The study of the novel hypotensive peptide, Adrenomedullin (AM) and Proadrenomedullin N-terminal 20 Peptide (PAMP)

(1)人血浆中具有免疫反应性的AM：在心血管和肾脏疾病中，肾上腺髓质素（AM）和PAMP的浓度显著升高。我们已经证明，人血浆中大多数AM的免疫反应性代表甘氨酸延伸AM (iAM)，中间形式，并且成熟AM （mAM）的浓度远低于iAM，在心力衰竭或肾功能衰竭患者中发现血浆中mAM和iAM水平几乎以恒定的比例升高。血浆AM的升高与疾病的严重程度密切相关，提示AM不仅对疾病的进一步恶化起作用。2 . AM的心血管作用：长期输注AM对WKY大鼠和SHR均有有效的降压作用，且在血浆AM浓度在生理限度内时，尿量和Na+排泄均未增加。此外，长期输注肾上腺髓质素对高血压和假手术大鼠的血浆肾素活性和血浆醛固酮浓度均有明显降低。我们已经证明，培养的新生大鼠心肌细胞产生和分泌AM，分泌AM抑制这些细胞的蛋白质合成。因此，AM可能作为调节心脏生长的自分泌或旁分泌因子作用于心肌细胞。(3) PAMP的分布和分子形态：测定了免疫反应性（ir-） PAMP在猪组织中的分布。肾上腺髓质中可见高浓度的ir-PAMP。每个猪组织样品的反相高效液相色谱分析显示，ir-PAMP存在两个主要峰：一个峰出现在与正品猪PAMP相同的位置；另一个未知峰较早被洗脱。从猪肾上腺髓质中纯化了该未知肽，并确定了其完整的氨基酸序列。该肽为具有c端酰胺结构的PAMP[9-20]，命名为PAMP-12。麻醉大鼠静脉注射PAMP-12具有明显的剂量依赖性降压作用。这些数据表明，il - pamp的主要成分PAMP-12和PAMP-20一样，都是由AM前体加工而成，并可能参与心血管控制。少

(1) Immunoreactive AM in human plasma :Significantly higher concentrations of adrenomedullin (AM) and PAMP were shown in the cardiovascular and renal diseases. We have demonstrated that most of the AM immunoreactivity in human plasma represents the glycine-extended AM (iAM), intermediate form, and that the concentration of mature AM (mAM) is much lower than that of iAM, Both the mAM and iAM levels in plasma were found to be elevated in patients with heart failure or renal failure at almost the constant ratio. The elevation of plasma AM was closely related to severity of the diseases, suggesting not only the role of AM acting against further deterioration of the diseases(2) Cardiovascular effects of AM :Chronically infused AM has a potent hypotensive effect in both WKY rats and SHR without an increase in urinary volume or Na+ excretion at a plasma AM concentration within the physiological limit. In addition, chronically infused adrenomedullin had a hypotensive effect accompanied by sign … More ificant reductions of plasma renin activity and plasma aldosterone concentration in 2K-lC hypertensive and sham-operated rats.We have demonstrated that cultured neonatal rat cardiomyocytes produce and secrete AM, and the secreted AM inhibits the protein synthesis of these cells. Thus, AM may act on cardiomyocytes as an autocrine or a paracrine factor modulating the cardiac growth.(3) Distribution and molecular form of PAMP :The distribution of immunoreactive (ir-) PAMP was determined in porcine tissues. High concentrations of ir-PAMP were observed in the adrenal medulla. Reversed-phase high performance liquid chromatography in each porcine tissue sample revealed that two major peaks of ir-PAMP existed : one emerged at a position identical to that of authentic porcine PAMP ; the other unknown peak was eluted earlier. The unknown peptide was purified to homogeneity from porcine adrenal medulla, and its complete amino acid sequence was determined. This peptide was found to be PAMP[9-20] with a C-terminal amide structure, and was named PAMP-12. Intravenous injections of PAMP-12 in anesthetized rats showed a significant hypotensive effect in a dose-dependent fashion. These data indicate that PAMP-12, a major component of ir-PAMP, is processed from the AM precursor, as is PAMP-20, and may participate in cardiovascular control. Less