Cardiac rhabdomyomas exhibit a fetal pattern of atrial natriuretic peptide immunoreactivity

Rhabdomyomas are the most common heart tumors seen in infancy. However, whether they represent hamartomas or true neoplasms derived from cardiomyocytes is still controversial. The fetal pattern of atrial natriuretic peptide (ANP) expression (predominant in the atrial and ventricular subendocardium) becomes altered during the early postnatal period to that typical of the adult (all atrial cardiomyocytes and some cells in the ventricular impulse-conducting system). To better comprehend the nature and origin of cardiac rhabdomyomas, we investigated the immunohistochemical expression of ANP in seven surgically excised ventricular specimens and two necropsy cases of multiple, atrial, and ventricular rhabdomyomas in children aged 1 to 34 days. Immunogold labeling for ANP at the ultrastructural level was also performed on three ventricular tumors. Although all atrial tumors were immunoreactive for ANP, these usually showed a variable number of faintly positive cardiomyocytes, contrasting with the diffuse and intense immunoreactivity of the surrounding atrial myocardium. ANP was detected in the ventricular tumors of five (56%) of the nine cases. The positive ventricular tumor cells predominated in the subendocardium and areas with prominent fibrous tissue, usually around blood vessels. Immunoelectron microscopy of the ventricular tumors demonstrated rare, positive cytoplasmic granules surrounded by membranes, usually located near the nuclei. We conclude that cardiac rhabdomyomas exhibit a fetal pattern of ANP immunoreactivity, which suggests delayed maturation of the tumoral cardiomyocytes, reinforcing the notion that cardiac rhabdomyomas are fetal hamartomas.     

Case report of a heart transplantation in a 16-year-old male

We examined ultrastructural changes and did immunohistochemical studies of atrial natriuretic peptide (ANP) in biopsied samples obtained from the heart of a 16-year-old Japanese boy with dilated cardiomyopathy and from the transplanted donor heart. In the right ventricle of the diseased heart, a small number of atrial granules containing ANP were found in the perinuclear area of the cardiomyocytes and near areas lacking some myofibrils. Although no evidence of rejection was seen in the right ventricle of the transplanted donor heart under the light microscope, electron microscopy revealed moderate degeneration of cardiomyocytes and injuries to capillary endothelial cells. We did not find atrial granules, although the serum ANP level was elevated. These data suggest that the ultrastructural changes in the transplanted heart were related to a mild rejection, the effects of cyclosporin, or the effects of a domino heart transplantation from a patient with cystic fibrosis. Because of the absence of atrial granules in the right venticle, it is postulated that the high serum ANP level may be attributed to merely an increased secretion of ANP from atrial granules in the atria, without secretion of ANP in the ventricles.     

Atrial natriuretic peptide in human urine

Summary A highly sensitive radioimmunoassay to measure atrial natriuretic peptide (ANP) concentration in urine has been established, and its clinical usefulness is presented. ANP in urine was stable at 4° C for several days and was easily measured by our radioimmunoassay. The average ANP excretion in 65 healthy persons was 25.0±1.4 ng/day (mean ± SEM) and the fractional excretion of ANP was 0.7±0.05%. In 14 patients with congestive heart failure, the average ANP excretion was 119.2±29.4 ng/day, which decreased to 53.3±11.0 after successful treatment.Abbreviations ANP atrial natriuretic peptide - hANP human atrial natriuretic peptide - RIA radioimmunoasay - NSB non specific bound - FE_ANP the fractional excretion of atrial natriuretic peptide - FE_Na the fractional excretion of sodium - SIADH the syngrome of inappropriate secretion of antidiuretic hormone     

Cardiac natriuretic peptides and continuously monitored atrial pressures during chronic rapid pacing in pigs

Changes in atrial natriuretic peptide (ANP), N-terminal proatrial natriuretic peptide and brain natriuretic peptide (BNP) were evaluated in relation to continuously monitored atrial pressures in a pacing model of heart failure. Pigs were subjected to rapid atrial pacing (225 beats min-1) for 3 weeks with adjustments of pacing frequencies if the pigs showed overt signs of cardiac decompensation. Atrial pressures were monitored by a telemetry system with the animals unsedated and freely moving. Left atrial pressure responded stronger and more rapidly to the initiation of pacing and to alterations in the rate of pacing than right atrial pressure. Plasma natriuretic peptide levels were measured by radioimmunoassay and all increased during pacing with BNP exhibiting the largest relative increase (2.9-fold increase relative to sham pigs). Multiple regression analysis with dummy variables was used to evaluate the relative changes in natriuretic peptides and atrial pressures and the strongest correlation was found between BNP and left atrial pressure with R 2=0.81. Termination of pacing resulted in rapid normalization of ANP values in spite of persistent elevations in atrial pressures. This may reflect an increased metabolism or an attenuated secretory response of ANP to atrial stretch with established heart failure. In conclusion, 3 weeks of rapid pacing induced significant increases in atrial pressures and natriuretic peptide levels. All the natriuretic peptides correlated with atrial pressures with BNP appearing as a more sensitive marker of cardiac filling pressures than ANP and N-terminal proatrial natriuretic peptide.     

Atrial natriuretic peptide in peripheral organs other than the heart

Summary The heart atria represent the major site of synthesis of atrial natriuretic peptide (ANP) in mammals including man, and its function as a regulator of water and salt homeostasis has been repeatedly suggested. However, more recently ANP has been located in organs not intimately related to cardiovascular physiology, e.g. the adrenals, lungs, and gut, as well as tissues belonging to the lymphatic, reproductive or endocrine systems. Thus, ANP might serve many more physiological roles than originally thought, but the functional significance of ANP in these non-cardiac tissues is presently poorly understood.Abbreviations ANP atrial natriuretic peptide - IR-ANP immunoreactive atrial natriuretic peptide - LH luteinizing hormone - ACTH adrenocorticotrophic hormone - RP-HPLC reverse phase high pressure liquid chromatography - mRNA messenger ribonucleic acid - RIA radioimmunoassay - CNS central nervous system     

Cardiac natriuretic peptide hormones during artificial cardiac pacemaker stimulation and left heart catheterization

Summary Brain natriuretic peptide (BNP) is synthesized and released predominantly in the ventricular myocardium whereas atrial natriuretic peptide (ANP) is produced mainly in the atria. This study evaluated whether artificial pacemaker stimulation or left heart catheterization results in specific changes in BNP and ANP plasma levels. Both BNP and ANP responded sensitively to changes in pacemaker stimulation (single-chamber pacemakers; pacing rates of 72 and 92/min) and during the left heart catheterization procedure. However, whereas higher pacing resulted in a more pronounced increase in plasma BNP levels, a stronger ANP release followed catheterization. This incongruous rise in ANP and BNP plasma concentrations points to at least partly independent mechanisms govering the release of BNP and ANP.Abbreviations ANP atrial natriuretic peptide - BNP brain natriuretic peptide     

Mechanisms of mechanical load-induced atrial natriuretic peptide secretion: role of endothelin, nitric oxide, and angiotensin II

There are three members in the natriuretic peptide hormone family, atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, brain natriuretic peptide), and C-type natriuretic peptide (CNP), that are involved in the regulation of blood pressure and fluid homeostasis. CNP is found principally in the central nervous system and vascular endothelial cells while ANP and BNP are cardiac hormones. ANP is synthesized mainly in the atria of the normal adult heart, while BNP is produced by both the atria and ventricles. The mechanisms controlling ANP release have been the subject of intense research, and are now fairly well understood. The major determinant of ANP secretion is myocyte stretch. Although much less is known about the factors regulating BNP release from the heart, myocyte stretch has also been reported to stimulate BNP release from both atria and ventricles. However, whether wall stretch acts directly or via factors such as endothelin-1, nitric oxide, or angiotensin II liberated in response to distension has not been established. Recent studies show that by stimulating endothelin type A receptors endothelin plays an important physiological role as a mediator of acute-volume load-induced ANP secretion from atrial myocytes in conscious animals. In fact, endogenous paracrine/autocrine factors liberated in response to atrial wall stretch rather than direct stretch appears to be responsible for activation of ANP secretion in response to volume load, as evidenced by almost complete blockade of ANP secretion during combined inhibition of endothelin type A/B and angiotensin II receptors. Furthermore, under certain experimental conditions angiotensin II and nitric oxide may also exert a significant modulatory effect on stretch-activated ANP secretion. The molecular mechanisms by which endothelin-1, angiotensin II, and nitric oxide synergistically regulate stretch-activated ANP release are yet unclear.     

The natriuretic peptides: universal volume controllers

Since the discovery of the natriuretic effect of atrial natriuretic peptide (ANP), a family of other natriuretic peptides similar to ANP were isolated, including atriopeptin, vessel dilator, long-acting natriuretic peptide, urodilatin, and brain natriuretic peptide (BNP) to name a few. ANP was noted to possess natriuretic and diuretic properties that controlled increases in intravascular volume. ANP was also found to be elevated in conditions of increased intraocular pressure and biliary obstruction. BNP was found to be elevated in conditions of increased intracranial pressure, pointing towards its role in controlling cerebrospinal fluid volume. While at the cellular level, ANP controlled individual cell size. This makes the natriuretic peptides not only controllers of intravascular volume, but also modulators of a myriad of cavity volumes down to the control of individual cell volume.     

Distribution patterns of PCNA and ANP in perinatal stages of the developing rat heart

Distribution patterns of proliferating cell nuclear antigen (PCNA) and atrial natriuretic peptide (ANP) were determined immunohistochemically and morphometrically in atrium and ventriculum of the developing rat heart in different stages of the perinatal period. During the prenatal period, PCNA and ANP were localized in opposite patterns, particularly in trabecular myocytes. A distinct reduction in the percentage of PCNA-positive nuclei was detected starting at day 19 of the prenatal period, and these cells were rarely observed on postnatal days 30 and 60. In cardiomyocytes, a distinct increase in ANP positivity was found, whereas PCNA positivity was very low. It is concluded that PCNA expression gradually decreased from prenatal day 19 onwards, whereas ANP expression increased in atria throughout the prenatal and postnatal periods, except for a decrease in ANP expression in ventricles from prenatal day 21 onwards. The opposite expression patterns of PCNA and ANP in trabecular myocytes of ventricles indicate that ANP may have antimitogenic/antiproliferative effects in trabecular myocytes.     

Brain natriuretic peptide

Plasma levels of various neurohumoral factors are activated and have an important role of the pathophysiology of congestive heart failure (CHF). Atrial natriuretic peptide (ANP) and brain (or B-type) natriuretic peptide (BNP) are secreted from cardiomyocytes in response to atrial or ventricular wall stretch. The natriuretic peptides have a fundamental role in cardiovascular remodeling, volume homeostasis, and the response to myocardial injury. Clinical investigations of these peptides have focused on their diagnostic usefulness for heart failure and left ventricular dysfunction and their prognostic usefulness after acute coronary syndromes and heart failure. In patients with left ventricular systolic dysfunction, a high plasma BNP level is an independent prognostic predictor of CHF patients, suggesting that the compensatory activity of the cardiac natriuretic peptide system is attenuated as mortality increases in chronic CHF patients with high plasma levels of ANP and BNP. BNP is more useful than ANP for diagnosis and management of CHF. Recently, rapid BNP assay is available in our country, rapid measurement of BNP in the emergency department may improve the evaluation and treatment of patients with acute dyspnea and thereby reduced the time to discharge and the total cost of treatment. In addition, BNP-guided treatment of heart failure may reduce total cardiovascular events, and delayed time to first event combination with intensive clinically guided treatment.     

利尿钠肽在诊断心力衰竭中的应用价值

探讨利尿钠肽的水平对心力衰竭（心衰）早期诊断的应用价值。采用放免法、ELISA法检测了129例心衰患者血浆中的心房利尿钠肽（ANP）、脑利尿钠肽（BNP）、N末端脑钠肽前体蛋白（NT-proBNP）水平,并与30例健康对照者进行了比较分析。结果显示,心衰患者血浆中的ANP、BNP、NT-proBNP显著高于健康对照组,且均随着NYHA分级的升高而逐渐增加,其含量在NYHA Ⅳ级时到达最高,心衰患者的血浆ANP、NT-proBNP水平与LVEF呈明显负相关。检测血浆中的ANP、BNP、NT-proBNP含量简便、快捷,可用于心衰诊断及NYHA分级判断。     

Origin and characterization of atrial natriuretic peptide in the rat parotid gland

Summary The heart atria represent the major site of synthesis for atrial natriuretic peptide (ANP) which exerts potent natriuretic, diuretic and vasoactive functions. Recently, ANP-immunoreactivity has been detected in extracardial organs involved in water and electrolyte homeostasis, such as the intestine and certain exocrine glands. The present study investigates ANP in the parotid gland. It was found by immunohistochemical techniques that the peptide is localized in ductal cells of the gland. An analysis of the immunoreactive material by high-pressure liquid chromatography and radioimmunoassay revealed the prohormone of ANP (ANP 1-126) and the biologically active fragment (ANP 99-126). Furthermore, Northern blot hybridization disclosed the presence of mRNA coding for ANP. It is suggested that ANP is synthesized and released from the parotid gland and functions in the control of saliva production.     

HS-142-1, a novel non-peptide ANP antagonist, blocks the cyclic GMP production elicited by natriuretic peptides in PC12 and NG108-15 cells.

HS-142-1 is a novel non-peptide antagonist for atrial natriuretic peptide (ANP) receptor. The effect of HS-142-1 on the cyclic GMP production elicited by natriuretic peptides in neuronal cell lines, PC12 and NG108-15 was examined. Natriuretic peptides such as ANP, brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) enhanced cyclic GMP production in a dose-dependent manner. HS-142-1 inhibited cyclic GMP accumulation elicited by natriuretic peptides in a dose-dependent fashion in both cells. The results suggest that HS-142-1 will be an important tool for identification and understanding of the mechanisms by which natriuretic peptides act in nervous systems.     

Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation

Atrial fibrillation is a common arrhythmia that is hereditary in a small subgroup of patients. In a family with 11 clinically affected members, we mapped an atrial fibrillation locus to chromosome 1p36-p35 and identified a heterozygous frameshift mutation in the gene encoding atrial natriuretic peptide. Circulating chimeric atrial natriuretic peptide (ANP) was detected in high concentration in subjects with the mutation, and shortened atrial action potentials were seen in an isolated heart model, creating a possible substrate for atrial fibrillation. This report implicates perturbation of the atrial natriuretic peptide-cyclic guanosine monophosphate (cGMP) pathway in cardiac electrical instability.     

Pathophysiologic role of natriuretic peptides

To evaluate the pathophysiologic role of atrial natriuretic peptide (ANP) in hypertension, hemodynamic effects of human ANP and antiserum against rat ANP were investigated in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Intravenous administration of human ANP caused greater hypotension associated with a decrease of cardiac output in SHR than in WKY, which suggests that SHR have enhanced responsiveness to exogenous ANP. The antiserum increased blood pressure and cardiac output, with the latter being significantly greater in SHR than in WKY. These results suggest that endogenous ANP counteract, in part, the maintenance of hypertension. In addition, hemodynamic and renal excretory effects of brain natriuretic peptide (BNP), a novel natriuretic peptide identified from porcine, were studied in SHR and WKY. BNP caused marked natriuresis and hypotension in a dose-dependent fashion, as observed with ANP. Not only ANP but also BNP may have a role in the regulation of blood pressure and water-electrolyte balance.     

过表达miR-130a-3p对心肌细胞肥大的缓解作用研究

本研究旨在探索miR-130a-3p对心肌细胞肥大的作用及其可能机制。通过胸主动脉缩窄法(TAC)构建压力超负荷所致心肌肥厚小鼠模型。使用去甲肾上腺素(NE)刺激SD乳鼠原代心肌细胞(NRCMs)及H9c2大鼠心肌细胞系,诱导这两种心肌细胞发生肥大表型转变。检测miR-130a-3p的表达变化,并进一步探索其对心肌细胞肥大是否有调控作用。结果表明,miR-130a-3p在肥厚心肌组织、肥大NRCMs及H9c2细胞中的表达均明显降低。给予miR-130a-3p mimics使其过表达后,H9c2细胞中肥大标志基因心房利钠肽(ANP)、脑利钠肽(BNP)和肌球蛋白重链β(β-MHC)的表达较对照组(mimics N.C.+NE组)明显下调,且细胞面积明显减小。而给予miR-130a-3p inhibitor抑制其表达后,肥大心肌细胞中ANP、BNP、β-MHC的表达进一步上升,且细胞面积进一步增加。Western blot检测发现,过表达miR-130a-3p后心肌细胞中磷酸化Akt和磷酸化mTOR的表达水平下调。以上结果提示,miR-130a-3p mimics可缓解心肌细胞肥大的程度;其inhibitor则可使心肌细胞肥大进一步加剧。过表达miR-130a-3p可能通过影响Akt通路来缓解H9c2心肌细胞肥大的程度。     

Plasma ANP during hypertonic NaCl infusion in man

To determine the relationship between hyperosmolality and immunoreactive atrial natriuretic peptide of heart atrial plasma six healthy men were given 0.06 ml kg^-1 min^-1 855 mmol 1^-1 NaCI, i.v., for 2 h. The right atrial pressure and atrial plasma atrial natriuretic peptide were measured. During the infusion, right atrial pressure was kept constant by lowering the legs of the subject in a supine position downwards if any increase in the pressure was seen. There was a significant and linear increase in atrial serum osmolality, from 288 ± 3.3 to 307 ± 3.2mOsm kg^-l (P < 0.001). No statistically significant changes in right atrial pressure were seen. Regression analysis revealed that there was a statistically significant correlation between serum osmolality and plasma ANP in three subjects (responders) (r²: 0.5 241 , 0.8 965 , 0.6695). In three other subjects (nonresponders), there was no correlation between osmolality and ANP. The mean basal osmolality of responders was 280 mOsm kg^-1 and the mean basal osmolality of nonresponders was 295 mOsm kg^-1. In contrast, all subjects responded with an increase in plasma ANP (P < 0.05) after RAP had been increased by tilting the legs of the subject upwards for 30 min. We conclude that the right atrial pressure regulates the release of atrial natriuretic peptide. Serum hyperosmolality may also contribute to the the regulation of atrial natriuretic peptide independently of the right atrial pressure in man.     

Effect of atropine on plasma atrial natriuretic peptide concentration in healthy subjects

This work shows that an intravenous infusion of atropine increases the concentration of atrial natriuretic peptide (ANP) in the plasma of healthy subjects. The effect is discussed in reference to the heart rate and the role of the autonomic nervous system in the control of ANP secretion by atrial cardiocytes.     

Increase in plasma atrial natriuretic peptides during acute volume expansion in hypertensive man

A new hormonal system originating from cardiac atria has recently been discovered. These peptide hormones have important functions in the regulation of blood volume and fluid homeostasis. We have measured plasma concentrations of atrial natriuretic peptides (ANP) in two patients during acute volume expansion. ANP concentrations increased in relation to an increase in right atrial pressure, and significant diuresis/natriuresis was observed. We conclude that hormonal as well as neuronal mechanisms are activated by acute volume loading in man.     

利钾尿肽与心钠素摩尔比在老年原发性高血压中的作用

目的:探讨利钾尿肽(KP)与心钠素摩尔比变化在老年原发性高血压发病中的意义。方法:用放射免疫分析方法测定老年高血压患者血浆、老年自发性高血压大鼠(SHR)血浆及心房和心室组织的KP和心钠素(ANP)含量。结果:高血压患者血浆KP、ANP水平与对照组比较无显著差异。但是,KP与ANP的摩尔比显著低于对照组(P＜0.05),SHR血浆KP、ANP水平显著高于对照组(WKY)(P＜0.01和P＜0.05),KP/ANP摩尔比则显著低于WKY(P＜0.01)。SHR心房KP含量高于心室(P＜0.05),但与对照组WKY比较无显著差异。结论:KP含量及KP与ANP的比例关系的改变,在老年原发性高血压发病中起着一定的作用。