Molecular Biology of Vasoactive Substances

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We isolated mouse BNP cDNA and genomic clones, and generated transgenic mice with elevated plasma BNP concentration accompanied with high plasam c GMP concentration. These mice provide a useful model system to assess the roles of BNP.We also isolated hamster BNP and ANP cDNAs to examine pathophysiological roles of natriuretic peptides in cardiomyopathic hamsters. Using cultured rat vascular smmoth muscle cells, we demonstrated that the beta2-adrenergic receptor stimulation duwnregulates the C receptor through the decrease in the transcriptional rate of the C receptor gene and that the activation of sympathetic nervous system augments the biological responsiveness to natriuretic peptides by attenuating their metabolic clearance in vascular walls. The concentration of CNP in the medium was incresed 60 fold in the vascular endothelial cell/vascular smooth muscle cell coculture with direct contact compared with that in endothelial cell alone. We demonstrated that the augmented production of CNP in the coculture is in part regulated by TGF-beta.We isolated two novel transcripts of human endothelin A receptor gene, which contained deletion of exon 4 and 3 and exon 4 resulting from alternative RNA splicing. These transcripts were observed in various human tissues suggesting that this alternative RNA splicing might contribute to the regulation of endothelin A receptor gene expression.We cloned human prostacyclin receptor cDNA and elucidated its abundant gene expression in the cardiovascular system. We also isolated five distinct cDNA clones of human PGE receptor EP_3 subtype and revealed the presence of multiple signal transduction systems of PGE/EP_3 isoform.