Cardiovascular Consequences of Peptidase Inhibition
肽酶抑制的心血管后果
基本信息
- 批准号:9257457
- 负责人:
- 金额:$ 46.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-01 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Coronary EventAdultAffectAgonistAlcohol or Other Drugs useAngiotensin IIAngiotensin ReceptorAngiotensin-Converting Enzyme InhibitorsAntidiabetic DrugsAntihypertensive AgentsArginineAttenuatedBlood GlucoseBlood PressureBlood VesselsC FiberCardiovascular systemCaringCessation of lifeChronicClinical TreatmentClinical TrialsDataDiabetes MellitusDipeptidyl PeptidasesDipeptidyl-Peptidase IVDoseDrug usageEnzyme InhibitionEventForearmGastric Inhibitory PolypeptideGlucoseHeart DiseasesHeart RateHeart failureHospitalizationHypertensionHypoglycemiaIndividualInjuryInterruptionKidneyKidney DiseasesKidney FailureLeadMetabolic syndromeMicrovascular DysfunctionMyocardial InfarctionNerveNon-Insulin-Dependent Diabetes MellitusNorepinephrineOralOutcomePatientsPeptide HydrolasesPeptidesPeptidyl-Dipeptidase APeroxisome Proliferator-Activated ReceptorsPharmaceutical PreparationsPlacebosPrevalenceProlinePublishingReceptor InhibitionReceptor, Angiotensin, Type 1Recording of previous eventsRenin-Angiotensin SystemReportingRetinal DiseasesRiskRisk FactorsRodentStrokeSubstance PSulfonylurea CompoundsSympathetic Nervous SystemTestingTimeVascular PermeabilitiesVasodilationWeight Gainaprepitantbasecardiovascular risk factordiabetes riskdiabeticenzyme substrateglucagon like peptideglucagon-like peptideglucagon-like peptide 1heart disease riskhemodynamicsinhibitor/antagonistmacrovascular diseaseneuropeptide Ypeptide analogpersonalized strategiespreventpublic health relevancerandomized placebo controlled trialreceptorresponsestandard of carethrombolysistreatment strategyvasoconstriction
项目摘要
DESCRIPTION (provided by applicant): Dipeptidyl peptidase IV (DPP4) inhibitors are orally available antidiabetic agents that decrease blood glucose by preventing the degradation of incretins such as glucagon-like peptide 1 and gastric inhibitory peptide. The global market for DPP4 inhibitors has been forecast to reach $10.1 billion by the year 2017. Diabetics are at increased risk of cardiovascular death. Interruption of the renin-angiotensin system (RAS) reduces cardiovascular events in patients with diabetes and risk of heart disease. In clinical trials examining the cardiovascular effects of DPP4 inhibitors, over eighty percent of patients were taking angiotensin- converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Understanding the interactive cardiovascular effects of DPP4 inhibitors and RAS inhibiting drugs is of the utmost importance. In addition to preventing degradation of incretins, DPP4 inhibitors prevent degradation of other peptides with a penultimate amino-terminus arginine or proline, including the ACE substrate substance P. During ACE inhibition, an increased proportion of substance P is degraded by DPP4. Inhibition of both DPP4 and ACE potentiates effects of substance P in rodents. Substance P causes vasodilation and vascular permeability, but also stimulates release of norepinephrine and the DPP4 substrate neuropeptide Y (NPY) from nerve terminals. Sympathetic activation by substance P could have deleterious effects in hypertension and heart failure. We have discovered a hemodynamic interaction between DPP4 inhibition and ACE inhibition that may reduce the beneficial cardiovascular effects of ACE inhibitors. Specifically, we have found that DPP4 inhibition decreases the blood pressure response to acute maximal ACE inhibition and increases heart rate and circulating norepinephrine in individuals with the metabolic syndrome. In addition, we have found that intra- arterial substance P stimulates vascular release of norepinephrine when both DPP4 and ACE are inhibited. We propose to test the overarching hypothesis that DPP4 inhibition attenuates the antihypertensive effect of chronic ACE inhibition by increasing activation of the sympathetic nervous system by endogenous substance P. In Aim 1, we will test the hypothesis that DPP4 inhibition decreases the anti-hypertensive effect of chronic ACE inhibition, but not angiotensin receptor blockade, in patients with type 2 diabetes. We will assess
the contribution of endogenous substance P to the effects of combined DPP4 and ACE inhibition using the substance P (NK1) receptor blocker aprepitant. In Aim 2, we will test the hypothesis that substance P increases norepinephrine spillover and net vascular release of NPY through an NK1 receptor-dependent mechanism during combined DPP4 and ACE inhibition in individuals with type 2 diabetes. In Aim 3, we will test the hypothesis that DPP4 inhibition also prevents the degradation of NPY, leading to increased vasoconstriction and forearm norepinephrine spillover in diabetics. Results of these studies could affect treatment of millions of people with diabetes and high blood pressure.
描述(由申请方提供):二肽基肽酶IV(DPP 4)抑制剂是一种口服降糖药,通过防止肠促胰岛素(如胰高血糖素样肽1和胃抑制肽)降解来降低血糖。据预测,到2017年,DPP 4抑制剂的全球市场将达到101亿美元。 糖尿病患者心血管死亡的风险增加。阻断肾素-血管紧张素系统(RAS)可降低糖尿病患者的心血管事件和心脏病风险。在检查DPP 4抑制剂的心血管作用的临床试验中,超过80%的患者服用血管紧张素转换酶(ACE)抑制剂或血管紧张素受体阻滞剂(ARB)。了解DPP 4抑制剂和RAS抑制药物的相互作用对心血管的影响至关重要。 除了防止肠降血糖素的降解外,DPP 4抑制剂还防止具有倒数第二个氨基末端精氨酸或脯氨酸的其他肽的降解,包括ACE底物物质P。在ACE抑制期间,增加的P物质比例被DPP 4降解。抑制DPP 4和ACE增强P物质在啮齿动物中的作用。P物质引起血管舒张和血管通透性,但也刺激去甲肾上腺素和DPP 4底物神经肽Y(NPY)从神经末梢释放。P物质激活交感神经可能对高血压和心力衰竭产生有害影响。 我们已经发现了DPP 4抑制和ACE抑制之间的血流动力学相互作用,这可能会降低ACE抑制剂的有益心血管作用。具体地说,我们已经发现,在代谢综合征患者中,DPP 4抑制降低了对急性最大ACE抑制的血压反应,并增加了心率和循环去甲肾上腺素。此外,我们发现当DPP 4和ACE都被抑制时,动脉内P物质刺激血管释放去甲肾上腺素。 我们建议测试的首要假设,即DPP 4抑制减弱慢性ACE抑制的抗高血压作用,通过增加内源性P物质的交感神经系统的激活。在目的1中,我们将测试的假设,DPP 4抑制降低慢性ACE抑制的抗高血压作用,但不血管紧张素受体阻滞剂,在2型糖尿病患者。我们将评估
内源性P物质对使用P物质(NK 1)受体阻断剂阿瑞匹坦联合抑制DPP 4和ACE的作用的贡献。在目标2中,我们将测试的假设,P物质增加去甲肾上腺素溢出和净血管释放的NPY通过NK 1受体依赖的机制,在2型糖尿病患者的DPP 4和ACE抑制。在目标3中,我们将检验这样的假设,即DPP 4抑制也阻止了NPY的降解,导致糖尿病患者血管收缩和前臂去甲肾上腺素溢出增加。 这些研究的结果可能会影响数百万糖尿病和高血压患者的治疗。
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)
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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:
$ 46.34万 - 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:
10186795 - 财政年份:2020
- 资助金额:
$ 46.34万 - 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:
$ 46.34万 - 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:
$ 46.34万 - 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:
$ 46.34万 - 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:
$ 46.34万 - 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:
$ 46.34万 - 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:
$ 46.34万 - 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:
$ 46.34万 - 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:
$ 46.34万 - 项目类别: