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Regulation of potassium (K+) excretion was examined in an experimental setting that reflects the dietary conditions for humans in Paleolithic times (high, episodic intake of K+ with organic anions; low intake of NaCl), because this is when major control mechanisms were likely to have developed.The major control of K+ secretion in this setting is to regulate the number of luminal K+ channels in the cortical collecting duct. Following a KCl load, the K+ concentration in the medullary interstitial compartment rose; the likely source of this medullary K+ was its absorption by the H+/K+-ATPase in the inner medullary collecting duct. As a result of the higher medullary K+ concentration, the absorption of Na+ and Cl− was inhibited in the loop of Henle, and this led to an increased distal delivery of a sufficient quantity of Na+ to raise K+ excretion markedly, while avoiding a large natriuresis. In addition, because K+ in the diet was accompanied by ‘future’ bicarbonate, a role for bicarbonate in the control of K+ secretion via ‘selecting’ whether aldosterone would be a NaCl-conserving or a kaliuretic hormone is discussed.This way of examining the control of K+ excretion provides new insights into clinical disorders with an abnormal plasma K+ concentration secondary to altered K+ excretion, and also into the pathophysiology of calcium-containing kidney stones.