A subset of critically ill patients has been described with low plasma aldosterone (Aldo) despite elevated plasma renin activity (PRA). In order to investigate possible mechanisms for these findings, the present study evaluated the Aldo response to exogenous ACTH or metoclopramide (MCP) in normal subjects and in patients admitted to the medical ICU. In addition, measurements of clinical status (Acute Physiology and Chronic Health Evaluation [APACHE II]) and atrial natriuretic peptide (ANP) were correlated with adrenal status. Critically ill patients were subdivided into normal (greater than 2) and subnormal (less than 2) Aldo-to-PRA ratio (Aldo/PRA). Patients with basal Aldo less than 70 ng/dl exhibited subnormal Aldo responses to ACTH, regardless of basal Aldo/PRA. However, normal responses to MCP were noted regardless of basal Aldo/PRA. No correlation between Aldo/PRA and APACHE II score or ANP levels was found. We conclude that critically ill patients with dissociated Aldo and renin can generate a normal Aldo response to MCP. This suggests that this syndrome is due to functional and potentially reversible dysfunction of the zona glomerulosa of the adrenal cortex.