Regulation of aldosterone biosynthesis by Na+/H+ antiport: relationships between intracellular pH and angiotensin II.
Recent studies on the regulation of aldosterone biosynthesis have revealed that inhibitors of sodium influx, e.g. amiloride, can inhibit adrenal steroidogenesis with a pharmacological profile suggestive of a Na+/H+ antiport system. We have examined the existence of a Na+/H+ antiport system and its regulation of Na influx and intracellular pH (pHi) in bovine adrenal zona glomerulosa cells. NH4Cl-induced 22Na uptake by zona glomerulosa cells was dose dependently inhibited by ethylisopropylamiloride (EIPA), amiloride, and benzamil with ED50 values of 0.02, 4.30, and 199 microM, respectively. Angiotensin II (AII; 100 nM) caused an initial transient acidification, followed by prolonged alkalinization. The hormone equipotently increased pHi and stimulated aldosterone secretion, with ED50 values of 1.2 and 1.4 nM, respectively. AII-induced alkalinization was suppressed by EIPA, amiloride, and benzamil, with ED50 values of 0.6, 79, and 440 microM, respectively. This increase in pHi induced by AII was dependent upon the extracellular sodium concentration (ED50 values = 2.8 mM) and was blunted in sodium-free medium. AII-stimulated aldosterone synthesis was also inhibited by EIPA, amiloride, and benzamil, with ED50 values of 0.07, 34, and 330 microM, respectively. The time course of activation by angiotensin II on aldosterone secretion was also dependent upon extracellular sodium concentration during a 2-h period. These results document that intracellular pH is regulated through the Na+/H+ exchange system and suggest that the pH change induced by AII might be associated with its regulation of steroidogenesis in bovine adrenal zona glomerulosa cells.
Horiuchi
T
T
Laboratory of Molecular Pharmacology, Clinical Research Institute of Montreal, Quebec, Canada.
Nguyen
T T
TT
Cragoe
E J
EJ
De Léan
A
A
D000450:Aldosterone / Q000096:biosynthesis* / Q000378:metabolism; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology*; D002417:Cattle; D004114:Dimethadione / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D017923:Sodium-Hydrogen Exchangers; D013997:Time Factors; D015384:Zona Glomerulosa / Q000032:analysis / Q000166:cytology / Q000378:metabolism*
D002352:Carrier Proteins; D017923:Sodium-Hydrogen Exchangers; D000804:Angiotensin II; D000450:Aldosterone; D000584:Amiloride; D004114:Dimethadione