RESUMO
Cardiac natriuretic peptides (NP) are involved in cardiorenal regulation and in lipolysis. The NP activity is largely dependent on the ratio between the signaling receptor NPRA and the clearance receptor NPRC. Lipolysis increases when NPRC is reduced by starving or very-low-calorie diet. On the contrary, insulin is an antilipolytic hormone that increases sodium retention, suggesting a possible functional link with NP. We examined the insulin-mediated regulation of NP receptors in differentiated human adipocytes and tested the association of NP receptor expression in visceral adipose tissue (VAT) with metabolic profiles of patients undergoing renal surgery. Differentiated human adipocytes from VAT and Simpson-Golabi-Behmel Syndrome (SGBS) adipocyte cell line were treated with insulin in the presence of high-glucose or low-glucose media to study NP receptors and insulin/glucose-regulated pathways. Fasting blood samples and VAT samples were taken from patients on the day of renal surgery. We observed a potent insulin-mediated and glucose-dependent upregulation of NPRC, through the phosphatidylinositol 3-kinase pathway, associated with lower lipolysis in differentiated adipocytes. No effect was observed on NPRA. Low-glucose medium, used to simulate in vivo starving conditions, hampered the insulin effect on NPRC through modulation of insulin/glucose-regulated pathways, allowing atrial natriuretic peptide to induce lipolysis and thermogenic genes. An expression ratio in favor of NPRC in adipose tissue was associated with higher fasting insulinemia, HOMA-IR, and atherogenic lipid levels. Insulin/glucose-dependent NPRC induction in adipocytes might be a key factor linking hyperinsulinemia, metabolic syndrome, and higher blood pressure by reducing NP effects on adipocytes.
Assuntos
Adipócitos/metabolismo , Glucose/farmacologia , Coração/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Natriurese/efeitos dos fármacos , Peptídeos Natriuréticos/metabolismo , Receptores do Fator Natriurético Atrial/metabolismo , Adipócitos/efeitos dos fármacos , Idoso , Células Cultivadas , Feminino , Humanos , Insulina/sangue , Gordura Intra-Abdominal/citologia , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Lipídeos/sangue , Masculino , Receptores do Fator Natriurético Atrial/antagonistas & inibidores , Receptores do Fator Natriurético Atrial/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
A sensitive radioimmunoassay for atrial natriuretic peptide was used to examine the relation between circulating atrial natriuretic peptide and cardiac filling pressure in normal human subjects, in patients with cardiovascular disease and normal cardiac filling pressure, and in patients with cardiovascular disease and elevated cardiac filling pressure with and without congestive heart failure. The present studies establish a normal range for atrial natriuretic peptide in normal human subjects. These studies also establish that elevated cardiac filling pressure is associated with increased circulating concentrations of atrial natriuretic peptide and that congestive heart failure is not characterized by a deficiency in atrial natriuretic peptide, but with its elevation.
Assuntos
Fator Natriurético Atrial/sangue , Insuficiência Cardíaca/sangue , Adulto , Idoso , Doenças Cardiovasculares/sangue , Feminino , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , RadioimunoensaioRESUMO
Botulinum neurotoxins, responsible for the neuroparalytic syndrome botulism, are the deadliest of known biological toxins. The work described in this study was based on a three-zone pharmacophore model for botulinum neurotoxin serotype A light chain inhibition. Specifically, the pharmacophore defined a separation between the overlaps of several different, non-zinc(II)-coordinating small molecule chemotypes, enabling the design and synthesis of a new structural hybrid possessing a Ki=600 nM (+/-100 nM).
Assuntos
Toxinas Botulínicas Tipo A/antagonistas & inibidores , Neurotoxinas/antagonistas & inibidores , Inibidores de Proteases/química , Toxinas Botulínicas Tipo A/metabolismo , Desenho de Fármacos , Neurotoxinas/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Zinco/químicaRESUMO
Endothelin, a newly discovered endothelial-derived peptide, has been demonstrated in vitro to have potent vasocontractile properties and has been speculated to play a role in vivo in arterial pressure-volume homeostasis. The present studies in anesthetized dogs were designed to determine the action of endothelin on cardiovascular-renal and endocrine function in vivo as in acute arterial pressure-volume regulation. Intravenous infusion of endothelin (50 ng/kg per min) increases arterial pressure by increasing peripheral vascular resistance but in association with an increase in coronary vascular resistance and decreases in cardiac output. Renal blood flow and glomerular filtration rate were markedly reduced in association with a sustained reduction in sodium excretion and an increase in plasma renin activity. Atrial natriuretic factor, vasopressin, and aldosterone were also elevated. These results indicate that endothelin is a potent vasoconstrictor that elevates systemic blood pressure in association with marked decreases in cardiovascular and renal function. This peptide may function as a counterregulatory hormone to the effects of endothelial-derived vasodilator agent(s).
Assuntos
Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Peptídeos/farmacologia , Animais , Débito Cardíaco/efeitos dos fármacos , Cães , Endotelinas , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/irrigação sanguínea , Masculino , Renina/sangue , Resistência Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacosRESUMO
The renal natriuretic actions of endogenous atrial natriuretic factor are enhanced by neutral endopeptidase inhibition (NEP-I). Recognizing that activation of the renin-angiotensin-aldosterone system in congestive heart failure (CHF) antagonizes the renal actions of atrial natriuretic factor, we hypothesized that angiotensin II antagonism with converting enzyme inhibition would potentiate the renal actions of NEP-I in CHF. To test this hypothesis, the renal responses to a specific NEP-I (SQ 28,603) were assessed in dogs with eight days of experimental CHF produced by rapid ventricular pacing. The renal natriuretic responses to NEP-I in experimental CHF were significant. In the same model of CHF, chronic angiotensin antagonism with converting enzyme inhibition potentiated both renal hemodynamic and excretory responses to NEP-I. The potentiated renal hemodynamic response included significant increases in glomerular filtration rate and filtration fraction. In the CHF group with angiotensin antagonism, an intrarenal infusion of low-dose angiotensin abolished the potentiated renal responses to NEP-I, supporting the concept that intrarenal angiotensin antagonism, rather than improved systemic hemodynamics or potentiation of other peptide systems, mediated the enhanced renal responses to NEP-I in the presence of converting enzyme inhibition.
Assuntos
Alanina/análogos & derivados , Angiotensina II/antagonistas & inibidores , Insuficiência Cardíaca/fisiopatologia , Rim/efeitos dos fármacos , Neprilisina/antagonistas & inibidores , Angiotensina II/fisiologia , Animais , Fator Natriurético Atrial/farmacologia , GMP Cíclico/sangue , Cães , Hemodinâmica/efeitos dos fármacos , Masculino , Neprilisina/farmacologia , Sódio/metabolismoRESUMO
The current studies were designed to investigate the functional significance of elevated endogenous atrial natriuretic factor (ANF) in acute congestive heart failure (CHF). Integrated cardiorenal and endocrine function were measured in three models of acute low-output congestive heart failure with comparably reduced cardiac output (CO) and mean arterial pressure (MAP). Acute CHF was produced by rapid right ventricular pacing (group I, n = 5) which decreases CO and increases atrial pressures and plasma ANF. In group II, n = 5, thoracic inferior vena caval constriction (TIVCC) was produced to decrease venous return and CO but without increases in atrial pressure or plasma ANF. In group III, n = 5, TIVCC was performed and exogenous ANF infused to achieve plasma concentrations observed in acute CHF. In acute CHF with increases in endogenous ANF, sodium excretion (UNaV), renal blood flow (RBF), plasma renin activity (PRA), and plasma aldosterone (PA) were maintained despite decreases in CO and MAP. In contrast, TIVCC with similar reductions in CO and MAP but without increases in ANF resulted in decreases in UNaV and RBF and increases in PRA and PA. Exogenous administration of ANF in TIVCC to mimic levels in acute CHF prevented sodium retention, renal vasoconstriction, and activation of renin and aldosterone. These studies demonstrate that endogenous ANF serves as an important physiologic volume regulator in acute CHF to maintain sodium excretion and possibly participate in the suppression of activation of the renin-angiotensin-aldosterone system despite the stimulus of arterial hypotension.
Assuntos
Fator Natriurético Atrial/fisiologia , Insuficiência Cardíaca/fisiopatologia , Aldosterona/sangue , Animais , Pressão Sanguínea , Débito Cardíaco , Constrição , Modelos Animais de Doenças , Cães , Feminino , Insuficiência Cardíaca/etiologia , Ventrículos do Coração/fisiopatologia , Masculino , Natriurese , Circulação Renal , Renina/sangue , Veia Cava InferiorRESUMO
Experiments were designed to determine whether a heterogeneity of endothelium-dependent relaxations in arteries from different vascular beds exists in experimental congestive heart failure (CHF) and to determine the mediators of those responses. CHF was produced in dogs by rapid ventricular pacing for 15 d. Rings of coronary, femoral, and renal arteries with and without endothelium from control and CHF dogs were suspended in organ chambers for measurement of isometric force. In arteries contracted with prostaglandin F2 alpha, endothelium-dependent relaxations to BHT 920 (an alpha 2-adrenergic agonist) were increased in coronary arteries from dogs with CHF (maximal relaxation: control -15 +/- 9% vs CHF -92 +/- 5%; n = 5-6; P < 0.05), with a modest enhancement in renal arteries. Relaxations to adenosine diphosphate and the calcium ionophore were unchanged. Relaxations to BHT 920 in CHF were reduced by NG monomethyl-L-arginine (L-NMMA) and pertussis toxin but not by indomethacin. These data suggest that endothelium-dependent relaxations are affected heterogeneously in CHF. The enhanced response to alpha 2-adrenergic agonists in the coronary artery is mediated by nitric oxide through a mechanism sensitive to inhibition by pertussis toxin. This selective increase in endothelium-dependent relaxations in the coronary artery may contribute to preserving coronary blood flow during CHF.
Assuntos
Vasos Coronários/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/fisiologia , Músculo Liso Vascular/fisiopatologia , Óxido Nítrico/biossíntese , Acetilcolina/farmacologia , Difosfato de Adenosina/farmacologia , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Fator Natriurético Atrial/sangue , Azepinas/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Calcimicina/farmacologia , Débito Cardíaco/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Dinoprosta/farmacologia , Cães , Endotélio Vascular/fisiologia , Endotélio Vascular/fisiopatologia , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/metabolismo , Artéria Femoral/fisiopatologia , Insuficiência Cardíaca/metabolismo , Hemodinâmica/efeitos dos fármacos , Técnicas In Vitro , Indometacina/farmacologia , Contração Isométrica/efeitos dos fármacos , Contração Isométrica/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Óxido Nítrico/antagonistas & inibidores , Toxina Pertussis , Valores de Referência , Artéria Renal/efeitos dos fármacos , Artéria Renal/metabolismo , Artéria Renal/fisiopatologia , Renina/sangue , Resistência Vascular/efeitos dos fármacos , Fatores de Virulência de Bordetella/farmacologia , ômega-N-MetilargininaRESUMO
Asymptomatic or early left ventricular dysfunction in humans is characterized by increases in circulating atrial natriuretic peptide (ANP) without activation of the renin-angiotensin-aldosterone system (RAAS). We previously reported a canine model of early left ventricular dysfunction (ELVD) produced by rapid ventricular pacing and characterized by an identical neurohumoral profile and maintenance of the natriuretic response to volume expansion (VE). To test the hypothesis that elevated endogenous ANP suppresses the RAAS and maintains sodium excretion in ELVD, we assessed the effects of antagonism of ANP on cardiorenal and neurohumoral function in ELVD. Chronic ANP suppression was produced by bilateral atrial appendectomies before the production of ELVD by rapid ventricular pacing (ELVD-APPX, n = 5). This group was compared with a separate group with ELVD and intact atrial appendages (ELVD-INTACT, n = 8). ELVD-APPX was characterized by lower circulating ANP (50 +/- 11 vs. 158 +/- 37 pg/ml, P < 0.05), activation of plasma renin activity (PRA) (9.4 +/- 2.4 vs. 0.6 +/- 0.4 ng/ml per h, P < 0.05) and aldosterone (36.4 +/- 12.5 vs. 2.5 +/- 0.0 ng/dl, P < 0.05) when compared to ELVD-INTACT. In comparison to the ELVD-INTACT group, sodium excretion was decreased before and during VE in the ELVD-APPX group. Acute ANP antagonism was produced by administration of the particulate guanylate cyclase coupled natriuretic peptide receptor antagonist, HS-142-1, to seven conscious dogs with ELVD and intact atrial appendages (ELVD-INTACT). HS-142-1 decreased plasma concentrations and renal generation of the ANP second messenger, cGMP, and was associated with activation of PRA and sodium retention with enhanced tubular sodium reabsorption. These data support a significant role for elevated endogenous ANP in the maintenance of sodium excretion and regulation of the RAAS in experimental ELVD.
Assuntos
Fator Natriurético Atrial/sangue , Disfunção Ventricular Esquerda/metabolismo , Aldosterona/sangue , Animais , Fator Natriurético Atrial/antagonistas & inibidores , GMP Cíclico/análise , Modelos Animais de Doenças , Cães , Átrios do Coração/cirurgia , Hemodinâmica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/fisiologia , Masculino , Polissacarídeos/farmacologia , Renina/sangue , Sistema Renina-Angiotensina/fisiologia , Sistemas do Segundo Mensageiro/efeitos dos fármacosRESUMO
This study reports the cardiovascular and renal actions of a novel and newly synthesized 27-amino acid peptide termed vasonatrin peptide (VNP). VNP is a chimera of atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP). This synthetic peptide possesses the 22-amino acid structure of CNP, which is a cardiovascular selective peptide of endothelial origin and is structurally related to ANP. VNP also possesses the five-amino acid COOH terminus of ANP. The current study demonstrates both in vitro and in vivo that VNP possesses the venodilating actions of CNP, the natriuretic actions of ANP, and unique arterial vasodilating actions not associated with either ANP or CNP.
Assuntos
Fator Natriurético Atrial/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Proteínas do Tecido Nervoso/farmacologia , Sequência de Aminoácidos , Animais , Artérias/efeitos dos fármacos , Artérias/fisiologia , Fator Natriurético Atrial/síntese química , Fator Natriurético Atrial/química , GMP Cíclico/sangue , Cães , Humanos , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Dados de Sequência Molecular , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Peptídeo Natriurético Tipo C , Proteínas do Tecido Nervoso/química , Conformação Proteica , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Veias/efeitos dos fármacos , Veias/fisiologiaRESUMO
In normal mammals, atrial natriuretic factor (ANF) is present within atrial myocardial cells but is absent from ventricular myocardium. In primitive organisms ANF is present within both atria and ventricle, suggesting that the ventricle may participate both in the synthesis and release of the hormone. The current study was designed to test the hypothesis that ventricular ANF develops as a homeostatic response to intravascular volume overload. Studies were performed on cardiac tissue obtained from (i) normal and cardiomyopathic hamsters, (ii) autopsied humans with and without cardiac disease, and (iii) living humans with congestive heart failure (CHF) undergoing diagnostic right ventricular endomyocardial biopsy. The myocardium was examined for the presence of immunoreactive ANF using a two-stage immunohistochemical technique, with nonimmune rabbit sera used as a negative control. There was unequivocal evidence of focal subendocardial deposits of immunoreactive ANF present in both of the ventricles of all six cardiomyopathic hamsters, four of five autopsied human subjects with CHF, and five of seven biopsied humans. No immunoreactive ANF was observed within the ventricular myocardium of control hamsters or normal humans. Utilizing crude tissue homogenates and radioimmunoassay techniques, the quantity of ANF was determined in cardiac atria, ventricles, and noncardiac skeletal muscle. Heart failure is characterized by a reduction in atrial ANF and an increase in ventricular ANF. This study demonstrates immunoreactive ANF is present within the ventricular myocardium in cardiomyopathic hamsters and humans with CHF, and suggests that the ventricle may be capable of responding to chronic volume overload by producing ANF.
Assuntos
Fator Natriurético Atrial/análise , Insuficiência Cardíaca/metabolismo , Miocárdio/análise , Animais , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Cricetinae , Feminino , Insuficiência Cardíaca/patologia , Ventrículos do Coração/análise , Ventrículos do Coração/patologia , Humanos , Técnicas Imunoenzimáticas , Masculino , Mesocricetus , Pessoa de Meia-Idade , Miocárdio/patologia , RadioimunoensaioRESUMO
Atrial natriuretic factor (ANF) is a peptide hormone of cardiac origin elevated in acute congestive heart failure (CHF), which is degraded by the enzyme neutral endopeptidase 24.11 (NEP). This study was designed to investigate the pulmonary and urinary clearance of ANF before and after the initiation of acute experimental CHF in dogs, and to assess the contribution of enzymatic degradation to these clearances in CHF. This study demonstrated a significant clearance of plasma ANF across the pulmonary circulation at baseline, and a tendency for pulmonary clearance to decrease in CHF (1115 +/- 268 to 498 +/- 173 ml/min, NS). The pulmonary extraction of ANF present at baseline was not altered with acute CHF (36.0 +/- 7.8 to 34.9 +/- 12.1%, NS). NEP inhibition (NEPI) abolished both the clearance and extraction of plasma ANF across the lung in CHF. Similarly, significant urinary clearance of ANF was present at baseline, and in acute CHF the urinary clearance of ANF decreased (0.14 +/- 0.02 to 0.02 +/- 0.01 ml/min, P less than 0.05). NEPI prevented the decrease in the urinary clearance of ANF, and enhanced the renal response to endogenous ANF, independent of further increases in plasma ANF during CHF. This study supports an important role for NEP in the pulmonary and urinary metabolism of endogenous ANF during acute CHF.
Assuntos
Fator Natriurético Atrial/metabolismo , Insuficiência Cardíaca/metabolismo , Rim/metabolismo , Pulmão/metabolismo , Doença Aguda , Animais , Fator Natriurético Atrial/urina , Pressão Sanguínea , GMP Cíclico/metabolismo , Cães , Taxa de Depuração Metabólica , Inibidores de Proteases/farmacologiaRESUMO
Adrenomedullin (ADM) is a newly discovered endogenous vasorelaxing and natriuretic peptide. Recently, we have reported that plasma ADM is increased in severe congestive heart failure (CHF) in humans and that increased immunohistochemical staining is observed in the failing human ventricular myocardium. The present study was designed to test the hypothesis that the failing human ventricle secretes ADM and that circulating ADM progressively increases with the severity of clinical CHF. Plasma ADM was significantly increased in human CHF (39.8 +/- 3.6 pg/ml, P < 0.001 vs. normal) as compared with normal subjects (14.4 +/- 2.7 pg/ml). Plasma ADM was increased in mild CHF (NYHA class II, 30.1 +/- 3.4 pg/ml, P < 0.01 vs. normal), moderate CHF (NYHA class III, 31.5 +/- 3.0 pg/ml, P < 0.01 vs. normal), and severe CHF (NYHA class IV, 66.1 +/- 9.4 pg/ml, P < 0.001 vs. normal). In 13 patients with CHF in whom plasma samples were obtained from aorta (AO), coronary sinus (CS) and anterior interventricular vein (AIV), there was a significant step-up in plasma ADM between AO and AIV (50.6 +/- 9.3 pg/ml and 62.1 +/- 11.1 pg/ml, respectively, P < 0.01) and between AO and CS (50.6 +/- 9.3 pg/ml and 58.6 +/- 11.4 pg/ml, respectively, P < 0.05). The current study demonstrates that the failing human heart secretes ADM in human CHF suggesting contribution to the increase in plasma ADM, and indicates for the first time an additional endocrine system of cardiac origin which is activated in human CHF and may function in cardiorenal regulation.
Assuntos
Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Peptídeos/sangue , Vasodilatadores/sangue , Adrenomedulina , Fator Natriurético Atrial/sangue , Creatinina/sangue , Feminino , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The effects of secretin vasodilation on peritubular capillary Starling forces and absolute proximal reabsorption were examined in the rat. Secretin was infused at 75 mU/kg per min into the aorta above the left renal artery. Efferent plasma flow increased from 125 +/- 28 to 230 +/- 40 nl/min with secretin infusion. Single nephron filtration rate (44 +/- 6 vs. 44 +/- 7 nl/min) and absolute proximal reabsorption (21 +/- 5 vs. 21 +/- 4 nl/min) were not significantly changed. Peritubular capillary and interstitial hydrostatic pressures increased with secretin infusions (from 9 +/- 0.4 to 15 +/- 0.7 mmHg and from 3 +/- 0.2 to 4 +/- 0.2 mmHg, respectively). Both peritubular capillary and interstitial oncotic pressures decreased (from 25 +/- 2 to 20 +/- 2 mmHg and from 10 +/- 1 to 4 +/- 1 mmHg, respectively) during secretin infusion. The net reabsorption pressure for peritubular capillary uptake significantly decreased from 9 +/- 2 to 5 +/- 2 mmHg and the coefficient of reabsorption increased from 3 +/- 1 to 6 +/- 2 nl/min per mmHg. We conclude that although secretin causes a vasodilation and decreases net reabsorption pressure, absolute proximal reabsorption is unchanged. Peritubular capillary uptake is maintained, and since net reabsorption pressure is decreased, the coefficient of reabsorption is increased.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Secretina/fisiologia , Vasodilatadores/fisiologia , Absorção , Animais , Taxa de Filtração Glomerular/efeitos dos fármacos , Pressão Hidrostática , Túbulos Renais Proximais/metabolismo , Masculino , Pressão Osmótica , Ratos , Ratos Endogâmicos , Secretina/administração & dosagem , Vasodilatadores/administração & dosagemRESUMO
Endothelin (ET) is a potent vasoconstrictor peptide which is elevated in plasma in congestive heart failure. Recent studies suggest an important role for angiotensin II (AII) in the activation of ET in cultured cardiomyocytes. Chronic thoracic inferior vena caval constriction (TIVCC) is a model of reduced cardiac output that mimics the neurohumoral activation observed in congestive heart failure. We hypothesized that activation of the renin-angiotensin system in TIVCC plays a role in the activation of ET and that the elevation of endogenous ET contributes to the systemic and renal vasoconstriction that characterizes this model of venous congestion. We studied conscious dogs after 7 d of TIVCC in the presence or absence of chronic angiotensin converting enzyme inhibition with enalapril. TIVCC resulted in marked activation of plasma AII and ET in plasma, right atrium, lung, and renal medulla which was further localized to cardiomyocytes, pulmonary, and renal epithelial cells. Chronic angiotensin converting enzyme inhibition abolished the increases in plasma AII and ET during TIVCC. Acute endothelin A receptor blockade with FR-139317 resulted in significant decreases in mean arterial pressure and systemic vascular resistance in TIVCC. We conclude that activation of the renin-angiotensin system contributes to the activation of circulating and local ET in TIVCC and that this activation plays an important role in the regulation of arterial pressure and systemic vascular resistance in this model of congestive failure.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Endotelinas/metabolismo , Insuficiência Cardíaca/metabolismo , Animais , Azepinas/farmacologia , Modelos Animais de Doenças , Cães , Hemodinâmica/efeitos dos fármacos , Indóis/farmacologia , Masculino , Veia Cava InferiorRESUMO
The cardiovascular system is regulated by hemodynamic and neurohumoral mechanisms. These regulatory systems play a key role in modulating cardiac function, vascular tone, and structure. Although neurohumoral systems are essential in vascular homeostasis, they become maladaptive in disease states such as hypertension, coronary disease, and heart failure. The clinical success of ACE inhibitors has led to efforts to block other humoral systems. Neutral endopeptidase (NEP) is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site. NEP is the major enzymatic pathway for degradation of natriuretic peptides, a secondary enzymatic pathway for degradation of kinins, and adrenomedullin. The natriuretic peptides can be viewed as endogenous inhibitors of the renin angiotensin system. Inhibition of NEP increases levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) of myocardial cell origin, and C-type natriuretic peptide (CNP) of endothelial cell origin as well as bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide and kinin systems, vasopeptidase inhibitors reduce vasoconstriction, enhance vasodilation, improve sodium/water balance, and, in turn, decrease peripheral vascular resistance and blood pressure and improve local blood flow. Within the blood vessel wall, this leads to a reduction of vasoconstrictor and proliferative mediators such as angiotensin II and increased local levels of bradykinin (and, in turn, nitric oxide) and natriuretic peptides. Preliminary clinical experiences with vasopeptidase inhibitors are encouraging. Thus, the combined inhibition of ACE and neutral endopeptidase is a new and promising approach to treat patients with hypertension, atherosclerosis, or heart failure.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Sistema Cardiovascular/enzimologia , Inibidores Enzimáticos/uso terapêutico , Peptídeo Hidrolases/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Sistema Cardiovascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Cininas/metabolismo , Natriuréticos/metabolismo , Neprilisina/antagonistas & inibidores , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Sistema Vasomotor/efeitos dos fármacos , Sistema Vasomotor/fisiologiaRESUMO
BACKGROUND-Mechanical load and humoral stimuli such as endothelin (ET) and angiotensin II (Ang II) are potent modulators of cardiac structure and endocrine function, specifically gene expression and production and release of atrial natriuretic peptide (ANP). We define the contribution of mechanical load compared with neurohumoral stimulation in vivo with specific focus on myocardial and circulating ANP during chronic myocardial unloading produced by thoracic inferior vena caval constriction (TIVCC). METHODS AND RESULTS-TIVCC was produced by banding the IVC for 10 days in 7 dogs, whereas in the 6 control dogs, the band was not constricted. TIVCC was characterized by a decrease in cardiac output, right atrial pressure, and left ventricular (LV) end-diastolic diameter and marked activation of ET and Ang II in plasma and atrial and ventricular myocardium. Despite neurohumoral stimulation, LV mass index and myocyte diameters in unloaded hearts decreased, reflecting myocyte atrophy. The total number of myocytes in the LV remained unchanged. Atrial stores of ANP increased, but plasma ANP did not change, in association with a trend toward ANP gene expression to decrease in unloaded hearts. CONCLUSIONS-Chronic mechanical unloading of the heart results in myocardial atrophy and lack of activation of ANP synthesis despite marked neurohumoral stimulation by the growth promoters ET and Ang II.
Assuntos
Angiotensina II/farmacologia , Glândulas Endócrinas/fisiologia , Endotelinas/farmacologia , Miocárdio/patologia , Neurotransmissores/metabolismo , Animais , Fator Natriurético Atrial/metabolismo , Constrição Patológica , Cães , Masculino , Miocárdio/metabolismo , Estresse Mecânico , Veia Cava InferiorRESUMO
BACKGROUND: Endothelin-converting enzyme-1 (ECE-1) processes big endothelin-1 (ET-1) to ET-1, a peptide implicated in atheroma formation. ECE-1 exists in 2 isoforms (ECE-1alpha and ECE-1beta), the result of alternative splicing of a common gene. Neutral endopeptidase (NEP) is a genetically distinct metallopeptidase that degrades the natriuretic peptides. These peptides mediate antiproliferative and vasodilating actions. We sought to demonstrate the distribution of the 2 ECE-1 isoforms in experimental atherosclerosis, to determine the effects of chronic NEP-I on plasma cGMP concentrations, vascular wall ECE-1 activity, and ET-1 concentration, and to correlate these actions with atheroma formation. Our hypothesis was that chronic NEP-I, in association with augmented cGMP, would inhibit ECE-1 conversion of big ET-1 to active ET-1, thus reducing tissue ET-1 concentrations and associated atheroma formation. METHODS AND RESULTS: Cholesterol-fed New Zealand White rabbits (n=8, 1% cholesterol diet) and NEP-I-treated cholesterol-fed New Zealand White rabbits (n=8; candoxatril, 30 mg/kg per day, Pfizer) were euthanized after 8 weeks of feeding. ECE-1alpha and ECE-1beta immunoreactivity was present in the aortas of both groups. Compared with control values, plasma cGMP concentrations were increased (2.8+/-0.6 versus 8.4+/-1.2 pmol/mL, P<0.05), ECE-1 activity was attenuated (68+/-3% versus 32+/-8%, P<0. 05), aortic tissue ET-1 concentrations were reduced (4.6+/-0.5 versus 3.2+/-0.3 pg/mg protein, P<0.05), and atheroma formation was attenuated (62+/-6% versus 34+/-5%, P<0.01) by NEP-I. CONCLUSIONS: These studies suggest that ECE-1 is present and functionally active in the vascular wall in atherosclerosis. Inhibition of ECE-1 by NEP-I represents a novel approach to interruption of the endothelin system in this cardiovascular disease state.
Assuntos
Arteriosclerose/enzimologia , Ácido Aspártico Endopeptidases/metabolismo , Isoenzimas/metabolismo , Neprilisina/antagonistas & inibidores , Animais , Aorta/enzimologia , Ácido Aspártico Endopeptidases/análise , Fator Natriurético Atrial/metabolismo , Doença Crônica , GMP Cíclico/metabolismo , Dieta Aterogênica , Modelos Animais de Doenças , Endotelina-1/metabolismo , Enzimas Conversoras de Endotelina , Endotelinas/metabolismo , Técnicas In Vitro , Isoenzimas/análise , Masculino , Metaloendopeptidases , Neprilisina/metabolismo , Precursores de Proteínas/metabolismo , Coelhos , Fatores de Tempo , Vasoconstrição/fisiologiaRESUMO
BACKGROUND: Neutral endopeptidase 24.11 (NEP) is a metalloprotease that is localized in the greatest abundance in the kidney and degrades natriuretic peptides, such as atrial natriuretic peptide (ANP). Mild congestive heart failure (CHF) is characterized by increases in circulating ANP without activation of the renin-angiotensin-aldosterone system (RAAS) or sodium retention. In contrast, severe CHF is characterized by sodium retention and coactivation of both ANP and the RAAS. METHODS AND RESULTS: We defined the acute cardiorenal actions of the NEP inhibitor candoxatrilat (8 microg. kg(-1). min(-1)) in 4 groups of anesthetized dogs (normal, n=8; mild CHF, n=6; severe CHF, n=5; and severe CHF with chronic AT(1) receptor antagonism, n=5). Mild CHF was produced by rapid ventricular pacing at 180 bpm for 10 days and severe CHF at 245 bpm for 10 days. In mild CHF, urinary sodium excretion and glomerular filtration rate were greatest in response to acute NEP inhibition compared with the response in either control animals or those with severe CHF. Furthermore, an increase in glomerular filtration rate was observed only in mild CHF in association with increases in renal blood flow and decreases in renal vascular resistance and distal tubular sodium reabsorption. Urinary ANP and cGMP excretion, markers for renal biological actions of ANP, were greatest in mild CHF. The renal actions observed in mild CHF were attenuated in severe CHF and not restored by chronic AT(1) receptor antagonism. CONCLUSIONS: The results of the present study demonstrate that acute NEP inhibition in mild CHF results in marked increases in renal hemodynamics and sodium excretion that exceed that observed in control animals and severe CHF. These studies underscore the potential therapeutic role for NEP inhibition to enhance renal function in mild CHF, an important phase of CHF that is marked by selective activation of endogenous ANP in the absence of an activated RAAS.
Assuntos
Fator Natriurético Atrial/sangue , Insuficiência Cardíaca/metabolismo , Rim/enzimologia , Rim/fisiopatologia , Neprilisina/antagonistas & inibidores , Doença Aguda , Antagonistas de Receptores de Angiotensina , Animais , Modelos Animais de Doenças , Cães , Frequência Cardíaca , Rim/química , Masculino , Neprilisina/metabolismo , Marca-Passo Artificial , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Função VentricularRESUMO
This study investigated the presence of atrial natriuretic factor in ventricular tissue obtained from humans with dilated or restrictive heart disease. In 17 patients with ventricular dilation and impaired systolic function and in 8 patients with restrictive heart disease and preserved systolic function, the presence of ventricular atrial natriuretic factor was investigated in tissue obtained by ventricular endomyocardial biopsy. The objective of the study was to determine if the ventricular presence of atrial natriuretic factor is dependent on ventricular dilation. Left ventricular end-diastolic volume index was greater in the group with dilated cardiomyopathy than in the group with restrictive cardiomyopathy (134 +/- 13 versus 78 +/- 5 ml/m2, p less than 0.05); end-diastolic pressure was elevated in the two groups (20 +/- 2 versus 25 +/- 4 mm Hg, p = NS). With the use of immunohistochemical techniques, ventricular atrial natriuretic factor was clearly detected in 15 of the 17 patients with dilated cardiomyopathy and in 6 of the 8 patients with restrictive cardiomyopathy. This study demonstrates the high prevalence of ventricular atrial natriuretic factor in living patients with either systolic or diastolic dysfunction. Whereas in the atria, stretch or dilation may be an important stimulus, atrial natriuretic factor in the ventricular chamber occurs independent of dilation.
Assuntos
Fator Natriurético Atrial/metabolismo , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Restritiva/metabolismo , Ventrículos do Coração/química , Endocárdio/química , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Miocárdio/química , Volume Sistólico/fisiologiaRESUMO
Atrial natriuretic peptide hormone of cardiac origin, which is released in response to atrial distension and serves to maintain sodium homeostasis and inhibit activation of the renin-angiotensin-aldosterone system. Congestive heart failure is a clinical syndrome characterized by increased cardiac volume and pressure overload with an inability to excrete a sodium load, which is associated with increased activity of systemic neurohumoral and local autocrine and paracrine mechanisms. Circulating atrial natriuretic peptide is greatly increased in congestive heart failure as a result of increased synthesis and release of this hormone. Atrial natriuretic peptide has emerged as an important diagnostic and prognostic serum marker in congestive heart failure. In early heart failure, it may play a key role in preserving the compensated state of asymptomatic left ventricular dysfunction. Despite increased circulating atrial natriuretic peptide in heart failure, the kidney retains sodium and is hyporesponsive to exogenous and endogenous atrial natriuretic peptide. The mechanism for the attenuated renal response is multifactorial and includes renal hypoperfusion, activation of the renin-angiotensin-aldosterone and sympathetic nervous systems. Therapeutic strategies to potentiate the biologic actions of atrial natriuretic peptide may prolong the asymptomatic phase and delay progression to overt congestive heart failure.