Small changes in sodium concentration [( Na]) are not generally considered to have a major direct effect on aldosterone secretion. However, a marked disruption in the renin-aldosterone relationship has been observed in a variety of hypernatremic and hyponatremic states. Therefore, we evaluated the hypothesis that small changes in [Na] have a potent direct effect on angiotensin II- and potassium-stimulated aldosterone secretion. The left adrenal gland, abdominal aorta, and surrounding periadrenal tissue were surgically isolated from mongrel dogs and perfused with Ringers bicarbonate solution at a pressure of approximately 57 mm Hg. Infusion of a KCl test solution at the beginning and end of most experiments produced similar increases in aldosterone secretion, thus documenting the stability of these preparations. After a stable response was established to either a low dose of angiotensin II or a small increase in perfusate [K], the [Na] was changed by adding or removing NaCl. Changing perfusate [Na] from 152 to 139 mM during the infusion of either angiotensin II or potassium caused 20- to 25-fold increases in aldosterone secretion. Increasing perfusate [Na] from 145 to 152 mM inhibited aldosterone secretion to a greater extent during stimulation by lower doses (40-50 pg/ml) than by higher doses (80-100 pg/ml) of angiotensin II. These data demonstrate that during moderate stimulation by angiotensin II or potassium, small changes in [Na] have a powerful inverse effect on aldosterone secretion by a direct action on the canine adrenal gland.