RESUMO
In heart failure (HF), the cardiac hormone natriuretic peptides (NPs) atrial (ANP), B-type (BNP), and C-type (CNP) play a key role to protect cardiac remodeling. The proprotein convertases corin and furin process their respective pro-NPs into active NPs. Here we define in a canine model of HF furin and corin gene and protein expression in normal and failing left atrium (LA) or ventricle (LV) testing the hypothesis that the NP proproteins convertases production is altered in experimental HF. Experimental canine HF was produced by rapid right ventricular pacing for 10 days. NPs, furin, and corin mRNA expression were determined by quantitative RT-PCR. Protein concentration or expression was determined by immunostaining, radioimmunoassay, or Western blot. Furin and corin proteins were present in normal canine LA and LV myocardium and vasculature and in smooth muscle cells. In normal canines, expression of NPs was dominant in the atrium compared with the ventricle. In experimental early stage HF characterized with marked atrial fibrosis, ANP, BNP, and CNP mRNA, and protein concentrations were higher in HF LA but not HF LV compared with normals. In LA, corin mRNA and protein expressions in HF were lower, whereas furin mRNA and protein expressions were higher than normals. NPs and furin expressions were augmented in the atrium in experimental early stage HF and, conversely, corin mRNA and protein expressions were decreased with atrial remodeling. Selective changes of these NP convertases may have significance in the regulation of pro-NP processing and atrial remodeling in early stage HF.
Assuntos
Furina/metabolismo , Insuficiência Cardíaca/enzimologia , Ventrículos do Coração/enzimologia , Miocárdio/enzimologia , Peptídeos Natriuréticos/metabolismo , Precursores de Proteínas/metabolismo , Serina Endopeptidases/metabolismo , Animais , Western Blotting , Estimulação Cardíaca Artificial , Modelos Animais de Doenças , Cães , Fibrose , Furina/genética , Átrios do Coração/enzimologia , Átrios do Coração/patologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Ventrículos do Coração/patologia , Humanos , Imuno-Histoquímica , Masculino , Miocárdio/patologia , Peptídeos Natriuréticos/genética , Precursores de Proteínas/genética , RNA Mensageiro/metabolismo , Radioimunoensaio , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina Endopeptidases/genética , Fatores de Tempo , Remodelação VentricularRESUMO
Both cardiovascular and renal diseases are common and frequently coexist in the same patient. Indeed, renal dysfunction has been shown to be a more powerful independent predictor of poor outcomes in heart failure (HF) than left ventricular ejection fraction or functional class. Furthermore, acute kidney injury is a frequent therapeutic concern in heart failure. Consequently, there has been much interest in developing new renoprotective treatments and novel biomarkers to monitor renal function. Additionally, given the crucial cardiorenal interaction and interdependence, the concept of a cardiorenal syndrome with five different subtypes has been advanced to better categorize patients and facilitate research.
Assuntos
Insuficiência Cardíaca/epidemiologia , Nefropatias/epidemiologia , Injúria Renal Aguda/epidemiologia , Biomarcadores/sangue , Síndrome Cardiorrenal/epidemiologia , Comorbidade , Progressão da Doença , Diuréticos/uso terapêutico , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Hemofiltração , Humanos , Rim/fisiopatologia , Nefropatias/diagnóstico , Nefropatias/fisiopatologia , Monitorização Fisiológica/métodos , PrognósticoRESUMO
Alternative RNA splicing may provide unique opportunities to identify drug targets and therapeutics. We identified an alternative spliced transcript for B-type natriuretic peptide (BNP) resulting from intronic retention. This transcript is present in failing human hearts and is reduced following mechanical unloading. The intron-retained transcript would generate a unique 34 amino acid (aa) carboxyl terminus while maintaining the remaining structure of native BNP. We generated antisera to this carboxyl terminus and identified immunoreactivity in failing human heart tissue. The alternatively spliced peptide (ASBNP) was synthesized and unlike BNP, failed to stimulate cGMP in vascular cells or vasorelax preconstricted arterial rings. This suggests that ASBNP may lack the dose-limiting effects of recombinant BNP. Given structural considerations, a carboxyl-terminal truncated form of ASBNP was generated (ASBNP.1) and was determined to retain the ability of BNP to stimulate cGMP in canine glomerular isolates and cultured human mesangial cells but lacked similar effects in vascular cells. In a canine-pacing model of heart failure, systemic infusion of ASBNP.1 did not alter mean arterial pressure but increased the glomerular filtration rate (GFR), suppressed plasma renin and angiotensin, while inducing natriuresis and diuresis. Consistent with its distinct in vivo effects, the activity of ASBNP.1 may not be explained through binding and activation of NPR-A or NPR-B. Thus, the biodesigner peptide ASBNP.1 enhances GFR associated with heart failure while lacking the vasoactive properties of BNP. These findings demonstrate that peptides with unique properties may be designed based on products of alternatively splicing.
Assuntos
Processamento Alternativo/efeitos dos fármacos , Desenho de Fármacos , Rim/efeitos dos fármacos , Peptídeo Natriurético Encefálico/genética , Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Bovinos , Cães , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Dados de Sequência Molecular , Peptídeo Natriurético Encefálico/química , Peptídeo Natriurético Encefálico/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores do Fator Natriurético Atrial/metabolismoRESUMO
BACKGROUND: We previously reported the feasibility of an acute, orally delivered, newly developed, conjugated form of human B-type natriuretic peptide (hBNP) in normal animals. The objective of the present study was to extend our findings and to define the chronic actions of an advanced oral conjugated hBNP (hBNP-054) administered for 6 days on sodium excretion and blood pressure. We also sought to establish the ability of this new conjugate to acutely activate cGMP and to reduce blood pressure in an experimental model of angiotensin II (ANG II) -mediated hypertension. METHODS AND RESULTS: First, we developed additional novel conjugated forms of oral hBNP that were superior to our previously reported hBNP-021 in reducing blood pressure in 6 normal dogs. We then tested the new conjugate, hBNP-054, chronically in 2 normal dogs to assess its biological actions as a blood pressure-lowering agent and as a natriuretic factor. Second, we investigated the effects of acute oral hBNP-054 or vehicle in 6 dogs that received continuous infusion of ANG II to induce hypertension. After baseline determination of mean blood pressure (MAP) and blood collection for plasma hBNP and cGMP, all dogs received continuous ANG II infusion (20 ng . kg(-1) . min(-1), 1 mL/min) for 4 hours. After 30 minutes of ANG II, dogs received oral hBNP-054 (400 microg/kg) or vehicle in a random crossover fashion with a 1-week interval between dosing. Blood sampling and MAP measurements were repeated 30 minutes after ANG II administration and 10, 30, 60, 120, 180, and 240 minutes after oral administration of hBNP-054 or vehicle. In the chronic study in normal dogs, oral hBNP-054 effectively reduced MAP for 6 days and induced a significant increase in 24-hour sodium excretion. hBNP was not present in the plasma at baseline in any dogs, and it was not detected at any time in the vehicle group. However, hBNP was detected throughout the duration of the study after oral hBNP-054, with a peak concentration at 30 minutes of 1060+/-818 pg/mL. In the acute study, after ANG II administration, plasma cGMP was not activated after vehicle, whereas it was significantly increased after oral hBNP-054 (P=0.01 between the 2 groups). Importantly, MAP was significantly increased after ANG II throughout the acute study protocol. However, although no changes occurred in MAP after vehicle administration, oral hBNP-054 reduced MAP for >2 hours (from 138+/-1 mm Hg after ANG II to 124+/-2 mm Hg at 30 minutes, 124+/-2 mm Hg at 1 hour, and 130+/-5 mm Hg at 2 hours after oral hBNP-054; P<0.001). CONCLUSIONS: This study reports for the first time that a novel conjugated oral hBNP possesses blood pressure-lowering and natriuretic actions over a 6-day period in normal dogs. Furthermore, hBNP-054 activates cGMP and reduces MAP in a model of acute hypertension. These findings advance the concept that orally administered chronic BNP is a potential therapeutic strategy for cardiovascular diseases such as hypertension.
Assuntos
Angiotensina II/toxicidade , Hipertensão/tratamento farmacológico , Peptídeo Natriurético Encefálico/análogos & derivados , Peptídeo Natriurético Encefálico/administração & dosagem , Administração Oral , Sequência de Aminoácidos , Angiotensina II/sangue , Animais , Cães , Esquema de Medicação , Hipertensão/sangue , Hipertensão/induzido quimicamente , Masculino , Dados de Sequência Molecular , Peptídeo Natriurético Encefálico/sangue , Distribuição AleatóriaRESUMO
Congestive heart failure (CHF) is characterized by fluid and water retention, which frequently is a therapeutic challenge. Most conventional diuretics act primarily as saluretics, i.e. they inhibit renal tubular electrolyte reabsorption, which due to osmotic pressure promotes excretion of isotonic fluid. Arginine vasopressin (AVP) via the V(1A) receptor vasoconstricts and via the V(2) receptor promotes water reabsorption in the renal collecting duct by inserting aquaporin-2 water channels into the luminal membrane. Novel V(2) receptor antagonists act as powerful aquaretics, i.e. they excrete free water. We review the pharmacology of non-selective V(1A)/V(2) receptor antagonists and selective V(2) receptor antagonists currently in clinical development.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Arginina Vasopressina/metabolismo , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Azepinas/farmacologia , Azepinas/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico , Insuficiência Cardíaca/metabolismo , Humanos , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Pirróis , Receptores de Vasopressinas/classificação , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , TolvaptanRESUMO
Heart failure (HF) is a common disease that continues to be associated with high morbidity and mortality warranting novel therapeutic strategies. Cyclic guanosine monophosphate (cGMP) is the second messenger of several important signaling pathways based on distinct guanylate cyclases (GCs) in the cardiovascular system. Both the nitric oxide/soluble GC (NO/sGC) as well as the natriuretic peptide/GC-A (NP/GC-A) systems are disordered in HF, providing a rationale for their therapeutic augmentation. Soluble GC activation with conventional nitrovasodilators has been used for more than a century but is associated with cGMP-independent actions and the development of tolerance, actions which novel NO-independent sGC activators now in clinical development lack. Activation of GC-A by administration of naturally occurring or designer natriuretic peptides is an emerging field, as is the inhibition of enzymes that degrade endogenous NPs. Finally, inhibition of cGMP-degrading phosphodiesterases, particularly phosphodiesterase 5 provides an additional strategy to augment cGMP-signaling.
Assuntos
GMP Cíclico/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Peptídeos Natriuréticos/metabolismo , Animais , Ativadores de Enzimas/farmacologia , Inibidores Enzimáticos/farmacologia , Guanilato Ciclase/efeitos dos fármacos , Guanilato Ciclase/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Óxido Nítrico/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais , Guanilil Ciclase SolúvelRESUMO
Circulating levels of the BNP system can help in the diagnosis of cardiovascular disease and provide prognostic information not only for patients who have HF but also for the general population and other patient groups. Changes over time also carry prognostic information, and studies are assessing BNP-guided treatment strategies. With the identification of circulating molecular forms of BNP, new insights regarding the biology of the BNP system are emerging that may improve the diagnostic and prognostic value of BNP. Likewise, accounting for rs198389 (a common single nucleotide polymorphism that increases BNP levels) may help to further refine the use of components of the BNP system as biomarkers.
Assuntos
Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/terapia , Peptídeo Natriurético Encefálico/sangue , Biomarcadores/sangue , Doença Crônica , Insuficiência Cardíaca/sangue , Humanos , Peptídeo Natriurético Encefálico/fisiologia , Peptídeos Natriuréticos/sangue , Peptídeos Natriuréticos/fisiologia , Prognóstico , Fatores de TempoRESUMO
BACKGROUND: Renal dysfunction is an important independent prognostic factor in heart failure (HF). Cardiac resynchronization therapy (CRT) improves functional status and left ventricular (LV) function in HF patients with ventricular dyssynchrony, but the impact of CRT on renal function is less defined. We hypothesized that CRT would improve glomerular filtration rate as estimated by the abbreviated Modification of Diet in Renal Disease equation (eGFR). METHODS AND RESULTS: The Multicenter InSync Randomized Clinical Evaluation (MIRACLE) study evaluated CRT in HF patients with NYHA Class III-IV, ejection fraction Assuntos
Estimulação Cardíaca Artificial/métodos
, Taxa de Filtração Glomerular/fisiologia
, Insuficiência Cardíaca/terapia
, Rim/fisiopatologia
, Fator Natriurético Atrial/sangue
, Nitrogênio da Ureia Sanguínea
, Baixo Débito Cardíaco/fisiopatologia
, Baixo Débito Cardíaco/terapia
, Creatinina/sangue
, Método Duplo-Cego
, Feminino
, Seguimentos
, Insuficiência Cardíaca/sangue
, Hematócrito
, Hemoglobinas/análise
, Humanos
, Nefropatias/fisiopatologia
, Masculino
, Peptídeo Natriurético Encefálico/sangue
, Placebos
, Estudos Retrospectivos
, Resultado do Tratamento
, Função Ventricular Esquerda/fisiologia
RESUMO
Natriuretic peptides (NPs) secreted by the heart in response to volume overload are pleiotropic molecules with vasodilating, diuretic, natriuretic, antiproliferative, and antifibrotic actions. Functioning of the NP system is altered in congestive heart failure (CHF), suggesting that support of the NP system might be beneficial in treatment of acute and chronic CHF. Several approaches alone or in combination with other pharmacologic therapies have been shown to enhance function of the NP system: direct administration of native and designer NPs, inhibition of degradation of NPs and their second messenger (cyclic guanosine monophosphate ), and stimulation of cGMP generation. Despite increasing numbers of studies using NPs in therapy of acute and chronic CHF, several controversies regarding safety, efficacy, and dosing of NPs need to be addressed. Moreover, further research is warranted to identify the stages and etiologies of CHF that may profit from NP therapy.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Peptídeos Natriuréticos/metabolismo , Peptídeos Natriuréticos/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , Doença Aguda , Doença Crônica , GMP Cíclico/metabolismo , GMP Cíclico/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Peptídeo Natriurético Encefálico/metabolismo , Peptídeo Natriurético Encefálico/uso terapêutico , Peptídeo Natriurético Tipo C/metabolismo , Peptídeo Natriurético Tipo C/uso terapêutico , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema Renina-Angiotensina/fisiologia , Medição de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: The objective of this study was to address the feasibility and the biological activity of orally administered human brain natriuretic peptide (hBNP). Proprietary technology has been developed in which short, amphiphilic oligomers are covalently attached to peptides. The conjugated peptides are intended to have an improved pharmacokinetic profile and to enable oral administration. We hypothesized that novel oral conjugated hBNP (CONJ-hBNP) increases plasma hBNP, activates cGMP, and reduces mean arterial pressure (MAP). METHODS AND RESULTS: This randomized crossover-designed study tested the biological activity of oral CONJ-hBNP compared with oral native hBNP in normal conscious dogs. Measurements of MAP, plasma hBNP, and cGMP were made at baseline (BL) and repeated at 10, 30, 60, 120, 180, and 240 minutes after oral administration. Plasma hBNP was not detectable in dogs at BL. Plasma hBNP was detected after native hBNP and CONJ-HBNP administration. However, plasma hBNP concentration was significantly higher after CONJ-hBNP than after native hBNP administration (P=0.0374 between groups). Plasma cGMP increased after CONJ-hBNP for 60 minutes (from 10.8+/-3 to 36.8+/-26 pmol/mL; P<0.05), whereas it did not change after native hBNP (P=0.001 between groups). MAP decreased at 10 minutes and remained decreased for 60 minutes after CONJ-hBNP (from 113+/-8 to 101+/-12 mm Hg after 10 minutes to 97.5+/-10 mm Hg after 30 minutes to 99+/-13 mm Hg after 60 minutes) while remaining unchanged after native hBNP (P=0.0387 between groups). CONCLUSIONS: This study reports for the first time that novel conjugated oral BNP activates cGMP and significantly reduces MAP, thus implying an efficacious coupling of CONJ-hBNP to the natriuretic receptor-A. These data advance a new concept of orally administered chronic BNP therapy for cardiovascular diseases.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , GMP Cíclico/sangue , Peptídeo Natriurético Encefálico/farmacologia , Administração Oral , Animais , Estudos Cross-Over , Cães , Humanos , Hipotensão/induzido quimicamente , Masculino , Modelos Animais , Peptídeo Natriurético Encefálico/administração & dosagem , Peptídeo Natriurético Encefálico/sangueRESUMO
Cardiotrophin-1 (CT-1), a member of the interleukin-6 superfamily, and endothelin-1 (ET-1) are potent hypertrophic factors in cardiomyocytes. Although CT-1 and ET-1 gene expression in the heart is upregulated in experimental heart failure, their role in the activation of the cardiac fibroblast is unknown. This study was designed to identify the presence and action of CT-1 and its receptor complex, glycoprotein130 (gp130) and leukemia inhibitory factor (LIF) receptor, on cardiac fibroblast growth in cultured adult canine cardiac fibroblasts. In addition, we investigated the interaction between CT-1/gp130/LIF receptor and ET-1/endothelin type A (ET(A)) receptor axis. Immunohistochemistry was performed using the indirect immunoperoxidase method, while we assessed the cell cycle of cardiac fibroblasts by flow cytometry, DNA synthesis by [(3)H]thymidine incorporation, and collagen synthesis by [(3)H]proline incorporation, respectively. CT-1 and gp130/LIF receptor were widely present in the cytoplasm of the cardiac fibroblasts. Exogenous CT-1 markedly stimulated [(3)H]thymidine and [(3)H]proline incorporations (P<0.01), with accumulation of cells in the S phase. Blockade of gp130 or LIF receptor inhibited basal growth as well as CT-1- or ET-1-stimulated cardiac fibroblast growth. The specific ET(A) receptor antagonist, BQ123, significantly inhibited CT-1-stimulated DNA synthesis. This study demonstrates that CT-1 and its receptors are present in cardiac fibroblasts. In addition, growth of these cells stimulated by endogenous and exogenous CT-1 requires gp130/LIF receptor as well as ET(A) receptor activation. We conclude that gp130/LIF receptor and ET(A) receptor activation are essential for cardiac fibroblast growth by CT-1 and that there is synergism with ET-1/ET(A) receptor axis.
Assuntos
Citocinas/farmacologia , Fibroblastos/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores de Citocinas/metabolismo , Receptores de Endotelina/metabolismo , Animais , Anticorpos/farmacologia , Western Blotting , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Citosol/metabolismo , Cães , Endotelina-1/farmacologia , Endotelina-2/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Substâncias Macromoleculares , Glicoproteínas de Membrana/antagonistas & inibidores , Miocárdio/citologia , Miocárdio/metabolismo , Receptor de Endotelina A , Receptores de Citocinas/antagonistas & inibidores , Receptores de OSM-LIF , Frações SubcelularesRESUMO
Cardiac fibroblasts (CFs) produce extracellular matrix proteins and participate in the remodeling of the heart. It is unknown if brain natriuretic peptide (BNP) is synthesized by CFs and if BNP participates in the regulation of extracellular matrix turnover. In this study, we examined the production of BNP in adult canine CFs and the role of BNP and its signaling system on collagen synthesis and on the activation of matrix metalloproteinases (MMPs). BNP mRNA was detected in CFs, and a specific radioimmunoassay demonstrated that BNP(1-32) was secreted into the media at a rate of 11.2+/-1.0 pg/10(5) cells per 48 hours (mean+/-SEM). The amount of BNP secretion was significantly (P<0.01) augmented by 10(-7) mol/L tumor necrosis factor-alpha in a time-dependent manner. BNP significantly (P<0.01) inhibited de novo collagen synthesis as assessed by [3H]proline incorporation, whereas zymographic MMP-2 (gelatinase) abundance was significantly (P<0.05) stimulated by BNP between 10(-7) and 10(-6) mol/L. In addition, protein expression of MMP-1, -2, and -3 and membranous type-1 MMP was significantly increased by 10(-6) mol/L BNP. The cGMP analogue 8-bromo-cGMP (10(-4) mol/L) mimicked the BNP effect, whereas inhibition of protein kinase G by KT5823 (10(-6) mol/L) significantly (P<0.05) attenuated BNP-induced zymographic MMP-2 abundance. In summary, this study reports that BNP is present in cultured CFs and that BNP decreases collagen synthesis and increases MMPs via cGMP-protein kinase G signaling. These in vitro findings support a role for BNP as a regulator of myocardial structure via control of cardiac fibroblast function.
Assuntos
GMP Cíclico/análogos & derivados , Indução Enzimática/fisiologia , Fibroblastos/metabolismo , Ventrículos do Coração/citologia , Metaloproteinases da Matriz/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Animais , Células Cultivadas , Colágeno/biossíntese , Meios de Cultivo Condicionados/química , Meios de Cultivo Condicionados/metabolismo , GMP Cíclico/metabolismo , GMP Cíclico/farmacologia , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Cães , Indução Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Imuno-Histoquímica , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/farmacologia , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/metabolismo , Prolina/metabolismo , Prolina/farmacocinética , RNA Mensageiro/metabolismo , Radioimunoensaio , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaAssuntos
Guanilato Ciclase/fisiologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Ensaios Clínicos como Assunto , Endotélio Vascular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/enzimologia , Heme/fisiologia , Humanos , Morfolinas/farmacologia , Óxido Nítrico/fisiologia , Pirazóis/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/fisiologia , Guanilil Ciclase Solúvel , Vasodilatadores/farmacologia , Sistema Vasomotor/fisiologiaRESUMO
BACKGROUND: While both the endothelin-1 (ET-1) and renin-angiotensin systems (RAS) are activated in congestive heart failure (CHF), the temporal sequence of this activation remains unclear. Understanding this pattern of neurohumoral activation may aid in understanding the significance of ET-1 in CHF and provide strategies for ET-1 antagonism. Although acute endothelin (ET) receptor antagonism improves systemic hemodynamics in CHF, clinical trials with chronic ET receptor antagonism report worsening CHF symptoms. METHODS AND RESULTS: In a canine model of progressive left ventricular dysfunction, we demonstrated activation of myocardial and plasma ET-1 without activation of the RAS during transition to overt CHF, suggesting that ET-1 contributes to this transition. We next evaluated the effects of chronic oral ET-A receptor antagonism on neurohumoral function, renal hemodynamics, and sodium excretion in pacing-induced CHF. After 7 days of treatment (n=7) with ET-A receptor antagonism (with LU135252), sodium excretion did not improve in treated versus untreated CHF (n=6). Furthermore, both plasma renin activity and plasma ET-1 increased with ET-A receptor blockade. CONCLUSIONS: Activation of the myocardial and plasma ET-1 systems precedes activation of the myocardial and plasma RAS in CHF. ET-A receptor antagonism in experimental CHF further activates the RAS without improving sodium excretion. These findings suggest an important role for ET-1 in the progression of CHF and a potential mechanism for the exacerbation of CHF symptoms observed in clinical trials with chronic ET receptor antagonism. Further studies with combined modulation of the ET and other neurohumoral systems in CHF are required.
Assuntos
Antagonistas do Receptor de Endotelina A , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/urina , Sistema Renina-Angiotensina , Sódio/urina , Animais , Progressão da Doença , Cães , Endotelina-1/sangue , Insuficiência Cardíaca/sangue , Hemodinâmica , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Fenilpropionatos/farmacologia , Pirimidinas/farmacologia , Renina/sangueRESUMO
BACKGROUND: Omapatrilat (OMA), a vasopeptidase inhibitor, simultaneously inhibits angiotensin-converting enzyme (ACE) and neutral endopeptidase, which degrades vasodilatory factors (eg, ADM) and natriuretic peptides. Based on the beneficial cardiorenal and humoral properties of the natriuretic peptides, we hypothesized that an acute vasopeptidase inhibitor with or without diuretic would result in more favorable cardiorenal and hormonal actions than ACE inhibition plus diuretic (ACEI+D) in congestive heart failure. METHODS AND RESULTS: We compared the actions of OMA alone and with diuretic (OMA+D) to ACEI+D in a model of pacing-induced congestive heart failure. OMA+D decreased pulmonary arterial and pulmonary capillary wedge pressures to a greater level than OMA alone or ACEI+D. Glomerular filtration rate was lower with ACEI+D than with either OMA group. Plasma renin activity and aldosterone immediately increased with ACEI+D, whereas OMA+D resulted in higher plasma renin activity and a delayed increase in aldosterone. OMA alone did not increase plasma renin activity and aldosterone, but resulted in a sustained increase in plasma adrenomedullin, with higher urinary atrial natriuretic peptide, adrenomedullin, and cGMP excretions than with ACEI+D. CONCLUSIONS: Acute administration of OMA with or without diuretic results in more favorable cardiorenal and humoral responses in experimental congestive heart failure than does ACEI+D. There is no acute activation of renin and aldosterone with OMA alone such as occurs with ACEI+D and OMA+D. Thus, OMA with or without a diuretic possesses beneficial cardiorenal and humoral actions comparable to those observed with ACEI+D that can be explained by potentiation of natriuretic peptides.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Diuréticos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Inibidores de Proteases/farmacologia , Piridinas/farmacologia , Tiazepinas/farmacologia , Adrenomedulina , Aldosterona/sangue , Animais , Fator Natriurético Atrial/urina , Estimulação Cardíaca Artificial , GMP Cíclico/urina , Modelos Animais de Doenças , Cães , Quimioterapia Combinada , Taxa de Filtração Glomerular/efeitos dos fármacos , Insuficiência Cardíaca/fisiopatologia , Testes de Função Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Testes de Função Renal , Masculino , Neprilisina/antagonistas & inibidores , Peptídeos/sangue , Peptídeos/urina , Peptidil Dipeptidase A/metabolismo , Pressão Propulsora Pulmonar/efeitos dos fármacos , Renina/sangue , Resultado do TratamentoRESUMO
BACKGROUND: The renal actions of brain natriuretic peptide (BNP) in congestive heart failure (CHF) are associated with increased diuresis and natriuresis, preserved glomerular filtration rate (GFR), and lack of activation of the renin-angiotensin-aldosterone system (RAAS). In contrast, diuretic-induced natriuresis may be associated with reduced GFR and RAAS activation. The objective of this study was to test the hypothesis that exogenous BNP enhances the renal diuretic and natriuretic actions of furosemide (Fs) and retards the activation of aldosterone in a model of CHF. METHODS AND RESULTS: CHF was produced in 2 groups of dogs by ventricular pacing. One group received continuous (90-minute) intravenous Fs (1 mg x kg(-1) x h(-1)). A second group (Fs+BNP) received 45-minute intravenous coinfusion of Fs (1 mg x kg(-1) x h(-1)) and low-dose (2 pmol x kg(-1) x min(-1)) BNP followed by 45-minute coinfusion of Fs (1 mg x kg(-1) x h(-1)) and high-dose (10 pmol x kg(-1) x min(-1)) BNP. Fs increased urinary flow, but the effect of Fs+BNP was greater. Similarly, urinary sodium excretion was higher in the Fs+BNP group. Although GFR tended to decrease in the Fs group, it increased in the Fs+BNP group (35+/-3 to 56+/-4*) (* indicates P<0.05 versus baseline) (P<0.0001 between groups). Plasma aldosterone increased with Fs (41+/-10 to 100+/-11* ng/dL) but was attenuated in the Fs+BNP group (44+/-11 to 54+/-9 ng/dL low-dose and to 47+/-7 ng/dL high-dose) (P=0.0007 between groups). CONCLUSIONS: Fs+BNP has more profound diuretic and natriuretic responses than Fs alone and also increases GFR without activation of aldosterone. Coadministration of BNP and loop diuretic is effective in maximizing natriuresis and diuresis while preserving renal function and inhibiting activation of aldosterone.
Assuntos
Diurese/efeitos dos fármacos , Diuréticos/farmacologia , Furosemida/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Natriurese/efeitos dos fármacos , Peptídeo Natriurético Encefálico/farmacologia , Animais , Débito Cardíaco/efeitos dos fármacos , Estimulação Cardíaca Artificial , GMP Cíclico/sangue , GMP Cíclico/urina , Diuréticos/administração & dosagem , Diuréticos/uso terapêutico , Cães , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Furosemida/administração & dosagem , Furosemida/uso terapêutico , Taxa de Filtração Glomerular/efeitos dos fármacos , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Peptídeo Natriurético Encefálico/administração & dosagem , Peptídeo Natriurético Encefálico/uso terapêutico , Norepinefrina/sangue , Circulação Renal/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
BACKGROUND: BAY 41-2272 is a recently introduced novel orally available agent that directly stimulates soluble guanylate cyclase (sGC) and sensitizes it to its physiological stimulator, nitric oxide. To date, its therapeutic actions in congestive heart failure (CHF) remain undefined. We characterized the cardiorenal actions of intravenous BAY 41-2272 in a canine model of CHF and compared it to nitroglycerin (NTG). METHODS AND RESULTS: CHF was induced by rapid ventricular pacing for 10 days. Cardiorenal and humoral function were assessed at baseline and with administration of 2 doses of BAY 41-2272 (2 and 10 micro g x kg(-1) x min(-1); n=8) or NTG (1 and 5 micro g x kg(-1) x min(-1); n=6). Administration of 10 micro g x kg(-1) x min(-1) BAY 41-2272 reduced mean arterial pressure (113+/-8 to 94+/-6 mm Hg; P<0.05), pulmonary artery pressure (29+/-2 to 25+/-2 mm Hg; P<0.05), and pulmonary capillary wedge pressure (25+/-2 to 20+/-2 mm Hg; P<0.05). Cardiac output (2.1+/-0.2 to 2.3+/-0.2 L/min; P<0.05) and renal blood flow (131+/-17 to 162+/-18 mL/min; P<0.05) increased. Glomerular filtration rate was maintained. There were no changes in plasma renin activity, angiotensin II, or aldosterone. NTG mediated similar hemodynamic changes and additionally decreased right atrial pressure and pulmonary vascular resistance. CONCLUSION: The new sGC stimulator BAY 41-2272 potently unloaded the heart, increased cardiac output, and preserved glomerular filtration rate without activation of the renin-angiotensin-aldosterone system in experimental CHF. These beneficial properties make direct sGC stimulation with BAY 41-2272 a promising new strategy for the treatment of cardiovascular diseases such as CHF.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Aldosterona/sangue , Angiotensina II/sangue , Animais , Débito Cardíaco/efeitos dos fármacos , Estimulação Cardíaca Artificial , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Guanilato Ciclase , Testes de Função Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Injeções Intravenosas , Testes de Função Renal , Masculino , Nitroglicerina/farmacologia , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Renina/sangue , Sistema Renina-Angiotensina/efeitos dos fármacos , Guanilil Ciclase SolúvelRESUMO
Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are secreted by the heart and play important roles in the compensation of congestive heart failure with their vasodilating, natriuretic, antiproliferative, lusitropic and neurohumoral-modulating properties. Based on these beneficial properties, exogenous BNP was developed as a new treatment for congestive heart failure and approved in the US for acute decompensated heart failure. New therapeutic strategies for heart failure that are currently being investigated include chronic subcutaneous BNP administration and intermittent BNP infusions. Furthermore, strategies combining exogenous BNP with an inhibitor of the BNP-degrading enzyme neutral endopeptidase could contribute to maximising the actions of BNP and reduce the amount of exogenous BNP needed.
Assuntos
Fator Natriurético Atrial/metabolismo , Insuficiência Cardíaca/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Ativação Enzimática , Guanilato Ciclase/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Rim/fisiopatologia , Miocárdio/metabolismo , Natriurese/fisiologia , Peptídeo Natriurético Encefálico/administração & dosagem , Peptídeo Natriurético Encefálico/uso terapêuticoRESUMO
Adrenomedullin (ADM) is a vasoactive and natriuretic peptide. While it is known that ADM is increased in failing human ventricles, the expression of ADM in human ventricular allografts remains unknown. The present study was designed to investigate tissue localization and intensity of ADM expression in ventricular biopsy specimens and to characterize ventricular ADM in human cardiac allografts. Thirty-three post-transplant endomyocardial biopsy specimens were examined immunohistochemically. The average score (range: 0-4) of ADM immunoreactivity (IR) was 2.4+/-0.9 (mean+/-standard deviation). Right ventricular (RV) systolic pressure was significantly increased with high ADM-IR (p=0.048) and the ADM-IR positively associated with myocyte size (r(2)=0.23, p=0.010). In contrast, ADM-IR was not associated with systemic blood pressure, serum creatinine, cyclosporine concentration, cardiac fibrosis, or allograft rejection. The present study shows that ADM-IR is present in human ventricular endomyocardium after transplantation, and ADM-IR is associated with the magnitude of RV pressure and myocyte size, suggesting an important role for ventricular ADM in the counteraction against overload as well as in the progress of myocyte hypertrophy after heart transplantation.