Pathophysiology of congestive heart failure: role of atrial natriuretic factor and therapeutic implications.

Endogenous atrial natriuretic factor (ANF) serves a functional role to maintain sodium homeostasis and inhibit activation of the renin-angiotensin-aldosterone system in acute congestive heart failure despite arterial hypotension. However, as heart failure progresses, maximal synthesis and release of ANF from both the atrial and ventricular myocardium may occur resulting in relative ANF deficiency. This relative deficiency of ANF results in a progressive inability to excrete sodium and antagonize the renin-angiotensin-aldosterone system. Consequently, agents that increase circulating ANF and (or) enhance its local action have potential therapeutic efficacy. Recent studies suggest that inhibitors of neutral endopeptidase 24.11, which block ANF degradation, potentiate the natriuretic action of endogenous ANF independent of systemic or renal hemodynamics. This action does not parallel increases in plasma ANF and is associated with marked increases in urinary ANF and cyclic guanosine monophosphate consistent with enhanced local action of the peptide. In addition, agents that selectively bind to biologically inactive ANF clearance receptors increase endogenous plasma ANF and promote increases in renal sodium excretion. These studies suggest a therapeutic role for neutral endopeptidase inhibition and clearance receptor blockade, while advancing our understanding of the pathophysiology of ANF in congestive heart failure.     

Studies on the role of the pituitary in the control of atrial natriuretic factor secretion and sodium excretion

Recent work suggests that hypophysectomized (HYPOX) rats show low levels of atrial natriuretic factor (ANF) and an attenuated diuresis and natriuresis to blood volume expansion. The purpose of this was (i) to examine the effect of various hormone replacements on ANF and renal excretion in HYPOX rats and (ii) to compare the renal responses to exogenous ANF in intact and HYPOX rats. Groups of rats received subcutaneous pellet implant of either dexamethasone (DEX), thyroxine (T4), or a placebo. Approximately 1 week later, they were anesthetized and subjected to a 20% blood volume expansion. DEX rats had a higher mean arterial pressure than placebo-treated rats while both MAP and heart rate were higher in T4 rats. Only the DEX rat showed augmented renal responses to volume expansion while no group showed significant changes in plasma ANF concentration during volume expansion. In a second series, groups of HYPOX rats received renal capsular transplants of either six hemi-pituitaries or six pieces of muscle which markedly raised serum prolactin levels in the hemi-pituitary group. The hemi-pituitary rats showed a greater diuresis and natriuresis during volume expansion than the muscle group and also showed a transient increase in plasma ANF. In addition, groups of either intact or HYPOX rats were anesthetized and received intravenous bolus injections of ANF. Both intact and HYPOX rats showed a very similar diuresis and natriuresis to exogenous ANF. However, potassium excretion was markedly reduced in HYPOX rats. The results show that DEX augments the renal responses to volume expansion by some mechanism which does not involve changes in plasma ANF. Thyroxine increases mean arterial pressure and heart rate in HYPOX rats but does not augment the renal or ANF responses to volume expansion. Chronic elevations in prolactin increase the renal response to volume expansion. Finally, the kidneys of HYPOX rats are capable of increasing sodium and water output in response to large doses of exogenous ANF.     

Current indications of plasma atrial natriuretic peptide measurements in human diseases

The discovery of atrial natriuretic peptide (ANP) has modified our current understanding of the regulation of sodium metabolism. This peptide, of which the second messenger is cyclic guanosine monophosphate (cyclic GMP), is released by the atrial myocytes in response to increased atrial stretch and has for essential function to diminish the venous return to the heart. Radioimmunoassays have demonstrated that plasma ANP and cyclic GMP levels are increased in various diseases such as congestive heart failure (CHF), renal insufficiency, and, to a lesser extent, diabetes mellitus and liver cirrhosis with ascites. Plasma ANP is of prognostic value in CHF and reflects the effective central volemia in renal failure so that its assay as well as that of plasma cyclic GMP seem of interest in these diseases. Further studies are needed to assess the pathophysiological significance of ANP in diabetes mellitus and cirrhosis, and to define the indications of the treatment by enkephalinase inhibitors which increase endogenous ANP levels by lowering the catabolism of this hormone.     

The gene for rat atrial natriuretic factor

Atrial natriuretic factor (ANF), a peptide hormone recently isolated from heart atria, appears to play an important role in the regulation of extracellular fluid volume and blood pressure. Indeed, natural and synthetic ANF rapidly and markedly stimulate natriuresis and diuresis and produce smooth muscle relaxation. Consistent with the hypothesis that ANF is a novel hormone, it was recently shown that ANF is present in circulation, and high affinity membrane receptors specific for ANF have been described in renal, vascular, and adrenal tissues. These important biological activities suggest that conditions like hypertension could be associated with defective ANF gene expression. We and others have shown by cDNA cloning that ANF is part of a larger precursor, pro-natriodilatin (PND). We now describe the isolation and structural analysis of the rat PND gene. Southern blot analysis of rat genomic DNA suggests the presence of a single PND gene per haploid genome. The PND coding sequences are interrupted by two short introns. A long alternating purine-pyrimidine tract (GT)9GATG(GT)27 is found 111 base pairs downstream of the polyadenylation site; such sequences could adopt Z-DNA configuration and they have been associated with sequences that appear very active in intergenic recombination. Comparison of the rat and human PND genomic sequences shows highest homology in 5'-flanking as well as in coding sequences. The rat PND gene will be a useful model to study the physiology and pathology of this important regulator of the cardiovascular system.     

Ghrelin,a novel growth hormone-releasing peptide,in the treatment of chronic heart failure

Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, which has been identified as an endogenous ligand for growth-hormone secretagogues receptor (GHS-R). This peptide also causes a positive energy balance by stimulating food intake and inducing adiposity through growth hormone-independent mechanisms. In addition, ghrelin has some cardiovascular effects, as indicated by the presence of its receptor in blood vessels and the cardiac ventricles. In vitro, ghrelin inhibits apoptosis of cardiomyocytes and endothelial cells. In humans, infusion of ghrelin decreases systemic vascular resistance and increases cardiac output in patients with heart failure. Repeated administration of ghrelin improves cardiac structure and function and attenuates the development of cardiac cachexia in rats with heart failure. These results suggest that ghrelin has cardiovascular effects and regulates energy metabolism through GH-dependent and -independent mechanisms. Thus, administration of ghrelin may be a new therapeutic strategy for the treatment of severe chronic heart failure (CHF).     

Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones

This report summarizes the recent rapid development of research on neutral endopeptidase 24.11 (enkephalinase; NEP) and on two other metalloenzymes, meprin and endopeptidase 24.15. NEP cleaves a variety of active peptides, including enkephalins, at the amino side of hydrophobic amino acids. The cDNA for human, rat, and rabbit NEP has been cloned and the deduced protein sequences revealed a high degree of homology (93-94%). Site-directed mutagenesis proved that an active site glutamic acid is involved in catalysis and two active site histidines are responsible for binding the zinc cofactor. Although NEP was originally discovered in the kidney, it is widely distributed in the body including specific structures in the central nervous system, lung, male genital tract, and intestine and in neutrophils, fibroblasts, and epithelial cells. In tissues and cells NEP is bound to plasma membrane through a hydrophobic membrane-spanning domain near the NH2 terminus, but it is present in soluble form in urine and blood. In addition to enkephalins, NEP cleaves kinins, chemotactic peptide, atrial natriuretic factor (ANF), and substance P in vivo. NEP in the lung is a major inactivator of substance P, which constricts the airway smooth muscles. Because of the possible involvement of NEP in the metabolism of opioid peptides and the cardiac hormone ANF, orally active inhibitors have been synthesized. Compounds that inhibit both aminopeptidase and NEP were reported to prolong the analgesic effects of enkephalins. Other inhibitors given per os prolonged the renal effects of exogenous ANF. A newly synthesized specific inhibitor of NEP was also active in animal experiments as an analgesic. Studies on the structure and function of NEP should lead to further development of therapeutically applicable inhibitors.     

Regulation of expression of atrial and brain natriuretic peptide,biomarkers for heart development and disease

The mammalian heart expresses two closely related natriuretic peptide (NP) hormones, atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). The excretion of the NPs and the expression of their genes strongly respond to a variety of cardiovascular disorders. NPs act to increase natriuresis and decrease vascular resistance, thereby decreasing blood volume, systemic blood pressure and afterload. Plasma levels of BNP are used as diagnostic and prognostic markers for hypertrophy and heart failure (HF), and both ANF and BNP are widely used in biomedical research to assess the hypertrophic response in cell culture or the development of HF related diseases in animal models. Moreover, ANF and BNP are used as specific markers for the differentiating working myocardium in the developing heart, and the ANF promoter serves as platform to investigate gene regulatory networks during heart development and disease. However, despite decades of research, the mechanisms regulating the NP genes during development and disease are not well understood. Here we review current knowledge on the regulation of expression of the genes for ANF and BNP and their role as biomarkers, and give future directions to identify the in vivo regulatory mechanisms. This article is part of a Special Issue entitled: Heart failure pathogenesis and emerging diagnostic and therapeutic interventions.     

Characterization of a long-acting recombinant human serum albumin-atrial natriuretic factor (ANF) expressed in Pichia pastoris

The cardiac hormone atrial natriuretic factor (ANF) combines pharmacological properties of drugs used to treat essential hypertension (EH), congestive heart failure (CHF) and acute myocardial infarction (AMI). Treatment of CHF or AMI patients with an intravenous (iv) infusion of the circulating form of ANF (ANF(99-126)) produces significant clinical improvement. The short half-life (5 min) and peptide nature of ANF impose logistic restrictions for chronic administration. To increase its half-life, we fused ANF and human serum albumin (HSA) mini-genes by recombination in Pichia pastoris. The activity of three configurations of the fusion protein was tested in vitro and in vivo. The fusion protein that comprised of C-terminus HSA connected to N-terminus ANF via a hexaglycine linker showed the best outcome; it increased cGMP production in vitro. In vivo an iv bolus of HSA-ANF into mice increased significantly plasma cGMP levels and lowered blood pressure (BP) for up to 6 h hence successfully extended ANF half-life in plasma while retaining its biological activity. HSA-ANF represents the basis for development in the chronic therapeutic use of ANF.     

Nonpeptidic endothelin-converting enzyme inhibitors and their potential therapeutic applications

Endothelins (ETs) are potent vasoconstrictors, promitogens, and inflammatory mediators. They have been implicated in the pathogenesis of various cardiovascular, renal, pulmonary, and central nervous system diseases. Since the final step of the biosynthesis of ETs is catalyzed by a family of endothelin-converting enzymes (ECEs), inhibitors of these enzymes may represent novel therapeutic agents. Currently, seven isoforms of these metalloproteases have been identified; they all share a significant amino acid sequence identity with neutral endopeptidase 24.11 (NEP), another metalloprotease. Therefore, it is not surprising that the majority of ECE inhibitors also possess potent NEP inhibitory activity. To date, three classes of ECE inhibitors have been synthesized: dual ECE/NEP inhibitors, triple ECE/NEP/ACE inhibitors, and selective ECE inhibitors. Potential clinical applications of these compounds in hypertension, chronic heart failure, restenosis, renal failure, and cerebral vasospasm deduced from studies with relevant animal models are reviewed.     

重组人脑利钠肽的临床应用进展

近年来,随着心力衰竭、肺动脉高压的病理生理及分子机制的深入研究,使上述疾病在临床药物治疗方面有了很大的进步,其中人脑利钠肽(BNP)作为体内唯一天然的肾素-血管紧张素-醛固酮拮抗剂在诊断及治疗心力衰竭等方面均引起了广泛关注,但由于其在心衰状态下降解快且生物活性明显减弱而限制了临床应用。因此,在心力衰竭治疗上补充外源性BNP成为了又一研究热点。重组人脑利钠肽(rhBNP)是一种人工合成的内源性激素,具有扩张血管、排钠利尿、降低心脏前后负荷、抑制肾素-血管紧张素-醛固酮系统和交感神经系统等作用,能够有效的改善充血性心力衰竭患者的血流动力学障碍。新近研究表明,rhBNP在治疗心血管疾病方面疗效显著,本文将就其在临床中的应用予以综述。     

Guanylyl cyclase / atrial natriuretic peptide receptor-A: role in the pathophysiology of cardiovascular regulation

Atrial natriuretic factor (ANF), also known as atrial natriuretic peptide (ANP), is an endogenous and potent hypotensive hormone that elicits natriuretic, diuretic, vasorelaxant, and anti-proliferative effects, which are important in the control of blood pressure and cardiovascular events. One principal locus involved in the regulatory action of ANP and brain natriuretic peptide (BNP) is guanylyl cyclase / natriuretic peptide receptor-A (GC-A/NPRA). Studies on ANP, BNP, and their receptor, GC-A/NPRA, have greatly increased our knowledge of the control of hypertension and cardiovascular disorders. Cellular, biochemical, and molecular studies have helped to delineate the receptor function and signaling mechanisms of NPRA. Gene-targeted and transgenic mouse models have advanced our understanding of the importance of ANP, BNP, and GC-A/NPRA in disease states at the molecular level. Importantly, ANP and BNP are used as critical markers of cardiac events; however, their therapeutic potentials for the diagnosis and treatment of hypertension, heart failure, and stroke have just begun to be realized. We are now just at the initial stage of molecular therapeutics and pharmacogenomic advancement of the natriuretic peptides. More investigations should be undertaken and ongoing ones be extended in this important field.     

Recent advances in natriuretic peptide research

The natriuretic peptides are a family of related hormones that play a crucial role in cardiovascular and renal homeostasis. They have recently emerged as potentially important clinical biomarkers in heart failure. Natriuretic peptides, particularly brain natriuretic peptide (BNP) and the inactive N-terminal fragment of BNP, NT-proBNP, that has an even greater half-life than BNP, are elevated in heart failure and therefore considered to be excellent predictors of disease outcome. Nesiritide, a recombinant human BNP, has been shown to provide symptomatic and haemodynamic improvement in acute decompensated heart failure, although recent reports have suggested an increased short-term risk of death with nesiritide use. This review article describes: the current use of BNP and its inactive precursor NT-proBNP in diagnosis, screening, prognosis and monitoring of therapy for congestive heart failure, the renoprotective actions of natriuretic peptides after renal failure and the controversy around the therapeutic use of the recombinant human BNP nesiritide.     

Degradation and clearance of atrial natriuretic factors (ANF)

Atrial natriuretic factor, the first well defined natriuretic hormone is synthesized in the human heart as 151 aminoacid (AA) preprohormone and stored as 126 AA prohormone in atrial granules. Upon appropriate stimulation, the prohormone is cleaved into a 98 AA N-terminal fragment and a 28 AA C-terminal fragment, the biological active ANF(99-126), both circulating in plasma. Circulating ANF(99-126) is cleared by various organs, such as lung, liver and intestine, kidney and upper and lower limbs. Reported arterial-venous extraction ratios vary greatly, but are not much different between organs, the average extraction ratio being about 35%. Due to marked differences of organ blood flow, the contribution of various organs to total body ANF clearance differs considerably. Major mechanisms for ANF clearance are uptake by clearance receptors and degradation by an endoprotease (EC 3.4.24.11.). Clearance receptors, distinct from the receptors mediating the biological actions of ANF, have been demonstrated in various organs. Characterization of the ANF degrading enzyme activity has been performed in kidney tissue. Whether and how pathophysiological states affect ANF clearance is still poorly understood. Inhibition of clearance by ANF analogues binding to clearance receptors and by inhibitors of degrading peptidase can increase the biological action of circulating ANF. This may prove to be a therapeutic approach in diseases with smooth muscle contraction or volume overload.     

Atrial natriuretic factor as a marker in congestive heart failure

Cardiac overload is associated with an overexpression of the atrial natriuretic-factor (ANF) gene in experimental models and in man. Sites of ANF gene overexpression are the atria but also the ventricular myocardium. This recruitment phenomenon of the ventricle to synthesise and secrete ANF is directly dependent on the increase in stress-stretch relationship in each cardiocyte. Therefore, the levels of plasma ANF and its second messenger, cyclic glycophosphate mutase in plasma and urine appear as markers of congestive heart failure in animal models and in man. Particularly, plasma ANF has been recognized recently as independent prognostic factor in congestive heart failure.     

Atrial natriuretic factor decreases renal dopamine turnover and catabolism without modifying its release

Atrial natriuretic factor (ANF) and dopamine (DA) are both important regulators of sodium and water transport across renal proximal tubules. Many evidences suggest that some of ANF inhibitory effects on sodium and water reabsorption are mediated by dopaminergic mechanisms. We have previously reported that ANF stimulates extraneuronal DA uptake in external renal cortex by activation of NPR-A receptors coupled to cGMP signal and PKG. Moreover, ANF enhanced DA-induced inhibition of Na(+)-K(+) ATPase activity. The aim of the present study was to evaluate if ANF could alter also renal DA release, catabolism and turn over. The results indicate that ANF did not affect basal secretion of the amine in external renal cortex or its KCl-induced release, but diminished DA turn over. Moreover, ANF diminished COMT and did not alter MAO activity. In conclusion, present results as well as previous findings show that ANF modifies DA metabolism in rat external renal cortex by enhancing DA uptake and decreasing COMT activity. All those effects, taken together, may favor DA accumulation into renal cells and increase its endogenous content and availability. This would permit D1 receptor recruitment and stimulation and in turn, Na(+), K(+)-ATPase activity over inhibition that results in decreased sodium reabsorption. Therefore, ANF and DA could act via a common pathway to enhance natriuresis and diuresis.     

Biochemical mechanisms of atrial natriuretic factor action

Since atrial natriuretic factor (ANF) is a natriuretic and vasodilatory hormone, its mechanisms of action expectedly involve so-called negative pathways of cell stimulation, notably cyclic nucleotides. Indeed, the guanylate cyclase-cyclic GMP (cGMP) system appears to be the principal mediator of ANF's action. Specifically, particulate guanylate cyclase, a membrane glycoprotein, transmits ANF's effects, as opposed to the activation of soluble guanylate cyclase such agents as sodium nitroprusside. The stimulation of particulate guanylate cyclase by ANF manifests several characteristics. One of them is the functional irreversibility of stimulation with its apparent physiological consequences: the extended impact of ANF on diuresis and vasodilation in vivo lasts beyond the duration of increased plasma ANF levels and is accompanied by a prolonged elevation of cGMP. Another characteristic is the parallelism between guanylate cyclase stimulation and increases of cGMP in extracellular fluids. cGMP egression appears to be an active process, yet its physiological implications remain to be uncovered. In heart failure, cGMP continues to reflect augmented ANF levels, suggesting that in this disease, the lack of an ANF effect on sodium excretion is due to a defect distal to cGMP generation. In hypertension, where ANF levels are either normal or slightly elevated, probably secondary to high blood pressure, the ANF responsiveness of the particulate guanylate cyclase-cGMP system, the hypotensive effects, diuresis and natriuresis are exaggerated. The implications of this exaggerated responsiveness of the ANF-cGMP system in the pathophysiology of hypertension and its potential therapeutic connotations remain to be evaluated.     

Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling.

Endothelins build a peptide family composed of three isoforms, each of them containing 21 amino acids. Endothelin-1 is the isoform mainly responsible for any cardiovascular action and therefore the sole scope of this review. Endothelin-1 is the most potent endogenous vasoconstrictor known; in addition it acts as a potent (co)mitogen. There is a substantial body of experimental evidence that endothelin-1 may contribute not only to sustained vasoconstriction, but also to remodeling within the cardiovascular system. Thus, with the help of endothelin receptor antagonists (available for a few years) the involvement of mainly ETA receptors in structural diseases such as heart failure, pulmonary hypertension, atherosclerosis, restenosis, systemic hypertension, and chronic renal failure has been shown. These data make endothelin receptor antagonists, and especially those selective for the ETA receptor, promising agents for the treatment of chronic cardiovascular diseases associated with remodeling. Currently several chemically distinct, orally available members of this novel class of therapeutic agents are under clinical investigation.     

Effects of synthetic ANF (rANF(3-28)) on sympathetic neurotransmission in the isolated perfused rat kidney.

The effects of synthetic atrial natriuretic factor (rANF(3-28)) on sympathetic neurotransmission in the isolated perfused rat kidney was examined. ANF (10(-10)-10(-7) M) had no significant effect on stimulus-induced (1 Hz, 2 min) overflow of endogenous norepinephrine (NE) from the rat kidney. ANF also failed to affect stimulus-induced overflow which was markedly enhanced as a result of prejunctional beta-adrenoceptor activation with isoproterenol (10(-6)M). However, over the same concentration range ANF markedly attenuated the vasoconstrictor response to nerve stimulation. In addition, ANF significantly reduced the renal vasoconstrictor responses to intra-arterial injections of NE and angiotensin II. These results suggest that, while ANF potently inhibits renal sympathetic neurotransmission by inhibition of vascular responsiveness to vasoconstrictor stimuli, ANF does not appear to have a prejunctional effect to alter NE release from renal sympathetic nerves.