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T Nakahashi

Publications and source records attributed to T Nakahashi.

At least 19 recordsLinked to original sources
PubMed2000

Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor.

Brain-derived neurotrophic factor (BDNF) is an abundant neurotrophin in brain and peripheral nerves, where it affects neural development, survival and repair after injury. BDNF has been detected in rat and human blood, but the source of circulating BDNF is not established. BDNF messenger and peptide were detected in cultured cells and in the culture medium of human umbilical vein endothelial cells. The expression of BDNF was up-regulated by elevation of intracellular cAMP and down-regulated by Ca(2+) ionophore, bovine brain extract and laminar fluid shear stress. These results suggest that vascular endothelial cells may contribute to circulating BDNF.

Animals↗
PubMed2000

[Current state and related factors in examinations of those who have had contact with tuberculosis].

OBJECTIVE: This study investigated the current conditions of identifying tuberculosis contacts and enforcing their examinations in Public Health Centers and examined related factors. METHODS: The study subjects were 431 index cases with tuberculosis who were newly registered between 1995 and 1997 at four Public Health Centers in Tokyo and Yokohama. Based on case registration card information and interviews with public health nurses in charge, the data of identification of contacts and enforcement of examination of their contacts were collected. RESULTS: The proportion of index cases with insufficient identification of contacts was 28.3%, particularly the non-family contact data being insufficient. From logistic regression analysis: index cases aged 20-39 years; contact with many people; "a moderate risk index of infection" cases; and being homeless were factors significantly related to insufficient identification of contacts. The proportion of contacts who were examined in individual contact examinations was 59.1%, that of mass contact examinations was 80.4%. From logistic regression analysis: negative index cases on sputum smear; and no history of routine health examinations for the past 3 years or a complete lack of information were factors significantly related to insufficient enforcement of individual contact examinations. As to mass contact examinations, not interviewing index cases was a factor significantly related to insufficient enforcement. Further individual and mass contact examinations differed in quality according to Public Health Center. The incidence in close contacts with active tuberculosis was 1.0%, and was especially high in members of the same household and friends of the newly diagnosed. CONCLUSIONS: This study showed that the current contact examinations for tuberculosis are insufficient. In addition it was shown that an adequate identification of contacts and a complete enforcement of contact examinations are urgent needs in Japan.

Adolescent↗
PubMed1999

[Multicenter prospective survey of prognosis of hypertensive elderly outpatient under antihypertensive treatment--morbidity and mortality of cardiovascular diseases and cancer].

Although calcium-channel blockers and angiotensin-I-converting enzyme inhibitors are often used for treatment of hypertension in the elderly in Japan compared to those in the United States and in European countries, there have been few investigations on the prognosis of the elderly receiving these antihypertensive treatments. The Research Group for "Guidelines on the Treatment of Hypertension in the Elderly" collaborated with the Comprehensive Research Projects on Aging and Health group of the Ministry of Health and Welfare of Japan in performing a 3-year survey on the outcome of 700 hypertensive elderly outpatients (> or = 60 years) receiving treatment of antihypertensive drugs. Antihypertensive drugs including dihydropyridine-type calcium channel blockers, beta blockers, angiotensin-I-converting enzyme inhibitors, diltiazem, diuretics and old-type antihypertensives (hydralazine, budralazine, and centrally acting drugs such as clonidine, methyldopa and guanabenz) were administered to 71.3%, 30.4%, 26.2%, 14.0%, 8.6%, and 6.4% of the 642 elderly patients surveyed for three years, at the time of registration, respectively. Morbidity and mortality rates of total cerebro-cardiovascular diseases, stroke, and heart diseases, were 27.6 and 7.81/1,000 patient-years, 15.1 and 3.6/1,000 patient-years, 10.4 and 4.2/1,000 patient-years, respectively. These results were similar or even better than those of megatrials of antihypertensive treatments for elderly patients in Europe and United States. After adjustment for potential confounding factors, multiple logistic analysis revealed that a past history of ischemic heart disease, use of the old-type antihypertensive drugs, male gender, and diastolic high blood pressure were independent risk factors for the morbidity of cerebro-cardiovascular diseases taking the group of non-cerebro-cardiovascular disease as the reference group. We also identified 22 cases of newly occurred malignancies including 7 fatal cases. However, none of the antihypertensives was significantly related to the occurrence of malignancies. These results lead support to the tendencies in the use of antihypertensive drugs in Japan.

Aged↗
PubMed1998

Hydrogen peroxide induces up-regulation of Fas in human endothelial cells.

Hydrogen peroxide (H2O2), an oxidant generated by inflammatory cells, is an important mediator of injury of endothelial cells (ECs). Here we show that H2O2 induces up-regulation of the expression of Fas, a death signal, in human ECs in culture. Flow cytometric analysis with a mAb against human Fas showed that incubation for 24 h with H2O2 induced a dose-dependent increase in the level of Fas in ECs. Coincubation with catalase, which rapidly degrades H2O2, inhibited H2O2-induced up-regulation of Fas. H2O2 also induced a dose-dependent increase in Fas mRNA level. A significant increase in Fas mRNA levels was observed from 6 h after stimulation with H2O2. Vanadate, a protein phosphatase inhibitor, significantly enhanced Fas mRNA and protein levels in H2O2-treated ECs. On the other hand, genistein, a tyrosine kinase inhibitor, inhibited H2O2-induced Fas mRNA expression. Furthermore, a flow cytometric method with propidium iodide staining and electron microscopic analysis showed that incubation with an agonistic Ab against Fas (anti-Fas IgM) induced apoptosis in H2O2-treated cells. These findings suggest that H2O2 induces up-regulation of Fas in ECs and that activation of protein tyrosine kinase may be involved in the mechanism of H2O2-induced Fas expression. Therefore, Fas-mediated apoptosis may have a pathologic role in H2O2-induced EC injury and thereby provide a new therapeutic target.

Apoptosis↗
PubMed1998

Endothelin-1 enhances nitric oxide-induced cell death in cultured vascular smooth-muscle cells.

Increased expression of endothelin-1 (ET-1) immunoreactivity is demonstrated in the active atherosclerotic plaque. Here we show that both ETA and ETB receptors are expressed in rat vascular smooth-muscle cells (VSMCs). ET-1 binding to ETB receptors enhances nitric oxide-induced cell death in VSMCs. These findings suggest that ET-1 may participate in the mechanism of cell death (apoptosis) in the plaque through activation of ETB-mediated pathways and that a selective ETB receptor antagonist could be useful in preventing acute plaque alterations, such as plaque rupture.

Amino Acid Sequence↗
PubMed1998

Exogenous ouabain is accumulated in the adrenals and mimics the kinetics of endogenous digitalis-like factor in rats.

Ouabain has been isolated as an endogenous pathogenetic factor in salt-induced hypertension and has been shown to be rich in the adrenals. In this study, organ accumulation of orally administered [3H]ouabain was examined in rats. Exogenous [3H]ouabain was accumulated in high levels in the adrenals, especially in the zona intermedia, and was not metabolized in the rat. Accumulated [3H]ouabain mimicked the movement of "endogenous" digitalis-like factor, since 1) the plasma [3H]ouabain level decreased in bilaterally adrenalectomized rats, 2) the plasma [3H]ouabain level increased accompanied by a decrease in [3H]ouabain content in the adrenals in reduced renal mass hypertensive rats, and 3) [3H]ouabain levels in plasma and in the adrenals increased in spontaneously hypertensive rats, as compared with those in respective control animals. Moreover, the rat diet contained a relatively high amount of ouabain-like immunoreactivity (OLI), and the ratio of the [3H]ouabain content to OLI in each organ was comparable to that of the daily intake of dietary [3H]ouabain to OLI. Furthermore, high 3H-radioactivities were also observed in the adrenals of rats that ingested [3H]digoxin and [3H]digitoxin. These data suggest that exogenous ouabain, related cardiotonic glycosides of plant origin, or both accumulate in the adrenals and, at least in part, act as "endogenous" digitalis-like factor(s).

Adrenal Cortex↗
PubMed1997

Interleukin-2 modulates the responsiveness to angiotensin II in cultured vascular smooth muscle cells.

Preincubation with interleukin-2 (IL-2), a T cell-derived cytokine, enhanced the increase in intracellular Ca2+ ([Ca2+]i) induced by angiotensin II (AII) in vascular smooth muscle cells (VSMC). IL-2 itself did not affect the basal [Ca2+]i level or the maximal response of [Ca2+]i increase induced by AII. Furthermore, IL-2-induced enhancement was not observed in the absence of extracellular Ca2+, suggesting that IL-2 enhances Ca2+ influx induced by AII. IL-2 also enhanced the stimulation of DNA synthesis induced by AII, although IL-2 alone did not stimulate DNA synthesis. Genistein, an inhibitor of protein tyrosine kinases, significantly inhibited IL-2-induced enhancement of both Ca2+ influx and DNA synthesis induced by AII. A neutralizing antibody against heparin-binding epidermal growth factor-like growth factor (HB-EGF) partially inhibited IL-2-induced enhancement of DNA synthesis induced by AII. These findings suggest that autocrine HB-EGF is partially involved in the mechanism of IL-2-induced enhancement of DNA synthesis. On the other hand IL-2 stimulated both glycosaminoglycan (GAG) and prostacyclin syntheses and enhanced the stimulation of both GAG and prostacyclin syntheses induced by AII. Therefore, IL-2 may play important roles in the pathogenesis of atherosclerosis and vascular disease by modulating the responsiveness to AII in VSMC.

Angiotensin II↗
PubMed1997

Possible participation of Fas-mediated apoptosis in the mechanism of atherosclerosis.

Apoptosis is a programmed cell death that plays a major role during development, homeostasis, and in many diseases. Recent evidence has demonstrated the death of vascular smooth muscle cells (VSMCs) within advanced human atheroma. In the rat balloon-injury model, apoptotic cells were specifically identified in the neointima. The presence of apoptotic cells was demonstrated by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). To clarify the mechanisms that trigger apoptosis in atherosclerotic lesions, we examined whether cytokines released from macrophages can modulate Fas, a death signal, in cultured human VSMCs. Simultaneous treatment with interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) but not with each cytokine alone induced upregulation of Fas in VSMCs. However, coincubation with NG-monomethyl-L-arginine, an inhibitor of nitric oxide (NO) synthesis, inhibited the upregulation of Fas induced by IL-1 and TNF-alpha. Incubation with sodium nitroprusside, a NO donor, also induced upregulation of Fas in VSMCs. Furthermore, fluorescent nuclear staining with Hoechst 33258 revealed that monoclonal antibody to human Fas significantly enhanced NO-induced apoptotis in VSMCs. These findings suggest that macrophage-derived cytokines can induce upregulation of Fas through a NO-dependent mechanism in VSMCs. Thus, Fas-mediated apoptosis may regulate apoptotic death of VSMCs during atherogenesis.

Animals↗
PubMed1997

Activated T cells induce up-regulation of Fas antigen in cultured endothelial cells.

Recent evidence has shown that apoptotic cells are present in human atherosclerotic lesions. However, the molecular mechanism of the induction of apoptosis in atherosclerotic lesions is not clear. Since T cells are present in almost all stages of atherosclerosis, we examined whether T cells can modulate the expression of Fas, a death signal, in endothelial cells (ECs), using a coculture system. Human umbilical vein ECs were cultured alone or cocultured with human peripheral T cells activated with phorbol myristate acetate and ionomycin. Flow cytometric (FACscan) analysis showed that Fas antigen was up-regulated in ECs when ECs were cocultured for 24 h with activated T cells. However, Fas antigen was not up-regulated in ECs cocultured with non-activated T cells. The up-regulation of Fas antigen induced by coculturing ECs with activated T cells was partially, but significantly, neutralized by antibody against interferon-gamma (IFN-gamma). Actually, incubation with IFN-gamma induced a dose-dependent increase in the level of Fas antigen in ECs cultured alone. These findings indicate that activated T cells induce up-regulation of Fas antigen in ECs. Thus, the Fas system induced by activated T cells could participate in the mechanism of EC injury in atherosclerotic lesions.

Apoptosis↗
PubMed1996

Calcitonin prevents CCl4-induced hydroperoxide generation and cytotoxicity possibly through C1b receptor in rat hepatocytes.

The effects of calcitonin (CT) on oxyradical generation and cellular damage induced by carbon tetrachloride (CCl4) were investigated in rat hepatocytes. Addition of CCl4 to the cells concentration dependently increased intracellular production of hydroperoxides and release of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The hepatocytes expressed mRNA for a CT receptor, C1b. Coaddition of CT to the cells concentration dependently suppressed the CCl4-induced increase in hydroperoxide production and also decreased the release of AST and ALT. The suppressive effect of CT on hydroperoxide production was reversed by further addition of H7 or by pretreatment with phorbol 12-myristate 13-acetate for 24 h. These results suggest that CT prevents CCl4-induced oxyradical production and cellular damage through activation of protein kinase C in hepatocytes.

Animals↗
PubMed1996

A case of renovascular hypertension with marked polyuria after percutaneous transluminal renal angioplasty.

A 43-year-old female patient with hypertension was diagnosed as having one-kidney renovascular hypertension with dysfunction of the contralateral kidney, and percutaneous transluminal renal angioplasty was carried out. Marked polyuria was observed during the 2- to 72-hour postoperative period. During the 12- to 18-hour period of polyuria, the urine volume was 8.9 liters/6 h, which was 62% of the glomerular filtration, and was accompanied by high fractional excretion of sodium and of potassium and a high urine beta 2-microglobulin level. The mechanism of polyuria in this case is discussed.

Adult↗
PubMed1996

Parathyroid hormone-related protein inhibits indothelin-1 production.

The effect of human parathyroid hormone-related protein, a powerful vasodilator, on endothelin-1 production in cultured bovine pulmonary arterial endothelial cells was studied. Treatment with parathyroid hormone-related protein(1-34) at concentrations of 10(-9) to 10(-6) mol/L for 24 hours caused dose-dependent suppression of the secretion of endothelin-1, with maximal suppression at 10(-7) mol/L to 74% of the control value. This inhibitory effect was completely abolished by coincubation with 100 ng/mL pertussis toxin, an inhibitor of GTP binding protein. Furthermore, addition of Ng-monomethyl-L-arginine, an inhibitor of nitric oxide synthase, at 10(-3) mol/L significantly blocked the suppressive effect of parathyroid hormone-related protein (1-34) on endothelin-1 secretion, and further addition of 5x10(-3) mol/L L-arginine significantly attenuated the blocking effect of N(G)-monomethyl-L-arginine. Parathyroid hormone-related protein (1-34) at 10(-7) mol/L resulted in an approximately fivefold increase in intracellular cGMP level. Northern blot analysis revealed that parathyroid hormone-related protein (1-34) inhibited both basal and thrombin-induced endothelin-1 gene expression. These findings suggest that the vasodilating property of parathyroid hormone-related protein may be mediated in part through its inhibitory effect on endothelin-1 production, which is probably mediated through nitric oxide and cGMP in endothelial cells. Thus, a feedback regulatory mechanism may exist between parathyroid hormone-related protein and endothelin-1 in the vascular wall.

Animals↗
PubMed1996

Nitric oxide induces upregulation of Fas and apoptosis in vascular smooth muscle.

Interleukin-1 induced a time-dependent release of high levels of nitric oxide from rat vascular smooth muscle cells up to 96 hours. A time-dependent release of lactate dehydrogenase was also induced by Interleukin-1 from 72 to 96 hours after its stimulation. In situ nick end-labeling assay revealed that incubation for 48 hours with interleukin-1 induced a positive staining of fragmented nuclei. However, NG-monomethyl-L-arginine, an inhibitor of nitric oxide synthase, inhibited both lactate dehydrogenase release and DNA fragmentation induced by interleukin-1. Furthermore, sodium nitroprusside, a nitric oxide donor, also induced lactate dehydrogenase release and DNA fragmentation. Fluorescent staining of DNA revealed patches of irregularly dispersed, brightly staining, and condensed chromatin in rat vascular smooth muscle cells treated with sodium nitroprusside. Flow cytometric analysis with monoclonal antibody against human Fas revealed that expression of Fas was upregulated by sodium nitroprusside in human vascular smooth muscle cells. Methylene blue, an inhibitor of soluble guanylate cyclase, did not affect sodium nitroprusside-induced upregulation of Fas. Furthermore, 8-bromo-guanosine 3':5'-cyclic monophosphate, an analogue of cGMP, did not upregulate Fas expression. These findings indicate that nitric oxide released from vascular smooth muscle cells may induce apoptosis in vascular smooth muscle cells themselves and also induced upregulation of Fas via a cGMP-independent mechanism. Thus, nitric oxide could trigger the remodeling of atherosclerotic plaques.

Animals↗
PubMed1996

[Guidelines on treatment of hypertension in the elderly, 1995--a tentative plan for comprehensive research projects on aging and health-- Members of the Research Group for "Guidelines on Treatment of Hypertension in the Elderly", Comprehensive Research Projects on Aging and Health, the Ministry of Health and Welfare of Japan].

We propose the following guidelines for treatment of hypertension in the elderly. 1. Indications for Treatment. 1) Age: Lifestyle modification is recommended for patients aged 85 years and older. Antihypertensive therapy should be limited to patients in whom the merit of the treatment is obvious. 2) Blood pressure: Systolic BP > 160 mmHg, diastolic BP > 90 approximately 10 mmHg. Systolic BP < age + 100 mmHg for those aged 70 years and older. Patients with mild hypertension (140-160/ 90-95 mmHg) associated with cardiovascular disease should be considered for antihypertensive drug therapy. 2. Goal of Therapy for BP: The goal BP in elderly patients is higher than that in younger patients (BP reduction of 10-20 mmHg for systolic BP and 5-10 mmHg for diastolic BP). In general, 140-160/< 90 mmHg is recommended as the goal. However, lowering the BP below 150/85 should be done with caution. 3. Rate of Lowering BP: Start with half the usual dose, observe at the same dose for at least four weeks, and reach the target BP over two months. Increasing the dose of antihypertensive drugs should be done very slowly. 4. Lifestyle Modification: 1) Dietary modification: (1) Reduction of sodium intake is highly effective in elderly patients due to their high salt-sensitivity. NaCl intake of less than 10 g/day is recommended. Serum Na+ should be occasionally measured. (2) Potassium supplementation is recommended, but with caution in patients with renal insufficiency. (3) Sufficient intake of calcium and magnesium is recommended. (4) Reduce saturated fatty acids. Intake of fish is recommended. (2) Regular physical activity: Recommended exercise for patients aged 60 years and older: peak heart rate 110/minute, for 30-40 minutes a day, 3-5 days a week. (3) Weight reduction. (4) Moderation of alcohol intake, smoking cessation. 5. Pharmacologic Treatment: 1) Initial drug therapy. First choice: Long-acting (once or twice a day) Ca antagonists or ACE inhibitors. Second choice: Thiazide diuretics (combined with potassium-sparing diuretic). 2) Combination therapy. (1) For patients without complications, either of the following is recommended. i) Ca antagoinst + ACE inhibitor, ii) ACE inhibitor + Ca antagonist (or low-dose diuretics), iii) diuretic + Ca antagonist (or ACE inhibitor), iv) beta-blockers, alpha 1-blockers, alpha + beta blockers can be used according to the patho-physiological state of the patient. (2) For patients with complications. Drug(s) should be selected according to each complication. 3) Relatively contraindicated drugs. beta-Blockers and alpha 1-blockers are relatively contraindicated in elderly patients with hypertension in Japan. Centrally acting agents such as reserpine, methyldopa and clonidine are also relatively contraindicated beta-Blockers are contraindicated in patients with congestive heart failure, arteriosclerosis obliterans, chronic obstructive pulmonary disease, diabetes mellitus (or glucose intolerance), or bradycardia. These conditions are often present in elderly subjects. Elderly subjects are susceptible to alpha 1-blocker-induced orthostatic hypotension, since their baroreceptor reflex is diminished. Orthostatic hypotension may cause falls and bone fractures in the elderly.

Aged↗
PubMed1995

cGMP upregulates nitric oxide synthase expression in vascular smooth muscle cells.

8-Bromo-guanosine 3':5'-cyclic monophosphate (8-Br-cGMP), an analogue of cyclic guanosine monophosphate (cGMP), induced a time- and dose-dependent enhancement of interleukin-1-induced nitric oxide production in vascular smooth muscle cells. Human atrial natriuretic polypeptide, which stimulates cGMP accumulation in vascular smooth muscle cells, also enhanced interleukin-1-induced nitric oxide release at a concentration of 100 nmol/L. In contrast, coincubation with 10 mumol/L methylene blue, an inhibitor of soluble guanylate cyclase, inhibited interleukin-1-induced nitric oxide release from vascular smooth muscle cells. Furthermore, coincubation with 8-Br-cGMP also enhanced the interleukin-1-induced increase in inducible nitric oxide synthase messenger RNA in vascular smooth muscle cells. However, the enhancement of nitric oxide production induced by 8-Br-cGMP was significantly prevented by coincubation with neutralizing antibody against tumor necrosis factor-alpha. Furthermore, 8-Br-cGMP enhanced the interleukin-1-induced increase in tumor necrosis factor-alpha messenger RNA level in vascular smooth muscle cells. These findings indicate that cGMP may upregulate inducible nitric oxide synthase gene expression through the stimulation of tumor necrosis factor-alpha production in vascular smooth muscle cells. Thus, there may be a positive feedback mechanism between nitric oxide and the cGMP system in vascular smooth muscle cells.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1995

Endothelin-1 enhances nitric oxide-induced cytotoxicity in vascular smooth muscle.

Prolonged incubation with 1 nmol/L interleukin-1 induced high levels of nitric oxide release and cytotoxicity in vascular smooth muscle cells. NG-Monomethyl-L-arginine, an inhibitor of nitric oxide synthesis, inhibited interleukin-1-induced cytotoxicity at a concentration of 3 mmol/L. Furthermore, prolonged incubation with 0.1 mmol/L sodium nitroprusside, a nitric oxide donor, also induced cytotoxicity. On the other hand, endothelin-1 at concentrations from 10(-10) to 10(-7) mol/L induced a concentration-dependent enhancement of cytotoxicity induced by interleukin-1. However, endothelin-1 did not affect interleukin-1-induced nitric oxide production. Coculture study of vascular smooth muscle cells and endothelial cells without direct cell contact revealed that incubation for 72 hours with interleukin-1 induced high levels of nitric oxide release from cocultured vascular smooth muscle cells to the same degree as release from vascular smooth muscle cells alone. However, interleukin-1-induced cytotoxicity was more enhanced in cocultured vascular smooth muscle cells than in vascular smooth muscle cells alone. Furthermore, coincubation with 20 nmol/L BQ-485, an antagonist of one type of endothelin receptor (ETA), prevented the enhancement of interleukin-1-induced cytotoxicity in cocultured vascular smooth muscle cells. These findings suggest that endothelin-1 secreted from endothelial cells may enhance nitric oxide-induced cytotoxicity by means of the ETA receptor in vascular smooth muscle cells.

Animals↗
PubMed1995

Nitric oxide mediates cytotoxicity and basic fibroblast growth factor release in cultured vascular smooth muscle cells. A possible mechanism of neovascularization in atherosclerotic plaques.

To define the pathophysiological role of nitric oxide (NO) released from vascular smooth muscle cells (VSMC), we examined whether NO released from VSMC induces cytotoxicity in VSMC themselves and adjacent endothelial cells (EC) using a coculture system. Prolonged incubation with interleukin-1 (IL-1) induced large amounts of NO release and cytotoxicity in VSMC. NG-Monomethyl-L-arginine, an inhibitor of NO synthesis, inhibited both NO release and cytotoxicity induced by IL-1. In contrast, DNA synthesis in cocultured EC was not inhibited but rather stimulated by prolonged incubation with IL-1 or sodium nitroprusside (SNP), a NO donor. However, IL-1 and SNP did not stimulate but inhibited DNA synthesis in EC alone. On the other hand, conditioned medium from VSMC incubated for a long period with IL-1 or SNP stimulated DNA synthesis in EC alone. Furthermore, the concentration of basic fibroblast growth factor in the conditioned medium was increased and correlated with the degree of cytotoxicity in VSMC. These results indicate that NO released from VSMC induces VSMC death, which results in release of basic fibroblast growth factor, which then stimulates adjacent EC proliferation. Thus, NO released from VSMC may participate in the mechanism of neovascularization in atherosclerotic plaques.

Animals↗