DOCSLIB.ORG

Dual ACE/NEP Inhibitors – More Than Playing the ACE Card

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Dual ACE/NEP Inhibitors – More Than Playing the ACE Card Journal of Human Hypertension (2006) 20, 478–481 & 2006 Nature Publishing Group All rights reserved 0950-9240/06 $30.00 www.nature.com/jhh COMMENTARY Dual ACE/NEP inhibitors – more than playing the ACE card KAM Jandeleit-Dahm Baker Heart Research Institute, Danielle Alberti JDRF Centre for Diabetes Complications, Wynn Domain, Melbourne, Victoria, Australia Journal of Human Hypertension (2006) 20, 478–481. doi:10.1038/sj.jhh.1002018; published online 16 March 2006 Background lin-1 (ET-1).3,4 Atrial natriuretic peptide mediates increased urine production, natriuresis and urinary Vasopeptidase inhibition is a novel therapeutic cGMP excretion. Furthermore, ANP inhibits renin approach in the treatment of cardiovascular diseases and aldosterone secretion.5 such as hypertension and heart failure. The concept However, long-term studies with NEP inhibitors of dual inhibition of the two enzymes, angiotensin have demonstrated only limited beneficial effects in converting enzyme (ACE) and neutral endopep- heart failure and hypertension, mainly due to a loss tidase (NEP) by a single molecule has shown of efficacy. This has been explained as the long-term major benefits and potentially superiority versus antihypertensive effect of NEP inhibitors may be other agents in various experimental models of 1 offset by a counteracting activation of the renin– hypertension, heart failure and renal disease. The angiotensin system (RAS) and the sympathetic underlying presumed rationale for the combined nervous system and/or by downregulation of ANP inhibition of ACE and NEP is to block the vasocons- receptors.6 trictor angiotensin II (AII) and simultaneously increase the vasodilator, atrial natriuretic peptide (ANP) by decreasing its enzymatic degradation. Furthermore, both vasoactive hormones, AII and Angiotensin converting enzyme/neutral ANP appear to have actions beyond their haemody- endopeptidase inhibitors namic effects. AII meditates proliferation, fibrosis, inflammation and oxidative stress whereas ANP has Based on a large body of experimental evidence it antiproliferative and antifibrotic effects. Both pep- has become evident that the RAS, the kallikrein- tides have been postulated to act as endogenous kinin pathway and the natriuretic peptides are antagonists to each other.2 important modulators of cardiovascular homeosta- sis. These findings have provided the impetus to develop inhibitors that simultaneously block AII Neutral endopeptidase inhibition and increase ANP, peptides which are regulated by endothelial, membrane bound zinc-dependent en- On the basis of the positive results with ACE zymes, ACE and NEP, two enzymes with significant inhibition in a range of cardiovascular diseases, structural homology. including hypertension, diabetes and renal disease Thus, the introduction of dual metallopeptidase several investigators have started to study the inhibitors should be considered a new therapeutic potentially added beneficial effects by blocking concept in cardiovascular disease. In various ex- other endogenous enzymes involved in peptide perimental models of hypertension, heart disease activation or degradation. One of these enzymes is and renal disease combined ACE/NEP inhibition led NEP, a metallopeptidase similar in structure and to more potent and synergistic hemodynamic and distribution to ACE. renal effects than selective inhibitors of the indivi- Neutral endopeptidase catalyses the degradation dual enzymes. The antihypertensive7 and antifibro- of various endogenous vasodilator peptides includ- tic effects8–10 were associated with enhanced ing ANP, BNP, CNP, substance P and bradykinin as vasodilation, natriuresis and improved myocardial well as vasoconstrictor peptides including endothe- function.11 Part of the beneficial effects of ACE inhibitors in Correspondence: Dr KAM Jandeleit-Dahm, Baker Heart Research hypertension and heart failure as well as in the Institute, Danielle Alberti JDRF Centre for Diabetes Complica- acute stages after myocardial infarction12 have been tions, Wynn Domain, Commercial Road, Melbourne 3004, Victoria, Australia. attributed to the inhibition of kinin degradation E-mail: [email protected] resulting in increased endothelial NO bioavailabil- Published online 16 March 2006 ity. Neutral endopeptidase also inhibits kinin Dual ACE/NEP inhibitors – more than playing the ACE card KAM Jandeleit-Dahm 479 degradation thus increasing kinin concentrations. 9% (Po0.05). The OCTAVE study also showed Part of the beneficial effect of omapatrilat in cardiac that omapatrilat had superior antihypertensive ischemia and reperfusion injury12 appears to be effects compared to enalapril. In that trial, however, mediated via the increased kinin concentrations angioedema was observed in 2.17% of the popula- resulting from ACE and NEP inhibition. As the tion in the omapatrilat-treated groups versus 0.68% inhibition of bradykinin breakdown by ACE and in the enalapril treated group. In Afro-American NEP is additive, excess bradykinin accumulation subjects the incidence was even higher (5.54 versus may be the cause of angioedema observed with some 1.62%, respectively). This effect has been attributed ACE/NEP inhibitors and, in particular, with omapa- to firstly the rapid increase in bradykinin and its trilat. Indeed, omapatrilat has recently been shown metabolite BK-8 by simultaneously blocking both to induce extravasation in high doses.13 As the BK degrading pathways and secondly by potentially various ACE/NEP inhibitors differ in their ability a direct effect of the agent to promote extravasa- and relative potency to inhibit ACE versus NEP this tion.13 Based on these findings and, in particular, may not only influence the magnitude of kinin the incidence of this potentially life threatening production but also the antihypertensive, cardio side effect it appears unlikely that omapatrilat vascular and antifibrotic effects. will become routine medication for hypertension, Omapatrilat is the ACE/NEP inhibitor that has especially in the Afro-American population. been most extensively studied. Omapatrilat is a In terms of cardioprotection in chronic heart fail- potent, long acting dual metalloproteinase inhibitor ure, the IMPRESS study25 did not show a statistically (ACE IC50 ¼ 5 nmol/l, NEP IC50 ¼ 8 nmol/l) and ex- significant difference between the omapatrilat and the erts prolonged antihypertensive effects in several lisinopril-treated groups after 12 weeks of treatment. experimental models of hypertension including the However, a positive trend for a beneficial effect with DOCA salt hypertensive model and the SHR.14 omapatrilat on heart failure was noted. Further studies have also demonstrated cardio- It remains controversial as to whether dual ACE/ renal protection including in myocardial ischemia NEP inhibitors confer superior cardiovascular ef- and reperfusion injury15 and in DOCA salt hyper- fects when compared to ACE inhibition alone. The tensive rats where reduced cardiac and renal fibrosis IMPRESS study25 investigating the effect of omapa- has been observed.14 In chronic heart failure, trilat versus lisinopril on exercise tolerance and omapatrilat has been shown to improve myocardial morbidity in patients with heart failure suggested an structure and function as well as being superior to advantage of omapatrilat over lisinopril. Although ACE inhibition alone.9,10,16 both treatments similarly improved exercise tread- In progressive nephropathy, ACE/NEP inhibition mill test results there was a trend in favor of was renoprotective not only by inhibiting ACE and omapatrilat on the combined end point of death or increasing ANP but also by reducing renal ET-1 admission for worsening heart failure (P ¼ 0.052) production and NO bioavailability.17–20 Further- and a significant benefit of omapatrilat in the more, more recently the beneficial renal effects of composite of death, admission or discontinuation omapatrilat have been attributed to its ability to of study treatment for worsening heart failure. increase levels of the vasodilator Angiotensin 1–7, Omapatrilat improved NYHA class more than as assessed by urinary excretion of this peptide.21 lisinopril and furthermore had some beneficial In a recent study, it was demonstrated that ACE/ effects on circulating neurohormones and cyto- NEP inhibition has beneficial functional and struc- kines.26 However, more recently, the results of the tural vasoprotective effects reducing atherosclero- omapatrilat versus enalapril randomized Trial of sis,20,22 arterial stiffness and pulse pressure.23 Not utility in reducing Events (OVERTURE) trial did not only has omapatrilat been shown to reduce early show a difference in the magnitude of improvement fatty streak development22 but also the advanced in ventricular size or function after 1 year when and more complex atherosclerotic lesions observed comparing omapatrilat to enalapril treatment in in diabetes.20 This interesting finding extends the 321 patients with heart failure (NHHA classification potential utility of such agents. II or more).27,28 The Omapatrilat in Persons with Enhanced Risk of Atherosclerotic Events (OPERA) was planned to specifically investigate patients with Clinical evidence for a superior cardio- high cardiovascular risk aged above 65 years and vascular effect of ACE/NEP inhibition with hypertension,29 however, was abandoned due versus ACE inhibition to insufficient recruiting. The results of these clinical studies show that The OCTAVE study investigated the effect of there is a need to develop novel
Load more

Recommended publications
  • WHO Drug Information Vol. 12, No. 3, 1998
    WHO DRUG INFORMATION VOLUME 12 NUMBER 3 • 1998 RECOMMENDED INN LIST 40 INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES WORLD HEALTH ORGANIZATION • GENEVA Volume 12, Number 3, 1998 World Health Organization, Geneva WHO Drug Information Contents Seratrodast and hepatic dysfunction 146 Meloxicam safety similar to other NSAIDs 147 Proxibarbal withdrawn from the market 147 General Policy Issues Cholestin an unapproved drug 147 Vigabatrin and visual defects 147 Starting materials for pharmaceutical products: safety concerns 129 Glycerol contaminated with diethylene glycol 129 ATC/DDD Classification (final) 148 Pharmaceutical excipients: certificates of analysis and vendor qualification 130 ATC/DDD Classification Quality assurance and supply of starting (temporary) 150 materials 132 Implementation of vendor certification 134 Control and safe trade in starting materials Essential Drugs for pharmaceuticals: recommendations 134 WHO Model Formulary: Immunosuppressives, antineoplastics and drugs used in palliative care Reports on Individual Drugs Immunosuppresive drugs 153 Tamoxifen in the prevention and treatment Azathioprine 153 of breast cancer 136 Ciclosporin 154 Selective serotonin re-uptake inhibitors and Cytotoxic drugs 154 withdrawal reactions 136 Asparaginase 157 Triclabendazole and fascioliasis 138 Bleomycin 157 Calcium folinate 157 Chlormethine 158 Current Topics Cisplatin 158 Reverse transcriptase activity in vaccines 140 Cyclophosphamide 158 Consumer protection and herbal remedies 141 Cytarabine 159 Indiscriminate antibiotic
    [Show full text]
  • Next Generation Multifunctional Angiotensin Receptor Blockers
    Hypertension Research (2009) 32, 826–834 & 2009 The Japanese Society of Hypertension All rights reserved 0916-9636/09 $32.00 www.nature.com/hr REVIEW Next generation multifunctional angiotensin receptor blockers Theodore W Kurtz1 and Uwe Klein2 Angiotensin receptor blockers (ARBs) are well-tolerated drugs that are known to be useful for inhibiting activity of the renin– angiotensin (RAS) system, treating hypertension and reducing the risk for cardiovascular disease. However, inhibition of the RAS does not control all pathophysiological mechanisms of hypertension or cardiovascular risk and many patients continue to suffer from cardiovascular events and metabolic disturbances despite being treated with an ARB, an angiotensin-converting enzyme inhibitor or both, in addition to other standard therapies for cardiovascular disease. Recently, it has become apparent that bifunctional molecules can be designed that do more than just block AT1 receptors and that can target additional mechanisms of hypertension, cardiovascular disease and diabetes besides just increased activity of the renin–angiotensin system. Specifically, next generation ARBs are becoming available that are intended to not only antagonize AT1 receptors, but also block endothelin receptors, function as nitric oxide donors, inhibit neprilysin activity and increase natriuretic peptide levels, or stimulate the peroxisome proliferator-activated receptor c (PPARc). In this review, we: (1) discuss the potential importance of multifunctional ARBs that can reduce cardiovascular and metabolic
    [Show full text]
  • Combined Neprilysin and Renin–Angiotensin System Inhibition in Heart Failure with Reduced Ejection Fraction: a Meta-Analysis
    European Journal of Heart Failure (2016) doi:10.1002/ejhf.603 Combined neprilysin and renin–angiotensin system inhibition in heart failure with reduced ejection fraction: a meta-analysis Scott D. Solomon1*, Brian Claggett1, John J.V. McMurray2, Adrian F. Hernandez3, and Gregg C. Fonarow4 1Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 2University of Glasgow, Glasgow, UK; 3Duke University, Durham, NC, USA; and 4Ronald Reagan-UCLA Medical Center, Los Angeles, CA, USA Received 1 March 2016; revised 25 May 2016; accepted 3 June 2016 Aims The combined neprilysin/renin–angiotensin system (RAS) inhibitor sacubitril/valsartan reduced cardiovascular death or heart failure hospitalization, cardiovascular death, and all-cause mortality in a large outcomes trial. While sacubitril/valsartan is the only currently available drug in its class, there are two prior clinical trials in heart failure with omapatrilat, another combined neprilysin/RAS inhibitor. Using all available evidence can inform clinicians and policy-makers. ..................................................................................................................................................................... Methods We performed a meta-analysis using data from three trials in heart failure with reduced EF that compared combined and results neprilysin/RAS inhibition with RAS inhibition alone and reported clinical outcomes: IMPRESS (n = 573), OVERTURE (n = 5770), and PARADIGM-HF (n = 8399). We assessed the pooled hazard ratio (HR) for all-cause death or heart failure hospitalization, and for all-cause mortality in random-effects models, comparing combined neprilysin/RAS inhibition with ACE inhibition alone. The composite outcome of death or heart failure hospitalization was reduced numerically in patients receiving combined neprilysin/RAS inhibition in all three trials, with a pooled HR of 0.86, 95% confidence interval (CI) 0.76–0.97, P = 0.013.
    [Show full text]
  • Narrative Review in the Current Role of Angiotensin Receptor- Neprilysin Inhibitors
    518 Review Article on Heart Failure Update and Advances in 2021 Page 1 of 9 Narrative review in the current role of angiotensin receptor- neprilysin inhibitors Jose B. Cruz Rodriguez1, Cameron Cu2, Tariq Siddiqui1 1Division of Cardiovascular Diseases, 2Department of Internal Medicine, Texas Tech University Health Science Center El Paso, El Paso, TX, USA Contributions: (I) Conception and design: All authors; (II) Administrative support: JB Cruz Rodriguez, T Siddiqui; (III) Provision of study materials or patients: JB Cruz Rodriguez, C Cu; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Jose B. Cruz Rodriguez. Division of Cardiovascular Diseases, Texas Tech University Health Science Center El Paso. 4800 Alberta Avenue, El Paso, TX 79905, USA. Email: [email protected]. Abstract: Heart failure (HF) accounts for a tremendous burden on health care systems and the society. Since the landmark PARADIGM-HF trial, sacubitril/valsartan, the first in the class of angiotensin receptor neprilysin inhibitor (ARNI) showed superiority to enalapril in patients with HF with reduced ejection fraction (HFrEF). We performed a narrative literature review, hand-searched the reference lists of included articles and relevant reviews. Inhibition of neprilysin increases bradykinin, natriuretic peptides and adrenomedullin levels counteract the neurohormal activation that leads to sodium retention, vasoconstriction, and cardiac remodeling. In PARADIGM-HF the primary outcome of CV death or HF hospitalization was reduced 20% in the ARNI group (HR 0.80, P<0.001) similar to mortality due to cardiovascular cause (HR 0.80, P<0.001) in patients with HFrEF, rendering a number needed to treat of 21 patients.
    [Show full text]
  • Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact
    Journal of Cardiac Failure Vol. 21 No. 9 2015 Review Article Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact JONATHAN BUGGEY, MD,1 ROBERT J. MENTZ, MD,1,2 ADAM D. DEVORE, MD,1,2 AND ERIC J. VELAZQUEZ, MD1,2 Durham, North Carolina ABSTRACT Heart failure (HF) is an increasingly common syndrome associated with high mortality and economic burden, and there has been a paucity over the past decade of new pharmacotherapies that improve outcomes. However, recent data from a large randomized controlled trial compared the novel agent LCZ696, a dual-acting angiotensin receptor blocker and neprilysin inhibitor (ARNi), with the well estab- lished angiotensin-converting enzyme (ACE) inhibitor enalapril and found significant reduction in mortal- ity among the chronic reduced ejection fraction HF population. Preclinical and clinical data suggest that neprilysin inhibition provides beneficial outcomes in HF patients by preventing the degradation of natriuretic peptides and thereby promoting natriuresis and vasodilatation and counteracting the negative cardiorenal effects of the up-regulated renin-angiotensin-aldosterone system. Agents such as omapatrilat combined neprilysin and ACE inhibition but had increased rates of angioedema. Goals of an improved safety profile provided the rationale for the development of the ARNi LCZ696. Along with significant reductions in mortality and hospitalizations, clinical trials suggest that LCZ696 may improve surrogate markers of HF severity. In this paper, we review the preclinical and clinical data that led to the develop- ment of LCZ696, the understanding of the underlying mechanistic action, and the robust clinical impact that LCZ696 may have in the near future.
    [Show full text]
  • 207620Orig1s000
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 207620Orig1s000 SUMMARY REVIEW Cross Discipline Team Leader Review 4. Nonclinical Pharmacology/Toxicology According to Dr. Link’s review, the preclinical toxicology program was well-conducted and thorough and the application can be approved from a pharmacology/toxicology perspective. Toxicology:3 Target organs for LCZ696 and/or sacubitril toxicity included the kidney, red blood cells, heart and gastrointestinal tract. In brief, findings included: renal juxtaglomerular hypertrophy/hyperplasia in the rat and monkey and renal tubular changes (tubular basophilia, cytoplasmic vacuolation and single cell necrosis) in the monkey; reversible changes in hematology parameters (e.g., decreases in red blood cell count, hemoglobin concentration, hematocrit, and reticulocytes); decreased heart weights without histopathological findings; and reversible microscopic changes of focal glandular stomach mucosal erosion and mixed cell inflammation in rats and emesis and diarrhea without histologic correlates in the cynomolgus monkey. According to Dr. Link, these findings reflected adaptive responses or resulted from exaggerated pharmacodynamic responses to high doses and do not raise concern for safe use in humans. See pages 240 to 242 of Dr. Link’s review for further discussion of these findings. Genotoxicity and carcinogenicity: According to the Carcinogenicity study review, sacubitril had no effect on survival or tumor incidence in mice or rats. In genetic toxicity studies of LCZ696, sacubitril, and the active metabolite LBQ657, there was no evidence of genotoxic potential. Reproductive toxicology: LCZ696 had no effect on fertility in rats. In embryo-fetal development studies in rats and rabbits, treatment with LCZ696 during organogenesis resulted in increased embryo-fetal lethality at clinically relevant doses.
    [Show full text]
  • Angiotensin Receptor-Neprilysin Inhibition (ARNI) in Heart Failure
    Int J Heart Fail. 2020 Apr;2(2):73-90 https://doi.org/10.36628/ijhf.2020.0002 pISSN 2636-154X·eISSN 2636-1558 Review Article Angiotensin Receptor-Neprilysin Inhibition (ARNI) in Heart Failure Barry Greenberg , MD Sulpizio Family Cardiovascular Center and University of California, San Diego Medical Center, La Jolla, CA, USA Received: Jan 1, 2020 ABSTRACT Revised: Mar 1, 2020 Accepted: Mar 4, 2020 Recognition that neurohormonal activation plays a central role in the pathogenesis of heart Correspondence to failure (HF) led to the development of angiotensin converting enzyme inhibitors (ACEIs), Barry Greenberg, MD angiotensin receptor blockers, mineralocorticoid receptor antagonists and beta blockers. Sulpizio Family Cardiovascular Center and University of California, San Diego Medical While there has been substantial success with these neurohormonal blocking drugs in Center, 9454 Medical Center Drive, La Jolla, patients with HF with reduced ejection fraction (HFrEF), persistently high rates of morbidity CA 92037-7411, USA. and mortality in this population underscore the need for more effective therapies. As part E-mail: [email protected] of the systemic neurohormonal activation that takes place in patients with HF, systems that counteract the adverse effect of the renin angiotensin aldosterone system (RAAS) and Copyright © 2020. Korean Society of Heart Failure sympathetic nervous system (SNS) are also activated. Evidence that neprilysin metabolizes This is an Open Access article distributed many of the effector molecules produced by these counter-regulatory systems raised the under the terms of the Creative Commons possibility that inhibition of this enzyme might be beneficial. However, since angiotensin Attribution Non-Commercial License (https:// II is a substrate of neprilysin, inhibition of the enzyme alone would increase levels of this creativecommons.org/licenses/by-nc/4.0) peptide.
    [Show full text]
  • Vasopeptidase Inhibition with Omapatrilat in Chronic Heart Failure: Acute and Long-Term Hemodynamic and Neurohumoral Effects Dougal R
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 39, No. 12, 2002 © 2002 by the American College of Cardiology Foundation ISSN 0735-1097/02/$22.00 Published by Elsevier Science Inc. PII S0735-1097(02)01881-8 Vasopeptidase Inhibition With Omapatrilat in Chronic Heart Failure: Acute and Long-Term Hemodynamic and Neurohumoral Effects Dougal R. McClean, MD,* Hamid Ikram, MD, PHD,* Sukh Mehta, MD,† J. Thomas Heywood, MD,‡ Michel F. Rousseau, MD,§ Alan L. Niederman, MD,࿣ Rafael F. Sequeira, MD,¶ Eckart Fleck, MD,# Steven N. Singh, MD,** Benoit Coutu, MD,†† Peter Hanrath, MD,‡‡ Michel Komajda, MD,§§ Catherine C. Bryson,࿣࿣ Chunlin Qian, PHD,࿣࿣ James J. Hanyok, PHARMD,࿣࿣ for the Omapatrilat Hemodynamic Study Group Christchurch, New Zealand; San Bernadino and Loma Linda, California; Brussels, Belgium; Fort Lauderdale and Miami, Florida; Berlin and Aachen, Germany; Washington, DC; Montreal, Canada; Paris, France; and Princeton, New Jersey OBJECTIVES We investigated the acute and long-term hemodynamic and neurohumoral effects of the vasopeptidase inhibitor omapatrilat in human heart failure. BACKGROUND Angiotensin-converting enzyme (ACE) inhibition constitutes a major advance in the treatment of chronic heart failure (CHF). Simultaneous inhibition of both neutral endopep- tidase and ACE with omapatrilat may represent a new treatment strategy in CHF. METHODS Three hundred and sixty-nine patients with symptomatic heart failure were randomized to double-blind treatment with omapatrilat (first 190 patients: 2.5 mg, 5 mg or 10 mg; last 179 patients: 2.5 mg, 20 mg or 40 mg once daily) for 12 weeks.
    [Show full text]
  • Telmisartan Versus Angiotension-Converting
    Journal of Human Hypertension (2009) 23, 339–349 & 2009 Macmillan Publishers Limited All rights reserved 0950-9240/09 $32.00 www.nature.com/jhh ORIGINAL ARTICLE Telmisartan versus angiotension- converting enzyme inhibitors in the treatment of hypertension: a meta-analysis of randomized controlled trials Z Zou1,3, G-L Xi2,3, H-B Yuan1, Q-F Zhu1 and X-Y Shi1 1Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai, People’s Republic of China and 2Center for New Drug Evaluation, Institute of Basic Medical Science, Second Military Medical University, Shanghai, People’s Republic of China Telmisartan and angiotensin-converting enzyme inhibi- 0.33–2.62). Telmisartan also showed a greater DBP tors (ACEIs) are both effective and widely used response rate than enalapril (relative risk (RR) 1.15, antihypertensive drugs targeting renin–angiotensin– 95% CI 1.05–1.26), ramipril (RR 1.34, 95% CI 1.11–1.61) aldosterone system. The study aimed to estimate the and perindopril (RR 1.22, 95% CI 1.05–1.41). There was efficacy and tolerability of telmisartan in comparison no statistical difference in DBP reduction or therapeutic with different ACEIs as monotherapy in the treatment of response rate between telmisartan and lisinopril (WMD hypertension. Cochrane Central Register of Controlled À0.30, 95% CI À0.65 to 0.05; RR 0.99, 95% CI 0.80–1.23, Trials, PubMed and Embase were searched for relevant respectively). Telmisartan had fewer drug-related studies. A meta-analysis of all randomized controlled adverse events than enalapril (RR 0.57, 95% CI 0.44–0.74), trials fulfilling the predefined criteria was performed.
    [Show full text]
  • Vasopeptidase Inhibition Restores Renovascular Endothelial Dysfunction in Salt-Induced Hypertension
    J Am Soc Nephrol 12: 2280–2287, 2001 Vasopeptidase Inhibition Restores Renovascular Endothelial Dysfunction in Salt-Induced Hypertension THOMAS QUASCHNING,* LIVIUS V. D’USCIO,* SIDNEY SHAW,† HERMANN-JOSEF GRO¨ NE,‡ FRANK RUSCHITZKA,§ and THOMAS F. LU¨ SCHER§ *Cardiovascular Research, Institute of Physiology, University of Zu¨rich, Zu¨rich, Switzerland; †Clinical Research, Inselspital, University of Bern, Bern, Switzerland; ‡Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; and §Cardiovascular Center and Cardiology, University of Zu¨rich, Zu¨rich, Switzerland. Abstract. Renovascular hemodynamics plays a pivotal role in 6%; P Ͻ 0.05) as well as contractions to endothelin-1 (ET-1) the regulation of BP. The effect of the vasopeptidase inhibitor (98 Ϯ 5% versus 128 Ϯ 5%; P Ͻ 0.05) and big ET-1 (47 Ϯ 6% omapatrilat (O) and the ACE-inhibitor captopril (C) on endo- versus 116 Ϯ 7%; P Ͻ 0.05) were markedly reduced as thelial function in the renal circulation in salt-induced hyper- compared with control animals, whereas standardized aortic tension were investigated. Dahl salt-sensitive rats (n ϭ 6 per weight and heart weight (4.9 Ϯ 0.4 versus 3.2 Ϯ 0.3 g/kg; group) on standard or salt-enriched chow were treated for 8 wk P Ͻ 0.05) increased. Treatment with O restored endotheli- with O (36 Ϯ 4 mg/kg per d), C (94 Ϯ 2 mg/kg per d), or um-dependent relaxations (88 Ϯ 6%; P Ͻ 0.05 versus C) placebo. Renal arteries were suspended in organ chambers for and contractions to ET-1 (120 Ϯ 6%) and big ET-1 (98 Ϯ isometric tension recording.
    [Show full text]
  • Reacciones Adversas Causadas Por Fármacos Activos En El Sistema Renina Angiotensina Aldosterona: Descripción De Un Nuevo Síndrome
    Programa de Doctorado en Medicina Clínica REACCIONES ADVERSAS CAUSADAS POR FÁRMACOS ACTIVOS EN EL SISTEMA RENINA ANGIOTENSINA ALDOSTERONA: DESCRIPCIÓN DE UN NUEVO SÍNDROME Tesis Doctoral presentada por ANA MARGARITA MONTORO DE FRANCISCO Directores: DR. MELCHOR ÁLVAREZ DE MON SOTO DRA. AMELIA GARCÍA LUQUE Alcalá de Henares, 2016 A mi familia. Agradecimientos Esta tesis doctoral se ha realizado en el Servicio de Alergología del Hospital Central de la Defensa “Gómez Ulla;” quiero agradecer a la Dirección del Hospital y a los Jefes de los Servicios la posibilidad que me han dado para poder llevar a cabo este trabajo desde el año 2009. A la Doctora Amelia García Luque del Servicio de Farmacología Clínica por su orientación, apoyo, ánimo y ayuda desde los momentos preliminares hasta las correcciones del manuscrito. Destacar su afán de superación contagioso y sobre todo su accesibilidad y calor humano. A todos los miembros del Servicio de Alergología, especialmente al Doctor José María Mateos Galván, con quién coincidí en los dos primeros años mi formación como especialista en Alergología por su espíritu crítico y capacidad de análisis. A los médicos internos residentes que he tutorizado desde 2009 por su buena actitud y colaboración. A la Doctora María Rubio Sotés, Jefa de Servicio de Alergología del Hospital General Universitario Gregorio Marañón por su impagable ejemplo y sus consejos durante mis años de formación. A las enfermeras del Servicio de Alergología: Esperanza, Paloma, Teresa y Beatriz por su colaboración desinteresada. A todos los pacientes que han participado en este trabajo por su buena disposición y constancia en su colaboración. A mis padres, porque sin ellos no habría logrado ninguna de las metas que me propuse y no sería lo que soy hoy.
    [Show full text]
  • Vasopeptidase Inhibition: a New Treatment Approach for Endothelial Dysfunction
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Kidney International, Vol. 63, Supplement 84 (2003), pp. S54–S57 Vasopeptidase inhibition: A new treatment approach for endothelial dysfunction THOMAS QUASCHNING,JAN GALLE, and CHRISTOPH WANNER Department of Medicine, Division of Nephrology, University Clinic Wu¨rzburg, Wu¨rzburg, Germany Vasopeptidase inhibition: A new treatment approach for endo- of potent paracrine mediators such as nitric oxide (NO), thelial dysfunction. Angiotensin-converting enzyme (ACE) in- angiotensin II, and endothelin-1 (Fig. 1). The different hibition is a well-established principle in the treatment of endo- circulating and local systems show important synergisms thelial dysfunction. Numerous preclinical and clinical studies have clearly demonstrated the beneficial effects of inhibiting and interactions. They may either have synergistic effects the renin-angiotensin-aldosterone system (RAS) in states of im- or may be the functional counterpart of another system paired endothelial function. The successful use of ACE inhibi- in a subtle multivariate balance. As such, atrial natriuretic tors encouraged attempts to inhibit other key enzymes in the peptides (ANP) counteract the effects of angiotensin II. regulation of vascular tone, such as the neutral endopeptidase (NEP). Similar to ACE, NEP is an endothelial cell surface metal- Since effects of endothelium-derived substances are not loproteinase that is involved in the degradation of several regu- limited to vasoconstriction or vasodilatation, but may also latory peptides, including the natriuretic peptides, and, thus, include regulation of mitogenesis, endothelial dysfunc- NEP inhibition augments vasodilatation and natriuresis through tion not only affects the function of the cardiovascular increased levels of atrial natriuretic peptide (ANP).
    [Show full text]