Mechanism(s) Underlying Hypotensive Response to ARB/NEP Inhibition
ARB/NEP 抑制引起低血压反应的机制
基本信息
- 批准号:10186795
- 负责人:
- 金额:$ 71.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-15 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdrenergic beta-AntagonistsAdverse effectsAffectAlteplaseAminopeptidase PAngioneurotic EdemaAngiotensin IAngiotensin IIAngiotensin ReceptorAngiotensin-Converting Enzyme InhibitorsAntidiabetic DrugsAntihypertensive AgentsAtrial Natriuretic FactorBiological AssayBlood PressureBlood flowBradykininBradykinin B2 ReceptorBrain natriuretic peptideC-Type Natriuretic PeptideCatecholaminesCessation of lifeChemicalsClinicalComplexDiabetes MellitusDiagnosisDipeptidyl PeptidasesDiuresisDiureticsDoseDrug InteractionsEFRACEnalaprilEndothelinEndotheliumFDA approvedFiberFibrinolysisForearmGenderGrantHeartHeart failureHospitalizationHypotensionImmunoassayInvestigational DrugsKidneyKidney FailureLabelLeadLife ExpectancyMeasuresMedicineMineralocorticoid ReceptorMolecularMorbidity - disease rateN-terminalNatriuresisNatriuretic PeptidesNeprilysinPatientsPeptidesPeptidyl-Dipeptidase APharmaceutical PreparationsPrevalenceProdrugsRaceRandomized Clinical TrialsReceptor, Angiotensin, Type 1Renin-Angiotensin-Aldosterone SystemResearchSensorySubstance PSubstance P ReceptorTestingTitrationsTreatment FailureUnited StatesVascular PermeabilitiesVasodilationVasodilator AgentsWorkaprepitantbaseblood pressure reductioncardiovascular pharmacologyclinical practiceexperiencehemodynamicshospital readmissionicatibantimprovedindividual patientinhibitor/antagonistmortalitynovelnovel drug classnovel therapeuticspeptide Ppreventprospectivereceptorresponsesalureticside effectvalsartan
项目摘要
PROJECT SUMMARY
Twenty percent of people in the United States will develop heart failure during their lives. Despite beneficial
effects of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta blockers,
and mineralocorticoid receptor antagonists on mortality, the five-year life expectancy of a patient with heart failure
is fifty percent. In 2015, the FDA approved LCZ696 (Entresto™), a molecular complex of the ARB valsartan and
sacubitril, a neprilysin (neutral endopeptidase-24.11) inhibitor prodrug, after LCZ696 reduced mortality compared
to enalapril in a randomized clinical trial in patients with heart failure, reduced ejection fraction, and increased
circulating brain natriuretic peptide (BNP) or N-terminal (NT) proBNP. LCZ696 also reduces rehospitalization in
acutely decompensated heart failure. Nevertheless, LCZ696 has been underutilized in clinical practice, and
concerns regarding hypotension have impeded use. The mechanism(s) through which the combined ARB and
neprilysin inhibitor reduces blood pressure are not fully known. Neprilysin degrades many vasoactive peptides
including the natriuretic peptides, angiotensins (Ang) I and II, endothelins, bradykinin, and substance P. In heart
failure patients, LCZ696 increases BNP, a neprilysin substrate, while decreasing the non-neprilysin substrate
NT-proBNP, suggesting that LCZ696 potentiates effects of the natriuretic peptide. On the other hand, natriuretic
peptides are poor substrates for neprilysin compared to bradykinin and substance P, which can have beneficial
effects on blood pressure, diuresis, natriuresis, fibrinolysis and remodeling but also contribute to adverse effects
like hypotension and angioedema. Our research group has extensive experience studying the contribution of
peptides to drugs that inhibit vasopeptidases such as ACE, dipeptidyl peptidase-4 (DPP4), and neprilysin. In this
proposal, we test the overarching hypothesis that bradykinin contributes to vasodilator, blood pressure and renal
effects of combined angiotensin receptor blockade/neprilysin inhibition. In Aim 1, we will test the hypothesis that
LCZ696 potentiates the effects of intra-arterial bradykinin, substance P, or BNP compared to valsartan alone.
We will test this hypothesis in the presence and absence of a DPP4 inhibitor, as it may enhance effects of
neprilysin inhibition. In Aim 2, we will test the hypothesis that endogenous bradykinin contributes to hypotensive,
natriuretic and diuretic effects of LCZ696 during initiation and up-titration in heart failure patients using a
bradykinin B2 receptor antagonist. In Aim 3, we will probe the contribution of endogenous substance P to effects
of LCZ696 using a substance P (NK1) receptor antagonist. In the combined Aims 2 and 3, we will assess
individual patient factors such as race, gender, BNP (measured both by clinical immunoassay and by specific
mass spectrometric assay), and NEP activity that predict blood pressure response to LCZ696. These studies
will provide novel information about the mechanism(s) of action of combined angiotensin receptor blockade and
neprilysin inhibition, and lead to new strategies to minimize adverse effects while maximizing beneficial effects
of this promising new class of drugs for heart failure.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Nancy J. Brown其他文献
Les effets secondaires aigus des inhibiteurs de l’enzyme de conversion de l’angiotensine dont l’angioœdème, différents dans leur étiologie clinique, partagent une physiopathologie semblable
血管紧张素转化酶抑制剂的第二效应与血管紧张素转化酶的效果不同,与临床病因学不同,与病理生理学相似
- DOI:
- 发表时间:
2008 - 期刊:
- 影响因子:0
- 作者:
A. Désormeaux;James Brian Byrd;Nancy J. Brown;A. Adam - 通讯作者:
A. Adam
Coordinated responses of plasma 20-HETE and soluble epoxide hydrolase to salt in normal subjects: alterations in salt-sensitive normotension
- DOI:
10.1016/j.jash.2014.03.254 - 发表时间:
2014-04-01 - 期刊:
- 影响因子:
- 作者:
Fernando Elijovich;Nancy J. Brown;Ginger L. Milne;Cheryl L. Laffer - 通讯作者:
Cheryl L. Laffer
Abstracts from the 10th C1-inhibitor deficiency workshop
- DOI:
10.1186/s13223-017-0198-5 - 发表时间:
2017-06-15 - 期刊:
- 影响因子:2.400
- 作者:
Alvin H. Schmaier;Marco Cicardi;Avner Reshef;Dumitru Moldovan;Attila Mócsai;Margarita López-Trascasa;Alberto López Lera;Nancy J. Brown;Anastasios E. Germenis;Rafael Filippelli-Silva;Diego A. Duarte;Renan P. Martin;Camila L. Veronez;Michel Bouvier;Michael Bader;Claudio M. Costa-Neto;João Bosco Pesquero;Xavier Charest-Morin;François Marceau;Georges-É. Rivard;Arnaud Bonnefoy;Éric Wagner;Márta L. Debreczeni;Zsuzsanna Németh;Erika Kajdácsi;Endre Schwaner;László Cervenak;Gábor Oroszlán;András Szilágyi;Ráhel Dani;Péter Závodszky;Péter Gál;József Dobó;Jacques Hébert;Matthieu Vincent;Jean-Nicolas Boursiquot;Hugo Chapdeleine;Marylin Desjardins;Benoit Laramée;Rémi Gagnon;Nancy Payette;Oleksandra Lepeshkina;Delphine Charignon;Arije Ghannam;Denise Ponard;Christian Drouet;Kusumam Joseph;Baby G. Tholanikunnel;Daniel J. Sexton;Allen P. Kaplan;Stefania Loffredo;Maria Bova;Anne Lise Ferrara;Angelica Petraroli;Chiara Suffritti;Nóra Veszeli;Andrea Zanichelli;Henriette Farkas;Gianni Marone;Samuel Luyasu;Bertrand Favier;Ludovic Martin;Kinga Viktória Kőhalmi;György Temesszentandrási;Katalin Várnai;Lilian Varga;Bruce L. Zuraw;Annette Feussner;Michael A. Tortorici;Dipti Pawaskar;Huamin Henry Li;John Anderson;Jonathan A. Bernstein;Ying Zhang;Ingo Pragst;Emel Aygören-Pürsün;Kraig Jacobson;Jim Christensen;Arthur Van Leerberghe;Yi Wang;Jennifer Schranz;Inmaculada Martinez-Saguer;Daniel Soteres;Urs Steiner;Vesna Grivcheva Panovska;William Rae;Werner Aberer;Aarnoud Huissoon;Anette Bygum;Markus Magerl;Jochen Graff;Hilary Longhurst;Ramón Lleonart;Lei Fang;Melanie Cornpropst;Desiree Clemons;Amanda Mathis;Phil Collis;Sylvia Dobo;William P. Sheridan;Marcus Maurer;Marc A. Riedl;Timothy Craig;Aleena Banerji;Mustafa Shennak;William Yang;Jovanna Baptista;Paula Busse;Ira Kalfus;Andrew McDonald;Shawn Qian;Anthony Roberts;Con Panousis;Tim Green;Andreas Gille;Maria Zamanakou;Gedeon Loules;Dorottya Csuka;Fotis Psarros;Faidra Parsopoulou;Matthaios Speletas;Davide Firinu;Tiziana Maria Angela De Pasquale;Alessandra Zoli;Anna Radice;Stefano Pizzimenti;Emmanouil Manoussakis;George N. Konstantinou;Valeria Bafunno;Vincenzo Montinaro;Mauro Cancian;Maurizio Margaglione;Konrad Bork;Karin Wulff;Guenther Witzke;Jochen Hardt;Laurence Bouillet;Teresa Caballero;Anete S. Grumach;Christelle Pommie;Irmgard Andresen;Carmen Escuriola Ettingshausen;Zeynep Gutowski;Karin Andritschke;Richard Linde;Noémi Andrási;Tamás Szilágyi;Iris Leibovich-Nassi;Christine Symons;John Dempster;Isabelle Boccon-Gibod;Anne Pagnier;Audrey Lehmann;Kristian B. Kreiberg;Sandra A. Nieto;Raquel Martins;Renata Martins;Alejandra Menendez;Solange O. R. Valle;Margarita Olivares;Maria E. Hernandez-Landeros;Elma Nievas;Natalia Fili;Olga M. Barrera;René Bailleau;Ana Maria Gallardo-Olivos;Masumi Grau;Julian Rodriguez-Galindo;Marlon J. O. Carabantes;Edison Zapata-Venegas;Mario Martinez Alfonso;Maria Rosario-Grauert;Manuel Ratti;Daniel Vaszquez;Dario Josviack;Luis Fernando Landivar-Salinas;Oscar M. E. Calderón-Llosa;Rolando Campilay-Sarmiento;Pablo Raby;Jose Fabiani;William R. Lumry;Henrike Feuersenger;Douglas J. Watson;Thomas Machnig;Donatella Lamacchia;Adriana Hernanz;Ana Alvez;Mariana Lluncor;Maria Pedrosa;Rosario Cabañas;Nieves Prior;Patrik Nordenfelt;Mats Nilsson;Anders Lindfors;Carl-Fredrik Wahlgren;Janne Björkander;Roman Hakl;Pavel Kuklínek;Irena Krčmová;Jana Hanzlíková;Martina Vachová;Radana Zachová;Marta Sobotková;Jana Strenková;Jiří Litzman;Maria Palasopoulou;Gerasimina Tsinti;Panagiota Gianni;Maria Kompoti;Sofia Garrido;Wojciech Dyga;Anna Bogdali;Aleksander Obtułowicz;Mikolajczyk Tomasz;Ewa Czarnobilska;Krystyna Obtulowicz;Teofila Książek;Anna Koncz;Dominik Gulyás;Maria Staevska;Milos Jesenak;Katarina Hrubiskova;L. Bellizzi;A. Relan;Maddalena A. Wu;Antonio Castelli;Riccardo Colombo;Gianmarco Podda;Marta Del Medico;Emanuele Catena;Francesco Casella;Francesca Perego;Nada Afifi Afifi;Eleonora Tobaldini;Nicola Montano;Marta Sánchez-Jareño;Marcin Stobiecki;Krystyna Obtułowicz;Irina Guryanova;Ekaterina Polyakova;Viktar Lebedz;Andrej Salivonchik;Svetlana Aleshkevich;Mikhail Belevtsev;Melanie Nordmann-Kleiner;Susanne Trainotti;Janina Hahn;Jens Greve;Liudmyla Zabrodska;Maria L. Oliva Alonso;Rosangela P. Tórtora;Alfeu T. França;Marcia G. Ribeiro;Lisa Fu;Amin Kanani;Gina Lacuesta;Susan Waserman;Stephen Betschel;Melissa I. Espinosa;Francisco A. Contreras;Martin Hrubisko;Ludmila Vavrova;Peter Banovcin;Maryam Ayazi;Mohammad Reza Fazlollahi;Shiva Saghafi;Sajedeh Mohammadian;Susan Nabilou Deshiry;Kiana Bidad;Raheleh Shokouhi Shoormasti;Iraj Mohammadzadeh;Mohammad Hassan Bemanian;Seyed Alireza Mahdaviani;Zahra Pourpak;Anna Valerieva;Mariela Vasileva;Tsvetelina Velikova;Elena Petkova;Vasil Dimitrov;Ruggero Di Maulo;Raz Somech;Hava Golander;Erika J. Sifuentes;Catherine Mansard;Anne Gompel;Bernard Floccard;Claire Blanchard-Delaunay;David Launay;Olivier Fain;Alain Sobel;Stéphane Gayet;Stéphanie Amarger;Guillaume Armengol;Yann Ollivier;Ariane Zélinsky-Gurung;Pierre-Yves Jeandel;Gisèle Kanny;Brigitte Coppéré;Marie Dubrel;Fabien Pelletier;Aurélie Du Thanh;Sébastien Trouiller;Jérôme Laurent;Claire De Moreuil;Christine Audouin Pajot;Alexandre Belot;Ana Rodríguez;Dasha Roa;Alicia Prieto;Maria Luisa Baeza;Borislava Krusheva;Stephanie K. A. Almeida;Rosemeire N. Constantino-Silva;Nyla Melo;Joanna Araujo Simoes;Sandra Mitie U. Palma;Jane da Silva;Bruna F. de Azevedo;Eli Mansour;Teresa González-Quevedo;Carmen Marcos;Teófilo Lobera;Blanca Sáenz de San Pedro;Ernie Avilla;Jacquie Badiou;Karen Binkley;Rozita Borici-Mazi;Linda Howlett;Paul K. Keith;Anne Rowe;Peter Waite;Aurore Billebeau;Isabelle Boccon-Gibbod;Kristina Lis;Yael Laitman;Eitan Friedman;N. M. Gokmen;O. Gulbahar;H. Onay;Z. P. Koc;A. Z. Sin - 通讯作者:
A. Z. Sin
Nancy J. Brown的其他文献
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{{ truncateString('Nancy J. Brown', 18)}}的其他基金
Mechanism(s) Underlying Hypotensive Response to ARB/NEP Inhibition
ARB/NEP 抑制引起低血压反应的机制
- 批准号:
9884685 - 财政年份:2020
- 资助金额:
$ 71.09万 - 项目类别:
Mechanism(s) Underlying Hypotensive Response to ARB/NEP Inhibition
ARB/NEP 抑制引起低血压反应的机制
- 批准号:
10456298 - 财政年份:2020
- 资助金额:
$ 71.09万 - 项目类别:
Mechanism(s) Underlying Hypotensive Response to ARB/NEP Inhibition
ARB/NEP 抑制引起低血压反应的机制
- 批准号:
10755424 - 财政年份:2020
- 资助金额:
$ 71.09万 - 项目类别:
Mechanism(s) Underlying Hypotensive Response to ARB/NEP Inhibition
ARB/NEP 抑制引起低血压反应的机制
- 批准号:
10620715 - 财政年份:2020
- 资助金额:
$ 71.09万 - 项目类别:
Variation in Soluble Epoxide Hydrolase Activity and Human Insulin Sensitivity
可溶性环氧化物水解酶活性和人胰岛素敏感性的变化
- 批准号:
10170332 - 财政年份:2018
- 资助金额:
$ 71.09万 - 项目类别:
Variation in Soluble Epoxide Hydrolase Activity and Human Insulin Sensitivity
可溶性环氧化物水解酶活性和人胰岛素敏感性的变化
- 批准号:
9981733 - 财政年份:2018
- 资助金额:
$ 71.09万 - 项目类别:
Cardiovascular Consequences of Peptidase Inhibition
肽酶抑制的心血管后果
- 批准号:
9257457 - 财政年份:2015
- 资助金额:
$ 71.09万 - 项目类别:
Cardiovascular Consequences of Peptidase Inhibition
肽酶抑制的心血管后果
- 批准号:
9270750 - 财政年份:2015
- 资助金额:
$ 71.09万 - 项目类别:
Cardiovascular Consequences of Peptidase Inhibition
肽酶抑制的心血管后果
- 批准号:
8960866 - 财政年份:2015
- 资助金额:
$ 71.09万 - 项目类别:
Recombinant Neuregulin for the treatment of Heart Failure
重组神经调节蛋白治疗心力衰竭
- 批准号:
7867106 - 财政年份:2010
- 资助金额:
$ 71.09万 - 项目类别: