The present study was performed to assess the sensitivity of the renin-angiotensinaldosterone axis to small changes in plasma potassium concentration within the physiologic range. Small increments in potassium levels were accomplished by graded constant infusions of potassium chloride over 2 h (0.17 meq/min; 0.33 meq/min; 0.5 meq/min) in 8 normal subjects on a 10 meq sodium-100 meq potassium intake. Plasma levels of aldosterone, renin activity, angiotensin II, cortisol, potassium and sodium were measured at frequent intervals. There were no significant changes observed in plasma sodium, renin activity or angiotensin II levels while cortisol levels declined in the expected diurnal pattern. During the 0.17 meq/min (10 meq/h) infusion potassium levels did not increase significantly until 120 min while plasma aldosterone levels rose significantly at 30-60 min. The mean increment above control during the lowest infusion rate was 0.2 meq/liter (5%) for plasma potassium and 13 ng/100 ml (46%) for plasma aldosterone. Although there was a stepwise increase in the increments above control of both potassium and aldosterone levels as the rate of the infusion was increased, the most sensitive area of the dose response curve appears to be 0.1–0.5 meq/liter. In six normal subjects the potassium-lowering effect of glucose ingestion (0.25 g/kg/15 min over a 2-h period) was assessed. The mean maximal potassium decrement below control 0.3 meq/liter (8%) at 90 min was coincident with the mean plasma aldosterone decrement below control of 11 ng/100 ml (46%). Plasma aldosterone then rose to peak levels at 180 min (mean increment 22 ng/100 ml above nadir) while potassium levels remained below control. The rise in plasma aldosterone was associated with a parallel but more rapid rise in plasma renin activity, peaking at a level 108% above control. Ninety minutes after the termination of the glucose ingestion, plasma aldosterone returned to control levels but now in the setting of reduced levels of plasma potassium and elevated levels of plasma renin activity. The data support an important role for physiologic changes in extracellular potassium concentration in the control of aldosterone secretion and indicate that interpretation of studies assessing acute changes in plasma aldosterone must carefully consider minor simultaneous changes in plasma potassium levels. The data also document that acute changes in extracellular potassium concentration play a role in the regulation of renin secretion.