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Biomedical subjects

Masato Tsutsui

Publications and source records attributed to Masato Tsutsui.

At least 37 records · Page 2Linked to original sources
PubMed2004

Granulocyte macrophage-colony stimulating factor increases the expression of histamine and histamine receptors in monocytes/macrophages in relation to arteriosclerosis.

OBJECTIVE: To study the effect of granulocyte macrophage-colony-stimulating factor (GM-CSF) on histamine metabolism in arteriosclerosis, the expression of histidine decarboxylase (HDC; histamine-producing enzyme), histamine receptors 1 and 2 (HH1R and HH2R), and GM-CSF was investigated in human and mouse arteriosclerotic carotid arteries. Furthermore, the molecular mechanisms of GM-CSF-induced HDC and HH1R expression in monocytic U937 cells were investigated. METHODS AND RESULTS: Immunohistochemistry showed that atherosclerotic human coronary and mouse ligated carotid arteries contained HDC-expressing macrophages. Gene expression of HDC, HH1R, HH2R, and GM-CSF was also detected in the lesions. In U937 cells, GM-CSF enhanced histamine secretion and gene expression of HDC and HH1R. A promoter assay showed that GM-CSF enhanced gene transcription of HDC and HH1R but not HH2R. CONCLUSIONS: The present results indicate that HDC and HHR are expressed in arteriosclerotic lesion, and that GM-CSF induces HDC and HH1R expression in monocytes. Locally produced histamine might participate in atherogenesis by affecting the expression of atherosclerosis-related genes in monocytes and smooth muscle cells. The presence of histamine-producing macrophages and gene expression of histamine receptors and GM-CSF was demonstrated in arteriosclerotic lesions. In monocytic U937 cells, GM-CSF upregulated the expression of histamine and HH1R. Coordinated expression of histamine and its receptors by GM-CSF would participate in atherogenesis by affecting monocytic and SMC gene expression.

Animals↗
PubMed2004

Stimulation of catecholamine synthesis by environmental estrogenic pollutants.

Environmental estrogenic pollutants are compounds that have been shown to have estrogenic effects on fetal development and reproductive systems. Less attention, however, has been paid to their influence on neuronal functions. We report here the effects of estrogenic pollutants on catecholamine synthesis in bovine adrenal medullary cells used as a model system of noradrenergic neurons. Treatment of cultured bovine adrenal medullary cells with p-nonylphenol and bisphenol A at 10 nM for 3 d stimulated [14C]catecholamine synthesis from [14C]tyrosine and tyrosine hydroxylase activity, an effect that was not inhibited by ICI 182,780, an antagonist of estrogen receptors. Significant effects of p-nonylphenol on [14C]catecholamine synthesis were observed at 0.1 nM, which is 45 times lower than that of the international regulatory standard (4.5 nM), and the maximum effects were around 10-100 nM. The concentrations (0.1-10 nM) used in the present study are similar to the range observed in rivers in the United States or Europe. On the other hand, short-term treatment of cells with 10 nM p-nonylphenol for 10 min also activated tyrosine hydroxylase, which was suppressed by U0126, an inhibitor of MAPK kinase. Furthermore, treatment of cells with p-nonylphenol for 5 min increased the phospho-p44/42MAPK in a concentration-dependent (1-1000 nM) manner, whereas p-nonylphenol (100 nm, 2 d) enhanced both levels of non-phospho- and phospho-p44/42MAPK. These findings suggest that short-term and long-term treatment of cells with estrogenic pollutants at environmental concentrations stimulates catecholamine synthesis and MAPK through an estrogen receptor-independent pathway.

Adrenal Medulla↗
PubMed2004

Asymmetric dimethylarginine produces vascular lesions in endothelial nitric oxide synthase-deficient mice: involvement of renin-angiotensin system and oxidative stress.

OBJECTIVE: Asymmetric dimethylarginine (ADMA) is widely believed to be an endogenous nitric oxide synthase (eNOS) inhibitor. However, in this study, we examined our hypothesis that the long-term vascular effects of ADMA are not mediated by inhibition of endothelial NO synthesis. METHODS AND RESULTS: ADMA was infused in wild-type and eNOS-knockout (KO) mice by osmotic minipump for 4 weeks. In wild-type mice, long-term treatment with ADMA caused significant coronary microvascular lesions. Importantly, in eNOS-KO mice, treatment with ADMA also caused an extent of coronary microvascular lesions that was comparable to that in wild-type mice. These vascular effects of ADMA were not prevented by supplementation of l-arginine, and vascular NO production was not reduced by ADMA treatment. Treatment with ADMA caused upregulation of angiotensin-converting enzyme (ACE) and an increase in superoxide production that were comparable in both strains and that were abolished by simultaneous treatment with temocapril (ACE inhibitor) or olmesartan (AT(1) receptor antagonist), which simultaneously suppressed vascular lesion formation. CONCLUSIONS: These results provide the first direct evidence that the long-term vascular effects of ADMA are not solely mediated by simple inhibition of endothelial NO synthesis. Direct upregulation of ACE and increased oxidative stress through AT(1) receptor appear to be involved in the long-term vascular effects of ADMA in vivo. This study demonstrates that asymmetrical dimethylarginine (ADMA) causes arteriosclerotic coronary lesions in mice in vivo through mechanisms other than simple inhibition of endothelial NO synthesis. Our findings should contribute to a better understanding of the pathophysiological role of ADMA in arteriosclerosis.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2004

Sites of positive allosteric modulation by neurosteroids on ionotropic gamma-aminobutyric acid receptor subunits.

Neurosteroids are known as allosteric modulators of ionotropic gamma-aminobutyric acid (GABA) receptors. Here, we investigated sites of positive allosteric modulation by allotetrahydrodeoxycorticosterone (5alpha-THDOC) at GABA receptors using the technique of chimeragenesis and the Xenopus oocyte expression system. Our findings have demonstrated that the region from transmembrane segment (TM) 4 to the C-terminus of the GABA(A) receptor alpha1 subunit is crucial for the action of 5alpha-THDOC, but insufficient for the action of another neurosteroid allopregnanolone, suggesting that a specific region critical for neurosteroid action at GABA receptors exists in the domain between TM4 and the C-terminus of GABA receptor subunits.

Allosteric Regulation↗
PubMed2004

Endothelial nitric oxide synthase-independent effects of an ACE inhibitor on coronary flow response to bradykinin in aged mice.

ACE inhibitors are known to ameliorate cardiovascular complications in aging; however, their effects on the coronary circulation in relation to aging and eNOS dependence remain to be examined. Coronary flow responses to bradykinin with or without ACE inhibitors were examined in Langendorff-perfused hearts from young (16-20 weeks) and aged (16-20 months) control and eNOS mice. Western blot analysis was performed for cardiac eNOS, nNOS, and ACE. Baseline coronary flow was comparable between young and aged mice of both strains. Aging did not affect bradykinin-induced coronary flow in either strain. Interestingly, both acute and chronic treatment with an ACE inhibitor markedly augmented the flow response in aged control and eNOS mice. Aged eNOS mice were markedly hypertensive and had larger ventricular mass than control mice. The antihypertensive effect of temocapril was greater in aged eNOS mice, associated with reduction in the ventricular weight in both strains. Western blot analysis demonstrated an increased expression of eNOS in aged control mice, and ACE expression was increased in eNOS mice. These results indicate that coronary flow response to bradykinin is preserved in aged mice even in the absence of eNOS, and an ACE inhibitor augments this response by both eNOS-dependent and -independent mechanisms.

Aging↗
PubMed2004

Up-regulated neuronal nitric oxide synthase compensates coronary flow response to bradykinin in endothelial nitric oxide synthase-deficient mice.

It has been reported that endothelium-dependent relaxations are preserved in isolated coronary arteries of endothelial nitric oxide synthase-deficient (eNOS-/-) mice with a possible involvement of nNOS. However, it remains to be examined whether nNOS compensates coronary flow response in a beating heart of eNOS-/- mice and if so, whether and where nNOS is up-regulated. Coronary flow response to bradykinin was examined in Langendorff-perfused hearts from WT and eNOS-/- mice. Bradykinin-induced coronary flow was greater in eNOS-/- mice than in WT mice, and indomethacin had no inhibitory effect on it. Bradykinin receptor antagonist HOE-140 abolished the bradykinin response in both strains. Non-selective NOSs inhibitor L-NNA inhibited the bradykinin-induced coronary flow in both strains, whereas specific inhibitors of nNOS, SMTC, and 7-NI, significantly attenuated the coronary flow response only in eNOS-/- mice. A guanylate cyclase inhibitor ODQ also attenuated the bradykinin response in eNOS-/- mice. Immunohistochemistry revealed the presence of nNOS mainly in coronary vascular smooth muscle cells (VSMCs) in both strains and Western blot analysis demonstrated a marked increase in cardiac nNOS expression in eNOS-/- mice. These results indicate that nNOS compensates coronary flow response to bradykinin in eNOS-/- mice, for which up-regulation of nNOS in VSMCs may be involved.

Animals↗
PubMed2004

Hyperhomocysteinemia is associated with human coronary atherosclerosis through the reduction of the ratio of endothelium-bound to basal extracellular superoxide dismutase.

BACKGROUND: Homocysteine is involved in coronary atherosclerosis through oxidative stress, so the present study investigated the association between plasma concentrations of homocysteine and extracellular superoxide dismutase (EC-SOD) in coronary artery disease (CAD). METHODS AND RESULTS: The study group comprised 154 consecutive male patients with suspected CAD who had undergone angiography. Plasma concentrations of homocysteine and EC-SOD, which was determined before (basal) and after heparin therapy, were measured and the difference was designated as endothelium-bound EC-SOD. The EC-SOD ratio (endothelium-bound/basal EC-SOD) was also evaluated as an index of binding capacity. The plasma homocysteine concentration in the stenosis (+) group (n=97, 12.0+/-4.6 micromol/L) was significantly higher than that of the stenosis (-) group (n=57, 10.2+/-3.0 micromol/L, p=0.004). Plasma homocysteine correlated positively with the basal EC-SOD (r=0.377, p<0.001) and negatively with the EC-SOD ratio (r=-0.199, p=0.014). When the group was subdivided according to either homocysteine or the EC-SOD ratio, there were 2 groups with high homocysteine concentration and of these atherosclerosis was reduced in the group with a high EC-SOD ratio. CONCLUSIONS: In CAD patients, homocysteine is involved in the significant release of EC-SOD from the endothelium. Furthermore, the higher EC-SOD binding capacity, even at high concentrations of homocysteine, suggested that homocysteine-induced atherosclerosis was suppressed.

Biomarkers↗
PubMed2004

Neuronal nitric oxide synthase as a novel anti-atherogenic factor.

Nitric oxide (NO) has multiple important actions that contribute to the maintenance of vascular homeostasis. NO is synthesized by three different isoforms of NO synthase (NOS), all of which have been reported to be expressed in human atherosclerotic vascular lesions. Although the regulatory roles of endothelial NOS (eNOS) and inducible NOS (iNOS) on the development of atherosclerosis have been described, little is known about the role of neuronal NOS (nNOS). Recent studies have demonstrated that nNOS also exerts important vasculoprotective effects in vivo. In a carotid artery ligation model, nNOS-knockout mice exhibited accelerated neointimal formation and constrictive vascular remodeling caused by blood flow disruption. In a rat balloon injury model, the selective inhibition of nNOS activity potently enhanced vasoconstrictor responses to a variety of calcium-mobilizing stimuli, and exacerbated neointimal formation. Moreover, in apolipoprotein E-knockout mice, deficiency of nNOS induced progression of aortic vascular lesion formation. In these models, nNOS was up-regulated in vascular lesions, and was predominantly expressed in the neointima and medial smooth muscle cells. These results provide the first direct evidence that nNOS plays important roles in suppressing arteriosclerotic vascular lesion formation. Thus, nNOS could be regarded as a novel anti-atherogenic factor.

Animals↗
PubMed2004

[A comparison of two methods for continuous cardiac output measurement: PulseCO VS CCO].

BACKGROUND: PulseCO (PulseCO) (PulseCO Hemodynamic Monitor, LiDCO Co., London, England) is a low invasive apparatus to measure cardiac output continuously from arterial pulse waveform. CCO (774 HF 75, Edwards Lifescience Co., California, USA) is a continuous cardiac monitor commonly used clinically. The purpose of this study is to compare the accuracy of these two methods for cardiac output measurement with the thermodilution technique (TDCO) as control. METHODS: To compare the accuracy of PulseCO with that of CCO, six patients with pulmonary-artery catheter inserted were recruited. PulseCO and CCO were measured continuously, and these CO values were compared with TDCO measurements every hour. RESULTS: Correlation with TDCO was examined in PulseCO (r=0.82) and CCO (r=0.80). CONCLUSIONS: PulseCO was low invasive, and showed a significantly better correlation with TDCO, compared with CCO.

Calibration↗
PubMed2003

Upregulation of vascular extracellular superoxide dismutase in patients with acute coronary syndromes.

OBJECTIVE: We examined the vascular expression levels of extracellular superoxide dismutase (EC-SOD), a major antioxidant enzyme in the cardiovascular system, in patients with acute coronary syndromes. METHODS AND RESULTS: Twenty-one consecutive patients with acute myocardial infarction (AMI), 14 patients with unstable angina, 11 patients with stable angina, and 20 control subjects were studied. The levels of vascular EC-SOD expression were assessed by the difference in plasma EC-SOD concentrations before and after intravenous heparan injection. In the patients with AMI, vascular EC-SOD expression (ng/mL) was significantly higher on day 1 after the onset of AMI (148+/-10) as compared with the control subjects (116+/-6, P<0.05). The vascular EC-SOD expression returned to the normal range on day 7 (104+/-8), and that level persisted thereafter. The vascular EC-SOD expression was also significantly higher in the patients with unstable angina (160+/-13) than in those with stable angina (122+/-10) or in the controls (116+/-6) (P<0.05 each). Moreover, in the patients with AMI, higher levels of vascular EC-SOD expression on day 1 were significantly associated with smaller myocardial infarct size (P<0.05). CONCLUSIONS: This is the first clinical demonstration showing that vascular EC-SOD may be upregulated in acute coronary syndromes in humans in vivo. EC-SOD may play an important protective role against increased oxidative stress during acute ischemic coronary events.

Acute Disease↗
PubMed2003

Stimulation of catecholamine synthesis by orexin-A in bovine adrenal medullary cells through orexin receptor 1.

Orexin-A has recently been identified as a new hypothalamic peptide working as a mediator in the regulation of feeding behavior and sleep control. To determine the role of orexin-A in peripheral metabolic processes, we examined direct effects of orexin-A on catecholamine synthesis and secretion in cultured bovine adrenal medullary cells. Incubation of cells with orexin-A (100 pM) for 20 min caused a small but significant increase in 14C-catecholamine synthesis from [14C]tyrosine, but not from L-3,4-dihydroxyphenyl[3-14C]alanine. Orexin-A (100 pM) potentiated the stimulatory effects of acetylcholine (0.3 mM) on 14C-catecholamine synthesis. Orexin-A significantly increased tyrosine hydroxylase activity, which was evident at 1 pM and maximal at 100 pM. 4 beta-Phorbol-12 beta-myristate-13 alpha-acetate, an activator of protein kinase C, did not enhance the stimulatory effects of orexin-A on tyrosine hydroxylase activity, while H-7 and staurosporine, inhibitors of protein kinase C, nullified the effects of orexin-A. Orexin-A had little effect on catecholamine secretion from the cells. Orexin receptor 1 (OX(1)R) but not orexin receptor 2 (OX(2)R) mRNA was detected in bovine adrenal medullary cells by reverse transcriptase-polymerase chain reaction. These findings suggest that orexin-A activates tyrosine hydroxylase and then stimulates catecholamine synthesis, probably via activation of the OX(1)R-protein kinase C pathway in adrenal medullary cells.

Acetylcholine↗
PubMed2003

Inhibition of the norepinephrine transporter function in cultured bovine adrenal medullary cells by bisphenol A.

We report here the effects of an environmental estrogen, bisphenol A, on norepinephrine (NE) transporter function in cultured bovine adrenal medullary cells. The effects of bisphenol A were compared to those of 17beta-estradiol. Bisphenol A significantly inhibited [3H]NE uptake by the cells in a concentration-dependent manner (1-100 microM). Kinetic analysis revealed that bisphenol A, as well as 17beta-estradiol, noncompetitively inhibited [3H]NE uptake. Bisphenol A and 17beta-estradiol inhibited the specific binding of [3H]desipramine to plasma membranes isolated from bovine adrenal medulla. As shown by Scatchard analysis of [3H]desipramine binding, bisphenol A increased the dissociation constant (K(d)) and decreased the maximal binding (B(max)), indicating a mixed type of inhibition. 17beta-Estradiol increased the K(d) without altering the B(max), thereby indicating competitive inhibition. The present findings suggest that bisphenol A inhibits the function of the NE transporter by acting on a site different from that of 17beta-estradiol in the adrenal medulla and probably in the brain noradrenergic neurons.

Adrenal Medulla↗
PubMed2003

Vasospastic angina in a 16-year-old female.

A 16-year-old female with a family history of coronary artery disease was referred to hospital because of recurrent chest oppression unrelated to exertion. Although a selective coronary angiogram showed no atherosclerotic lesions, coronary spasm was provoked by acetylcholine in the left coronary artery, accompanied by chest pain and depression of blood pressure. This is the youngest healthy young female to be diagnosed with coronary vasospasm by provocation test. Because there are no risk factors, the vasospasm must be related to unknown hereditary factors.

Adolescent↗
PubMed2003

[Laparoscopic cholecystectomy under general anesthesia for a woman in the 28th week of gestation].

Anesthesia for laparoscopic cholecystectomy under hypobaric pneumoperitoneum was given to a pregnant woman in 28th week of gestation. Anesthesia was induced by administering thiopental(5 mg.kg-1) and vecuronium (0.1 mg.kg-1). The lungs were artificially ventilated with oxygen, nitrous oxide, and low concentrations of sevoflurane to maintain the end-expiratory CO2 pressure at 30 to 35 mmHg. Before inducing anesthesia, a thoracic epidural catheter was inserted, and 2% mepivacaine was administered through the catheter. During the operative period, the operating field was secured by the pneumoperitoneum pressure at 8 mmHg and Fowler's and left down position. Mother's blood gases and the fetal heart beat monitored with the abdominal supersonic wave stayed steady through the perioperative periods. The pneumoperitoneum time was 34 minutes and the operation time was 40 minutes without any troubles. But we should pay much attention to anesthesia and operation in any pregnant patient.

Adult↗
PubMed2002

Vasculoprotective roles of neuronal nitric oxide synthase.

Nitric oxide (NO) has multiple important actions that contribute to the maintenance of vascular homeostasis. NO is synthesized by three different isoforms of NO synthase (NOS), all of which have been reported to be expressed in human atherosclerotic vascular lesions. Although the regulatory roles of endothelial NOS (eNOS) and inducible NOS (iNOS) on the development of atherosclerosis have been described, little is known about the role of neuronal NOS (nNOS). Here, we show that nNOS also exerts important vasculoprotective effects in vivo. In a carotid artery ligation model, nNOS gene-deficient (nNOS-KO) mice exhibited accelerated neointimal formation and constrictive vascular remodeling caused by blood flow disruption. In a rat balloon injury model, the selective inhibition of nNOS activity potently enhanced vasoconstrictor responses to a variety of calcium-mobilizing stimuli, suppressed tissue cGMP concentrations, a marker of vascular NO production, and exacerbated neointimal formation. In both models, nNOS was absent before injury and was up-regulated only after the injury, and was predominantly expressed in the neointima and medial smooth muscle cells. These results provide the first direct evidence that nNOS plays important roles in suppressing arteriosclerotic vascular lesion formation in vivo.

Angioplasty, Balloon↗
PubMed2002

Long-term treatment with N(omega)-nitro-L-arginine methyl ester causes arteriosclerotic coronary lesions in endothelial nitric oxide synthase-deficient mice.

BACKGROUND: N(omega)-nitro-L-arginine methyl ester (l-NAME) is widely used to inhibit endothelial synthesis of NO in vivo. However, it is controversial whether the long-term vascular effects of l-NAME are mediated primarily by inhibition of endothelial NO synthesis. We addressed this point in mice that are deficient in the endothelial NO synthase gene (eNOS-KO mice). METHODS AND RESULTS: Wild-type and eNOS-KO mice received l-NAME in drinking water for 8 weeks. In wild-type mice, long-term treatment with l-NAME caused significant medial thickening and perivascular fibrosis in coronary microvessels but not in large coronary arteries. Importantly, in eNOS-KO mice, treatment with l-NAME also caused an extent of medial thickening and perivascular fibrosis in coronary microvessels that was comparable to that in wild-type mice and that was not prevented by supplementation of L-arginine. Vascular NO and cGMP levels were not significantly reduced by l-NAME treatment, and no expression of inducible or neuronal NO synthase was noted in microvessels of eNOS-KO mice, suggesting an involvement of NO-independent mechanisms. Treatment with l-NAME caused an upregulation of vascular ACE and an increase in cardiac lucigenin chemiluminescence that were comparable in both strains and that were abolished by simultaneous treatment with temocapril (ACE inhibitor) or CS866 (angiotensin II type 1 receptor antagonist) along with the suppression of vascular lesion formation. CONCLUSIONS: These results provide the first direct evidence that the long-term vascular effects of l-NAME are not mediated by simple inhibition of endothelial NO synthesis. Direct upregulation of local ACE and increased oxidative stress appear to be involved in the long-term vascular effects of l-NAME in vivo.

Acridines↗
PubMed2002

Up-regulation of noradrenaline transporter in response to prolonged exposure to ketamine.

We previously reported that the intravenous anaesthetic ketamine acutely inhibits the activity of the noradrenaline transporter (NAT) by acting on a site partly overlapping the desipramine binding site. Here we report the effects of a prolonged exposure to ketamine on the functional activity and number of NAT and its mRNA in cultured bovine adrenal medullary cells. Treatment of cells with ketamine (10-1000 microM) for 1-24 h resulted in a transient decrease and subsequent increase in [(3)H]noradrenaline (NA) uptake by the cells. Saturation analysis showed that ketamine (100 microM, 12 h) increased the V(max) value of [(3)H]NA uptake without any change in the K(m) value. Ketamine also increased the specific binding of [(3)H]nisoxetine to plasma membranes isolated from the cells. Scatchard analysis of [(3)H]nisoxetine binding revealed that ketamine increased the B(max) value without altering the K(d) value, suggesting an increase in the number of NAT in the plasma membrane. The stimulatory effect of ketamine on [(3)H]NA uptake was blocked by cycloheximide, an inhibitor of protein synthesis. Treatment of cells with ketamine for 12-24 h enhanced the expression of NAT mRNA. The present findings demonstrated that prolonged exposure to ketamine increases the functional activity of NAT and its mRNA. This may imply that ketamine negatively modulates sympathetic nervous activity through an up-regulation of NAT during long anaesthesia.

Adrenal Medulla↗