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Title: Serotoninergic control of adrenal zona glomerulosa function
Author: Davies, E.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1991
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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 ll (All), adrenocorticotrophic hormone (ACTH) and potassium (K+ ) are considered to be the major physiological regulators of aldosterone secretion, serotonin (5-hydroxytryptamine, 5HT) is a potent stimulus for aldoesterone secretion both in vivo and in vitro in man and the rat. However, the physiological and pathophysiological role of 5HT in the control of mineralocorticoid secretion remains unclear. Unlike the cardiovascular and central nervous system (CNS), where specific 5HT receptors have been identified and categorised into the 5HT1a, 5HT1b, 5HT1c, 5HT1d, 5HT2 and 5HT3 sub-types, specific receptors for 5HT in the adrenal zona flomerulosa (ZG), and the second messenger system to which they are coupled, have yet to be formally characterised. To resolve this, the effects of the selective 5HT receptor antagonists ketanserin (5HT2), methysergifde (5HT1/2), mesulergine (5HT1c/2), cyanopindolol (5HT1a/1b) and ICS 205/930 (5HT3) have been studied on the aldosterone response to 5HT in isolated rat adrenal ZG cells. The specificity of the antagonists was also investigated by observing the effects of the drugs on the aldosterone response to All, ACTH and K+ . The signal transduction mechanism for 5HT in the ZG was studied by measuring cyclic AMP and phosphatidylinositol (PI) turnover and comparing the results with those of All 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 5HT was also studied directly by radiolabelled calcium influx experiments. 5HT produced a dose-dependent increase in cyclic AMP and aldosterone secretion, whilst PI turnover was unaffected. The cyclic AMP and aldosterone responses to 5HT were inhibited by mesulergine, methysergide and ketanserin. The aldosterone response to All, but not ACTH or K+ , was also inhibited by these antagonists. Cyanopindolol and ICS 205/930 produced a small inhibition of 5HT 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 5HT. Radiolabelled calcium influx was stimulated by serotonin and this could be blocked by verapamil. In conclusion, the aldosterone response to 5HT in the ZG appears to be mediated predominantly by 5HT1c/5HT2 like receptors which modulate the steroid response to All and, in contrast to other 5HT responsive tissues, couple to the adenylate cyclase second messenger system.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available