Assuntos
Dermatite Atópica/metabolismo , Gânglios Espinais/metabolismo , Interleucinas/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Prurido/metabolismo , Animais , Comportamento Animal , Células Cultivadas , Dermatite Atópica/genética , Dermatite Atópica/fisiopatologia , Dermatite Atópica/psicologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiopatologia , Interleucinas/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Peptídeo Natriurético Encefálico/deficiência , Peptídeo Natriurético Encefálico/genética , Subunidade beta de Receptor de Oncostatina M/metabolismo , Prurido/genética , Prurido/fisiopatologia , Prurido/psicologia , Receptores de Interleucina/metabolismo , Transdução de Sinais , Canal de Cátion TRPA1/genética , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismoRESUMO
INTRODUCTION: Atrial and B-type Natriuretic Peptides (NP) are cardiac hormones with potent cardiovascular and metabolic effects. They signal through the NPRA/cGMP system and are inactivated by a clearance receptor NPRC and neutral endopeptidases (NEP). Recombinant ANP and BNP are currently used as drug treatment for acute decompensated congestive heart failure. Recent literature indicate that a defective NP system is linked to obesity and predict the risk of type 2 diabetes (T2D). Areas covered: This article reviews recent epidemiological, clinical and preclinical evidences that NP system deficiency may be causal of obesity and T2D. The molecular mechanisms of the NP pathway in several metabolic target tissues are presented. The therapeutic potential of NP in obesity and T2D is discussed. Expert opinion: Targeting the NP pathway may offer a novel therapeutic avenue for the management of obesity and T2D. The benefit/risk of drugs increasing circulating NP levels by blocking NPRC and NEP, and/or enhancing NPRA signaling should be assessed in obese and type 2 diabetic individuals.
Assuntos
Fator Natriurético Atrial/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo Natriurético Encefálico/metabolismo , Obesidade/tratamento farmacológico , Animais , Fator Natriurético Atrial/deficiência , Fator Natriurético Atrial/efeitos dos fármacos , Diabetes Mellitus Tipo 2/patologia , Humanos , Terapia de Alvo Molecular , Peptídeo Natriurético Encefálico/deficiência , Peptídeo Natriurético Encefálico/efeitos dos fármacos , Neprilisina/metabolismo , Obesidade/patologia , Receptores do Fator Natriurético Atrial/metabolismoRESUMO
Sexual dimorphisms are recognized in cardiovascular conditions such as hypertension, stroke, thrombosis and vasculitis. B-type natriuretic peptide (BNP) is a guanylyl cyclase A (GC-A) agonist. The anti-hypertensive, vasodilatory, anti-fibrotic, and anti-hypertrophic properties of BNP are well established in male animal models. Although circulating BNP levels are higher in women, when compared to age-matched men, the cardiovascular protective propensity of BNP in females is poorly understood. We assessed the cardiovascular consequences of BNP deletion in genetically null (Nppb-/-) female rat lines. Throughout the study, blood pressure (BP) remained uninfluenced by genotype, and cardiorenal consequences of BNP knock out remained minor. Unexpectedly, approximately 60% of Nppb-/- females developed mesenteric polyarteritis-nodosa (PAN)-like vasculitis in their life span, some as early as 4 months of age. Mesenteric lesions involved intense arterial remodeling, progressive inflammation, occluded lumens, and less frequently intestinal necrosis and multiple visceral arterial aneurysms. Cumulative pathologies resulted in a significant decline in survival of the Nppb-/- female. This study highlights BNP's vasoprotective propensity, bringing to light a possible sex specific difference in the cardiovascular protection provided by BNP. Defects in the BNP/GC-A/cGMP pathway may play a role in arteriopathies in women, while GC-A agonists may provide effective therapy for arteritis.
Assuntos
Artérias Mesentéricas/metabolismo , Peptídeo Natriurético Encefálico/deficiência , Remodelação Vascular , Vasculite/metabolismo , Animais , Pressão Sanguínea , Feminino , Humanos , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Artérias Mesentéricas/patologia , Artérias Mesentéricas/fisiopatologia , Peptídeo Natriurético Encefálico/genética , Poliarterite Nodosa/genética , Poliarterite Nodosa/metabolismo , Ratos Endogâmicos Dahl , Fatores Sexuais , Fatores de Tempo , Vasculite/genéticaRESUMO
Altered myocardial structure and function, secondary to chronically elevated blood pressure, are leading causes of heart failure and death. B-type natriuretic peptide (BNP), a guanylyl cyclase A agonist, is a cardiac hormone integral to cardiovascular regulation. Studies have demonstrated a causal relationship between reduced production or impaired BNP release and the development of human hypertension. However, the consequences of BNP insufficiency on blood pressure and hypertension-associated complications remain poorly understood. Therefore, the goal of this study was to create and characterize a novel model of BNP deficiency to investigate the effects of BNP absence on cardiac and renal structure, function, and survival. Genetic BNP deletion was generated in Dahl salt-sensitive rats. Compared with age-matched controls, BNP knockout rats demonstrated adult-onset hypertension. Increased left ventricular mass with hypertrophy and substantially augmented hypertrophy signaling pathway genes, developed in young adult knockout rats, which preceded hypertension. Prolonged hypertension led to increased cardiac stiffness, cardiac fibrosis, and thrombi formation. Significant elongation of the QT interval was detected at 9 months in knockout rats. Progressive nephropathy was also noted with proteinuria, fibrosis, and glomerular alterations in BNP knockout rats. End-organ damage contributed to a significant decline in overall survival. Systemic BNP overexpression reversed the phenotype of genetic BNP deletion. Our results demonstrate the critical role of BNP defect in the development of systemic hypertension and associated end-organ damage in adulthood.
Assuntos
Modelos Animais de Doenças , Hipertensão/etiologia , Peptídeo Natriurético Encefálico/fisiologia , Idade de Início , Animais , Complacência (Medida de Distensibilidade) , Morte Súbita Cardíaca/etiologia , Fibrose , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Hipertensão/genética , Hipertensão/patologia , Hipertensão/prevenção & controle , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Glomérulos Renais/patologia , Síndrome do QT Longo/etiologia , Contração Miocárdica/genética , Miocárdio/patologia , Peptídeo Natriurético Encefálico/deficiência , Peptídeo Natriurético Encefálico/genética , Fenótipo , Ratos , Ratos Endogâmicos Dahl , Proteínas Recombinantes de Fusão/metabolismo , Insuficiência Renal Crônica/etiologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaAssuntos
Insuficiência Cardíaca/tratamento farmacológico , Peptídeo Natriurético Encefálico/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Animais , Biomarcadores/sangue , Débito Cardíaco/efeitos dos fármacos , Modelos Animais de Doenças , Cães , Insuficiência Cardíaca/fisiopatologia , Humanos , Peptídeo Natriurético Encefálico/deficiência , Inibidores de Fosfodiesterase/uso terapêutico , Valores de Referência , Medição de Risco , Sensibilidade e EspecificidadeRESUMO
Mechanical alternans is observed in patients with severe left ventricular dysfunction. We report a case of dilated cardiomyopathy with mechanical alternans. He presented with a remarkable decrease in plasma brain natriuretic peptide (BNP) levels after beta-blocker therapy despite persistency of the mechanical alternans. Mechanical alternans may persist after improvement of hemodynamics, diastolic function, and plasma BNP levels. Mechanical alternans may reflect persistent organic or functional myocardial damage such as abnormal intracellular Ca(2+) cycling in cardiomyocytes.