Interaction of a Neutral Endopeptidase Inhibitor with an ANP-C Receptor Ligand in Anesthetized Dogs

Inhibition of important degradative pathways of atrial natriuretic peptide (ANP) in vivo could be a valuable therapeutic tool for regulating endogenous levels of ANP. The aim was to investigate the in vivo effects of both blockade of atrial natriuretic peptide clearance receptor and inhibition of neutral endopeptidase 24.11, an enzyme shown to be involved in ANP breakdown. Therefore, we infused a specific neutral endopeptidase inhibitor ((S)-thiorphan) and an ANP-C receptor ligand (AP 811) alone or in combination into anaesthetized beagle dogs.

Compared with vehicle controls, coadministration of (S)-thiorphan and AP 811 (100μg/kg/min and 10μg/kg/min, resp.) had greater effects on endocrine and renal parameters than administration of either substance alone.     

黄芪对心房收缩力及心房钠尿肽分泌的影响

目的：观察黄芪对家兔心房收缩力及心房钠尿肽分泌的影响。方法：采用家兔离体心房灌流模型，处理0.002,0.002 5,0.003 g·L^-1的黄芪水提取液观察家兔心房收缩力及心房钠尿肽分泌的变化，并选择最佳剂量探讨其作用机制。心房钠尿肽含量的测定采用放射免疫法。结果：3个剂量的黄芪水提取液使离体家兔心房每搏输出量由给药前的(694.70±0.01) μL·g^-1分别增加到(1 003.00±8.80)，(1 120.00±17.71)，(1 195.00±8.21) μL·g^-1(与给药前比较，分别P<0.05；P<0.01及P<0.001)；并使心房搏动压由给药前的(0.82±0.01) kPa分别增加至(0.86±0.01)，(0.96±0.01)，(1.02±0.01) kPa(与给药前比较，分别P<0.01；P<0.001及P<0.001)，且呈现浓度依赖性特征，表明黄芪可增加家兔心房收缩力。0.002 5 g·L^-1黄芪水提取液显著抑制心房钠尿肽的分泌［给药前心房钠尿肽含量为(18.74±0.02 ) ng·min^-1·g^-1，给药后为(12.97±0.14) ng·min^-1·g^-1；与给药前比较P<0.001］。L-型Ca²⁺通道阻断剂硝苯地平(1.0 μmol·L^-1)及逆向Na⁺-Ca²⁺交换体抑制剂KB-R 7943(10.0 μmol·L^-1)阻断了黄芪增强心房收缩力的作用，但均未能改变黄芪对心房钠尿肽分泌的抑制效应。结论：黄芪主要通过影响L-型Ca²⁺通道及Na⁺-Ca²⁺交换体增强心房收缩力，并对心房钠尿肽分泌具有抑制性调节作用。     

Subtype-specific roles of cAMP phosphodiesterases in regulation of atrial natriuretic peptide release

cAMP is known to control the release of atrial natriuretic peptide. To define the roles of cyclic nucleotide phosphodiesterase subtypes in the regulation of atrial natriuretic peptide (ANP) release, experiments were done with perfused beating rabbit atria. Phosphodiesterase 3 subtype-specific inhibitors, milrinone and cilostamide, inhibited myocytic ANP release with a concomitant increase in cAMP efflux. Similarly, trequinsin, another phosphodiesterase 3 inhibitor, decreased ANP release. A phosphodiesterase 4 subtype-specific inhibitor, rolipram, did not significantly change ANP release but increased AMP efflux. Also, 4-[(3-butoxy-4-methoxyphenyl)methyl]-2-imidazolidinone (Ro 20-1724), another phosphodiesterase 4 inhibitor, did not significantly change ANP release. The cAMP efflux was higher in the atrium treated with rolipram than in the atrium treated with milrinone or cilostamide. The data show that the cAMP pool, which is metabolized by phosphodiesterase 3, but not phosphodiesterase 4, is closely related to the basal regulation of atrial ANP release. The results suggest that intracellular cAMP is compartmentalized in the regulation of atrial ANP release, and that the release is controlled by a phosphodiesterase subtype-specific mechanism.     

烧伤病人休克期血浆ANP、BNP含量变化

目的 观察烧伤病人休克期血浆中ANP（心钠素）、BNP（脑钠素）含量变化，探讨其临床意义。方法 选取伤后8h内入院的烧伤休克期住院病人14例，抽取病人静脉血3mL，用放射免疫方法，检测ANP、BNP含量，并与正常成人作对照。结果 烧伤患者休克期血浆中ANP、BNP含量明显高于正常成人，差异有显著性（P〈0．01）；随烧伤面积增大ANP、BNP含量增大，BNP比ANP变化更为明显（P〈0．01）。结论 烧伤后血浆中ANP、BNP含量明显上升；BNP含量的变化比ANP更敏感；休克期ANP、BNP含量的变化可能与容量失衡有关。     

降压露对肾性高血压大鼠血浆ANP水平影响的实验研究

心钠素（ANP）是近年来研究高血压疾病的一个重要相关性指标。血浆ANP水平能从侧面反映药效物的降压机理。实验研究表明，降压露在降低肾性高血压大鼠血压的同时，还能明显升高其血浆ANP水平（P＜0．05－0．01），说明其降压机理可能与促进ANP分泌有关。     

Role of natriuretic peptides in the diagnosis and treatment of patients with carcinoid heart disease

Carcinoid heart disease (CHD) occurs in 20-70% of the patients with metastatic well-differentiated neuroendocrine tumours (NET). We evaluated whether natriuretic peptides (ANP or NT-proBNP) are useful in early detection of CHD. Blood samples from 32 patients with NET were compared with cardiac ultrasound follow-up. CHD was defined as thickening of the tricuspid valve in the presence of grade III-IV/IV tricuspid valve regurgitation. CHD was found in nine out of 32 patients (28%), all with symptoms of the carcinoid syndrome compared to 65% in the 23 patients without CHD (P=0.04). Median levels of NT-proBNP and 5-HIAA were significantly higher in patients with CHD (894 ng l(-1) and 815 micromol 24 h(-1)) compared to those without (89 and 206 ng l(-1), P<0.001 and P=0.007). No significant differences were detected in ANP levels (P=0.11). Dilatation of the right atrium and ventricle as well as thickening of the tricuspid valve and degree of regurgitation were statistically significant correlated with NT-proBNP levels. The accuracy of NT-proBNP in the diagnosis of CHD was higher than that of ANP. A significantly better survival was observed in case of normal NT-proBNP values. In conclusion, NT-proBNP is helpful as a simple marker in the diagnosis of CHD. Survival is better in patients with normal levels of NT-proBNP.     

糖肾通络方对早期糖尿病肾病患者血清内皮素、心钠素的影响

目的探讨糖肾通络方治疗糖尿病肾病(DN)的疗效及机理。方法45例DN患者随机分为糖肾通络方组(25例)及络丁新组(20例),采用中医证候积分法观察2组治疗前后的积分,采用放射免疫法检测2组治疗前后血中的内皮素(ET)、心钠素(ANP)含量,采用生化法检测血中空腹血糖(FBG)、糖化血红蛋白(HbA1c)、胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)含量及尿蛋白排泄率(UAER)。结果2组治疗后中医证候积分糖肾通络方组明显低于络丁新组(P<0.01),临床总有效率糖肾通络方组明显优于络丁新组(P<0.05),虽然2组患者血中ET、ANP和FBG、HbA1c及UAER均较治疗前明显下降(P<0.05,P<0.01),但糖肾通络方组下降明显优于络丁新组(P<0.05,P<0.01),治疗后糖肾通络方组的TC、TG、LDL-C下降,HDL-C升高较络丁新组明显(P<0.05,P<0.01)。结论糖肾通络方具有较好的调整血脂、血糖,尤其是改善全身症状、提高生活质量的作用,并且能够减低或阻止ANP、ET的产生和分泌,改善肾脏受损的微血管,促进肾小球硬化的修复,达到改善肾功能的目的。     

Isolation and structural analysis of the circulating human cardiodilatin (alpha ANP)

Summary A new method was applied to isolate a polypeptide hormone from human blood. The polypeptides from 1,000 1 of hemofiltrate with a molecular weight lower than 20 kDaltons were adsorbed to 2.5 kg alginic acid, then eluted, precipitated, and desalted on a G-25 Sephadex column, thus obtaining a crude lyophilised plasma polypeptide extract. These polypeptides were further submitted to ion-exchange chromatography. Thereafter, two steps of HPLC were carried out to purify a distinct polypeptide which was the circulating form of cardiodilatin (CDD) in this case. The amino acid analysis, C-terminal enzymatic cleavage by carboxypeptidase A, and sequence analysis showed that the only form of circulating cardiodilatin is the 28 amino acid residue containing molecule, cardiodilatin-99-126 cleaved from the C-terminus of cardiodilatin-126 and identical with alpha-ANP (alpha atrial natriuretic polypeptide). Other bioactive molecular forms of the polypeptide hormones of the cardiodilatin family were not detected in the hemofiltrate. The isolation procedure was followed up by a bioassay using in vitro vascular smooth muscle relaxation.Abkürzungsverzeichnis ANP atrial natriuretic polypeptide - CDD Cardiodilatin - HPLC high performance liquid chromatography - NA noradrenaline - OD optical density - RIA radioimmunoassay - RP reverse phase     

CGMP Levels Following ANF Challenge are Markers of Subsequent Successful Reversion of Lone Atrial Fibrillation to Sinus Rhythm

The aim of the present study was to assess whether cGMP release to ANP stimulation can be a biochemical marker of subsequent successful electrical cardioversion of lone atrial fibrillation to sinus rhythm. For this purpose, we studied 13 patients with chronic, lone atrial fibrillation of less than one year's duration who presented to our laboratory for electrical therapy of their arrhythmia. Prior to electrical cardioversion, peripheral venous cGMP levels were assessed at baseline and following an tntravenous challenge of 50 Ug human ANP. Venous blood samples for cGMP assessment were taken a) at baseline, b) 5 and 10 mins after the end of ANP infusion. ANOVA of repeated measures was used for statistical analysis. Eight of the study patients were successfully cardioverted to sinus rhythm, while the remaining 5 were not. Although no difference was noted between the two groups regarding the mean time of arrhythmia duration as well as left atrial and ventricular dimensions, ANP stimulation provoked significantly greater cGMP release in patients whose arrhythmia reverted to sinus rhythm, when compared with that of patients whose arrhythmia persisted (p<0.001). Therefore, cGMP levels following ANP challenge might discriminate between patients with chronic AF who are going to be successfully cardioverted and those who are not. These findings imply that the underlying atrial disease might be different in extent/nature between patients with lone AF responsive to cardioversion and those with resistant arrhythmia.     

Identification of a possible role for atrial natriuretic peptide in MDMA-induced hyperthermia

MDMA (3,4-methylenedioxymethamphetamine) induces thermogenesis in a mitochondrial uncoupling protein 3-dependent manner. There is evidence that this hyperthermia is mediated in part by the lipolytic release of free fatty acids, that subsequently activate uncoupling protein 3 in skeletal muscle mitochondria. We hypothesize that atrial natriuretic peptide (ANP), a strong lipolytic mediator, may contribute to the induction and maintenance of MDMA-induced thermogenesis. The specific aims of this study were to (1) determine if ANP is released following MDMA administration, and (2) use the ANP receptor antagonist, Anantin, to ascertain the role of ANP in MDMA-induced hyperthermia. ANP levels were measured in plasma at baseline, 10, 20, 30 and 60 min following MDMA (40 mg/kg, sc) administration in 16 male Sprague-Dawley rats. A robust increase in ANP was seen within 10 min of MDMA administration. ANP levels returned to baseline at 20 min and then gradually rose over the 60 min monitoring period. The administration of Anantin (40 mg, ip), 15 min before and after MDMA, significantly attenuated the MDMA-induced hyperthermia. We conclude that ANP signaling contributes to the hyperthermia induced by MDMA.