The atrial natriuretic peptide (ANP) is a peptide hormone which is synthesized, stored in and secreted from the cardiac atria. ANP binds to two different """"""""receptor"""""""" forms on the surface of its target cells at the periphery. One form, the so-called """"""""B-receptor"""""""", is ~ 130 kd in molecular weight, represents a small percentage of the total receptor population in most cell types and is linked to cGMP generation in the target cell. It is this receptor which is believed to mediate most of the known biological activities of ANP. The second receptor form, the so-called """"""""C-receptor"""""""" is ~ 65 kd in molecular weight, is the predominant receptor present in most cell types and yet, despite its prevalence, its role as a bioeffector of ANP remains conjectural. On the basis of some intriguing whole animal studies this receptor has been postulated to play an important role in the clearance of ANP from circulating plasma. More recent studies suggest that this receptor may be coupled in a regulatory fashion to adenylate cyclase and/or phospholipase C activity in target cells. Preliminary evidence from our laboratory suggests that levels of the C- receptor on bovine vascular smooth muscle cells are reduced dramatically by treatment with cAMP-promoting agonists (e.g. forskolin, PGE2 or 8-BrcAMP). Additional studies, carried out with bovine aortic endothelial cells indicate that both ANP receptor subtypes are reduced by pretreatment with the phorbol ester TPA, thrombin or physical stretch of the cell monolayer. The proposed study will attempt: (1) to identify and characterize other factors which regulate either C or B receptor activity and their respective transcript mRNA's in cultured vascular cells and to determine how these various factors interact with one another; (2) to determine whether the acute effects of the regulatory factors identified are mediated by post- translational modification of the receptor protein(s); and (3) to identify and characterize the molecular determinants which govern the expression of the genes for each of the respective receptors. It is anticipated that information gained from these studies will yield a more accurate assessment of ANP's integrative role in modulating cardiovascular homeostasis and provide us with some insight into possible pathophysiological mechanisms whereby malregulation of ANP bioactivity could result in abnormalities of arterial blood pressure.
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