Development of a CNP related drug as a new treatment for hypertension and arteriosclerosis.

CNP是利钠肽家族的第三个成员，被认为是一种神经肽。我们观察到人脑脊液中存在三种利钠肽，其中CNP是主要的利钠肽。我们发现CNP主要以CNP-53的形式存在于外周组织中，而CNP mRNA则存在于回肠空肠、睾丸、胸腺、肾上腺和颌下腺中。我们还发现CNP是由内皮细胞产生和分泌的。CNP的内皮素分泌受白细胞介素、转化生长因子、肿瘤坏死因子及脂多糖的调控。此外，感染性休克患者血浆中检测到CNP。ANP处理血管平滑肌细胞后，CNP的BNP降低了c受体的密度，这种下调的效力顺序为CNP>ANP>BNP。8-溴-cGMP显著降低血管平滑肌细胞c受体密度及其mRNA表达量。这些结果表明，c受体的下调是通过激活GC-B受体/cGMP途径诱导的。我们还发现β -肾上腺素能受体刺激通过降低c受体基因转录率下调c受体。小鼠CNP基因由至少两个外显子和一个内含子组成。小鼠原CNP包含126个氨基酸，其c端22残基肽与人类CNP相同。小鼠CNP基因的5'侧区包含一个典型的顺式调控元件阵列和一个二核苷酸CA重复序列。

CNP,the third member of the natriuretic peptide family, has been considered to act as a neuropeptide. We observed presence of three natriuretic peptides in human cerebrospinal fluid and that CNP was the major natriuretic peptide. We discovered that CNP was present mainly as CNP-53 in peripheral tissues and that CNP mRNA was present in ileum-jejum, testis, thymus, adrenal gland and submaxillary gland. We also discovered that CNP is produced and gecreted by the endothelial cells. The endothelinl secretion of CNP was regulated by interleukin Ialpha, Ibeta, transforming growth factor beta, tumor necrosis factor-alpha and also by lipopolysaccharide. Furthermore, CNP was detected in plasma of septic shock patients. The treatment of vascular smooth muscle cells with ANP,BNP of CNP decreased the C-receptor density and the rank order of potency for this downregulation was CNP>ANP>BNP.The rank order was the same as that for cGMP production and 8-bromo-cGMP significartly decreased the C-receptor density and its mRNA expression in vascular smooth muscle cells. These results suggest that the downregulation of the C-receptor is induced by the activation of the GC-B receptor/cGMP pathway. We also found that the beta2-adrenergic receptor stimulation downregulates the C-receptor through the decrease in the transcriptional rate of the C-receptor gene. The mouse CNP gene is composed of at least two exons and one intron. Mouse prepro CNP comprises 126 amimo acids and its C-terminal 22-residue peptide is identical to human CNP.The 5'-flanking region of the mouse CNP gene contains a characteristic array of cis-acting regulatory elements and a dinucleotide CA repeat.