kinase C inhibitors. In addition, dominant negative mutant of H-Ras and a MAP kinase kinase (MEK-1) inhibitor (PD98059) completely blocked ET-1-induced MAP kinase activation as well as [3H]leucine and [3H]thymidine uptake. Both AG1478 and PD98059 inhibited ET-1-induced phosphorylation and activation of p70S6K. Furthermore, rapamycin, a selective inhibitor of mammalian target of rapamycin, completely blocked ET-1-stimulated [3H]leucine and [3H]thymidine uptake. These results suggest that ETA receptor-mediated vascular growth by ET-1 requires both MAP kinase and p70S6K cascades mediated partly via Ca2+-dependent EGFR transactivation.

Animals↗

PubMed1999

Differential inhibitory actions by glucocorticoid and aspirin on cytokine-induced nitric oxide production in vascular smooth muscle cells.

Glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs) are widely used for the treatment of inflammatory and immune diseases. Nitric oxide (NO) has a diversity of physiological functions, but its excess production has been implicated in the inflammatory process. The present study was designed to elucidate the mechanisms by which glucocorticoids and NSAIDs affect inducible nitric oxide synthase (iNOS) expression in cultured rat vascular smooth muscle cells (VSMCs). Both interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha potently stimulated nitrite/nitrate (NOx) production with a concomitant expression of iNOS mRNA and protein as demonstrated by Northern and Western blot analysis, respectively. Both IL-1beta and TNF-alpha activated nuclear factor (NF)-kappaB as demonstrated by electrophoretic mobility shift assay. Dexamethasone, salicylate and aspirin, but not indomethacin, dose dependently inhibited cytokine-stimulated NOx production and iNOS protein expression. Dexamethasone decreased cytokine-induced NF-kappaB activation and iNOS mRNA expression, but neither salicylate nor aspirin affected NF-kappaB activation or iNOS mRNA expression. IL-1beta caused a rapid increase in phosphorylated IkappaB-alpha levels and subsequent transient decrease in IkappaB-alpha levels, an inhibitor of NF-kappaB, as revealed by Western blot analysis using specific antibodies for phosphorylated and nonphosphorylated IkappaB-alpha. These effects were blocked by pretreatment with dexamethasone. Aspirin dose dependently inhibited iNOS enzymatic activity, whereas salicylate and dexamethasone had limited effect. The present study demonstrates that 1) inhibitory effect of dexamethasone on cytokine-induced iNOS expression and NO production in rat VSMCs, although potentially acting at multiple levels, is partly mediated by inhibition of NF-kappaB activation resulting from decreased phosphorylation and degradation of IkappaB-alpha, 2) both salicylate and aspirin inhibit cytokine-stimulated NO production at translational and/or posttranslational levels without affecting NF-kappaB- mediated iNOS gene expression, and 3) aspirin directly inhibits iNOS enzyme activity. These data suggest the differential inhibitory mechanisms of iNOS-mediated NO synthesis by glucocorticoids and NSAIDs in the vasculature.

Animals↗

PubMed1999

Induction of max by adrenomedullin and calcitonin gene-related peptide antagonizes endothelial apoptosis.

Adrenomedullin is a novel vasodilatory peptide originally isolated from pheochromocytoma. Recently, we found that adrenomedullin acts as an autocrine/paracrine apoptosis survival factor for rat endothelial cells. In the present study, we show that adrenomedullin induces the expression of Max, a heterodimeric partner of c-Myc, which may contribute to its ability to rescue endothelial cells from apoptosis. Max is a basic-helix-loop-helix-leucine zipper protein that forms heterodimers with its alternative partners, Mad and Mxi-1, to behave as an antagonist for Myc-Max heterodimer through competition for common DNA targets. The expression of Max is reported to be constitutive and more stable than c-Myc, and serum induces immediate c-Myc stimulation followed by modest Max up-regulation. In quiescent rat endothelial cells, adrenomedullin stimulated the expression of Max without affecting c-Myc. Quantitation with real-time quantitative PCR detected on the ABI Prism 7700 Sequence Detection System revealed that adrenomedullin and calcitonin gene-related peptide (CGRP), as well as serum, up-regulated Max mRNA levels and that down-regulation of Max mRNA after serum deprivation was prevented by adrenomedullin. Neither adrenomedullin nor CGRP affected c-Myc expression. Transfection of a Max-expressing plasmid into endothelial cells rescued the apoptosis induced by serum deprivation. Neutralization with anti-adrenomedullin antiserum or blockade with a CGRP receptor antagonist, CGRP(8-37), reduced Max mRNA levels in growing endothelial cells and enhanced apoptosis after serum starvation. Introduction of an antisense oligodeoxynucleotide against Max mRNA using transferrin receptor-operated transfer led to inhibition of both adrenomedullin-induced up-regulation of Max transcripts and its cell survival effect, whereas random, sense, or missense oligonucleotides were without effect. The negative regulation of E-box-driven transcription by adrenomedullin was demonstrated by using preproendothelin-1 promoter containing c-Myc-Max binding consensus sequence; the promoter activity of preproendothelin-1 was reduced by cotransfecting Max- and Mad-expressing plasmids as well as addition of adrenomedullin and CGRP. The present results demonstrate that adrenomedullin antagonizes serum deprivation-induced endothelial apoptosis by up-regulation of the max gene in an autocrine/ paracrine manner.

Adrenomedullin↗

PubMed1999

Himehabu lectin, a novel inducer of Ca2+-release from the venom of the snake Trimeresurus okinavensis, in sarcoplasmic reticulum.

The lectin himehabu lectin (HHL) has recently been isolated from crude venom of the snake Trimeresurus okinavensis. Ca2+ -electrode and fluorescent Ca2+ -indicator experiments showed that HHL induced release of Ca2+ from the heavy fraction of skeletal muscle sarcoplasmic reticulum (HSR). The release of Ca2+ induced by caffeine from HSR was abolished by ryanodine, Mg2+ and ruthenium red, typical inhibitors of Ca2+ -release channels, whereas that induced by HHL was only partially reduced by these inhibitors. HHL, unlike caffeine, had no effect on [3H]ryanodine binding to HSR. These results suggest that HHL induces release of Ca2+ which is at least partially mediated through Ca2+ -release channels with novel pharmacological properties.

Animals↗

PubMed1999

Familial atrial septal defect and atrioventricular conduction disturbance associated with a point mutation in the cardiac homeobox gene CSX/NKX2-5 in a Japanese patient.

Atrial septal defect (ASD) is the most common form of congenital cardiac defect in humans. Recently, point mutations in the cardiac homeobox gene CSX/NKX2-5 have been reported to cause the autosomal dominant form of familial ASD. Notably, all the affected patients exhibit atrioventricular conduction disturbance and some of them died suddenly. The first case of familial ASD with a mutation of the CSX/NKX2-5 gene in a Japanese patient is reported here. Identification of CSX/NKX2-5 mutations in ASD patients would be very important because the existence of such mutations may predict sudden cardiac death.

Heart Block↗

PubMed1999

Simultaneous anterior-posterior approach for excision of malignant paraspinal tumor and subsequent reconstruction. Technical note.

In cases of primary malignant extradural tumors of the spine, the main goal of the surgery is en bloc resection and reconstruction of the spine. After placing the patient in the lateral position, an en bloc resection of a chondrosarcoma that arose from the right seventh rib head and invaded the adjacent vertebra was performed using a simultaneous anterior-posterior approach followed by spinal reconstruction. The technical details are reported. Paraspinal malignant tumors of the thoracic spine can be safely removed en bloc and the spine reconstructed using this approach.

Chondrosarcoma↗

PubMed1999

[A case of renal actinomycosis].

A case of renal actinomycosis is reported. A 63-year-old man was admitted to our hospital for further examinations of a right renal mass, complaining of dull pain in his right loin and progressive weight loss. Laboratory findings showed an anemia with a grossly raised ESR, CT, MRI and ultrasonography revealed a solid mass of the right kidney. Chest CT films revealed several infiltrates in the bilateral lobes. A diagnosis of neoplasm or inflammatory mass of the right kidney was considered, and the right nephrectomy was performed. Microscopically, characteristic colonies of actinomyces were seen, and histological diagnosis was renal actinomycosis. The patient made good progress after operation and was subsequently treated with penicillin.

Actinomycosis↗