title: Angiotensin-independent mechanism for aldosterone synthesis during chronic extracellular fluid volume depletion.
abstract: Wild-type (Agt+/+) and homozygous angiotensinogen deletion mutant (Agt-/-) littermates were placed on normal (NS) or low Na diet (LS) for 2 weeks. Plasma aldosterone levels (P(aldo)) were comparable during NS, and similarly elevated during LS in Agt+/+ and Agt-/-. Moreover, in both, the elevation in P(aldo) was accompanied by marked increase in adrenal zona glomerulosa cells and adrenal P450aldo mRNA. Agt-/- mice were distinguished from Agt+/+ mice by their higher plasma K level, by approximately 1.5 and approximately 3.8 mEq/liter during NS and LS, respectively. Within the Agt-/- group, P(aldo) was directly proportional to plasma K. The importance of K for the hyperaldosteronism during dietary Na restriction was verified by the observation that superimposition of K restriction led to hypotension in Agt+/+ and uniform death in Agt-/- mice along with a reduction in P(aldo) by 75 and 90%, respectively. Thus, suppression of potassium, but not angiotensin, led to a marked attenuation of hyperaldosteronism during dietary Na restriction. Therefore, (a) a powerful angiotensin-independent mechanism exists for the hyperaldosteronism during LS; (b) high K is a central component of this mechanism; (c) contrary to current belief, the tonic effect of high K on aldosterone synthesis and release does not require an intact renin-angiotensin system; and (d) normally, intermediary feedback signals for hyperaldosteronism, i.e., both hypotension and high K, are effectively masked by aldosterone actions.
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: S
authors.initials: S
authors.lastname: Okubo
authors.forename: F
authors.initials: F
authors.lastname: Niimura
authors.forename: H
authors.initials: H
authors.lastname: Nishimura
authors.forename: F
authors.initials: F
authors.lastname: Takemoto
authors.forename: A
authors.initials: A
authors.lastname: Fogo
authors.forename: T
authors.initials: T
authors.lastname: Matsusaka
authors.forename: I
authors.initials: I
authors.lastname: Ichikawa
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology; D000450:Aldosterone / Q000097:blood / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism* / Q000502:physiology*; D000808:Angiotensinogen / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure; D015152:Blotting, Northern; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D004039:Diet, Sodium-Restricted; D005110:Extracellular Space / Q000187:drug effects; D005818:Genetic Engineering; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000032:analysis / Q000378:metabolism; D007022:Hypotension / Q000139:chemically induced; D051379:Mice; D008817:Mice, Mutant Strains; D006899:Mixed Function Oxygenases / Q000235:genetics; D011188:Potassium / Q000097:blood / Q000378:metabolism* / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology; D017384:Sequence Deletion; D015398:Signal Transduction; D012964:Sodium / Q000494:pharmacology; D015384:Zona Glomerulosa / Q000166:cytology
chemical_list: D012333:RNA, Messenger; D000808:Angiotensinogen; D000804:Angiotensin II; D000450:Aldosterone; D012964:Sodium; D006899:Mixed Function Oxygenases; D019405:Cytochrome P-450 CYP11B2; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D011188:Potassium