To investigate the possible relationship of
hypertension and the N-terminus of the
atrial natriuretic factor (
ANF) prohormone which contains two
peptides [i.e. pro ANF-(1-30) and
pro-ANF-(31-67)] with blood pressure-lowering effects, we examined the circulating levels of the N-terminus of the
ANF prohormone in three patients with
pheochromocytomas before surgery, during an increase in their blood pressure with surgical manipulation of their
tumors, and after surgery when their blood pressures returned to normal. The circulating levels of the whole N-terminus [
amino acids 1-98;
pro-ANF-(1-98)] and pro-ANF-(31-67) from the midportion of the N-terminus of the
ANF prohormone were increased 2-fold in patients with both extraadrenal and intraadrenal
pheochromocytomas. In both the intraadrenal and extraadrenal patients N-terminus [
pro-ANF-(1-98)] and pro-ANF-(31-67) circulating levels increased further during surgical manipulation and returned to normal after surgical removal of their respective
tumors. Each of these
pheochromocytomas was found to have pro-ANF-(1-30) and -(31-67)-binding sites that were functional, since they could enhance the
guanylate cyclase-cGMP system 2-fold in these
pheochromocytomas. The entire 126
amino acids of the prohormone were present within each of the
pheochromocytomas, since both the whole N-terminus and C-terminus (i.e.
ANF) of the prohormone were present. Examination of the
pheochromocytomas by electron microscopy revealed electron-dense granules similar to those in the heart, which have been associated with the synthesis and storage of the
ANF prohormone. We conclude that 1) the whole N-terminus [
pro-ANF-(1-98)] and
pro-ANF-(31-67) of the
ANF prohormone circulate at higher concentrations in persons with
pheochromocytomas and return to normal with removal of the
tumors; 2)
pheochromocytomas contain specific binding sites for
pro-ANF-(1-30) and -(31-67); 3) these binding sites are functional, since
pro-ANF-(1-30) and -(31-67) could enhance the
enzyme guanylate cyclase within these
tumors; and 4) the entire 126
amino acids of the
ANF prohormone are present within these
tumors, which have electron-dense granules associated with
polypeptide hormone synthesis, suggesting that the
ANF prohormone is being synthesized within the
pheochromocytomas.