Inhibition of aldosterone biosynthesis by atriopeptins in rat adrenal cells.
The effect of synthetic atriopeptins on basal and stimulated aldosterone secretion was determined in isolated adrenal glomerulosa cells of the rat. Neither atriopeptin I (1-21) or III (1-24, i.e., the Phe-Arg-Tyr carboxy-terminal extension of atriopeptin I) altered basal aldosterone release. However, if the cells were prepared from adrenals of sodium-depleted rats, the basal aldosterone release was increased by 9-fold, compared with cells from normal rats. This elevated release was inhibited by 32% by atriopeptin I and atriopeptin III. Atriopeptin III was more potent than atriopeptin I. Angiotensin II and adrenocorticotropin stimulated the release of aldosterone in a concentration-related manner. Both atriopeptin I and atriopeptin III inhibited the stimulation by the peptides. Atriopeptin I inhibited angiotensin II- and adrenocorticotropin-induced aldosterone production by 50% at concentrations of 12 and 11 nM, respectively, and 0.5 and 0.2 nM, respectively, for atriopeptin III. Potassium-stimulated aldosterone production was also inhibited by atriopeptin I and atriopeptin III with 50% inhibition at concentrations of 10 and 0.4 nM, respectively. Shorter peptides (1-20, 1-19, and 3-19) were equipotent to atriopeptin I (1-21) as inhibitors of angiotensin II-induced steroidogenesis. To determine the site at which atriopeptins inhibit aldosterone synthesis, we used cyanoketone to inhibit 3 beta-hydroxy-dehydrogenase and dissociate the early and late pathways. Angiotensin II (2 nM) increased the synthesis of pregnenolone (early pathway), as well as the conversion of [3H]corticosterone to [3H]aldosterone (late pathway). Atriopeptin III inhibited basal pregnenolone synthesis by 36% and completely blocked angiotensin II-stimulated synthesis. The peptide similarly inhibited the late pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
Campbell
W B
WB
Currie
M G
MG
Needleman
P
P
D000311:Adrenal Glands / Q000187:drug effects*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000450:Aldosterone / Q000378:metabolism; D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor; D003345:Corticosterone / Q000378:metabolism; D004231:Diuresis / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D009124:Muscle Proteins / Q000494:pharmacology*; D009318:Natriuresis / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D004232:Diuretics; D000451:Mineralocorticoid Receptor Antagonists; D009124:Muscle Proteins; D010455:Peptides; D000804:Angiotensin II; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone