It is well established that ACTH and angiotensin II (Ang II) stimulate aldosterone secretion from rat adrenal zona glomerulosa cells in vitro and mediate their steroidogenic effects via the cyclic AMP (cAMP) pathway and phosphoinositide turnover respectively. α-MSH also stimulates aldosterone secretion from zona glomerulosa cells in vitro, and recent studies from our laboratory have shown that its steroidogenic effects are mediated by increases in inositol 1,4,5-trisphosphate (IP3) production. α-MSH also stimulates adenylyl cyclase activity, but only at concentrations that are supramaximal for stimulation of steroidogenesis. The observation that α-MSH-stimulated IP3 accumulation declines as the activity of adenylyl cyclase increases prompted further studies on the interactions of cAMP and phosphoinositide production.
The effects of α-MSH and ACTH on Ang II-stimulated steroidogenesis and IP3 accumulation were studied. On addition of increasing concentrations of ACTH, both the aldosterone and IP3 responses to Ang II were significantly inhibited; however, only high concentrations of α-MSH achieved this effect. These results suggest that cAMP or a cAMP-dependent event is able to inhibit phospholipase C activity. This hypothesis was tested by measuring IP3 production in Ang II-stimulated zona glomerulosa cells exposed to two different concentrations of α-MSH: 1 nmol/l, which stimulates the generation of IP3, and 1 μmol/l, which activates adenylyl cyclase. It was found that this high concentration of α-MSH significantly inhibited Ang II-stimulated aldosterone secretion and IP3 levels. In addition, α-MSH reduced 125I-labelled Ang II binding to rat adrenal zona glomerulosa cells. ACTH and cAMP also inhibited Ang II binding, thus supporting the hypothesis that cAMP (or a cAMP-mediated event) inhibits Ang II receptor function.
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