Angiotensin-independent mechanism for aldosterone synthesis during chronic extracellular fluid volume depletion.

Abstract

Wild-type ( Agt ϩ / ϩ ) and homozygous angiotensinogen deletion mutant ( Agt Ϫ / Ϫ ) 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 ϩ / ϩ and Agt Ϫ / Ϫ . Moreover, in both, the elevation in P aldo was accompanied by marked increase in adrenal zona glomerulosa cells and adrenal P450aldo mRNA. Agt Ϫ / Ϫ mice were distinguished from Agt ϩ / ϩ mice by their higher plasma K level, by ‫ف‬ 1.5 and ‫ف‬ 3.8 mEq/liter during NS and LS, respectively. Within the Agt Ϫ / Ϫ 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 ϩ / ϩ and uniform death in Agt Ϫ / Ϫ 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. ( J. Clin. Invest. 1997. 99:855-860.)

Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system

“…Since the adrenal glands in D -R -mice also lack AT 1A receptors, this augmented aldosterone excretion is likely due to marked renin stimulation (see below) generating a high level of angiotensin II that stimulates the AT 1B receptors in the adrenal cortex. Other pathways for aldosterone stimulation may also play a role (20). Yet blood pressures are significantly lower in D -R -mice completely lacking AT 1A receptors compared with those in the D + R -group, despite their higher aldosterone levels.…”

A New HOPE for Aldosterone Blockade?

“…Although angiotensin II is a major stimulus for the production of aldosterone, other stimuli such as potassium are also important ("aldosterone escape"), as illustrated by the ability to stimulate aldosterone production in the angiotensinogen-knockout mouse. 5 These data suggest that AB could add to the benefits of ACE-I in reducing mortality and morbidity in patients with vascular disease without known SLVD, as shown in the Heart Outcomes Prevention Evaluation (HOPE) 6 and European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA) 7 studies. To date, several mechanisms have been evaluated to understand the adverse effects of aldosterone on vascular function.…”

What Have We Learned from Gene Targeting Studies for the Renin Angiotensin System of the Kidney?

“…In a recent study (62), AngII was shown to be nonessential for secondary hyperaldosteronism during extracellular fluid volumedepletion, where potassium was found to function as an aldosterone inducer alternative to Ang II. In the study, plasma aldosterone levels were comparable during normal Na diet, and similarly elevated during low Na diet in wild-type and Agt-Imice, accompanied by marked increase in the number of adrenal zona glomarulosa cells and the mRNA level of an enzyme, P450aldo.…”