The Role of Cyclic Nucleotides in Atrial Natriuretic Peptide-Mediated Inhibition of Aldosterone Secretion*

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Abstract
Using freshly isolated bovine adrenal glomerulosa cells we examined the inhibitory effect of atrial natriuretic peptide (ANP) on aldosterone secretion stimulated by agonists that use either the Ca2+-phosphoinositide or cAMP messenger system. In a continuous perifusion system, angiotensin II (AII) induces a prompt initial rise in aldosterone secretion, followed by a sustained secretory response. Both phases of secretion are rapidly and idependently inhibited by ANP. The role of two cyclic nucleotides, cGMP and cAMP, as mediators of this ANP-induced inhibition was examined. The effect of 8-bromo-cGMP (1-100 .mu.M) or (Bu)2cGMP (1-50 .mu.M) on the AII-stimulated rate of secretion was studied in a perifusion system. Either analog, whether added early or late, maximally inhibited by 20-30% only the late or sustained phase of aldosterone secretion. The effect of ANP on cellular cAMP content was examined in a static incubation system. Although ANP caused a reduction in the cAMP content of cells stimulated with either AII or ACTH, it had little or no effect on the cAMP levels in cells stimulated with carbachol. In AII- and ACTH-stimulated cells, the relationship between reduced cAMP content and reduced secretion was explored. In the AII-stimulated cell inhibited by ANP, simple restoration of cAMP content with forskolin did not restore the secretory rate. Pertussis toxin treatment blocked the inhibitory effect of ANP on cAMP content, but did not block its inhibition of secretion. In the ACTH-stimulated cell, reversal of the ANP-induced reduction of cAMP with forskolin, partially restored the stimulated rate of secretion, although restoration of cAMP with a 10-fold higher dose of ACTH did not restore the stimulated rate of secretion in the presence of ANP. These results imply that both the ANP-induced rise in cGMP and the ANP-induced decrease in cellular cAMP content may contribute to the inhibition of steroidogenesis. However, these inhibitory messages do not induce either the magnitude or the temporal pattern of inhibition induced by ANP. Thus, in the adrenal multiple messenger systems may underlie the action of ANP.