检索结果-内蒙古大学图书馆

4-(3-chloro-4-methoxybenzyl) aminophthalazines: Synthesis and inhibitory activity toward phosphodiesterase 5

JOURNAL OF MEDICINAL CHEMISTRY 2000年第13期43卷 2523-2529页

作者： Watanabe, N Adachi, H Takase, Y Ozaki, H Matsukura, M Miyazaki, K Ishibashi, K Ishihara, H Kodama, K Nishino, M Kakiki, M Kabasawa, Y Eisai & Co Ltd Tsukuba Res Labs Tsukuba Ibaraki 3002635 Japan

We synthesized various 4-(3-chloro-4-methoxybenzyl)aminophthalazines substituted at the 1- and 6-positions and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) and their vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2 alpha (10(-5) M). The preferred substituents at the 1-position of the phthalazine were 4-hydroxypiperidino, 4-hydroxymethylpiperidino, 4-(2-hydroxyethyl)piperidino, and 4-oxopiperidino. Among these compounds, [4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino]-6-phthalazinecarbonitrile monohydrochloride (13) exhibited potent PDE5 inhibitory activity (IC50 = 0.56 nM) with > 1700-fold high selectivity over other PDE isozymes (PDE1-4). Compound 13 exhibited the most potent vasorelaxant action (EC50 = 13 nM) in this series of compounds. Compound 13 reduced mean pulmonary arterial pressure by 29.9 +/- 3.1% when administered intravenously at 30 mu g/kg to the chronically hypoxic rats and had an apparent oral bioavailability of about 19.5% in rats and was selected for further biological evaluation.

关键词： 3' 5'-环GMP磷酸二酯酶类抗高血压药/化学合成抗高血压药/化学抗高血压药/药代动力学抗高血压药/药理学生物利用度血压/药物作用冠状血管/药物作用冠状血管/生理学环核苷酸磷酸二酯酶类 5型地诺前列素/药理学高血压肺性/药物疗法高血压肺性/病理生理学肌松弛/药物作用肌平滑血管/药物作用肌平滑血管/生理学磷酸二酯酶抑制剂/化学合成磷酸二酯酶抑制剂/化学磷酸二酯酶抑制剂/药代动力学磷酸二酯酶抑制剂/药理学磷酸二酯水解酶类/代谢酞嗪类/化学合成酞嗪类/化学酞嗪类/药代动力学酞嗪类/药理学哌啶类/化学合成哌啶类/化学哌啶类/药代动力学哌啶类/药理学喹唑啉类/药理学大鼠 Sprague-Dawley 构效关系猪血管舒张药/化学合成血管舒张药/化学血管舒张药/药代动力学血管舒张药/药理学动物男(雄)性大鼠

来源：评论

学校读者我要写书评

暂无评论

Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction

引用

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第10期97卷 5456-5461页

作者： Kurrelmeyer, KM Michael, LH Baumgarten, G Taffet, GE Peschon, JJ Sivasubramanian, N Entman, ML Mann, DL Vet Affairs Med Ctr Winters Ctr Heart Failure Res Cardiol Sect Houston TX 77030 USA Baylor Coll Med DeBakey Heart Ctr Houston TX 77030 USA Immunex Corp Seattle WA 98101 USA

Previous studies have shown that proinflammatory cytokines, such as tumor necrosis factor (TNF), are expressed after acute hemodynamic: overloading and myocardial ischemia/infarction. To define the role of TNF in the setting of ischemia/infarction, we performed a series of acute coronary artery occlusions in mice lacking one or both TNF receptors. Left ventricular infarct size was assessed at 24 h after acute coronary occlusion by triphenyltetrazolium chloride (TTC) staining in wild-type (both TNF receptors present) and mice lacking either the type 1 (TNFR1), type 2 (TNFR2), or both TNF receptors (TNFR1/TNFR2). Left ventricular infarct size as assessed by TTC staining was significantly greater (P < 0.005) in the TNFR1/TNFR2-deficient mice (77.2% +/- 15.3%)when compared with either wild-type mice (46.8% +/- 19.4%) or TNFR1-deficient (47.9% +/- 10.6%) or TNFR2-deficient (41.6% +/- 16.5%) mice. Examination of the extent of necrosis in wild-type and TNFR1/TNFR2-deficient mice by anti-myosin Ab staining demonstrated no significant difference between groups;however, the peak frequency and extent of apoptosis were accelerated in the TNFR1/TNFR2-deficient mice when compared with the wild-type mice. The increase in apoptosis in the TNFR1/TNFR2-deficient mice did not appear to be secondary to a selective up-regulation of the Fas ligand/receptor system in these mice. These data suggest that TNF signaling gives rise to one or more cytoprotective signals that prevent and/or delay the development of cardiac myocyte apoptosis after acute ischemic injury.

关键词：急性病抗原 CD/遗传学抗原 CD/生理学细胞凋亡冠状血管/生理学冠状血管/病理生理学疾病模型动物小鼠近交C57BL 小鼠近交系小鼠基因敲除心肌梗死/遗传学心肌梗死/病理生理学心肌梗死/预防和控制心肌缺血/病理学心肌缺血/病理生理学心肌/病理学受体肿瘤坏死因子/遗传学受体肿瘤坏死因子/生理学受体肿瘤坏死因子 Ⅰ型肿瘤坏死因子α/生理学动物小鼠

来源：评论

学校读者我要写书评

暂无评论

Is endothelial function or dysfunction a systemic affair?

引用

EUROPEAN HEART JOURNAL 2000年第1期21卷 10-11页

作者： Conti, CR Univ Florida Gainesville FL 32611 USA

来源：评论

学校读者我要写书评

暂无评论

Preserved coronary flow reserve in viable myocardium: Further evidence for the microvascular hypothesis

引用

AMERICAN HEART JOURNAL 2001年第3期141卷 329-330页

作者： Angeja, BG Gibson, CM Univ Calif San Francisco Dept Med Div Cardiovasc San Francisco CA 94143 USA

The open-artery hypothesis has been well established in the treatment of acute myocardial infarction (AMI). Relief of obstruction to blood flow in the infarct-related epicardial artery has been shown to decrease mortality and other adverse outcomes after AMI.1,2 However, evidence is accumulating that events downstream to the epicardial obstruction, specifically within the small vessels supplying blood to the myocardium, are critical to infarct pathophysiology as well. Suspicion that an open artery is not sufficient to preserve myocardium started with the observation that, even in the setting of an open artery, sluggish flow in the infarct-related artery (Thrombolyis in Myocardial Infarction [TIMI] grade 2 flow) was associated with higher mortality than normal flow was (TIMI grade 3).3

关键词：冠状血管/生理学微循环心肌梗死/病理学心肌梗死/病理生理学心肌/病理学局部血流人类

来源：评论

学校读者我要写书评

暂无评论

Characterization of contractile P2 receptors in human coronary arteries by use of the stable pyrimidines uridine 5′-O-thiodiphosphate and uridine 5′-O-3-thiotriphosphate

引用

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第3期293卷 755-760页

作者： Malmsjö, M Hou, MY Harden, TK Pendergast, W Pantev, E Edvinsson, L Erlinge, D Univ Lund Hosp Dept Med Div Expt Vasc Res S-22185 Lund Sweden Univ N Carolina Sch Med Dept Pharmacol Chapel Hill NC USA Inspire Pharmaceut Inc Durham NC USA

The present study was designed to evaluate the relative contribution of the different contractile P2 receptors in endothelium-denuded human coronary arteries by use of extracellular nucleotides, including the stable pyrimidines uridine 5'-O-3-thiotriphosphate (UTP gamma S) and uridine 5'-O-thiodiphosphate (UDP beta S). The isometric tension of isolated vessel segments was recorded in vitro, and P2 receptor mRNA expression was examined by reverse transcription-polymerase chain reaction. alpha beta-Methylene-adenosine triphosphate (alpha beta-MeATP) elicited contractions at a low concentration (pEC(50) = 5.2), indicating the presence of contractile P2X receptors. The P2Y responses were analyzed after P2X receptor desensitization with 10 mu M alpha beta-MeATP. The stable nucleotides ATP gamma S and adenosine 5'-O-3-thiotriphosphate (ATP gamma S), which are agonists of P2Y(2) or P2Y(4) receptors, were approximately 2 log units more potent than the endogenous UTP and ATP (pEC(50) = 4.6 and 3.8 for UTP gamma S and ATP gamma S). The efficacy of these responses were approximately double that of the P2X agonist alpha beta-MeATP (E (max) = 125% for UTP gamma S, 126% for ATP gamma S and 68% for alpha beta-MeATP), suggesting a primary role for contractile P2Y(2/4) receptors. The P2Y(2) receptor agonist diadenosine tetraphosphate also stimulated contraction, whereas the selective P2Y(1) agonist adenosine 5'-O-thiodiphosphate and the selective P2Y(6) agonist UDP beta S had no effect. Reverse transcription-polymerase chain reaction analysis of mRNA from endothelium-denuded human coronary arteries demonstrated strong bands for P2Y(2) and P2X(1), although bands for P2Y(1), P2Y(4), and P2Y(6) receptor mRNA could also be detected. In conclusion, the stable pyrimidines UDP beta S and UTP gamma S are important tools for P2 receptor subtype characterization in intact tissues with ectonucleotidase activity. Extracellular nucleotides elicit contraction of human coronary arteries primarily

关键词：腺苷三磷酸/类似物和衍生物腺苷三磷酸/药理学冠状血管/药物作用冠状血管/生理学剂量效应关系药物聚合酶链反应 RNA 信使/分析受体嘌呤能P2/药物作用受体嘌呤能P2/遗传学受体嘌呤能P2/生理学硫代核苷酸类/药理学尿苷二磷酸/药理学尿苷三磷酸/类似物和衍生物尿苷三磷酸/药理学血管收缩/药物作用青少年成年人人类中年人

来源：评论

学校读者我要写书评

暂无评论

Enhanced endothelin_A receptor-mediated calcium mobilization and contraction in organ cultured porcine coronary arteries

引用

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期295卷 484-491页

作者： Hill, BJF Katwa, LC Wamhoff, BR Sturek, M Univ Missouri Sch Med Dept Physiol Columbia MO 65212 USA Univ Missouri Dalton Cardiovasc Res Ctr Vasc Biol Lab Columbia MO 65212 USA E Carolina Univ Sch Med Dept Physiol Greenville NC USA

Arterial injury models for coronary artery disease have demonstrated an enhanced expression and function of either the endothelin(A) or endothelin(B) (ETA or ETB) receptor subtype. We hypothesized that organ culture would enhance the physiological function of ET receptors in the porcine right coronary artery. Arteries were either cold stored (4 degreesC) or organ cultured (37 degreesC) for 4 days. After 4 days, the artery was either 1) sectioned into rings to measure the ET-1-induced isometric tension response (3 x 10(-10)-3 x 10(-7) M), or 2) enzymatically dispersed and the isolated smooth muscle cells imaged using fura-2 to measure the myoplasmic calcium (Ca-m) response to 3 x 10(-8) M ET-1 (similar to EC50). Isometric tension and Ca-m to ET-1 were measured in the absence and presence of bosentan (nonselective ETA or ETB receptor antagonist), BQ788 (ETB-selective antagonist), and BQ123 (ETA-selective antagonist). Compared with cold storage, organ culture induced a 2-fold increase in tension development (3 x 10(-7) M ET-1) and Ca-m (3 x 10(-8) M ET-1), which was inhibited with bosentan, thus confirming the enhanced responses to ET-1 were due to ET receptor activation. BQ123 also inhibited the enhanced contraction and Ca-m responses to ET-1. In contrast, BQ788 failed to inhibit tension development and Ca-m responses to ET-1 in organ culture and cold storage. Sarafotoxin 6C (ETB agonist) failed to elicit an increased Ca-m response in organ culture compared with cold storage. Our results indicate the increased tension development and Ca-m responses to ET-1 in organ culture are attributable to ETA receptors, and not ETB receptors.

关键词：抗高血压药/药理学钙/代谢冠状血管/药物作用冠状血管/生理学低温保存内皮缩血管肽1/药理学等长收缩/药物作用等长收缩/生理学动力学肌平滑血管/细胞学肌平滑血管/药物作用肌平滑血管/生理学寡肽类/药理学器官培养技术肽类环/药理学哌啶类/药理学受体内皮素A 受体内皮素B 受体内皮缩血管肽/激动剂受体内皮缩血管肽/拮抗剂和抑制剂受体内皮缩血管肽/生理学磺胺类/药理学猪血管收缩药/药理学蝰蛇毒液类/药理学动物

来源：评论

学校读者我要写书评

暂无评论

Power Doppler harmonic imaging: A feasibility study of a new technique for the assessment of myocardial perfusion

引用

AMERICAN HEART JOURNAL 2000年第2期139卷 245-251页

作者： Senior, R Kaul, S Soman, P Lahiri, A Northwick Pk Hosp Dept Cardiovasc Med Harrow HA1 3UJ Middx England Inst Med Res Harrow Middx England Univ Virginia Sch Med Charlottesville VA 22903 USA

Background The aim of the study was to assess the feasibility of a! new technique, power Doppler harmonic imaging (PDHI)I for assessing myocardial perfusion through a venous injection of microbubbles, with the use of a new ultrasound contrast agent. Methods and Results Fifteen patients with known coronary artery disease and a resting perfusion abnormality on Tc-99m sestamibi single-photon emission computed tomography (SPECT) underwent PDHI at rest during intravenous injections: of 2 to 3 mi of Sonovue (Bracco SpA, Milan, Italy), a new second-generation ultrasound contrast agent. Myocardial perfusion was determined to be present or absent by use of a 5-segment model by 2 blinded observers for both PDHI and SPECT Of a total of 75 possible myocardial segments, 7 (9%) were not analyzed because of obvious artifacts on PDHI. SPECT:showed perfusion defects in 40 of the remaining 68 segments, whereas PDHI showed 39 defects. There was high concordance between the 2 imaging modalities for the presence (93%) as well as the location (96% for the anteroseptal region, 93% for the inferoposterior region, and 87% for the apical region) of the defects. Conclusions These preliminary results suggest that PDHI is a feasible technique for the detection of resting myocardial perfusion defects in patients with coronary artery disease after a venous injection of a new second-generation ultrasound contrast agent.

关键词：造影剂冠状动脉循环/生理学冠心病/放射性核素显像冠心病/超声检查冠状血管/生理学冠状血管/超声检查可行性研究微球体体层摄影术发射型计算机单光子超声检查多普勒/方法成年人老年人人类男(雄)性中年人

来源：评论

学校读者我要写书评

暂无评论

Angiotensin II (AT₁) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy

引用

AMERICAN JOURNAL OF PATHOLOGY 2000年第1期157卷 111-122页

作者： Müller, DN Mervaala, EMA Dechend, R Fiebeler, A Park, JK Schmidt, F Theuer, J Breu, V Mackman, N Luther, T Schneider, W Gulba, D Ganten, D Haller, H Luft, FC Humboldt Univ Fac Med Charite Franz Volhard Clin D-13125 Berlin Germany Univ Helsinki Inst Biomed Helsinki Finland Max Delbruck Ctr Mol Med Berlin Germany Hannover Med Sch D-3000 Hannover Germany F Hoffmann La Roche Basel Switzerland Tech Univ Dresden Inst Pathol D-8027 Dresden Germany Scripps Res Inst Dept Immunol La Jolla CA 92037 USA

Tissue factor (TF), a main initiator of clotting, is upregulated in vasculopathy, We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT, receptor blockade inhibits TF expression in a model of ANG II-induced cardiac vasculopathy. Furthermore, we explored the mechanisms by examining transcription factor activation and analyzing the TF promoter. Untreated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) feature hypertension and severe left ventricular hypertrophy with focal areas of necrosis, and die at age 7 weeks. Plasma and cardiac ANG IT was three- to fivefold increased compared to Sprague-Dawley rats. Chronic treatment with valsartan normalized blood pressure and coronary resistance completely, and ameliorated cardiac hypertrophpy (p < 0.001). Valsartan prevented monocyte/macrophage infiltration, nuclear factor-KB (NF-kappa B) and activator protein-1 CAP-I) activation, and c-fos expression in dTGR hearts. NF-kappa B subunit p65 and TF expression was Increased in the endothelium and media of cardiac vessels and markedly reduced by valsartan treatment. To analyze the mechanism of TF transcription, we then transfected human coronary artery smooth muscle cells and Chinese hamster ovary cells overexpressing the AT, receptor with plasmids containing the human TF promoter and the luciferase reporter gene. ANG II induced the full-length TF promoter in both transfected cell Lines. TF transcription was abolished by AT, receptor blockade. Deletion of both AP-1 and NF-kappa B sites reduced ANG II-induced TF gene transcription completely, whereas the deletion of AP-1 sites reduced transcription. Thus, the present study clearly shows atl aberrant TF expression in the endothelium and media in rats with ANG II-induced vasculopathy. The beneficial effects of BT, receptor blockade in this model are mediated via the inhibition of NF-kappa B and AP-1 activation, thereby preventing TF expression, cardiac vasculopathy, and microin

关键词：血管紧张素Ⅱ/药理学动物基因修饰抗高血压药/药理学血液凝固因子/代谢血压/药物作用 CHO细胞细胞系冠心病/化学诱导冠心病/代谢冠心病/死亡率冠状血管/药物作用冠状血管/生理学仓鼠亚科细胞外基质蛋白质类/药物作用细胞外基质蛋白质类/代谢心室/药物作用心室/代谢炎症/病理生理学整合素α4β1 整合素类/药物作用整合素类/代谢 NF-κB/代谢原癌基因蛋白质c-fos/遗传学 RNA 信使/遗传学 RNA 信使/代谢大鼠 Sprague-Dawley 受体血管紧张素 1型受体血管紧张素 2型受体淋巴细胞归巢/药物作用受体淋巴细胞归巢/代谢四唑类/药理学凝血致活酶/药物作用凝血致活酶/遗传学凝血致活酶/代谢转录因子AP-1/代谢缬氨酸/类似物和衍生物缬氨酸/药理学血管阻力/药物作用动物人类大鼠

来源：评论

学校读者我要写书评

暂无评论

INVESTIGATION OF LOCAL BLOOD-FLOW BY NON-RADIOACTIVE MICROSPHERE MAPPING IN CLEARED TISSUE SLIDES

引用

BASIC RESEARCH IN CARDIOLOGY 1975年第4期70卷 401-405页

作者： VETTERLEIN, F UNIV GOTTINGEN INST PHARMAKOL & TOXIKOLLEHRSTUHL 2GEIST STR 9D-34 GOTTINGENFED REP GER

A method allowing the counting and mapping of non-radioactive microspheres in cleared thick tissue slides is described. The procedure is simple and enables a direct demonstration of the microspheres in the tissue and ... 详细信息

关键词：化学疗法肿瘤局部灌注冠状血管/生理学组织学技术肾/血液供给微球体肌/血液供给局部血流动物男(雄)性大鼠

来源：评论

学校读者我要写书评

暂无评论

Modified technique of delivering solutions to rat coronary arteries in the transplant setting

引用

TRANSPLANTATION PROCEEDINGS 1999年第8期31卷 3255-3256页

作者： Nourani, F Laufer, G Hollensteiner, H Bergmeister, H Buschle, M Khazen, C Ankersmit, J Traxler, H Wolner, E Losert, U Kocher, AA Univ Vienna Dept Cardiothorac Surg Vienna Austria Univ Vienna Ctr Biomed Res Vienna Austria Univ Vienna Dept Anat 1 Vienna Austria

来源：评论

学校读者我要写书评

暂无评论

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

请选择保存的检索档案：

请选择收藏分类：

通借通还

建议与咨询 留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

请选择保存的检索档案： 新增检索档案 确定 取消

请选择收藏分类： 新增自定义分类 确定 取消

通借通还

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

请选择保存的检索档案：

请选择收藏分类：