Ionophores for monovalent cations inhibit angiotensin-stimulated aldosteronogenesis.
We examined the effects of monensin (a sodium ionophore), valinomycin (a potassium ionophore), and nigericin (a nonspecific ionophore) on steroid production and its stimulation in bovine adrenal glomerulosa and fasciculata cells. All three ionophores at nanomolar concentrations inhibited angiotensin (AII)-stimulated aldosterone production; potassium-stimulated aldosteronogenesis was more sensitive, and cortisol synthesis by fasciculata cells was much less sensitive. Ionophores completely inhibited the early pathway of aldosteronogenesis and partially inhibited conversion of progesterone to aldosterone. Ionophores had no effect on pregnenolone production by isolated glomerulosa mitochondria. Monensin had no effect on AII binding, calcium flux, calcium transient, protein phosphorylation, or protein synthesis; valinomycin slightly inhibited these processes. Valinomycin lowered cell potassium and raised cell sodium, but its inhibition of aldosteronogenesis was not overcome by increasing extracellular potassium. Monensin and nigericin had no effect on cell potassium or sodium. Cellular ATP was decreased by valinomycin, but not by monensin or nigericin. Our results show that stimulation of aldosteronogenesis by AII and potassium is highly sensitive to ionophores of monovalent cations. Monensin and nigericin inhibit steroidogenesis at concentrations that have no other observed deleterious effects on glomeulosa cells. These results identify a distinguishing characteristic of adrenal glomerulosa cells and suggest a new pharmacologic approach to inhibition of aldosteronogenesis.
Hypertension Research Laboratory, William S. Middleton Memorial VA Hospital, Madison, Wisconsin 53705.
N E
NE
Hadjokas
T L
TL
Goodfriend
M E
ME
Elliott
S F
SF
Wen
D000255:Adenosine Triphosphate / Q000378:metabolism; D000450:Aldosterone / Q000096:biosynthesis*; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002412:Cations / Q000494:pharmacology*; D002417:Cattle; D066298:In Vitro Techniques; D007476:Ionophores / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008985:Monensin / Q000494:pharmacology; D009550:Nigericin / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D014176:Protein Biosynthesis; D013050:Spectrometry, Fluorescence; D014634:Valinomycin / Q000494:pharmacology; D015383:Zona Fasciculata / Q000187:drug effects / Q000378:metabolism; D015384:Zona Glomerulosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D002412:Cations; D007476:Ionophores; D000804:Angiotensin II; D014634:Valinomycin; D000450:Aldosterone; D000255:Adenosine Triphosphate; D008985:Monensin; D009550:Nigericin; D011188:Potassium; D002118:Calcium