Sites of action of angiotensin II, atrial natriuretic factor and guanabenz, on aldosterone biosynthesis.
It is well known that atrial natriuretic factor (ANF) inhibits aldosterone biosynthesis. Recent studies showed that amiloride can also inhibit adrenal steroidogenesis. Since the antihypertensive agent, guanabenz, is structurally related to amiloride, we have examined its action on aldosterone biosynthesis. The aim of this work was to localize the sites of action of angiotensin II (AII) and of ANF on steroidogenesis and to compare the effects of guanabenz to ANF. Trilostane, an inhibitor of 3 beta-hydroxysteroid dehydrogenase was used to separately study the early and late pathways of aldosterone biosynthesis. The different steps of steroidogenesis are stimulated by AII. ANF inhibits the formation of pregnenolone, the steps between progesterone and deoxycorticosterone, deoxycorticosterone and corticosterone and finally, corticosterone and aldosterone with ED50 of 114 +/- 17, 199 +/- 90, 14 +/- 3 and 92 +/- 34 pM of ANF, respectively, and around 70% of inhibition. These steps are also inhibited by guanabenz with ED50 of 66 +/- 17 microM for the formation of pregnenolone, 1.6 +/- 1.3, 3.3 +/- 1.7 and 29 +/- 4 microM for the last 3 steps. The percentage of inhibition by guanabenz was at least 80% for all the steps except for progesterone to deoxycorticosterone which is less than 35%. These results indicate that the major site of action of both AII and ANF could be at the level of intracellular signal transduction for the activation of mitochondrial steroidogenic enzymes or for the transport of steroids to mitochondria. We also showed that guanabenz mimics the inhibitory effects of ANF. This study with guanabenz suggests that it might be a prototype for a new family of antihypertensive agents.
Brochu
M
M
Laboratory of Molecular Pharmacology, Clinical Research Institute of Montréal, Montréal, Québec, Canada.
Ong
H
H
De Léan
A
A
D000305:Adrenal Cortex Hormones / Q000096:biosynthesis; D000450:Aldosterone / Q000096:biosynthesis*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D006143:Guanabenz / Q000494:pharmacology*; D015384:Zona Glomerulosa / Q000187:drug effects* / Q000378:metabolism
D000305:Adrenal Cortex Hormones; D000804:Angiotensin II; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D006143:Guanabenz