This study was designed to evaluate the mechanisms of adaptation to chronic potassium loading after bilateral adrenalectomy. Studies were performed in Sprague-Dawley rats subjected to 3 days of normal diet and 9 days of high KCl diet followed by adrenalectomy or sham operation on the thirteenth day and 9 additional days of potassium loading (groups 1 and 2, respectively). Animals that underwent adrenalectomy and intact animals, both receiving a normal diet, served as the control groups (groups 3 and 4, respectively). Plasma potassium, urinary potassium and sodium excretion rates, plasma aldosterone and insulin, and Na+-K+ ATPase activity in renal cortical and medullary homogenates were measured. Within 5 days of adrenalectomy the urinary potassium excretion rate in potassium-loaded rats that underwent adrenalectomy (group 1) reached the level observed in potassium-loaded intact rats (group 2), but a significant elevation in plasma potassium levels among rats in group 1 was noticed. In both of the potassium-loaded groups plasma insulin levels and renal cortical and medullary Na+-K+ ATPase activity were significantly higher compared with those in respective control groups receiving a normal diet. Acute clearance experiments carried out in adrenalectomized rats infusing the sera of the potassium-adapted rats that underwent adrenalectomy (obtained at the end of the chronic experiment) showed an uprise in urinary potassium excretion. This result was not observed after the infusion of control sera. These findings suggest that full renal adaptation to chronic potassium loading can be achieved in the absence of aldosterone through mechanisms that might be related to elevated plasma insulin levels (extrarenal); also, a humoral factor associated with the renal adaptation cannot be ruled out.