The genesis of idiopathic primary aldosteronism due to bilateral zona glomerulosa cell hyperplasia and the underlying pathogenesis of low renin essential hypertension are unknown. Both diseases show inappropriate elevation of plasma aldosterone relative to plasma renin activity and may reflect the spectrum of a single disease. We tested the hypothesis that autoimmune antibodies stimulate aldosterone secretion in one or both of these conditions. However, we found that immunoglobulins (Igs) and specifically, F(ab)2 fragments from normal individuals stimulate aldosterone secretion by rat adrenal glomerulosa cells. Monovalent Fab fragments did not stimulate. The maximal response to Ig was similar to that of angiotensin II. To study the mechanism whereby Igs stimulate and to evaluate the physiological role that Igs may play in regulating aldosterone secretion in vivo, the following questions will be addressed: a) Do most normal adults have aldosterone-stimulating immunoglobulins? What is the degree of variability in the stimulatory potency of Igs between individuals, sexes, or races? b) Which isotype(s) of Ig (IgG, IgA and/or IgM) stimulates aldosterone secretion in an individual serum ? c) Do Igs bind to a known receptor or to a unique receptor? d) What is the second messenger system activated by Igs? e) Do Igs alter the aldosterone secretory response to angiotensin II, potassium or ACTH? f) Does salt intake influence the in vitro aldosterone secretory response to Igs? g) Does the intact perfused adrenal respond to Ig? Purified Ig isotypes will be prepared from normal individuals. Acutely dispersed or cultured rat adrenal glomerulosa cells or the in situ perfused rat adrenal will be used for bioassays of aldosterone secretion. In normal individuals, aldosterone-stimulating Igs may play a significant role in salt balance by modulating the aldosterone secretory response to angiotensin II or potassium. In patients with idiopathic primary aldosteronism or low renin essential hypertension, unique aldosterone-stimulating Igs may prove to be causal in the pathogenesis. Alternatively, these patients may lack a protective inhibitor of aldosterone-stimulating Igs. Thus, this project may ultimately lead to an understanding of the genesis of hypertension in a specific subset of patients.