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Valsartan in Acute Myocardial Infarction trial (VALIANT): Rationale and design

AMERICAN HEART JOURNAL 2000年第5期140卷 727-734页

作者： Pfeffer, MA McMurray, J Leizorovicz, A Maggioni, AP Rouleau, JL Van de Werf, F Henis, M Neuhart, E Gallo, P Edwards, S Sellers, MA Velazquez, E Califf, R Brigham & Womens Hosp Div Cardiovasc Boston MA 02115 USA Univ Glasgow Clin Res Initiat Heart Failure Glasgow Lanark Scotland Univ Lyon Clin Pharmacol Unit Lyon France ANMCO Res Ctr Florence Italy Univ Toronto Div Cardiol Toronto ON Canada Leuven Coordinating Ctr Louvain Belgium Novartis Pharmaceut E Hanover NJ USA Novartis Pharma AG Basel Switzerland Duke Univ Med Ctr Durham NC USA

Background survivors of acute myocardial infarction (MI) complicated by heart failure and/or resulting in left ventricular dysfunction are at heightened risk for subsequent death and major nonfatal cardiovascular events. Inhibition of the renin-angiotensin system with an angiotensin-converting enzyme inhibitor has consistently been demonstrated to result in reductions in these risks by approximately 20%. The development of angiotensin II receptor blockers offers a new, more specific, and theoretically more complete pharmacologic mode to inhibit the adverse influence of angiotensin II. Methods Valsartan in Acute Myocardial Infarction (VALIANT) is a multicenter, double-blind, randomized, active controlled parallel group study comparing the efficacy and safety of long-term treatment with valsartan, captopril, and their combination in high-risk patients after MI. The trial is designed with 3 arms, giving equal statistical consideration to survival comparisons of captopril versus the angiotensin II receptor blocker valsartan, as well as the combination of captopril plus valsartan, compared with a proven effective dose of captopril. This 14,500-patient trial is designed with an 86% power to detect a 15% reduction in mortality rate with either use of valsartan compared with captopril. The trial encourages optimal individualization of other proven therapies in acute and chronic infarction, and the international patient body ensures good representation of multiple practice patterns. Conclusion VALIANT ii a large international investigative effort that will evaluate the role of valsartan in the menage ment of patients with MI associated with heart failure and/or left ventricular dysfunction. The use of a proven dose of captopril and the comparator arms with valsartan alone or in combination with captopril provides a unique test of whether the angiotensin II receptor blocker can make an additional improvement in clinical outcomes beyond angiotensin-converting enzyme inhibitors

关键词：血管紧张素ⅱ/代谢血管紧张素转换酶抑制药/治疗应用抗高血压药/治疗应用卡托普利/治疗应用死亡原因双盲法用药计划表药物疗法联合心肌梗死/药物疗法心肌梗死/死亡率比值比病人遴选比例危险度模型受体血管紧张素/拮抗剂和抑制剂研究设计样本大小四唑类/治疗应用缬氨酸/类似物和衍生物缬氨酸/治疗应用人类

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Renal tubulointerstitial fibrosis - New thoughts on its development and progression

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POSTGRADUATE MEDICINE 2000年第1期108卷 159-+页

作者： O'Donnell, MP Minneapolis Med Res Fdn Inc Minneapolis MN 55404 USA Hennepin Cty Med Ctr Dept Med Div Nephrol Minneapolis MN 55415 USA

Tubulointerstitial fibrosis, characterized by accumulation of extracellular matrix proteins, is a morphologic hallmark of chronic renal disease as well as a component of normal aging in the kidney and of chronic allograft nephropathy. In this article, the author describes patterns that have recently been proposed to explain the pathogenesis of tubulointerstitial injury. In addition, he discusses available and experimental pharmacologic interventions that may ameliorate renal fibrosis.

关键词：血管紧张素ⅱ/代谢上皮/生理学纤维化肾功能衰竭慢性/药物疗法肾功能衰竭慢性/病理学肾功能衰竭慢性/病理生理学肾小管/代谢肾小管/病理学肾小管/病理生理学转化生长因子β/生理学人类

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Pathological expression of renin and angiotensin II in the renal tubule after subtotal nephrectomy - Implications for the pathogenesis of tubulointerstitial fibrosis

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AMERICAN JOURNAL OF PATHOLOGY 1999年第2期155卷 429-440页

作者： Gilbert, RE Wu, LL Kelly, DJ Cox, A Wilkinson-Berka, JL Johnston, CI Cooper, ME Univ Melbourne Dept Med Heidelberg Vic 3081 Australia Univ Melbourne Austin & Repatriat Med Ctr Heidelberg Vic 3081 Australia Univ Melbourne Dept Physiol Heidelberg Vic 3081 Australia

The finding that the systemic renin-angiotensin system (RAS) is not activated in most types of chronic renal disease has led to the suggestion that a local, intrarenal RAS may be an important determinant in the relentless progression of renal disease. Therefore, cell specific changes in various components of the RAS in response to renal mass reduction and angiotensin converting enzyme (ACE) inhibition were examined. Thirty Sprague-Dawley rats mere randomly assigned to sham surgery, subtotal nephrectomy (STNx) alone or STNx treated with the ACE inhibitor, perindopril, and sacrificed after 12 weeks, In sham rats, renin mRNA and protein were only present in the juxtaglomerular apparatus, In contrast, in STNx kidneys, renin and angiotensin II expression mere noted predominantly in renal tubular epithelial cells in association with overexpression of the prosclerotic cytokine, transforming growth factor-beta 1 (TGF-beta 1), In perindopril-treated STNx rats expression of renin and TGF-beta 1 were similar to control animals. These finding indicate that following renal mass reduction there is pathological tubular expression of various components of the RAS, Furthermore, in contrast to the juxtaglomerular apparatus, tubular renin expression was reduced with. ACE inhibition. These changes within the intrarenal RAS may be pathogenetically Linked to the development of tubulointerstitial injury.

关键词：血管紧张素Ⅱ/分析血管紧张素ⅱ/代谢胶原/分析胶原/代谢免疫组织化学原位杂交肾/解剖学和组织学肾/病理学肾/外科学肾小管/解剖学和组织学肾小管/代谢肾小管/外科学肾切除术肾炎间质性/代谢肽基二肽酶A/分析肽基二肽酶A/代谢大鼠 Sprague-Dawley 肾素/分析肾素/代谢转化生长因子α/分析转化生长因子α/代谢转化生长因子β/分析转化生长因子β/代谢动物男(雄)性大鼠

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Structural comparison between type I and type II antagonists: Possible implications in the drug design of AT1 antagonists

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2000年第8期10卷 755-758页

作者： Roumelioti, P Tselios, T Alexopoulos, K Mavromoustakos, T Kolocouris, A Moore, GJ Matsoukas, JM Natl Hellen Res Fdn Inst Organ & Pharmaceut Chem Athens 11635 Greece Univ Patras Dept Chem Patras 26500 Greece Univ Calgary Dept Pharmacol & Therapeut Calgary AB T2N 4N1 Canada

Analogues of sarilesin (type I AT1 antagonists), and sarmesin (type II AT1 antagonists) with homoserine (hSer) at position 8 were prepared and bioassayed. The presence of a Tyr(4)-Ile(5)-His(6) bend found in sarmesin but not in sarilesin was identified. The obtained results coupled with conformational analysis studies, using a combination of NMR spectroscopy and computational chemistry, propose important conformational and stereoelectronic properties for agonist and antagonist activity at ATI receptors. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：血管紧张素Ⅰ/代谢血管紧张素Ⅱ/类似物和衍生物血管紧张素Ⅱ/化学合成血管紧张素Ⅱ/化学血管紧张素ⅱ/代谢血管紧张素Ⅱ/药理学血管紧张素受体拮抗剂药物设计磁共振波谱学模型分子受体血管紧张素/代谢构效关系子宫/药物作用动物女(雌)性大鼠

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Transport of [³H]losartan across isolated perfused rabbit proximal tubule

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期290卷 38-42页

作者： Edwards, RM Stack, EJ Trizna, W SmithKline Beecham Pharmaceut Dept Renal Pharmacol King Of Prussia PA 19406 USA

The transport of the angiotensin II receptor antagonist rosarian and its interaction with organic anion transport were examined in the isolated perfused rabbit proximal tubule. Losartan reversibly inhibited the secretion of para-aminohippurate (PAH) in a concentration-dependent manner (IC50 = 15 +/- 0.5 mu M). Other angiotensin II receptor antagonists also inhibited PAH secretion with similar potencies: eprosartan, 11 +/- 2.3 mu M;irbesartan, 17 +/- 2.2 mu M, and valsartan 3 +/- 0.6 mu M. [H-3]Losartan was secreted by the proximal tubule by a saturable and probenecid-sensitive mechanism. The affinity of losartan for the organic anion transporter (K-m = 12.3 +/- 1.8 mu M) was significantly greater than that of PAH (K-m = 88.5 +/- 10.7 mu M) [H-3]losartan secretion was stimulated in the presence of cu-ketoglutarate, suggesting that losartan, like PAH, enters the cell in exchange for a dicarboxylate. These results demonstrate that losartan and probably other nonpeptide angiotensin II receptor antagonists are secreted by an organic anion transporter that is similar to, if not identical with, the classic PAH transporter.

关键词：血管紧张素ⅱ/代谢酮戊二酸类/药理学肾小管近端/代谢洛沙坦/代谢灌流丙磺舒/药理学受体血管紧张素/拮抗剂和抑制剂肾脏用药/药理学 p-氨基马尿酸/代谢 p-氨基马尿酸/药理学动物男(雄)性兔

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Up-regulation of AT1 and AT₂ receptors in postinfarcted hypertrophied myocytes and stretch-mediated apoptotic cell death

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AMERICAN JOURNAL OF PATHOLOGY 2000年第5期156卷 1663-1672页

作者： Leri, A Liu, Y Li, BS Fiordaliso, F Malhotra, A Latini, R Kajstura, J Anversa, P New York Med Coll Dept Med Valhalla NY 10595 USA Ist Ric Farmacol Mario Negri Milan Italy

To determine whether up-regulation of AT(1) and AT(2) receptors occurred in hypertrophied myocytes after infarction and whether AT(2) played a role in stretch-mediated apoptosis, left ventricular myocytes were dissociated from the surviving portion of the wall 8 days after coronary occlusion and cardiac failure in rats. Control cells were obtained from sham-operated animals. Myocytes were stretched in an equibiaxial stretch apparatus and angiotensin II (Ang II) formation and cell death were measured 3 and. 12 hours later. AT(1) and AT(2) proteins were evaluated in freshly isolated myocytes and after stretch. The effects of AT(1) and AT(2) antagonists on stretch-induced Ang II synthesis and apoptosis were also established. Myocardial infarction increased AT(1) and AT(2) in myocytes and stretch further up-regulated these receptors. Ang II levels were higher in postinfarcted myocytes and this peptide increased with the duration of stretch in both groups of cells. Similarly, apoptosis increased with time in control and postinfarcted myocytes. Absolute values of Ang II and apoptosis were greater in myocytes from infarcted hearts at 3 and 12 hours after stretch. Addition of AT(1) blocker to cultures Inhibited stretch-activated apoptosis in both myocyte populations as well as the generation of Ang II in postinfarcted myocytes. In contrast, AT(2) antagonists had no impact on these cellular events. In conclusion, Ang II stimulated cell death through AT(1) receptor activation, whereas Ligand binding to AT(2) receptor did not alter Ang II concentration and apoptosis in normal and postinfarcted hypertrophied myocytes.

关键词：血管紧张素ⅱ/代谢细胞凋亡体重细胞死亡细胞大小细胞培养的心室/细胞学心室/代谢心室/病理生理学肥大左心室/代谢肥大左心室/病理学心肌梗死/代谢心肌梗死/病理学大鼠 Sprague-Dawley 受体血管紧张素/代谢应力物理时间因素增量调节动物男(雄)性大鼠

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Interaction between neutral endopeptidase and angiotensin converting enzyme inhibition in rats with myocardial infarction: Effects on cardiac hypertrophy and angiotensin and bradykinin peptide levels

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期289卷 295-303页

作者： Duncan, AM James, GM Anastasopoulos, F Kladis, A Briscoe, TA Campbell, DJ St Vincents Inst Med Res Fitzroy Vic 3065 Australia

Combined inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on Ang and BK levels in rats with myocardial infarction. We administered the NEP inhibitor ecadotril (0, 0.1, 1, 10, and 100 mg/kg/day), either alone or together with the ACE inhibitor perindopril (0.2 mg/kg/day) by 12-hourly gavage from day 2 to 28 after infarction. Ecadotril increased urine cyclic GMP and BK-(1-9) excretion. Perindopril potentiated the effect of ecadotril on urine cyclic GMP excretion. Neither perindopril nor ecadotril reduced cardiac hypertrophy when administered separately, whereas the combination of perindopril and 10 or 100 mg/kg/day ecadotril reduced heart weight/body weight ratio by 10%. Administration of ecadotril to perindopril-treated rats decreased plasma Ang-(1-7) levels, increased cardiac BK(1-9) levels, and increased Ang II levels in plasma, kidney, aorta, and lung. These data demonstrate interactions between the effects of NEP and ACE inhibition on remodeling of the infarcted heart and on Ang and BK peptide levels. Whereas increased cardiac BK-(1-9) levels may contribute to the reduction of cardiac hypertrophy, the reduction in plasma Ang-(1-7) levels and increase in Ang II levels in plasma and tissues may compromise the therapeutic effects of combined NEP/ACE inhibition.

关键词：血管紧张素ⅱ/代谢血管紧张素转换酶抑制药/药理学体重/药物作用缓激肽/代谢心脏扩大/并发症心脏扩大/病理学环GMP/尿药物协同作用吲哚类/药理学心肌梗死/并发症心肌梗死/代谢心肌梗死/病理学心肌梗死/病理生理学脑啡肽酶/拮抗剂和抑制剂肽基二肽酶A/血液培哚普利钾/尿蛋白酶抑制药/药理学放射免疫测定大鼠 Sprague-Dawley 肾素/血液钠/尿硫甲基氧代苯丙甘氨酸/类似物和衍生物硫甲基氧代苯丙甘氨酸/药理学动物男(雄)性大鼠

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Apoptosis of lung epithelial cells in response to TNF-α requires angiotensin II generation de novo

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JOURNAL OF CELLULAR PHYSIOLOGY 2000年第2期185卷 253-259页

作者： Wang, RQ Alam, G Zagariya, A Gidea, C Pinillos, H Lalude, O Choudhary, G Oezatalay, D Uhal, BD Michigan State Univ Dept Physiol E Lansing MI 48824 USA Michael Reese Hosp & Med Ctr Dept Med Chicago IL 60616 USA Michael Reese Hosp & Med Ctr Div Neonatol Chicago IL 60616 USA Michael Reese Hosp & Med Ctr Cardiovasc Inst Chicago IL 60616 USA

Recent work from this laboratory demonstrated that apoptosis of pulmonary alveolar epithelial cells (AEC) in response to fas requires angiotensin II (ANGII) generation de novo and binding to its receptor (Wang et at., 1999b, Am I Physiol Lung Cell Mol Physiol 277:L1245-L1250). These findings led us to hypothesize that a similar mechanism might be involved in the induction of AEC apoptosis by TNF-alpha. Apoptosis was detected by assessment of nuclear and chromatin morphology, increased activity of caspase 3, binding of annexin V, and by net cell loss inhibitable by the caspase inhibitor ZVAD-fmk. Purified human TNF-alpha induced dose-dependent apoptosis in primary type II pneumocytes isolated from rats or in the AEC-derived human lung carcinoma cell line A549. Apoptosis in response to TNF-alpha was inhibited in a dose-dependent manner by the nonselective ANGII receptor antagonist saralasin or by the nonthiol ACE inhibitor lisinopril;the inhibition of TNF-induced apoptosis was maximal at 50 mu g/ml saralasin (101% inhibition) and at 0.5 mu g/ml lisinopril (86% inhibition). in both cell culture models, purified TNF-alpha caused a significant increase in the mRNA for angiotensinogen (ANGEN), which was not expressed in unactivated cells. Transfection of primary cultures of rat AEC with antisense oligonucleotides against ANGEN mRNA inhibited the subsequent induction of TNF-stimulated apoptosis by 72% (P < 0.01). Exposure to TNF-alpha increased the concentration of ANGII in the serum-free extracellular medium by fivefold in A549 cell cultures and by 40-fold in primary AEC preparations;further, exposure to TNF-alpha for 40 h caused a net eel I loss of 70%, which was completely abrogated by either the caspase inhibitor ZVAD-fmk, lisinopril, or saralasin. Apoptosis in response to TNF-alpha was also completely inhibited by neutralizing antibodies specific for ANGII (P < 0.01), but isotype-matched nonimmune immunoglobulins had no significant effect. These data indicate that the

关键词：血管紧张素Ⅱ/生物合成血管紧张素ⅱ/代谢血管紧张素转换酶抑制药/药理学血管紧张素原/遗传学血管紧张素原/代谢细胞凋亡/药物作用细胞凋亡/生理学细胞系剂量效应关系药物上皮细胞/药物作用上皮细胞/生理学基因表达/生理学赖诺普利/药理学肺/细胞学肺/药物作用肺/生理学蛋白质加工转译后/生理学 RNA 信使/代谢受体血管紧张素/拮抗剂和抑制剂受体血管紧张素/代谢沙拉新/药理学肿瘤坏死因子α/药理学人类

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Angiotensin II and basic fibroblast growth factor mitogenic pathways in human fetal mesangial cells

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PEDIATRIC RESEARCH 2000年第5期47卷 614-621页

作者： Izevbigie, EB Gutkind, JS Ray, PE Childrens Res Inst Childrens Natl Med Ctr Ctr Mol Physiol Res Washington DC 20010 USA NIDR Oral & Pharyngeal Canc Brach Program NIH Bethesda MD 20892 USA

Angiotensin II (Ang II) and basic fibroblast growth factor (bFGF/FGF-2) play relevant roles in renal development. Since the signaling pathways modulating the mitogenic effects of Ang LI and bFGF in human fetal mesangial cells (HFMc) are not clearly defined, we carried out experiments to determine whether they would exert their mitogenic effects by modulating the activity of the mitogen-activated protein kinases (MAPK) [extracellular signal-regulated kinase-2 (ERK-2)] and cAMP signaling pathways. In confluent HFMc, bFGF (20 ng/mL) induced a significant 4-fold increase in ERK-2 activity and [H-3]-thymidine incorporation (6-fold). In contrast, under similar tissue culture conditions, Ang II (10(-6) M) induced a more modest increase in ERK-2 activity (2-fold) and [H-3]-thymidine incorporation (35 +/- 4%). The mitogen-activated protein kinase kinase-l (MEK-1) inhibitor PD098059 (25 mu M) almost completely abolished the bFGF-induced proliferation in HFMc but did not significantly affect Ang II proliferative effects, In the presence of the cAMP elevating agent isoproterenol, Ang II and bFGF induced opposite changes in cAMP accumulation and cell growth. Isoproterenol inhibited the basal and bFGF-induced proliferation of HFMc through a MEK-1/2-independent pathway that included the accumulation of cAMP, In contrast, isoproterenol increased Ang II mitogenic effects in correlation with a reduction in cAMP accumulation. We conclude that Ang II and bFGF modulate the proliferation of HFMc through the stimulation of different MEK-1/2-dependent and independent signaling pathways. Activation of MEK-1/2 is required but not sufficient fur mitogenesis in HFMc. The accumulation of cAMP in HFMc counteracts the mitogenic effects of bFGF by a MEK-1/1-independent pathway.

关键词：肾上腺素能β激动剂/药理学血管紧张素ⅱ/代谢血管紧张素Ⅱ/药理学细胞计数/药物作用细胞分裂/药物作用细胞培养的环AMP/代谢药物协同作用酶激活/药物作用酶抑制剂/药理学成纤维细胞生长因子2/代谢成纤维细胞生长因子2/药理学肾小球系膜/细胞学肾小球系膜/药物作用肾小球系膜/胚胎学肾小球系膜/代谢异丙肾上腺素/药理学 MAP激酶激酶1 MAP激酶激酶2 丝裂原活化蛋白激酶1/代谢丝裂原激活蛋白激酶激酶类/代谢丝裂原激活蛋白激酶类/代谢蛋白质丝氨酸苏氨酸激酶/代谢蛋白酪氨酸激酶类/代谢信号传导/药物作用胸苷/代谢人类

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拉萨(3658米)地区人体肾素活性、血管紧张Ⅱ及醛固酮的变化

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高原医学杂志 1986年第1期 23-28页

作者：雷淑贞西藏军区总医院

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