ATRIAL-NATRIURETIC-FACTOR SIGNIFICANTLY CONTRIBUTES TO THE MINERALOCORTICOID ESCAPE PHENOMENON - EVIDENCE FOR A GUANYLATE CYCLASE-MEDIATED PATHWAY

The mechanism underlying the mineralocorticoid escape phenomenon remai ns unknown. To assess the possible contribution of natriuretic peptide s to mineralocorticoid escape, rats were injected with 5 mg deoxycorti costerone acetate for 3 d. Plasma atrial natriuretic factor (ANF) rose to twice basal levels and atrial ANF content decreased significantly by 24 h of treatment. This coincided with renal escape and with a sign ificant increase in urinary cGMP excretion. Plasma ANF remained elevat ed and atrial ANF content continued to decline by 48 and 72 h while at rial ANF mRNA levels increased significantly only at 72 h. Plasma brai n natriuretic peptide did not increase during escape although atrial b rain natriuretic peptide mRNA levels increased significantly. Chronica lly administered HS-142-1 (HS), a specific antagonist of the guanylate cyclase-coupled natriuretic peptide receptors, significantly and dose -dependently impaired the escape phenomenon. The highest dose of HS co mpletely suppressed the increase in urinary cGMP. Despite the continue d suppression, partial escape was observed by the end of the observati on period. HS alone influenced neither plasma nor tissue or urine para meters. These findings show that despite activation of atrial ANF, blo ckade of the guanylate cyclase-coupled natriuretic peptide receptors i mpairs the ability of the kidney to escape the Na+ retaining effect of excess mineralocorticoid in a dose-dependent fashion. Later-acting, u nknown mechanisms eventually come into play to mediate the escape phen omenon through a guanylate cyclase-independent pathway. Therefore, ANF of cardiac origin appears to be a major factor initiating mineralocor ticoid escape through a guanylate cyclase-dependent pathway.