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Amitriptyline-induced release of endothelin-1 in isolated perfused and ventilated rat lungs

PHARMACOLOGY & TOXICOLOGY 1999年第6期85卷 288-293页

作者： Dahlin, KL Mörtberg, A Låstbom, L Ryrfeldt, A Karolinska Inst Inst Environm Med Div Inhalat Toxicol S-17177 Stockholm Sweden Karolinska Inst Dept Physiol & Pharmacol Stockholm Sweden

We have previously shown that tricyclic antidepressants can induce vaso- and bronchoconstriction as well as oedema formation in isolated perfused lungs. This is an effect similar to that seen clinically in adult respiratory distress syndrome. In order to investigate whether endothelin can be a mediator of this reaction, isolated perfused rat lungs were exposed to 0.1 mM amitriptyline via the pulmonary circulation, perfusate was collected and endothelin-l present in the perfusate and lavage fluids was determined by radioimmunoassay. A significant increase in perfusate concentration of endothelin-1 was noted, with the highest release seen within the first 10 min, of exposure. Histamine and thromboxane have also been proposed as mediators in induction of adult respiratory distress syndrome. However, no increased amounts of these mediators were detected in the perfusate. Experiments where lungs were exposed to exogenous endothelin-1 (0.1-1 nmol), both via the perfusate and via intratracheal instillation were conducted. Similar effects as observed with amitriptyline (0.1 mM) on lung function and perfusion flow were detected. In conclusion, the detection of endothelin-l release in our lung model proposes a role for endothelin-1 in amitriptyline-induced vaso- and bronchoconstriction and possibly in adult respiratory distress syndrome type reaction. Further studies with this model are interesting in order to elucidate mechanisms behind the complex issue of adult respiratory distress syndrome-induction.

关键词：阿米替林/药理学抗抑郁药三环/药理学内皮缩血管肽1/代谢组胺释放/药物作用肺/药物作用肺/代谢灌流大鼠 Sprague-Dawley 血栓烷B2/代谢动物女(雌)性大鼠

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Natriuretic peptide receptor-A negatively regulates mitogen-activated protein kinase and proliferation of mesangial cells: Role of cGMP-dependent protein kinase

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2000年第2期271卷 374-379页

作者： Pandey, KN Nguyen, HT Li, M Boyle, JW Tulane Univ Sch Med Dept Physiol New Orleans LA 70112 USA

We have examined the effect of atrial natriuretic peptide (ANP) and its guanylyl cyclase/natriuretic peptide receptor-A (NPRA) on mitogen-activated protein kinase/extracellular signal-regulated kinase 2 (MAPK/ERK2) activity in rat mesangial cells overexpressing NPRA. Agonist hormones such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), angiotensin II (ANG II), and endothelin-1 (ET-1) stimulated 2.5- to 3.5-fold immunoreactive MAPK/ERK2 activity in these cells. ANP inhibited agonist-stimulated activity of MAPK/ERK2 by 65-75% in cells overexpressing NPRA, whereas in vector-transfected cells, its inhibitory effect was only 18-20%. NPRA antagonist A71915 and KT5823, a specific inhibitor of cGMP-dependent protein kinase (PKG) completely reversed the inhibitory effect of ANP on MAPK/ERK2 activity. ANP also inhibited the PDGF-stimulated [H-3]thymidine uptake by almost 70% in cells overexpressing NPRA, as compared with only 20-25% inhibition in vector-transfected cells. These results demonstrate that ANP/NPRA system negatively regulates MAPK/ERK2 activity and proliferation of mesangial cells in a PKG-dependent manner. (C) 2000 Academic Press.

关键词：血管紧张素Ⅱ/代谢心钠素/代谢细胞分裂细胞培养的环GMP/代谢环GMP依赖性蛋白激酶类/生理学内皮缩血管肽1/代谢酶抑制剂/代谢成纤维细胞生长因子/代谢肾小球膜/细胞学肾小球膜/代谢鸟苷酸环化酶/拮抗剂和抑制剂鸟苷酸环化酶/代谢丝裂原活化蛋白激酶1/拮抗剂和抑制剂丝裂原活化蛋白激酶1/代谢肽碎片/代谢血小板源性生长因子/代谢沉淀素试验蛋白激酶抑制剂蛋白激酶类/代谢受体心钠素/拮抗剂和抑制剂受体心钠素/代谢四氢异喹啉类胸苷/代谢时间因素转染动物大鼠

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Molecular modeling of the complex of endothelin-1(ET-1) with the endothelin type A (ET_A) receptor and the rational design of a peptide antagonist

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JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS 2000年第6期17卷 957-964页

作者： Bhatnagar, S Rao, GS All India Inst Med Sci Dept Biophys New Delhi 110029 India

ET-1 is the most potent vasoconstrictor known to date, causing vasoconstriction when bound to the ETA receptor. Inhibitors of the binding of ET-I to the ETA receptor would be of immense value as potential therapeutic agents in the treatment of cardiovascular disorders such as angina and hypertension. We present here the rational design of such an inhibitor, which is arrived at on the basis of a model of theET-1/ ETA receptor complex proposed by us. The model is found to be consistent with binding and mutagenesis studies of ET-I as well as of BQ123, a known, potent ETA-selective antagonist which competes with ET-1 for receptor binding. BQ123 is a peptidic antagonist which is constrained to adopt a definite conformation on account of its cyclic nature, The noncyclic peptide antagonist designed by us also has a unique conformation because it contains two dehydro-Alanine (Delta Ala) residues which, on account of their planarity, cause the peptide backbone to bend in a specific and predictable manner. The folding rules for peptides containing Delta Ala were derived in our earlier studies. Energy minimization and modelling of the complex of the designed peptide with the ETA receptor indicate that the antagonist is ETA-selective and the binding is more stable and more specific as compared to that of BQ123.

关键词：抗高血压药/化学抗高血压药/药理学药物设计内皮缩血管肽1/拮抗剂和抑制剂内皮缩血管肽1/化学内皮缩血管肽1/代谢模型分子诱变定点肽类/化学合成肽类环/化学肽类环/药理学蛋白质结合蛋白质构象蛋白质折叠受体内皮素A 受体内皮缩血管肽/化学受体内皮缩血管肽/代谢信号传导血管收缩药/化学人类

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Endothelin receptor antagonism does not prevent the development of in vivo glyceryl trinitrate tolerance in the rat

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期295卷 578-585页

作者： Ratz, JD Fraser, AB Rees-Milton, KJ Adams, MA Bennett, BM Queens Univ Fac Hlth Sci Dept Pharmacol & Toxicol Kingston ON K7L 3N6 Canada

There is evidence that increased endothelial production of endothelin-1 (ET-1) may contribute to glyceryl trinitrate (GTN) tolerance. We used the competitive ETA receptor antagonist ZD2574 to determine whether chronic ETA receptor blockade affected the biochemical and functional responses to GTN during the development of GTN tolerance in vivo. Tolerance induced using transdermal GTN patches resulted in a 5.3 +/- 1.2-fold increase in the EC50 value for GTN relaxation in isolated aorta from GTN-tolerant rats. Coadministration of ZD2574 (100 mg kg(-1) t.i.d. for 3 days) during tolerance induction had no effect on GTN-induced relaxation. This dose of ZD2574 markedly blunted the pressor response to ET-1, indicating effective blockade of ETA receptors, and also abolished the initial transient depressor response to ET-1, indicating that blockade of endothelial ETB receptors also occurred using this dosage regimen for ZD2574. Consistent with the relaxation data, coadministration of ZD2574 had no effect on the decrease in GTN-induced cGMP accumulation or on the decrease in GTN biotransformation that occurred in aortae from GTN-tolerant animals. Radioimmunoassay data indicated that the GTN tolerance induction protocol caused a 2.3 +/- 0.4-fold and a 2.2 +/- 0.5-fold increase in total tissue ET-1 levels in tolerant aorta and vena cava, respectively. These data suggest that chronic inhibition of ET receptors by ZD2574 was not sufficient to prevent or diminish the tolerance-inducing effects of GTN, and that the increase in ET-1 levels observed in tolerant tissues may occur as a consequence of the vascular changes that occur during chronic GTN exposure.

关键词：主动脉胸/药物作用主动脉胸/代谢主动脉胸/生理学结合竞争性生物转化血压/药物作用环GMP/代谢药物耐受性/生理学内皮缩血管肽1/拮抗剂和抑制剂内皮缩血管肽1/代谢内皮缩血管肽1/生理学肌收缩/药物作用肌松弛/药物作用硝酸甘油/药代动力学硝酸甘油/药理学吡嗪类/药理学大鼠 Sprague-Dawley 受体内皮素A 受体内皮缩血管肽/拮抗剂和抑制剂受体内皮缩血管肽/代谢磺胺类/药理学血管舒张药/药代动力学血管舒张药/药理学动物男(雄)性大鼠

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Pharmacological profile of ZD1611, a novel, orally active endothelin ET_A receptor antagonist

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期290卷 1085-1091页

作者： Wilson, C Hunt, SJ Tang, E Wright, N Kelly, E Palmer, S Heys, C Mellor, S James, R Bialecki, R Zeneca Pharmaceut Macclesfield SK10 4TG Cheshire England

The endothelins (ETs), potent vasoconstrictor peptides, have been implicated in the pathogenesis of various cardiovascular disorders. In the present study, we describe the novel, potent, orally active, selective ETA receptor antagonist ZD1611 [3-(4-[3-(3- methoxy-5-methylpyrazin-2-ylsulfamoyl)-2-pyridyl]phenyl)-2,2-dimethylpropanoic acid]. ZD1611 competitively inhibited I-125-labeled ET-1 binding at human cloned ETA and ETB receptors with pIC(50) values of 8.6 +/- 0.1 and 5.6 +/- 0.1, respectively, showing 1000-fold selectivity for the ETA receptor. ZD1611 caused a parallel rightward shift of the concentration response curve to ET-1 in the rat isolated aorta yielding a concentration of antagonist that caused a 2-fold rightward shift in the ET-1-response curve (pA(2)) of 7.5 +/- 0.3. When administered i.v. to anesthetized rats and dogs, ZD1611 caused dose-related rightward shifts of partial dose-response curves to the precursor of ET-1, big ET-1. Threshold doses for significant antagonist activity were determined as 0.1 mg/kg and 0.3 mg/kg in the rat and dog, respectively. Importantly, ZD1611 was able to reverse an established big ET-l-induced presser response in pithed rats in the presence of continuous big ET-1 infusion. Failure of ZD1611 to inhibit the BQ3020 (ETB selective)-induced depressor response in pithed rats indicated alack of activity at the endothelial ET, receptor. ZD1611 was orally active in the rat at 0.3 mg/kg and had a duration of action of more than 7 h, and, in the dog, a dose of 0.6 mg/kg p.o. was active for at least 6 h. In conclusion, these data demonstrate that ZD1611 is a potent and orally active, selective ETA receptor antagonist with a long duration of action which may be of therapeutic use.

关键词：投药口服主动脉/药物作用主动脉/生理学结合竞争性剂量效应关系药物内皮缩血管肽1/代谢内皮缩血管肽1/药理学内皮缩血管肽类/药理学碘放射性同位素动力学肽碎片/药理学吡嗪类/代谢吡嗪类/药理学放射配体测定大鼠 Sprague-Dawley 受体内皮素A 受体内皮素B 受体内皮缩血管肽/拮抗剂和抑制剂磺胺类/代谢磺胺类/药理学动物狗女(雌)性人类男(雄)性小鼠大鼠

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Chronic carbon monoxide exposure in vivo induces myocardial endothelin-1 expression and hypertrophy in rat

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PHARMACOLOGY & TOXICOLOGY 1999年第4期85卷 192-197页

作者： Loennechen, JP Beisvag, V Arbo, I Waldum, HL Sandvik, AK Knardahl, S Ellingsen, O Norwegian Univ Sci & Technol Dept Physiol & Biomed Engn Med Tech Res Ctr N-7489 Trondheim Norway Natl Inst Occupat Hlth Dept Physiol N-0033 Oslo Norway

Smoking is associated with endothelial dysfunction and increased plasma levels of endothelin-l. The component of tobacco smoke inducing these effects is unknown. Carbon manoxide induces hypoxia, and there is evidence of carbon monoxide acting as a local mediator in both endothelial and smooth muscle cells. The purpose of this study was to determine whether chronic carbon monoxide exposure similar to that experienced by smokers affects myocardial endothelin-l expression. Sprague-Dawley female rats were exposed to carbon monoxide 100 ppm for one week or to 100 ppm for one week and 200 ppm for a second week. Carboxyhaemoglobin was 12+/-0.9% in the low and 23+/-1.1% in the high carbon monoxide exposure group. Endothelin-l expression was measured by competitive reverse transcriptase polymerase chain reaction. High carbon monoxide exposure increased endothelin-l mRNA by 54+/-12% (P<0.001) in the left ventricle and by 53+/-12% (P<0.001) in the right ventricle. In the low carbon monoxide exposure group corresponding changes were 43+/-14% (P=0.06) and 12+/-16% (P=0.29). Right ventricular weight increased by 18+/-7% (P=0.02) after high and by 16+/-5% (P=0.02) after low exposure. Left ventricular weight was elevated by 5+/-2% (P = 0.05) when both exposure groups were compared to controls. We conclude that chronic carbon monoxide exposure leading to carboxyhaemoglobin levels similar to those observed in smokers increases endothelin-l gene expression and induces myocardial hypertrophy in the rat.

关键词：一氧化碳/毒性碳氧血红蛋白/药物作用心脏扩大/化学诱导剂量效应关系药物内皮缩血管肽1/药物作用内皮缩血管肽1/代谢心室/药物作用心肌/代谢 RNA 信使/药物作用大鼠 Sprague-Dawley 逆转录聚合酶链反应动物女(雌)性大鼠

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A platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第1期97卷 360-364页

作者： Kakutani, M Masaki, T Sawamura, T Natl Cardiovasc Ctr Res Inst Dept Biosci Suita Osaka 5658565 Japan Japan Tobacco Inc Cent Pharmaceut Res Inst Takatsuki Osaka 5691125 Japan Osaka Univ Dept Mol Pathophysiol Grad Sch Pharmaceut Sci Suita Osaka 5650871 Japan

One crucial role of endothelium is to keep the innermost surface of a blood Vessel antithrombotic. However, the endothelium also expresses prothrombotic molecules in response to various stimuli. The balance between the antithrombotic and prothrombotic nature of the endothelium is lost under certain conditions. During atherosclerosis, the attachment of platelets to the vessel surface has been suggested to promote the proliferation of smooth muscle cells and intimal thickening as well as to affect the prognosis of the disease directly through myocardial infarction and stroke. Dysfunctional endothelium, which is often a result of the action of oxidized low-density lipoprotein (OxLDL), tends to be more procoagulant and adhesive to platelets. Herein, we sought the possibility that the endothelial lectin-like OxLDL receptor-1 (LOX-1) is involved in the platelet-endothelium interaction and hence directly in endothelial dysfunction. LOX-1 indeed worked as an adhesion molecule for platelets. The binding of platelets was inhibited by a phosphatidylserine-binding protein, annexin V, and enhanced by agonists for platelets. These results suggest that negative phospholipids exposed on activation on the surface of platelets are the epitopes for LOX-1. Notably, the binding of platelets to LOX-1 enhanced the release of endothelin-1 from endothelial cells, supporting the induction of endothelial dysfunction, which would, in turn, promote the atherogenic process. LOX-1 may initiate and promote atherosclerosis, binding not only OxLDL but also platelets.

关键词：膜联蛋白A5/药理学抗体/药理学动脉硬化/代谢血小板/代谢 CHO细胞胶原/药理学仓鼠亚科内皮缩血管肽1/代谢内皮血管/代谢内皮血管/病理学外源凝集素类/代谢脂蛋白类 LDL/药理学吞噬作用血小板活化/药物作用受体 LDL/代谢受体氧化LDL 清道夫受体 E类凝血酶/药理学动物牛人类

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Endothelin-secreting tumors and the idea of the pseudoectopic hormone secretion in tumors

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MEDICAL HYPOTHESES 1999年第4期52卷 329-333页

作者： Kurbel, S Kurbel, B Kovacic, D Sulava, D Krajina, Z Dmitrovic, B Sokcevic, M Osijek Clin Hosp Dept Oncol Osijek 31000 Croatia Univ Zagreb Univ Hosp Dubrava Dept Anesthesiol Zagreb Croatia Osijek Clin Hosp Surg Clin Osijek 31000 Croatia Victoria Sq Med Ctr St Albans Vic Australia Univ Zagreb Clin Tumors Zagreb Croatia Osijek Clin Hosp Dept Pathol Osijek 31000 Croatia

Ectopic hormone secretion in tumor cells is here described as an amplification of hormone production already present in normal, nonendocrine tumor-originated tissue. This idea is tested on the available data regarding endothelin-l (ET-I) secreting tumors. The endothelins are ubiquitous regulatory peptides produced by various tissues. The precursor cells of many tumor types secrete endothelins. ET-1 protein expression was detected in situ in all tested prostate cancers as well as in normal prostate tissue. The majority of hepatocellular carcinomas produce ET-I, while ET-1 is secreted by the normal hepatic stellate cells. Human breast cancer cells produce immunoreactive ET-I. Similar data exist for pancreatic tissue, the thyroid and large bowel. We can conclude that tumor cells might sustain endothelin secretions already present in the normal tumor-originated tissue. The model that is presented of the pseudoectopic hormone secretion consists of relations between a few parameters. The proportion of hormone-secreting tumors (T(h)) among all tumors (T) of that organ depends on the amount of the hormone-secreting cells (C(h)) among all cells (C) susceptible to malignant transformation. The corrective factor (k) was introduced in the expression T(h)/T=C(h)/C*k to represent specific conditions altering the malignant transformation probability for a certain normal hormone-secreting cell. In prostate, breast and colon, the k value is predicted to be similar to 1, suggesting that ET-l-secreting normal cells are not more prone to the malignant transformation than their neighbours. In liver and pancreas, the incidence of ET-l-secreting tumors outnumbers the proportions of normal ET-l-secreting cells (k values similar to 1). In these organs, normal ET-l-secreting cells seem more likely to turn malignant in comparison to their neighbours, perhaps due to their function, position and exposition to oncogenic factors, or even due to their ET-1 secretion. There are similar data for thy

关键词：乳腺肿瘤/代谢乳腺肿瘤/病理生理学内皮缩血管肽1/代谢激素类/代谢肾肿瘤/代谢肾肿瘤/病理生理学模型生物学肿瘤/代谢肿瘤/病理生理学动物女(雌)性人类男(雄)性

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参芪地黄汤合猪苓散对早期糖尿病肾病患者血清SOD、MDA及ET-1的影响

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中国医师杂志 2018年第1期20卷 126-128页

作者：郑韬李霞广东省佛山市顺德区乐从医院 528315 广东省佛山市禅城区中心医院 528031

目的观察参芪地黄汤合猪苓散对早期糖尿病肾病血清超氧化物歧化酶(SOD)、丙二醛(MDA)及内皮素(ET)-1的影响。方法选取早期糖尿病肾病患者60例,采用随机数字表法分为对照组和观察组。对照组予常规基础治疗+缬沙坦,观察组在对照组基础上... 详细信息

目的观察参芪地黄汤合猪苓散对早期糖尿病肾病血清超氧化物歧化酶(SOD)、丙二醛(MDA)及内皮素(ET)-1的影响。方法选取早期糖尿病肾病患者60例,采用随机数字表法分为对照组和观察组。对照组予常规基础治疗+缬沙坦,观察组在对照组基础上另予参芪地黄汤合猪苓散,疗程均为16周。于治疗前后检测两组患者血肌酐(Scr)、24 h尿蛋白排泄率(UAER)、血清SOD、MDA及ET-1的变化。结果 (1)治疗后,两组Scr、24 h UAER、ET-1均较同组治疗前明显下降(P<0.05或P<0.01),且观察组更明显(P<0.05)。(2)治疗后,对照组SOD、MDA水平与同组治疗前比较差异无统计学意义(P>0.05);而观察组SOD较同组治疗前明显升高(P<0.05),MDA较同组治疗前明显下降(P<0.01)。结论参芪地黄汤合猪苓散可以改善早期糖尿病肾病患者肾功能,可能与其抑制氧化应激和改善血管内皮功能有关。

关键词：猪苓/投药和剂量生地黄/投药和剂量黄芪△/投药和剂量糖尿病’肾病/中药疗法超氧化物歧化酶/代谢丙二醛/代谢内皮缩血管肽1/代谢

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ET-1和PKM2在直肠癌组织中的表达与术前放疗效果的关系

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中国医师杂志 2017年第7期19卷 1010-1013页

作者：周菊梅梁荣朱苏雨吴峥席珍邹敏吕贇聂少麟湖南省肿瘤医院放疗科长沙410013 湖南省肿瘤医院结直肠外科长沙410013

目的探讨内皮素（ET）-1和M型丙酮酸激酶（PKM）-2蛋白在直肠癌组织中的表达与术前放疗效果的关系。方法采用免疫组化法检测96例直肠癌组织中ET-1和PKM2蛋白的表达情况，分析ET-1和PKM2蛋白在直肠癌组织的表达与术前放疗效果的关系。结... 详细信息

目的探讨内皮素（ET）-1和M型丙酮酸激酶（PKM）-2蛋白在直肠癌组织中的表达与术前放疗效果的关系。方法采用免疫组化法检测96例直肠癌组织中ET-1和PKM2蛋白的表达情况，分析ET-1和PKM2蛋白在直肠癌组织的表达与术前放疗效果的关系。结果ET—1蛋白高表达者59例（61．46％），PKM2蛋白高表达者54例（56．25％），ET-1蛋白高表达者或PKM2蛋白高表达者术前放疗后直肠癌组织的肿瘤消退分级（TRG）明显差于低表达者（P〈0．05）。ET-1蛋白和PKM2蛋白表达呈正相关（P=0．006）。结论ET-1和PKM2蛋白在直肠癌中的高表达与术前放疗抵抗密切相关，有望成为预判直肠癌的放疗敏感性和放疗增敏的新靶点。

关键词：内皮缩血管肽1/代谢丙酮酸激酶/代谢直肠肿瘤/放射疗法/代谢

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