A clearer understanding of the physiological mechanisms controlling aldosterone
secretion is likely to be of major importance in appreciating the significance of the
abnormalities found in patients with conditions such as essential hypertension.Although angiotensin II, adrenocorticotrophic hormone (ACTH) and potassium are
considered to be the major physiological regulators of aldosterone secretion, serotonin
(5-hydroxytryptamine, 5HT) is a potent stimulus for aldosterone secretion both in vivo and in
vitro in man and the rat. However, the physiological and pathophysiological role of serotonin
in the control of mineralocorticoid secretion remains unclear. Unlike the cardiovascular and
central nervous system (CNS), where specific serotonin receptors have been identified and
categorised into the 5HT-|a, 5HT-ib. 5HTic, 5HTich 5HT2 and 5HT3 sub-types, specific
receptors for serotonin in the adrenal zona glomerulosa and the second messenger system
to which they are coupled, have yet to be formally characterised. To resolve this, the effects
of the selective serotonin receptor antagonists ketanserin (5HT2), methysergide (5HT1/2).
mesulergine (5HT-|C/2), cyanopindolol (5HT1 a/ib) and ICS 205/930 (5HT3) have been
studied on the aldosterone response to serotonin in isolated rat adrenal zona glomerulosa
cells. The specificity of the antagonists was also investigated by observing the effects of the
drugs on the aldosterone response to angiotensin II, ACTH and potassium. The signal
transduction mechanism for serotonin in the zona glomerulosa was studied by measuring
cyclic AMP and phosphatidylinositol (PI) turnover and comparing the results with those of
angiotensin II and ACTH, which act through phospholipase C and adenylate cyclase
respectively. In addition, the role of calcium was investigated using the chelating agent
EGTA, the calcium channel inhibitors verapamil and nifedipine, the intracellular calcium
channel blocker TMB-8, and the calmodulin antagonist trifluoperazine (TFP). Transmembrane
calcium flux in response to serotonin was also studied directly by radiolabelled calcium influx
experiments.Serotonin produced a dose-dependent increase in cyclic AMP and aldosterone
secretion, whilst PI turnover was unaffected. The cyclic AMP and aldosterone responses to
serotonin were inhibited by mesulergine, methysergide and ketanserin. The aldosterone
response to angiotensin II, but not ACTH or potassium, was also inhibited by these
antagonists. Cyanopindolol and ICS 205/930 produced a small inhibition of serotonin
stimulated aldosterone and cyclic AMP secretion, but had no effect on the aldosterone
response to the other agonists. The presence of EGTA, verapamil, nifedipine, TMB-8 and
TFP also significantly inhibited aldosterone secretion in response to serotonin. Radiolabelled
calcium influx was stimulated by serotonin and this could be blocked by verapamil.In addition to the in vitro studies, two in vivo studies were also carried out. The effect of
acute serotonin enhancement was studied in rats with indwelling arterial cannulae. This
experimental model avoided the use of anaesthetics which can activate the renin-angiotensin
system (RAS). Plasma aldosterone was measured prior to and after administration of the
immediate precursor to serotonin, 5-hydroxytryptophan (5HTP). Aldosterone was elevated
45 minutes after administration of 5HTP, and this could be blocked, though not completely,
by pretreatment with both dexamethasone and captopril. The inhibitory effect of captopril
could be reversed by co-administration of angiotensin II. The effect of chronic serotonin
enhancement on adrenal zona glomerulosa growth was studied in rats given 5HTP for periods
of up to 2 weeks. 5HTP increased the width of the zona glomerulosa, although the effect was
less than that observed with sodium depletion. No changes were detected in plasma renin
activity (PRA), angiotensin II, corticosterone or aldosterone and the trophic effect could not
be reversed by chronic treatment with captopril or dexamethasone.In conclusion, the aldosterone response to serotonin in the zona glomerulosa appears
to be mediated predominantly by 5HT₁꜀ / 5HT₂ like receptors which modulate the steroid
response to angiotensin II and, in contrast to other serotonin responsive tissues, couple to
the adenylate cyclase second messenger system, in addition, influx of extracellular calcium,
which may act cooperatively with cyclic AMP to activate the cascade mechanism resulting in
steroidogenesis, is necessary for the action of serotonin. In vivo it appears that a number of
different mechanisms mediate the acute and chronic actions of serotonin. Acutely, serotonin
activates the hypothalamo-pituitary adrenal axis and the renin-angiotensin system, both of
which require to be intact for the full aldosterone response, although angiotensin II appears to
act purely in a permissive capacity. It is also likely that there is a direct action of serotonin on
the adrenal cortex. In contrast, chronic serotonin enhancement has no effect on the
renin-angiotensin system, the hypothalamo-pituitary adrenal axis or steroidogenesis,
although zona glomerulosa growth is stimulated, most probably by a direct action of serotonin,
although the possibility that serotonin could stimulate the production of another growth
factor(s), cannot be excluded at this stage. Therefore, chronically, there appears to be an
"escape" from continued mineralocorticoid augmentation by an as yet unidentified
mechanism.The specific interaction between serotonin, the angiotensin II receptor, the
renin-angiotensin system and the hypothalamo-pituitary adrenal axis may be important
regulatory components of mineralocorticoid secretion, and any disturbance in this fine
balance may lead to alterations in steroid secretion. Further studies are required to
investigate more fully the importance of serotonin in the physiology and pathophysiology of
the adrenal cortex
