降钙素基因相关肽和心房肽对犬冠脉的舒张作用

本实验利用冠脉内给药和离体血管灌流等方法观察比较了降钙素基因相关肽（ＣＧＲＰ）和心房肽（ＡＮＰ）对犬冠脉循环的影响及其对犬大小冠状动脉的舒张作用。结果显示,ＣＧＲＰ和ＡＮＰ均能明显增加冠脉血流量、降低大小冠脉阻力,两者均呈剂量依赖性舒张大小脉冠脉血管。ＡＮＰ的作用显著小于ＣＧＲＰ,其中大冠脉对两者的反应性显著小于小冠脉,ＣＧＲＰ和ＡＮＰ对冠脉的舒张作用均无内皮依赖性。结果提示,ＣＧＲＰ和ＡＮＰ直接     

血管钠肽、 C型钠尿肽和心房钠尿肽舒血管作用的对比

本实验采用离体血管灌流方法,观察和比较血管钠肽（ＶＮＰ）,Ｃ型钠尿肽（ＣＮＰ）和心房钠尿肽（ＡＮＰ）对大鼠肺动脉,腹主动脉和腹腔静脉的舒张作用。．结果表明,ＶＮＰ,ＣＮＰ和ＡＮＰ对离体大鼠的保留内皮与去内皮的肺动脉,腹主动脉和腹腔静脉均有浓度依赖性舒张作用。     

C型利钠利尿肽（CNP）——一种新的心血管活性物质

新发现的Ｃ型利钠利尿肽（ＣＮＰ）是心房利钠利尿肽（ＡＮＰ）家族中的一员,由内皮细胞产生,和血管平滑肌细胞ＡＮＰＲ－Ｂ受体结合,使外周静脉扩张和回心血量减少,导致心脏充盈压和心输出量降低,这是降压的主要机理,该肽无利钠利尿作用。ＣＮＰ的作用机制与ｃＧＭＰ（第二信使）没有关系。心衰时,血管对ＣＮＰ的反应性不变。因此,ＣＮＰ在来源、作用部位、作用特点、作用机制及病理状态下的反应性等与熟知的ＡＮＰ均有显著不同。     

降钙素基因相关肽对不同程度冠脉狭窄时的心脏功能的影响

本实验观察了冠脉内注射降钙素基因相关肽（ＣＧＲＰ０．３μｇ／ｋｇ）对正常及不同程度冠脉狭窄犬的心功能的影响。结果表明正常犬冠脉内注射ＣＧＲＰ后,平均动脉压（ＭＡＰ）下降１．２ｋＰａ（Ｐ＜０．０５）,同时,心率（ＨＲ）、心输出量（ＣＯ）、左室收缩压峰值（ＬＶＳＰ）均不同程度增加;左室舒张末压（ＬＶＥＤＰ）轻度降低。在中度狭窄３０ｍｉｎ后,冠脉内注射ＣＧＲＰ对ＨＲ、ＭＡＰ无明显影响;而重度狭窄后注射ＣＧＲＰ,ＭＡＰ由狭窄时降低逐渐增高,ＨＲ由增快而变慢。ＣＯ、ＬＶＳＰ均显著增高,ＬＶＥＤＰ降低,此作用较冠脉狭窄前更为明显。提示ＣＧＲＰ扩张冠脉动脉,增加冠脉血流量和心排血量,增强心肌收缩力,对缺血心脏功能有保护作用。     

利钠肽的结构、受体与生理作用

利钠肽 (ｎａｔｒｉｕｒｅｔｉｃｐｅｐｔｉｄｅ ,ＮＰ)是近 2 0年才发现的一类多肽 .到目前为止 ,人类共发现了 5种利钠肽 ,即心房利钠肽 (ａｔｒｉａｌｎａｔｒｉｕｒｅｔｉｃｐｅｐｔｉｄｅ ,ＡＮＰ )、脑利钠肽(ｂｒａｉｎｎａｔｒｉｕｒｅｔｉｃ ｐｅｐｔｉｄｅ,ＢＮＰ)、Ｃ型利钠肽 (Ｃ ｔｙｐｅｎａｔｒｉｕｒｅｔｉｃｐｅｐｔｉｄｅ ,ＣＮＰ)、Ｖ型利钠肽 (ｖｅｎｔｒｉｃｌｅｎａｔｒｉｕｒｅｔｉｃｐｅｐｔｉｄｅ,ＶＮＰ)和Ｄ型利钠肽 (ｄｅｎｄｒｏａｓｐｉｓｎａｔｒｉｕｒｅｔｉｃｐｅｐｔｉｄｅ ,ＤＮＰ) .ＶＮＰ和ＤＮＰ至今…     

三种钠尿肽抑制大鼠肺动脉平滑肌细胞增殖效应的比较

本文比较了心房钠尿肽（ＡＮＰ）、Ｃ－型钠尿肽（ＣＮＰ）、血管钠肽（ＶＮＰ）抑制肺动脉平滑肌细胞（ＰＡＳＭＣｓ）增殖的效应。用蛋白激酶Ｃ激动剂佛波酯（ＰＭＡ）刺激体外培养大鼠ＰＡＳＭＣｓ的增殖,以总蛋白含量和ＭＴＴ比色ＯＤ值为指标,观察三种钠尿肽对ＰＭＡ刺激大鼠ＰＡＳＭＣｓ增殖的影响。结果表明,ＰＭＡ（１０＾－９－１０＾－７ｍｏｌ／Ｌ）显著升高（Ｐ＜０．０５）ＰＡＳＭＣｓ的总蛋白含量和ＭＴＴＯＤ值,     

血管纳肽对大鼠肺动脉平滑肌细胞增殖的影响

肺动脉平滑肌细胞(ＰＡＳＭＣ)异常增殖是肺动脉高压发病的中心环节,也是其重要的病理改变之一,因此研究其增殖调控机制对于肺动脉高压的防治具有重要意义。ＰＡＳＭＣ异常增殖是细胞促增殖和抑增殖因素失去平衡的结果。以往的研究多集中于促增殖因子如内皮素、血管紧张素等,但是从治疗的角度看,抑增殖因子的研究具有更重要意义。研究表明,钠尿肽家族中心房钠尿肽(ＡＮＰ)和Ｃ钠尿肽(ＣＮＰ)具有抑制血管平滑肌、心肌等多种细胞增殖的作用。血管钠肽(ＶＮＰ)是人工合成的钠尿肽家族的新成员,结构与ＣＮＰ和ＡＮＰ具有很高的同源性,但有关Ｖ…     

心律失常豚鼠、猕猴心脏心钠素和抗心律失常肽免疫组织化学研究

本文采用免疫组化方法观察高血钾诱发的心律失常豚鼠（２０例）和猕猴（３例）心脏心钠素（ＡＮＰ）和抗心律失常肽（ＡＭ）免疫反应。结果显示：心律失常组豚鼠和猕猴心脏的ＡＮＰ和ＡＡＰ免疫反应比正常组的明显（Ｐ＜０．０５）,心房肌的ＡＮＰ和ＡＡＰ免疫反应比传导系的明显,但心室肌未见棕色反应产物。ＡＮＰ和ＡＡＰ免疫反应在心脏不同部位反应强度不同可能与心脏传出神经和心肌钙通道的分布有关。     

脑内血管紧张素Ⅱ系统在穹窿下器升压反应中的作用

文献报道脑内存在血管紧张素Ⅱ系统。与此一致,本工作用氨基甲酸乙脂麻醉、箭毒制动、人工呼吸的大鼠观察到：（１）穹窿下器（ＳＦＯ）、室旁核（ＮＰＶ）或ＮＰＶ的投射区：延髓头端腹外侧区（ＲＶＬＭ）、导水管周围灰质（ＰＡＧ）、蓝斑（ＬＣ）内注入血管紧张素Ⅱ（ＡⅡ）均引起升压反应;（２）ＳＦＯ升压反应可被双侧ＮＰＶ或ＲＶＬＭ内预先注入［Ｓａｒ１,Ｔｈｒ８］ＡⅡ（ＳＴＡⅡ,ＡⅡ拮抗剂）明显衰减,ＮＰＶ升压反应也可被ＲＶＬＭ内注入ＳＴＡⅡ削弱;（３）双侧ＰＡＧ用ＳＴＡⅡ预处理后,ＡⅡ引起的ＮＰＶ或ＳＦＯ升压反应均明显减小;（４）ＮＰＶ升压反应还可被双侧ＬＣ内预先注射ＳＴＡⅡ衰减,但ＳＦＯ升压反应不受影响。结合我们以往工作曾显示兴奋ＰＡＧ或ＬＣ均可作用于ＲＶＬＭ引起升压反应,目前的结果表明：ＳＦＯ内的ＡⅡ能神经元通过ＮＰＶ内ＡⅡ能神经元,不仅可直接作用于ＲＶＬＭ引起升压反应,而且还可间接通过ＰＡＧ作用于ＲＶＬＭ起升压作用,但ＬＣ不参与ＳＦＯ升压反应。     

八肽胆囊收缩素减轻肿瘤坏死因子诱导的离体兔肺动脉反应性变化及内皮细胞损伤

为探讨八肽胆囊收缩素（ＣＣＫ－８）缓解内毒素休克时肺动脉高压的作用机制,应用离体血管环张力测定技术及扫描电镜方法,观察了ＣＣＫ－８对肿瘤坏死因子α（ＴＮＦ－α）引起的肺动脉反应性及肺动脉内皮细胞超微结构变化的影响。结果显示：离体脑动脉经ＴＮＦ－α（４０００Ｕ／ｍｌ）孵育２ｈ对苯肾上腺素（ＰＥ）的收缩反应、对乙酰胆碱（ＡＣｈ）及硝普钠（ＳＮＰ）的内皮依赖性及非内皮依赖性舒张反应均无明显影响。ＴＮＦ－     

Cardiac natriuretic peptides and pancreatic islet blood flow in anesthetized rats.

The aim of the study was to evaluate effects of cardiac natriuretic peptides on splanchnic circulation, especially to the pancreatic islets. Pentobarbital-anesthetized rats were infused intravenously (0.01 ml/min for 20 min) with saline, atrial natriuretic peptide (ANP; 0.25 or 0.5 microg/kg BW/min), brain natriuretic peptide (BNP; 0.5 microg/kg BW/min) or C-type natriuretic peptide (CNP; 0.5 or 2.0 microg/kg BW/min). Splanchnic blood perfusion was then measured with a microsphere technique. Mean arterial blood pressure was decreased by ANP and BNP, but not by CNP. The animals given the highest dose of ANP became markedly hypoglycemic, whilst no such effects were seen in any of the other groups of animals. Total pancreatic blood flow was decreased by the highest dose of CNP, whereas no change was seen after administration of the other peptides. Islet blood flow was increased by the highest dose of ANP. Neither BNP nor CNP affected islet blood flow. None of the natriuretic peptides influenced duodenal, colonic or arterial hepatic blood flow. It is concluded that cardiac natriuretic peptides exert only minor effects on splanchnic blood perfusion in anesthetized rats. However, islet blood perfusion may be influenced by ANP.     

Natriuretic peptides in cardiovascular diseases

The natriuretic peptide family comprises atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), dendroaspis natriuretic peptide (DNP), and urodilatin. The activities of natriuretic peptides and endothelins are strictly associated with each other. ANP and BNP inhibit endothelin-1 (ET-1) production. ET-1 stimulates natriuretic peptide synthesis. All natriuretic peptides are synthesized from polypeptide precursors. Changes in natriuretic peptides and endothelin release were observed in many cardiovascular diseases: e.g. chronic heart failure, left ventricular dysfunction and coronary artery disease.     

Characterization of immunoreactive human C-type natriuretic peptide in brain and heart.

Amino acid sequence of human C-type natriuretic peptide (CNP) has recently been deduced to be identical to those of porcine and rat CNPs in the bioactive unit of C-terminal 22 residues (CNP-22) (1). Thus, tissue concentrations and molecular forms of immunoreactive (ir-) CNP in human brain and heart were determined or characterized using a radioimmunoassay established for porcine CNP. In human brain (hypothalamus and medullapons), ir-CNP was detected at a concentration of 1.04 pmol/g, being about 25 times or 70 times higher than ir-atrial (A-type) natriuretic peptide (ANP) or ir-brain (B-type) natriuretic peptide (BNP). CNP was present mainly as CNP-53, with CNP-22 as well as 13K CNP (presumed to be pro-CNP) as minor components. In heart, 1 approximately 5 pmol/g of ir-CNP was detected in both atrium and ventricle, but this ir-CNP was shown to be derived from crossreactivity of ANP. These results demonstrated that human CNP functions exclusively in the central nervous system in contrast to ANP and BNP which mainly function in the circulation system.     

Role of natriuretic peptides in regulation of conduit artery distensibility

Arterial distensibility, assessed by the pulse-wave velocity (PWV), is an independent predictor of cardiovascular risk. We investigated whether natriuretic peptides, acting locally, modify conduit artery distensibility in vivo. All studies were conducted in anesthetized sheep (n = 18) by using a validated ovine hindlimb model. In brief, the PWV was calculated, with the use of the foot-to-foot methodology, from two pressure waveforms recorded simultaneously with a high-fidelity dual pressure-sensing catheter placed in the common iliac artery. Drugs were infused either proximally, via the catheter to perfuse the segment of artery under study, or distally, via the sheath to control for any reflex changes in flow or sympathetic activation. First, the effects of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and c-type natriuretic peptide (CNP) were studied. Second, the role of endogenous ANP was investigated by infusing the natriuretic peptide receptor type A (NPRA)-selective receptor antagonist A71915. Third, A71915 was coinfused with ANP. Fourth, the NPRC-selective agonist cANF was infused. Infusion of CNP or des-[Gln18Ser19Gly20Leu21Gly22]-ANF-(4-23)-NH2 (cANF) had no effect on iliac PWV. However, infusion of ANP, and to a lesser degree BNP, resulted in a reduction in PWV (-9%; P < 0.01 and -6%; P < 0.05, respectively). A71915 increased iliac PWV from 2.97 +/- 0.13 to 3.06 +/- 0.13 m/s; P < 0.01. Coinfusion of A71915 with ANP completely abolished the effects of ANP (P < 0.01). Importantly, ANP-BNP infusion via the sheath did not alter PWV. In conclusion, ANP, and to a lesser extent BNP, modify large artery distensibility via the NPRA receptor. Neither CNP nor cANF altered PWV, suggesting that the NPRB and NPRC receptors do not acutely influence distensibility in vivo.     

The natriuretic peptide system in eels: a key endocrine system for euryhalinity?

The natriuretic peptide system of a euryhaline teleost, the Japanese eel (Anguilla japonica), consists of three types of hormones [atrial natriuretic peptide (ANP), ventricular natriuretic peptide (VNP), and C-type natriuretic peptide (CNP)] and four types of receptors [natriuretic peptide receptors (NPR)-A, -B, -C, and -D]. Although ANP is recognized as a volume-regulating hormone that extrudes both Na(+) and water in mammals, ANP more specifically extrudes Na(+) in eels. Accumulating evidence shows that ANP is secreted in response to hypernatremia and acts to inhibit the uptake and to stimulate the excretion of Na(+) but not water, thereby promoting seawater (SW) adaptation. In fact, ANP is secreted immediately after transfer of eels to SW and ameliorates sudden increases in plasma Na(+) concentration through inhibition of drinking and intestinal absorption of NaCl. ANP also stimulates the secretion of cortisol, a long-acting hormone for SW adaptation, whereas ANP itself disappears quickly from the circulation. Thus ANP is a primary hormone responsible for the initial phase of SW adaptation. By contrast, CNP appears to be a hormone involved in freshwater (FW) adaptation. Recent data show that the gene expression of CNP and its specific receptor, NPR-B, is much enhanced in FW eels. In fact, CNP infusion increases (22)Na uptake from the environment in FW eels. These results show that ANP and CNP, despite high sequence identity, have opposite effects on salinity adaptation in eels. This difference apparently originates from the difference in their specific receptors, ANP for NPR-A and CNP for NPR-B. VNP may compensate the effects of ANP and CNP for adaptation to respective media, because it has high affinity to both receptors. On the basis of these data, the authors suggest that the natriuretic peptide system is a key endocrine system that allows this euryhaline fish to adapt to diverse osmotic environments, particularly in the initial phase of adaptation.     

Discovery of a natriuretic peptide family and their clinical application

The identification of atrial natriuretic peptide (ANP) induced an explosive series of studies on the new peptide involved in control of the circulation, both in the basic and clinical fields. During the first decade of ANP research surprising progress has been made, revealing that the heart is an endocrine organ regulating the circulation system. ANP has been developed as a diagnostic tool and as a therapeutic drug for cardiac failure. In the second decade, brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were identified, unveiling new profiles of this peptide family. Although BNP is also a circulating hormone that shares a common receptor with ANP, it is different from ANP in its' synthesis and secretion. Plasma concentration of BNP reflects the severity of heart failure in patients in a dramatic fashion, much moreso than ANP. Thus, BNP has been developed as a powerful diagnostic tool for cardiovascular diseases. The third congener, CNP, having a receptor of its own, was initially thought to function only in the brain. CNP was subsequently found to be produced from vascular endothelial cells and macrophages, indicating that CNP is a local regulator and also an antiproliferative factor in the vascular cell system, rather than a circulating hormone. Trials for the clinical application of CNP have also been discussed.     

Atrial natriuretic peptide levels during development of chronic heart failure after myocardial infarction in rats

Serum levels of atrial natriuretic peptide (ANP) are elevated in chronic heart failure presumably due to dilatation of the left atrium resulting from increases in intracardiac pressures. To define the time course of changes in serum ANP levels and to determine the relationship to left ventricular end-diastolic pressure, rats were subjected to coronary artery ligation to produce myocardial infarction and left ventricular failure. Atrial natriuretic peptide levels were measured weekly for four weeks thereafter. In rats with myocardial infarction and elevation of left ventricular end-diastolic pressure there was no change in ANP levels at 7 and 14 days. However, at day 21 and 28, ANP levels were elevated more than 3 fold. There was a correlation between ANP levels and left ventricular end-diastolic pressures. There was no correlation between ANP levels and right atrial pressures or serum sodium concentrations. We conclude that the chronic elevation of left ventricular end-diastolic pressure is required to produce an increase in ANP after myocardial infarction which results in chronic heart failure.     

利钠肽家族基因与心血管疾病研究新进展

利钠肽家族是一组由心肌细胞分泌的激素,主要包括A型、B型和C型利钠肽,具有相似的基因结构和生理学效应,可对心血管系统产生血压调节、抗心肌肥厚、抗心肌纤维化和抗心肌弛缓等保护作用。利钠肽受体A、B和C亦介导多种生理活性,调节心血管稳态。利钠肽受体A选择性结合A型、B型利钠肽。利钠肽受体B结合C型利钠肽。利钠肽受体C结合各型利钠肽,通过受体介导的内化和退化作用清除血液循环中利钠肽。对利钠肽家族及其受体基因单核甘酸多态性及功能研究显示,其与多种心血管疾病(房颤、高血压、心力衰竭等)的易感性相关。利钠肽家族及其受体基因缺失的转基因小鼠表现为心肌肥厚、心肌纤维化,与高血压、心肌病及心力衰竭的发生发展相关。各种导致心肌肥厚和缺血性损伤的刺激均参与利钠肽及其受体基因的表达调控。临床将脑钠肽作为左室功能障碍和心力衰竭失代偿的一个预测指标。静脉注射重组脑钠肽已经成为治疗急性心力衰竭的有效手段。深入了解利钠肽家族基因变异及其信号调控有助于探索心血管疾病的病理生理机制,为临床诊疗开辟新思路。     

Increased levels of C-type natriuretic peptide in patients with idiopathic left ventricular dysfunction

C-type natriuretic peptide (CNP) is expressed in the vascular endothelium. It is not known whether CNP is specifically increased in patients with idiopathic left ventricular systolic dysfunction (ILVDys) with or without overt heart failure, and whether in these patients it is related with indicators of myocardial and/or endothelial/microvascular impairment. We determined plasma CNP levels in 51 ILVDys and in 60 controls. We observed a significant increase in patients with (7.0+/-0.9 pg/ml) or without (6.1+/-0.53 pg/ml) overt heart failure (p<0.001) in respect to controls (2.5+/-0.12 pg/ml). CNP was significantly correlated with LVEF (p<0.001), end-diastolic dimension (p<0.05), ANP (p<0.001) and BNP (p<0.001), interleukin-6 (p<0.001), total cholesterol (p<0.05), low-density lipoprotein (p=0.05), ratio total cholesterol/ high-density lipoprotein (p=0.05) and, in a subgroup of patients, with abnormal vasodilating capacity of the coronary microcirculation. In conclusion, CNP is activated in patients with LV dysfunction but without coronary artery disease, independently of the presence of overt heart failure and in tune with the extent of myocardial functional involvement. In these patients CNP is also related with both systemic and coronary indicators of endothelial/microvascular damage.