Sphingosine inhibits angiotensin-stimulated aldosterone synthesis.
Sphingosine and other protein kinase C inhibitors were tested for their ability to inhibit aldosterone synthesis by bovine adrenal glomerulosa cells. Sphingosine inhibited angiotensin (AII)-stimulated aldosterone synthesis (IC50 of 5 microM). At doses that totally blocked steroidogenesis, sphingosine did not affect protein synthesis or [125I]AII binding to cells. Sphingosine also inhibited dibutyryl cyclic AMP (dbcAMP)-stimulated aldosterone synthesis. Sphingosine inhibited pregnenolone synthesis from cholesterol, but not the conversion of progesterone or 20 alpha-hydroxycholesterol to aldosterone. These results suggest that sphingosine inhibits steroidogenesis at a locus close to that where stimulation occurs by AII and dbcAMP. Other protein kinase C inhibitors were tested. Retinal, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), and staurosporine inhibited aldosterone synthesis stimulated by AII and dbcAMP. Retinal and H-7 also inhibited progesterone conversion to aldosterone, and retinal blocked [125I]AII binding. Staurosporine was more specific, inhibiting AII-stimulated aldosteronogenesis at concentrations which had little effect on conversion of progesterone to aldosterone. Because they inhibited dbcAMP stimulation, none of the inhibitors was sufficiently specific to use as a probe of the role of protein kinase C. The IC50 of sphingosine suggests that this or related products of lipid hydrolysis could act as endogenous regulators of adrenal cell function.
Elliott
M E
ME
William S. Middleton Memorial Veterans Hospital, Madison, WI 53705.
Jones
H M
HM
Tomasko
S
S
Goodfriend
T L
TL
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000450:Aldosterone / Q000096:biosynthesis* / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D003994:Bucladesine / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D007546:Isoquinolines / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D013110:Sphingosine / Q000494:pharmacology*; D019311:Staurosporine; D015384:Zona Glomerulosa / Q000187:drug effects / Q000378:metabolism*
D000470:Alkaloids; D007546:Isoquinolines; D010879:Piperazines; D000804:Angiotensin II; D000450:Aldosterone; D010042:Ouabain; D003994:Bucladesine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D019311:Staurosporine; D013110:Sphingosine