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

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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.