Manipulation of stretch-induced atriopeptin prohormone release and processing in the perfused rat heart

Atriopeptin (AP) is stored as the prohormone AP-126 [atrial natriuretic factor-(1-26)] in atrial granules. Cultured atrial myocytes synthesize and release only prohormone into the medium. HPLC analysis of the coronary venous effluent of media from perfused rat hearts subjected to right atrial stretch indicated the presence of the C-terminal mature hormone AP-28 [atrial natriuretic factor-(99-126)] and little or no prohormone. Absence of calcium from the perfusion medium increased total AP release and surprisingly blocked the proteolytic cleavage of the prohormone. Similarly, addition of the proteolytic inhibitor aprotinin to the perfusion medium suppressed the processing of the endogenous AP-126 released by atrial stretch. Aprotinin would be restricted to the extracellular space, which is therefore implicated as the site of prohormone processing. This suggestion was validated by the demonstration that the perfused rat heart could readily cleave exogenous prohormone to mature hormone, a process blocked by aprotinin. Hypothetically, the stimulus-release-processing event initiated by atrial stretch may require the concerted action of the synthetic cell (i.e., atrial myocyte) and a processing cell or site (e.g., the adjacent atrial mesenchymal cell) for the production of the mature AP-28, which is the circulating molecular form of this endocrine system.