Intrarenal angiotensin II inhibition influences the actions of atrial natriuretic peptide

1. We previously found that kidneys isolated from salt-restricted rats were refractory to atrial natriuretic peptide compared with kidneys from salt-loaded rats. Because the intrarenal tissue renin-angiotensin system may modulate renal responses to atrial natriuretic peptide, we examined the effect of dietary NaCl loading on the responses of isolated perfused kidneys from normal rats to atrial natriuretic peptide, before and after the addition of angiotensin II receptor antagonists or angiotensin I converting enzyme inhibitors to the perfusate. 2. Atrial natriuretic peptide increased the glomerular filtration rate and sodium excretion of kidneys from NaCl-loaded rats. The addition of angiotensin receptor antagonists or converting enzyme inhibitors partially reversed the increments in glomerular filtration rate but not the increments in sodium excretion, leading to an increased fractional sodium excretion. In the absence of atrial natriuretic peptide, these agents did not affect glomerular filtration or sodium excretion. Kidneys from NaCl-restricted rats did not respond to atrial natriuretic peptide or to the inhibitors and antagonists, either separately or in combination. 3. After NaCl loading, the intrarenal renin-angiotensin system may augment the glomerular response to atrial natriuretic peptide while simultaneously inhibiting the natriuretic response to atrial natriuretic peptide. However, activation of the intrarenal renin-angiotensin system is not responsible for the refractoriness of kidneys from salt-restricted rats to atrial natriuretic peptide.     

Atrial natriuretic peptide inhibits the aldosterone response to angiotensin II in man

We have investigated the interaction between the recently discovered natriuretic factor alpha human atrial natriuretic peptide (alpha h-ANP) and the renin-angiotensin-aldosterone system in man. Angiotensin II infused with placebo produced a significant rise of plasma aldosterone concentration (mean +/- SEM increment 352 +/- 23 pmol/l, n = 7, P less than 0.001). The infusion of alpha h-ANP together with angiotensin II largely abolished the aldosterone response (P less than 0.001). Diastolic blood pressure rose in response to the infusion of angiotensin II with placebo (mean increment 21.0 +/- 0.9 mmHg, P less than 0.001). Systolic blood pressure increased to a lesser degree (mean increment 12.5 +/- 0.7 mmHg, P less than 0.001). The infusion of alpha h-ANP together with angiotensin II significantly blunted the diastolic pressor response (P less than 0.01). This ability of alpha h-ANP to blunt the pressor effect of angiotensin II may be important in the control of systemic blood pressure. The inhibition of angiotensin II-stimulated aldosterone release demonstrates that alpha h-ANP may not only be a circulating natriuretic factor in its own right but that it may also act as a modulator of a related endocrine system.     

Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide.

Using a specific radioimmunoassay for human brain natriuretic peptide (hBNP) with a monoclonal antibody, we have investigated its synthesis, secretion, and clearance in comparison with those of atrial natriuretic peptide (ANP) in normal subjects and patients with congestive heart failure (CHF). Mean BNP-like immunoreactivity (-LI) levels in normal atrium and ventricle were 250 and 18 pmol/g, respectively. The plasma BNP-LI level in normal subjects was 0.90 +/- 0.07 fmol/ml, which was 16% of the ANP-LI level. In contrast, the plasma BNP-LI level markedly increased in patients with CHF in proportion to its severity, and surpassed the ANP-LI level in severe cases. There was a significant step-up of the plasma BNP-LI level in the coronary sinus (CS) compared with that in the aortic root (Ao) and the difference between these BNP-LI levels, delta(CS-Ao)BNP, also increased with the severity of CHF. In addition, the step-up of the BNP-LI level in the anterior interventricular vein [delta(AIV-Ao)BNP] was comparable to delta(CS-Ao)BNP, indicating that BNP is secreted mainly from the ventricle. Predominant BNP synthesis in the ventricle was also confirmed by Northern blot analysis. Catheterization and pharmacokinetic studies revealed that hBNP is cleared from the circulation more slowly than alpha-hANP; this was in part attributed to lower (about 7%) binding affinity of hBNP to clearance receptors than that of alpha-hANP. A predominant molecular form of BNP-LI in the heart and plasma was a 3-kD form corresponding to hBNP. These results indicate that BNP is a novel cardiac hormone secreted predominantly from the ventricle, and that the synthesis, secretion and clearance of BNP differ from those of ANP, suggesting discrete physiological and pathophysiological roles of BNP in a dual natriuretic peptide system.     

Molecular biology of the natriuretic peptide system]

The natriuretic peptide system is composed of at least three distinct endogenous peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), and three receptors: ANP-A receptor/GC-A, ANP-B receptor/GC-B and the clearance receptor. This system influences the control of body fluid and blood pressure as cardiac hormones and local regulators. Recent advances in molecular biology have unravel the molecular mechanism of the natriuretic peptide system and have facilitated our understanding of it. The present review gives the current knowledge of the molecular biology of the natriuretic peptide system.     

Analytical correlation between plasma N-terminal pro-brain natriuretic peptide and brain natriuretic peptide in patients presenting with dyspnea

OBJECTIVES: We examined the analytical correlation N-terminal pro-brain natriuretic peptide (NT-proBNP) and brain natriuretic peptide (BNP). DESIGN AND METHODS: Electrochemiluminescence and fluorescence immunoassays were used to measure NT-proBNP and BNP levels, respectively. RESULTS: The analytical correlation was satisfactory using the equation: NT-proBNP = 8.56 x BNP + 91.7 and a correlation r = 0.85. The correlation was not influenced by age, gender and BMI of patients. CONCLUSIONS: We conclude that NT-proBNP correlates with BNP.     

Localization and regulation of renal receptors for angiotensin II and atrial natriuretic peptide.

The anatomical distribution of receptors for angiotensin II (Ang II) and atrial natriuretic peptide (ANP) within the kidney has been investigated by in vitro autoradiography. Ang II and ANP receptor binding occurs together in several sites in the kidney, including renal vasculature, glomeruli, proximal convoluted tubule of the outer cortex, and the vasa recta bundles of the inner stripe of the outer medulla. However, in the glomeruli, Ang II receptor binding occurs predominantly in mesangial cells, while ANP receptors are localized mainly to the visceral epithelial cells. In the inner medulla, there is a moderate density of ANP receptors in marked contrast with Ang II binding which is not detected in this site. Both Ang II and ANP receptors are modulated by alterations in sodium and fluid intake, and the peptides themselves. The overlapping distribution of receptors for these two peptide hormones in several intrarenal sites may provide an anatomical basis for their physiological interaction to regulate renal hemodynamics and tubular reabsorption of sodium and water.     

N-末端脑钠肽与心力衰竭的相关性

目的探讨血浆N-末端脑钠肽(NT-ProBNP)水平与心力衰竭程度的相关性。方法选择器质性心脏病心力衰竭患者443例(心力衰竭组)和同期住院的无器质性心脏病患者110例(对照组)作为研究对象,采用电化学发光全自动免疫分析仪测定两组患者血浆NT-ProBNP水平,评价NT-ProBNP水平与心力衰竭及心血管事件发生的关系。结果心力衰竭组NT-ProBNP水平显著高于对照组(P<0.05);且心力衰竭患者的NYHA心功能分级越高,NT-ProBNP水平越高(P<0.05),再发心血管事件发生率也越高。结论 NT-ProBNP在心力衰竭临床诊断、心功能分级及预后评估中具有重要的地位和价值,可作为监测心功能的良好指标。     

血管紧张素转换酶及脑利钠肽与心房颤动关系的临床分析

目的:观察非瓣膜性心房颤动(房颤)患者血清血管紧张素转换酶(ACE)和脑利钠肽(BNP)水平,探讨肾素-血管紧张素系统及脑利钠肽如何通过对左心房的影响在房颤发生与维持中发挥作用.方法:测定39例持续性心房颤动、31例阵发性心房颤动患者和30例对照组血清ACE、BNP水平及左心房内径大小,观察ACE和BNP对房颤的影响.结果:持续性房颤组左心房内径较阵发性房颤组和对照组明显增大(P＜0.05),持续性房颤组较对照组ACE和BNP水平均明显增加(P＜0.05).持续性房颤组与阵发性房颤组,阵发性房颤组与对照组相比,ACE及BNP虽有增加的趋势但均无统计学差异.回归分析显示ACE及BNP与左心房内径大小显著相关.结论:ACE与BNP可能通过左心房结构重构在房颤发生与维持中发挥重要作用.     

Pediatric brain natriuretic peptide and N-terminal pro-brain natriuretic peptide reference intervals

BACKGROUND: Brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) have been shown to be useful biomarkers for the diagnosis of heart failure. Pediatric reference intervals for these analytes have been reported in part. Previous studies lack large numbers in each group, have not covered all age ranges and have not compared results for BNP with NT-proBNP in simultaneously drawn samples. METHODS: We measured BNP in whole blood using the Biosite Triage point-of-care method and plasma NT-proBNP using the Dade RxL Dimension. We assessed between and within-day precision of both methods and after removing outliers employed the Hoffmann approach to calculate pediatric reference intervals over the age range of 0-21 y. We also compared the 2 methods on simultaneously drawn samples. RESULTS: Reference intervals revealed approximately 20-fold higher 97.5th percentiles for neonates than for children >3 y of age. 97.5th percentiles decreased significantly over the first 3 years of life. As shown by others, the CVs for the automated Dade RxL platform were somewhat lower than those for the POCT method. BNP and NT-proBNP correlated well in simultaneously drawn samples (r=0.947). DISCUSSION: Reference intervals for BNP and NT-proBNP are far higher in neonates and infants than in children older than three years of age. The reasons for this are unknown but resemble the elevated CK-MBs and troponins also found in neonates, although the 97.5th percentiles for these latter 2 cardiac markers decrease more rapidly to values found in older children by 6 months of age.     

Combined inhibition of angiotensin II and endothelin suppresses the brain natriuretic peptide response to developing heart failure

Blockade of AngII (angiotensin II) and ET (endothelin)-1, established and potential therapeutic strategies respectively, for heart failure, may have an adverse effect on the cardiac secretion of the natriuretic peptides, hormones with actions beneficial in this disease. The present study investigates the roles of AngII and ET-1 in regulating the stretch-induced release of the natriuretic peptides during the development of heart failure. On seven separate days, eight sheep underwent incremental left ventricular pacing (155, 190 and 225 beats/min for 90 min each) with concurrent infusions of a vehicle control, AngII, ET-1, AngII+ET-1, losartan [AT1 (AngII type 1) receptor antagonist], bosentan (ET(A)/ET(B) receptor antagonist) or losartan+bosentan. Pacing-induced rises in LAP (left atrial pressure) were amplified by the simultaneous administration of separate AngII and ET-1, and attenuated following blockade of the peptides, with maximum effects observed during combined treatments. Although these changes in atrial pressure were paralleled by concomitant alterations in circulating levels of both ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide), the plasma natriuretic peptide/atrial pressure relationship tended to be augmented by AngII and ET-1 and diminished by their blockade. A significant difference was demonstrated between the enhanced plasma BNP response to increasing LAP during combined AngII+ET-1 administration and decreased response during losartan+bosentan treatment ( P <0.05). A similar, but non-significant, trend was evident for ANP. The present study indicates dual AngII/ET-1 blockade diminishes BNP (and to a lesser extent ANP) secretion in developing heart failure, suggesting that augmentation of the natriuretic peptide system during the combination of these therapies may be of benefit.     

急性心肌梗死后血浆脑钠肽水平与心室重构的关系研究

目的探讨急性心肌梗死（AMI）后血浆脑钠肽（BNP）水平对心梗后心室重构的预测价值及判断作用。方法纳入120例首发AMI患者,根据心脏多普勒超声的检测情况分为心室重构组和心室非重构组。在发病后72h内及90d时,检测血浆BNP和ANP含量。出院后90d时随访。半年后进行超声检测,综合评价心室重构情况。结果纳入120例,成功随访101例。依据ΔLVEDVI值分为重构组39例,非重构组62例。重构组发病后72h内及90d时的血浆BNP、ANP水平均显著高于非重构组。BNP2水平与LVEDVI相关系数最大。多元线性回归分析显示,心梗发病90d时的血浆BNP水平与心室重构的关系最为密切,可作为独立预测指标。ROC曲线分析表明BNP对心室重构的判断价值大于ANP,其中BNP2价值最大。血浆BNP2≥410pg／mL,判断心室重构的敏感度为0．80,特异度为0．70。结论心梗后90d的血浆BNP水平可作为心室重构的独立相关指标,这对预测AMI患者发生心室重构提供了一一种新的无创且有效的实验室指标。     

B型钠尿肽及N端B型钠尿肽原水平与心力衰竭患者心功能的关系

目的研究心力衰竭（HF）患者B型钠尿肽（BNP）、N端B型钠尿肽原（NT—pro BNP）水平与HF患者心功能分级的相关性。方法分别采用免疫放射试验（IRMA）及酶联免疫吸附法（ELISA）测定86例HF患者和30例有呼吸困难的非HE患者（对照组）BNP、NT—proBNP水平并以多普勒超声诊断仪测定左窒射血分数（LVEF）。结果BNP、NT—proBNP水平随心功能NYHA分级程度的加重而显著增高,并与LVEF呈负相关,分别为r=-0．39,P〈0．0l;r=-0．35,P〈0．0l,HF患者BNP、NT—proBNP血浆浓度值呈高度相关（r=0．91,P〈0．001）。BNP、NT-proBNP用于HF诊断的效果以受试者工作特征（ROC）曲线下面积表示分别为0．916、0．926（P〉0．05）。结论BNP、NT—proBNP均可用于HF早期诊断及HF严重程度的评价,并可用于呼吸困难患者的鉴别诊断。     

Renal and hormonal actions of atrial natriuretic peptide during angiotensin II or noradrenaline infusion in man

In order to study the renal and hormonal actions of atrial natriuretic peptide (ANP) during background infusions with angiotensin II (ANG II) or noradrenaline (NA), 69 healthy subjects were examined in three main groups receiving a 90-min infusion with either placebo, ANG II (1.5 ng kg^?1 min^?1), or NA (25 ng kg^?1 min^?1). Each of these three main groups were subdivided into two groups receiving an infusion with either placebo or ANP (10 ng kg^?1 min^?1) for the last 60 min of the background infusion. Lithium clearance was used to evaluate segmental tubular reabsorption. ANG II alone caused a decrease in glomerular filtration rate (GFR), renal plasma flow, urinary absolute and fractional excretion of sodium, both proximal and distal fractional tubular sodium reabsorption, and urinary flow. NA alone caused a decrease in renal plasma flow. ANP alone caused a decrease in renal plasma flow. Urinary absolute and fractional excretion of sodium were increased and the distal fractional tubular reabsorption of sodium decreased, whereas the proximal fractional tubular reabsorption was unchanged by ANP. ANG II + ANP: during a background ANG II infusion, ANP still increased fractional excretion of sodium. Proximal fractional reabsorption was decreased, whereas distal fractional reabsorption of sodium was unchanged by ANP during ANG II infusion. The ANP-induced decreases in proximal absolute (?147 vs. +714 μmol min^?1 1.73 m^?2P = 0.05) and fractional (?1.7% vs. +0.6%, P<0.01) tubular sodium reabsorption were more pronounced, and the decrease in distal fractional tubular reabsorption of sodium (?0.1% vs. ?1.4%, P<0.05) less pronounced compared with when ANP was given alone. NA + ANP: during a background NA infusion, ANP still increased urinary sodium excretion and decreased distal fractional reabsorption. None of the ANP-induced absolute changes seen during background infusion with NA were significantly different from the ANP-induced changes seen during placebo background infusion. It is concluded that the natriuretic action of low-dose ANP seems to be preserved during background infusions with ANG II and NA in man. Net sodium excretion during the combined infusion with ANG II and ANP seems to reflect the sum of the opposing influences of each peptide. Low-dose ANP had a very modest but significant inhibitory effect on proximal tubular sodium reabsorption prestimulated by ANG II infusion.     

Cross-talk between the lungs in piglets

Hypothesis During alternating ventilation (AV) (i.e. differential ventilation (DV) of both lungs with a phase difference of half a ventilatory cycle) volume expansion of the inflated lung will occur partly by compression of the opposite lung.Objective We studied whether and how large an undulating flow would occur out of and into the non-ventilated lung during unilateral ventilation.Design In 20 anaesthetized, paralysed piglets (11.0±1.0 kg) DV was applied at a rate of 10 breaths per minute (bpm). In 6 animals, 15 and 20 bpm were also applied with the tidal volume adapted no normocapnia. As the measure of interaction (cross-talk) served the volume change in the non-ventilated lung, found by integration of the low signal, in percentage of the tidal volume to the other lung.Results In all pigs, tidal volume to the left lung (V_{T, l}=7.33±1.06 ml kg^–1) caused a volume change in the right lung of about 21% of V_{T, l} at 10 bpm. The right-to-left cross-talk was significantly lower and about 15% of V_{T, r} (9.07±1.21 ml kg^–1). At higher ventilatory rates, the l-to-r and the r-to-l cross-talk did not change.Conclusion During unilateral ventilation, volume expansion of the inflated lung occurs partly by compression of the opposite lung. The lower mean lung volume during AV compared to synchronous differential ventilation can be explained by such compression. The mechanism of compression is similar at different ventilatory rates.     

脑钠肽前体及氨基末端脑钠肽前体基因的克隆与表达

目的在大肠杆菌中表达脑钠肽前体(proBNP)及氨基末端前体蛋白(NT-proBNP)。方法采用分子生物学技术构建重组质粒PGEX-20T-proBNP和PGEX-20T-NT-proBNP,分别对其进行PCR、双酶切和测序鉴定,然后将已测序鉴定的包含两种重组质粒的工程菌,转化至大肠杆菌BL21菌中表达脑钠肽前体及氨基末端前体蛋白,并用Western-blot鉴定纯化的重组蛋白。结果在大肠杆菌中成功的表达脑钠肽前体及氨基末端前体蛋白,两种蛋白均以可溶性形式表达,更有利于保存其生物学活性。结论两种蛋白的成功表达将有利于后续的单抗制备及检测试剂盒的开发奠定基础。