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1.
Science ; 375(6584): 1011-1016, 2022 03 04.
Article in English | MEDLINE | ID: mdl-35143255

ABSTRACT

The Hayabusa2 spacecraft investigated the C-type (carbonaceous) asteroid (162173) Ryugu. The mission performed two landing operations to collect samples of surface and subsurface material, the latter exposed by an artificial impact. We present images of the second touchdown site, finding that ejecta from the impact crater was present at the sample location. Surface pebbles at both landing sites show morphological variations ranging from rugged to smooth, similar to Ryugu's boulders, and shapes from quasi-spherical to flattened. The samples were returned to Earth on 6 December 2020. We describe the morphology of >5 grams of returned pebbles and sand. Their diverse color, shape, and structure are consistent with the observed materials of Ryugu; we conclude that they are a representative sample of the asteroid.

2.
J Phys Condens Matter ; 25(9): 095004, 2013 Mar 06.
Article in English | MEDLINE | ID: mdl-23334402

ABSTRACT

Epitaxial thin oxide layers were grown by simultaneous aluminum deposition and oxidation on a Co(0001) single crystal, and the metal-oxide interface between the substrate and the grown layer was studied using photoelectron spectroscopy. The oxide layers were composed of two kinds of chemically different layers. Angle-resolved measurements were used to determine the compositions of oxide sub-layers and to reveal their respective thicknesses. The topmost oxide layers were up to 0.23 nm thick, determined by analysis of O 1s and Co 2p(3/2) photoelectron spectra. The results of the analysis show that the interface layer is composed of a mixture of oxygen and cobalt atoms and its thickness is approximately 0.6 nm. The analysis of Co 2p(3/2), Al 2p(3/2) and O 1s core level binding energies confirmed the presence of CoO in the interface layer and Al(2)O(3) in the topmost oxide layer.

3.
Clin Exp Allergy ; 41(11): 1568-78, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21801248

ABSTRACT

BACKGROUND: There is synteny in the CC-type chemokine gene clusters between humans (CCL2/MCP-1, CCL7MCP-3, CCL11/eotaxin, CCL8/MCP-2, CCL13/MCP-4, and CCL1/I-309) and mice (CCL2, CCL7, CCL11, CCL12/MCP-5, CCL8, and CCL1). OBJECTIVE: As many putative Bcl6/STAT-binding sequences are observed in the clusters, we examined the roles of a transcriptional repressor Bcl6 and the regional histone modification in the expression of these chemokine genes in pulmonary epithelium. METHODS: We generated transgenic (Tg) mice carrying the Bcl6 or the dominant-negative (DN)-Bcl6 gene under the control of the surfactant protein C (SPC) promoter that induces the exogenous gene expression in the distal lung epithelium. For in vitro studies, A549, alveolar type II-like epithelial cell line transfected with the SPC-DN-Bcl6 gene were stimulated with IL-4+TNF-α, and Bcl6 or STAT6 binding to and histone modification of the cluster in the transfectants were analysed by chromatin immunoprecipitation assays. Tg mice sensitized with ovalbumin (OVA) were challenged with OVA inhalation. The amounts of mRNAs in each sample were analysed by quantitative RT-PCR. RESULTS: The amount of Bcl6 bound to the cluster decreased in A549 cells stimulated with IL-4 and TNF-α, whereas STAT6 binding increased in association with regional histone H3-K9/14 acetylation and H3-K4 methylation. The expression of all chemokine genes in the gene cluster was augmented in activated A549 cells transfected with the DN-Bcl6 gene. We also induced allergic airway inflammation in Tg mice. Expression of the chemokine genes and infiltrated cell numbers in the lungs of these Tg mice with allergic airway inflammation were inversely correlated with the amount of Bcl6 in the lungs. CONCLUSION AND CLINICAL RELEVANCE: Expression of the pulmonary epithelium-derived CC-type chemokine genes in the cluster is orchestrated by the conserved machinery related to Bcl6. Thus, Bcl6 in pulmonary epithelium may be a critical regulator for pathogenesis of various pulmonary inflammatory diseases.


Subject(s)
Chemokines, CC/genetics , DNA-Binding Proteins/metabolism , Epithelial Cells/metabolism , Lung/metabolism , Respiratory Hypersensitivity/genetics , Respiratory Hypersensitivity/immunology , Animals , Antigens/immunology , Binding Sites , Cell Line , Chemokines, CC/immunology , DNA-Binding Proteins/genetics , Epithelial Cells/immunology , Gene Expression , Gene Expression Regulation , Gene Order , Histones/metabolism , Humans , Inflammation/genetics , Inflammation/immunology , Lung/immunology , Lung/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Ovalbumin/immunology , Proto-Oncogene Proteins c-bcl-6
4.
Phys Rev Lett ; 104(6): 062701, 2010 Feb 12.
Article in English | MEDLINE | ID: mdl-20366816

ABSTRACT

Reaction cross sections (sigma(R)) for 19C, 20C and the drip-line nucleus 22C on a liquid hydrogen target have been measured at around 40A MeV by a transmission method. A large enhancement of sigma(R) for 22C compared to those for neighboring C isotopes was observed. Using a finite-range Glauber calculation under an optical-limit approximation the rms matter radius of 22C was deduced to be 5.4+/-0.9 fm. It does not follow the systematic behavior of radii in carbon isotopes with N < or = 14, suggesting a neutron halo. It was found by an analysis based on a few-body Glauber calculation that the two-valence neutrons in 22C preferentially occupy the 1s(1/2) orbital.

5.
J Phys Condens Matter ; 21(18): 185011, 2009 May 06.
Article in English | MEDLINE | ID: mdl-21825457

ABSTRACT

The reaction of oxygen at low pressure with the Sn/Pd(110) system has been examined by photoelectron spectroscopy using synchrotron radiation. The c(2 × 2) and (3 × 1) reconstructions of the Sn/Pd(110) surface at 0.5 and 0.7 monolayers (ML) Sn coverage and a 1.75 ML Sn overlayer on the Pd(110) surface after flashing to 470 K were studied. The Sn 4d core level is strongly affected by O(2) adsorption while the Pd 3d core level shows very little change other than a decrease in intensity. Starting with a 10 L dose of oxygen, prominent changes in the spectra were observed for all Sn/Pd(110) surface alloys. Analysis of the Sn 4d core levels indicates that oxidation proceeds with the formation of well-defined states of Sn, which were identified as a Pd-Sn-O interface layer, SnO and SnO(2) oxides. The valence band spectra confirm this assignment. The Sn(2+) and Sn(4+) component signals originate from the topmost surface layer, i.e. tin atoms in more highly oxidized states constitute the topmost surface layer on top of the Pd-Sn-O interface. The presence of a sub-surface PdSn intermetallic alloy facilitates the tin oxide formation; the Sn-O phase formation is accompanied by Pd-Sn bond dissociation.

6.
Am J Dermatopathol ; 30(5): 477-80, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18806493

ABSTRACT

Elastic fibers are essential extracellular matrix macromolecules comprising an elastin core surrounded by fibrillin-rich microfibrils. Fibulin-5, a microfibril, has been identified as one of the secreted extracellular matrix proteins that shows function as a scaffold for elastic fibers. However, the distribution of fibulin-5 in the skin is not clear. We report a case of a 43-year-old woman with erythema and subsequent wrinkling that met the clinical and histological criteria for mid-dermal elastolysis. We investigate the mechanism by which this disease occurs. The distribution of elastin, CD68, matrix metalloproteinase (MMP)-9, and fibulin-5 was examined immunohistochemically from both erythematous and wrinkled skin. There were numerous CD68 and MMP-9-producing histiocytes and giant cells in the erythematous lesions. Faint fibrillar staining of fibulin-5 was found in the deep dermis. In the wrinkled skin, there were few CD68 histiocytes or giant cells. Elastin immunoreactivity disappeared from the mid-dermis. Fibulin-5 colocalized in the lower dermis, shorter than in the erythema. Mid-dermal elastolysis may be initiated by MMP-9 produced by histiocytes and giant cells through its degradation of elastic fibers. In the lower dermis of the wrinkled skin, the fragmented expression of fibulin-5 was associated with the incomplete reproduction of the elastic fibers.


Subject(s)
Dermis/metabolism , Elastic Tissue/metabolism , Elasticity/physiology , Erythema/metabolism , Extracellular Matrix Proteins/metabolism , Adult , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Dermis/pathology , Dermis/physiopathology , Elastic Tissue/pathology , Elastin/metabolism , Erythema/pathology , Erythema/physiopathology , Female , Histiocytes/metabolism , Histiocytes/pathology , Humans , Matrix Metalloproteinase 9/metabolism
7.
Nucl Med Commun ; 23(2): 175-9, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11891473

ABSTRACT

We report the estimation of left ventricular systolic pressure (LVSP) by a left ventricular (LV) volume-time curve obtained from electrocardiogram (ECG) gated 99mTc-tetrofosmin single photon emission computed tomography (SPECT) using quantitative gated SPECT (QGS). LVSP was calculated based on the following parameters: LV volumes, velocity and acceleration of LV contraction, aortic valve area and density of blood. The first three parameters can be derived from ECG gated SPECT. In 16 patients, the LV volume-time curve was obtained from ECG gated SPECT by using QGS. LVSP was estimated by the above-mentioned theory. The values of estimated peak LVSP were compared with those measured from a pressure transducer. There was a correlation between the values of peak LVSP estimated by the LV volume-time curve and those measured by pressure transducer (r=0.69, P<0.01). Using QGS, LVSP and the systolic LV pressure-volume relationship could be estimated by the LV volume-time curve.


Subject(s)
Algorithms , Gated Blood-Pool Imaging/methods , Ventricular Function, Left/physiology , Ventricular Pressure/physiology , Angina Pectoris/diagnostic imaging , Female , Humans , Male , Middle Aged , Models, Cardiovascular , Myocardial Infarction/diagnostic imaging , Myocardial Ischemia/diagnostic imaging , Organophosphorus Compounds , Organotechnetium Compounds , Radiopharmaceuticals , Sensitivity and Specificity
9.
Biotechniques ; 31(5): 1174, 1176, 1178 passim, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11730024

ABSTRACT

As of today, no practical method for large-scale functional anti-thrombosis agent screening exists. Based on the phenomenon that platelet activation results in the release of ATP from dense granules, we report the development and optimization of a 96-well microplate luciferase assay to assess platelet activation via luminescence detection of the released ATP. In addition, the assessment of re-calcification-induced clotting of citrated platelet-rich plasma (PRP) is also possible. Collagen, thrombin, U46619, and ADP were shown to induce platelet activation in a concentration- and time-dependent manner The assay is applicable to PRP, washed platelets, and whole blood. Fundamentally, this is an ideal protocol for screening large numbers of anti-thrombotic drugs because of its sensitivity and the low amount of platelets required to detect simultaneous platelet activation.


Subject(s)
Luminescent Measurements , Platelet Activation , Adenosine Diphosphate/metabolism , Adenosine Diphosphate/pharmacology , Adenosine Triphosphate/metabolism , Humans , Platelet Aggregation
10.
Thromb Res ; 104(2): 127-35, 2001 Oct 15.
Article in English | MEDLINE | ID: mdl-11672756

ABSTRACT

It has been reported that platelets from some healthy donors did not respond to epinephrine (Epi). To identify the cause for the lack of response, we examined the alpha(2) adrenoceptor in the platelets and their signal transduction pathways. No differences in the genomic (-2076 to 1526 bp) and coding region of alpha(2A) adrenoceptor complementary DNA (cDNA) were found between the responders (R) and nonresponders (NR). No expression of alpha(2B) or alpha(2C) adrenoceptor was detected in platelets. When UK14,304 was used to induce platelet aggregation, similar effect to Epi was observed between R and NR, and any involvement of the alpha(1) and beta adrenoceptor was ruled out. Radioligand binding assay showed similar number of alpha(2) binding sites between the two groups (139+/-25/platelet vs. 145+/-37/platelets). However, platelets from NR showed a weaker response to adenosine diphosphate (ADP, 52.3+/-17.8% vs. 80.5+/-8.7% from R, P<.01). In the presence of P2Y(1) antagonist adenosine 3',5'-diphosphosulfate (A3P5PS), ADP failed to induce platelet aggregation in NR (7.8+/-4.7% vs. 64.7+/-11.2% in R, P<.01). Addition of SQ22,536 to inhibit adenylyl cyclase did not convert NR to R. These observations demonstrate that there is an impaired platelet responsiveness to ADP as well as to Epi in NR, due to a difference in downstream of the signal transduction pathway but independent of adenylyl cyclase inhibition.


Subject(s)
Adenosine Diphosphate/pharmacology , Adrenergic alpha-Agonists/pharmacology , Blood Platelets/drug effects , Epinephrine/pharmacology , Membrane Proteins , Base Sequence , Binding Sites , Cyclic AMP/metabolism , Dose-Response Relationship, Drug , Drug Resistance , Humans , Platelet Aggregation/drug effects , Purinergic P2 Receptor Antagonists , Receptors, Adrenergic, alpha-2/genetics , Receptors, Adrenergic, alpha-2/metabolism , Receptors, Adrenergic, alpha-2/physiology , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2Y12 , Signal Transduction
11.
J Pharmacol Exp Ther ; 299(2): 652-8, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11602678

ABSTRACT

OPC-28326 has been reported to selectively increase femoral blood flow in open-chest dogs and autoperfused canine femoral artery preparations. Preliminary data indicated that OPC-28326 has a high affinity at the alpha2-adrenoceptor. In the present study, we tested OPC-28326 in isoflurane anesthetized rats at a dose of 3 mg/kg of body weight, given intraduodenally. OPC-28326 significantly increased femoral blood flow, by 44.7 +/- 13.8%, 45 min after drug administration, whereas carotid blood flow increased by only 3.6 +/- 5.5% (n = 6). Chinese hamster ovary cell lines overexpressing rat alpha2D-, alpha2B-, or alpha2C-adrenoceptor were established. These cells also coexpress luciferase, driven by cAMP elevation. In radioligand binding assays using cell membrane preparations, OPC-28326 dose dependently competed with [3H]RX821002 binding, with calculated K(i) values of 3840 +/- 887, 633 +/- 46, and 13.7 +/- 1.9 nM on alpha2D-, alpha2B-, and alpha2C-adrenoceptor, respectively. A similar affinity and rank order of potency were also found for OPC-28326 on the alpha2-subtypes using epinephrine as agonist in luciferase assays. No agonistic effect of OPC-28326 was detected on any of the alpha2-adrenoceptors. Finally, in situ hybridization performed on skeletal muscle tissue sections collected from rat hind limb (musculus gastrocnemius) demonstrated a high level expression of alpha2C in the vascular tissues. Thus, the abundance of alpha2C in the skeletal muscle may account for the selective effect of OPC-28326 in increasing femoral blood flow.


Subject(s)
Adrenergic alpha-2 Receptor Antagonists , Adrenergic alpha-Antagonists/pharmacology , Aniline Compounds/pharmacology , Femoral Vein/drug effects , Piperidines/pharmacology , Vasodilator Agents/pharmacology , Alprostadil/pharmacology , Animals , CHO Cells , Cloning, Molecular , Cricetinae , Hindlimb/drug effects , In Situ Hybridization , In Vitro Techniques , Luciferases/metabolism , Male , Radioligand Assay , Rats , Rats, Sprague-Dawley , Regional Blood Flow/drug effects , Yohimbine/pharmacology
12.
J Cardiovasc Pharmacol ; 38(5): 775-83, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11602824

ABSTRACT

The authors have recently shown that cilostazol, a type 3 cyclic nucleotide phosphodiesterase (PDE3) inhibitor, has a much weaker positive inotropic effect than milrinone, a PDE3 inhibitor of similar potency. They have also shown that cilostazol inhibits adenosine uptake, whereas milrinone has no such effect. This study investigated the possible cardiac functional significance of cilostazol on adenosine uptake inhibition. In isolated rabbit hearts, 10 microM of cilostazol elevated adenosine concentration in interstitial dialysate (0.16 +/- 0.01 microM, or approximately 0.81 microM in the interstitial space when adjusted for recovery rate of microdialysis) and coronary effluent (0.69 +/- 0.03 microM ). The values are significantly higher than those for 10 microM of milrinone (0.11 +/- 0.1 microM in interstitial dialysate and 0.2 +/- 0.04 microM in coronary effluent). Although cilostazol increased contractility, heart rate, and coronary flow in isolated rabbit hearts, the effect on contractility and heart rate was significantly augmented in the presence of an adenosine A 1 receptor antagonist. Conversely, an adenosine A 1 receptor agonist or an adenosine uptake inhibitor attenuated the positive inotropic effect of milrinone. These results indicate that adenosine uptake inhibition by cilostazol increases interstitial and circulatory adenosine concentration, and antagonizes PDE3 inhibition-induced contractility and heart rate increases through an adenosine A 1 receptor-mediated mechanism.


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Adenosine/metabolism , Heart/drug effects , Phosphodiesterase Inhibitors/pharmacology , Tetrazoles/pharmacology , Animals , Cilostazol , Contraindications , Cyclic Nucleotide Phosphodiesterases, Type 3 , Heart/physiology , Hemodynamics/drug effects , In Vitro Techniques , Male , Milrinone/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Rabbits , Vasodilator Agents/pharmacology
13.
Cardiovasc Drug Rev ; 19(4): 369-86, 2001.
Article in English | MEDLINE | ID: mdl-11830753

ABSTRACT

Cilostazol (Pletal), a quinolinone derivative, has been approved in the U.S. for the treatment of symptoms of intermittent claudication (IC) since 1999 and for related indications since 1988 in Japan and other Asian countries. The vasodilatory and antiplatelet actions of cilostazol are due mainly to the inhibition of phosphodiesterase 3 (PDE3) and subsequent elevation of intracellular cAMP levels. Recent preclinical studies have demonstrated that cilostazol also possesses the ability to inhibit adenosine uptake, a property that may distinguish it from other PDE3 inhibitors, such as milrinone. Elevation of interstitial and circulating adenosine levels by cilostazol has been found to potentiate the cAMP-elevating effect of PDE3 inhibition in platelets and smooth muscle, thereby augmenting antiplatelet and vasodilatory effects of the drug. In contrast, elevation of interstitial adenosine by cilostazol in the heart has been shown to reduce increases in cAMP caused by the PDE3-inhibitory action of cilostazol, thus attenuating the cardiotonic effects. Cilostazol has also been reported to inhibit smooth muscle cell proliferation in vitro and has been demonstrated in a clinical study to favorably alter plasma lipids: to decrease triglyceride and to increase HDL-cholesterol levels. One, or a combination of several of these effects may contribute to the clinical benefits and safety of this drug in IC and other disease conditions secondary to atherosclerosis. In eight double-blind randomized placebo-controlled trials, cilostazol significantly increased maximal walking distance, or absolute claudication distance on a treadmill. In addition, cilostazol improved quality of life indices as assessed by patient questionnaire. One large randomized, double-blinded, placebo-controlled, multicenter competitor trial demonstrated the superiority of cilostazol over pentoxifylline, the only other drug approved for IC. Cilostazol has been generally well-tolerated, with the most common adverse events being headache, diarrhea, abnormal stools and dizziness. Studies involving off-label use of cilostazol for prevention of coronary thrombosis/restenosis and stroke recurrence have also recently been reported.


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Adenosine/antagonists & inhibitors , Phosphodiesterase Inhibitors/pharmacology , Tetrazoles/pharmacology , Adenosine/metabolism , Angioplasty, Balloon, Coronary/adverse effects , Animals , Arterial Occlusive Diseases/drug therapy , Cell Division/drug effects , Cilostazol , Coronary Restenosis/prevention & control , Coronary Thrombosis/prevention & control , Cyclic AMP/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 3 , Fibrinolytic Agents/pharmacology , Humans , Hypolipidemic Agents/pharmacology , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/drug effects , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/therapeutic use , Platelet Aggregation Inhibitors/pharmacology , Randomized Controlled Trials as Topic , Stroke/prevention & control , Tetrazoles/chemistry , Tetrazoles/therapeutic use , Vasodilator Agents/pharmacology
14.
J Cardiovasc Pharmacol ; 36(3): 351-60, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10975593

ABSTRACT

Cilostazol (Pletal), a quinolinone derivative with a cyclic nucleotide phosphodiesterase type 3 (PDE3) inhibitory activity, was recently approved by the Food and Drug Administration for treatment of symptoms of intermittent claudication (IC). However, the underlying mechanisms of action are not entirely clear. In this study, we showed that cilostazol inhibited adenosine uptake into cardiac ventricular myocytes, coronary artery smooth muscle, and endothelial cells with a median effective concentration (EC50) approximately 10 microM. In vivo, cilostazol increased cardiac interstitial adenosine levels after a 2-min ischemia in rabbit hearts (329 +/- 92% increase vs. 102 +/- 29% ischemia alone). The combination of cilostazol and 2-min ischemia reduced infarction from subsequent 30-min regional ischemia and 3 h of reperfusion (infarct size was 18 +/- 4% vs. 53 +/- 3% in the hearts with 2-min ischemia alone or 48 +/- 2% in the hearts treated with cilostazol alone). In contrast, milrinone had no effect on either adenosine uptake or interstitial adenosine levels. These data show that cilostazol, unlike milrinone, inhibits adenosine uptake, and thus potentiates adenosine accumulation from a 2-min ischemia. Future studies are needed to investigate the role of adenosine in the treatment of IC by cilostazol.


Subject(s)
Adenosine/metabolism , Intermittent Claudication/drug therapy , Myocardial Ischemia/metabolism , Phosphodiesterase Inhibitors/pharmacology , Tetrazoles/pharmacology , Animals , Blood Pressure/drug effects , Cilostazol , Dose-Response Relationship, Drug , Heart Rate/drug effects , Humans , Male , Milrinone/pharmacology , Pentoxifylline/pharmacology , Rabbits , Tetrazoles/blood , Thioinosine/analogs & derivatives , Thioinosine/metabolism
15.
Acta Neurol Scand ; 101(3): 212-5, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10705946

ABSTRACT

A Guillain-Barré syndrome patient showed giant negative T waves on electrocardiography at the height of the disease, with large left ventricular hypokinesis on echocardiography and extensive defects on 123I-meta-iodobenzylguanidine myocardial scintigraphy. Gamma-globulin improved the neurological symptoms, and the above abnormalities resolved. We speculate that cardiac sympathetic nerve endings were transiently damaged, with consequent myocardial injury, due to norepinephrine toxicity.


Subject(s)
Guillain-Barre Syndrome/complications , Ventricular Dysfunction, Left/diagnosis , Ventricular Dysfunction, Left/etiology , 3-Iodobenzylguanidine/analogs & derivatives , Aged , Echocardiography/methods , Female , Guillain-Barre Syndrome/physiopathology , Heart/diagnostic imaging , Humans , Median Nerve/physiopathology , Neural Conduction/physiology , Peroneal Nerve/physiopathology , Severity of Illness Index , Sympatholytics , Systole/physiology , Tibial Nerve/physiopathology , Tomography, Emission-Computed, Single-Photon , Ventricular Dysfunction, Left/physiopathology
16.
Free Radic Res ; 33(6): 771-84, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11237099

ABSTRACT

The formation of peroxynitrite and nitrotyrosine was examined in a variety of in vitro and in vivo animal models and its relation to cell or tissue damage was examined. polymorphonuclear leukocyte (PMN)-induced injury to cardiac myocytes endothelial cells, activated PMN produced peroxynitrite. Peroxynitrite appears to be responsible for the injury but it was not a major mediator of endothelial cell injury. In the experiment of ischemia-reperfusion injury of the rat brain nitrotyrosine was formed in the peri-infarct and core-of infarct regions. The degradation curve of nitrotyrosine revealed that its t(1/2) was about 2.2 hours. In the radiation-induced lung injury of rats, nitrotyrosine was also formed but it was not the sole mechanism for the injury. Levels of nitrotyrosine correlated with the severity of myocardial dysfunction in the canine model of cytokine-induced cardiac injury. Inhibition of NO generation abolished the formation of peroxynitrite and nitrotyrosine in all experiments. In conclusion; although nitrotyrosine is formed in a variety of pathological conditions where the generation of NO is increased, its presence does not always correlate with the severity of injury.


Subject(s)
Disease , Tyrosine/analogs & derivatives , Tyrosine/metabolism , Animals , Brain Ischemia/metabolism , Cell Survival , Cells, Cultured , Coculture Techniques , Dogs , Endothelium, Vascular/metabolism , Lung Diseases/etiology , Lung Diseases/metabolism , Male , Myocardium/metabolism , Neutrophils/physiology , Radiation Injuries , Rats , Reperfusion Injury/metabolism
18.
J Cardiovasc Pharmacol ; 34(4): 497-504, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10511123

ABSTRACT

Cilostazol is a potent cyclic nucleotide phosphodiesterase (PDE) type 3 (PDE3) inhibitor that was recently approved by the Food and Drug Administration (FDA) for the treatment of intermittent claudication. Its efficacy is presumed to be due to its vasodilatory and platelet activation inhibitory activities. Compared with those treated with placebo, patients treated with cilostazol showed a minimal increase in cardiac adverse events. Because of its PDE3 inhibitory activity, however, the possibility that cilostazol exerts positive cardiac inotropic effects is a safety concern. Therefore we compared the effects of cilostazol with those of milrinone, a selective PDE3 inhibitor, on intracellular cyclic adenosine monophosphate (cAMP) levels in platelets, cardiac ventricular myocytes, and coronary smooth muscle cells. We also compared the corresponding functional changes in these cells. Cilostazol and milrinone both caused a concentration-dependent increase in the cAMP level in rabbit and human platelets with similar potency. Furthermore, cilostazol and milrinone were equally effective in inhibiting human platelet aggregation with a median inhibitory concentration (IC50) of 0.9 and 2 microM, respectively. In rabbit ventricular myocytes, however, cilostazol elevated cAMP levels to a significantly lesser extent (p < 0.05 vs. milrinone). By using isolated rabbit hearts with a Langendorff preparation, we showed that milrinone is a very potent cardiotonic agent; it concentration-dependently increased left ventricular developed pressure (LVDP) and contractility. Cilostazol was less effective in increasing LVDP and contractility (p < 0.05 vs. milrinone), which is consistent with the cardiac cAMP levels. The cardiac effect of OPC-13015, a metabolite of cilostazol with about sevenfold higher PDE3 inhibition, was similar to cilostazol. Whereas milrinone concentration-dependently increased cAMP in rabbit coronary smooth muscle cells, cilostazol did not have such an effect. However, both compounds increased coronary flow equally in rabbit hearts. Our results show that although cilostazol and milrinone both inhibit PDE3, cilostazol preferentially acts on vascular elements (platelets and flow). This unique profile of cilostazol is consistent with its beneficial and safe clinical outcomes in patients with intermittent claudication.


Subject(s)
Blood Platelets/drug effects , Cyclic AMP/metabolism , Milrinone/pharmacology , Myocardial Contraction/drug effects , Platelet Aggregation Inhibitors/pharmacology , Tetrazoles/pharmacology , Animals , Cilostazol , Collagen/pharmacology , Coronary Vessels/drug effects , Dose-Response Relationship, Drug , Heart Ventricles/drug effects , Humans , In Vitro Techniques , Male , Muscle, Smooth, Vascular/drug effects , Perfusion , Platelet Aggregation Inhibitors/metabolism , Rabbits , Tetrazoles/metabolism , Vasodilator Agents/pharmacology
19.
Angiology ; 50(8): 639-48, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10451231

ABSTRACT

Iodine 123 beta-methyl iodophenyl pentadecanoic acid (123I-BMIPP), a beta-methyl-branched fatty acid analogue, has been proven by experimental studies to reveal abnormalities in fatty-acid-related metabolism. This study was undertaken to validate the accuracy and limitations of 123I-BMIPP imaging at rest in detecting myocardial metabolic abnormalities and predicting coronary lesions in unstable angina (UA). One hundred UA patients without prior myocardial infarction were studied. 123I-BMIPP and thallium 201 chloride (201TlCl) imaging with single photon emission computed tomography (SPECT) and coronary and left ventricular cineangiography (LVC) were performed 1 week after the last episode of angina. There was reduced uptake of 123I-BMIPP imaging in 70 patients, reduced uptake of 201TlCl in 41, and abnormal LVC contraction in 49 patients. There were significant increases in severity scores of 123I-BMIPP imaging along with increases in the number of stenosed coronary arteries and the severity of stenosis in individual coronary arteries. There was a significant reduction in 123I-BMIPP severity scores 1 month after percutaneous transluminal coronary angioplasty (p < 0.01) and a significant correlation between the severity scores of 123I-BMIPP and LVC (r=0. 579, p<0.001). Overall rates of sensitivity and specificity in detecting significant coronary stenosis by 123I-BMIPP imaging were 74% and 86%, respectively, whereas rates of sensitivity and specificity in detecting significant coronary stenosis by 201TlCl were 31% and 91%, respectively. 123I-BMIPP sensitivity increases to 86% if only advanced coronary stenosis of >90% is included. In conclusion, 123I-BMIPP myocardial imaging is an effective method of predicting coronary artery lesions of UA patients without provocative test.


Subject(s)
Angina, Unstable/diagnostic imaging , Coronary Vessels/diagnostic imaging , Fatty Acids , Iodine Radioisotopes , Iodobenzenes , Rest , Tomography, Emission-Computed, Single-Photon , Adult , Aged , Aged, 80 and over , Angina, Unstable/metabolism , Cineangiography , Coronary Angiography , Coronary Vessels/metabolism , Female , Follow-Up Studies , Humans , Male , Middle Aged , Predictive Value of Tests
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