title: Stimulation of aldosterone secretion by benzodiazepines in bovine adrenocortical cells.
abstract: Previous studies have indicated that peripheral benzodiazepine receptor (PBR) ligands inhibit aldosterone secretion in isolated adrenal zona glomerulosa cells although positive responses have been demonstrated in other steroidogenic tissues. In the present study, aldosterone secretion was measured in bovine cells after 6 days of primary culture. At this time, basal aldosterone secretion was very low and cells appeared less sensitive to the steroidogenic effects of extracellular [K+] (maximal response required K+ concentration > 32 mmol/L) but were sensitised to angiotensin II (maximal response achieved with 3 nM) when compared with previous studies with freshly isolated cells. Diazepam concentration in the range 0.1 nM to 1 microM increased basal aldosterone secretion, an effect which was not enhanced by pre-treatment with diazepam. The effects were small compared with those of angiotensin II or K+. Over the same concentration range, diazepam also potentiated the stimulatory effects of sub-maximally effective concentrations of angiotensin II. When cells were treated with high-density lipoprotein (HDL-3) as a source of cholesterol, diazepam and the PBR ligands Ro5-4864 and PK11195 also stimulated aldosterone secretion at nanomolar concentrations. In addition, the conversion of added 11-deoxycorticosterone (DOC) to aldosterone was increased by nanomolar concentrations of diazepam and Ro5-4864 but inhibited by high micromolar concentrations of these drugs (100 microM). We conclude that adrenocortical responses to PBR ligands are complex. At high concentrations, inhibitory effects involving competition for steroidogenic enzymes and calcium channel blockage predominate. At low concentrations, an enhancement of basal, angiotensin-II and cholesterol-dependent aldosterone synthesis is revealed which may involve a PBR-mediated mitochondrial uptake of cholesterol and DOC.
authors.affiliation: MRC Blood Pressure Unit, Western Infirmary, Glasgow, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Kenyon
authors.forename: I
authors.initials: I
authors.lastname: Thomson
authors.forename: R
authors.initials: R
authors.lastname: Fraser
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology* / Q000187:drug effects; D000450:Aldosterone / Q000096:biosynthesis*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D003900:Desoxycorticosterone / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D015384:Zona Glomerulosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D008076:Cholesterol, HDL; D000960:Hypolipidemic Agents; D007546:Isoquinolines; D000804:Angiotensin II; D001569:Benzodiazepines; C028513:4'-chlorodiazepam; D003900:Desoxycorticosterone; D000450:Aldosterone; D002784:Cholesterol; D003975:Diazepam; D011188:Potassium; C037850:PK 11195