Physiologic Determinants Of K Secretion

The major mineralocorticoid in humans is aldosterone. Aldosterone stimulates potassium secretion by effecting several of the cellular determinants discussed above. First, aldosterone stimulates Na reabsorption across the luminal membrane which increases the electronegativity of the lumen, thereby increasing the electrical gradient favoring K secretion. Second, aldosterone increases intracellular K concentration by stimulating the activity of the Na/K ATPase in the basolateral membrane. Third, aldosterone directly increases the permeability of the luminal membrane to K. Thus, aldosterone increases the rate of K secretion by increasing cell K concentration, increasing luminal membrane K permeability, and making the luminal potential more negative.

A second important factor which affects K secretion is the rate of distal delivery of Na and water. Increased distal delivery of Na stimulates distal Na absorption which will make the luminal potential more negative and thus increase K secretion. Increased flow rates also increase K secretion. When K is secreted in the collecting duct the luminal K concentration rises, which decreases the diffusion gradient and slows further K secretion. At higher luminal flow rates, the same amount of K secretion will be diluted by the larger volume such that the rise in luminal K concentration will be less. Thus, increases in the distal delivery of Na and water stimulate K secretion by lowering luminal K concentration and making the luminal potential more negative.

While increased distal delivery of Na and water and increased aldosterone activity can each stimulate renal potassium secretion, under normal physiologic conditions these two determinants are inversely related (Fig. 1). It is for this reason that K excretion is independent of volume status. For example, under conditions of a contracted extracellular fluid volume aldosterone levels increase. At the same time, proximal salt and water absorption increases, resulting in decreased distal delivery of Na and water. Renal potassium excretion remains fairly constant under these conditions since the stimulatory effect of increased aldosterone is counterbalanced by the decreased delivery of filtrate to the distal nephron. A similar situation occurs in the setting of expansion of the extracellular fluid volume. In this setting, distal delivery of filtrate is increased as a result of decreased proximal tubular fluid reabsorption. Under conditions of volume expansion circulating aldosterone levels are decreased. The effect of

Osmotic diuretics Carbonic anhydrase inhibitors Loop diuretics Thiazide diuretics

î Proximal Na t Renin-Al I reabsorption

î Proximal Na t Renin-Al I reabsorption

4 Proximal Na Reabsorption i Renin-AII

i Distal Na delivery

î Aldosterone t Distal Na Delivery

I Aldosterone

* Renal K Excretion

FIGURE 1. Under normal circumstances increases or decreases in the effective arterial blood volume (EABV) result in reciprocal changes in distal Na delivery and circulating aldosterone levels such that renal K excretion is independent of volume changes. Administration of diuretics causes aldosterone and distal Na delivery to both increase such that renal K excretion is enhanced and hypokalemia ensues.

the increased delivery of Na and water to stimulate potassium excretion is opposed by decreased circulating aldosterone levels such that renal potassium excretion again remains constant. Thus, there is a balanced reciprocal relationship between urinary flow rates and circulating aldosterone levels which serves to maintain potassium balance during normal volume regulation. As discussed below, diuretic-induced hypokalemia is largely the result of disturbances in this relationship.

Diuretics which are associated with the development of hypokalemia exert effects on K transport mechanisms which are located at the drug's tubular site of action. Overall, these effects tend to be of lesser importance in the generation of hypokalemia as compared to secondary changes which are discussed below.

Osmotic Diuretics

Osmotic diuretics are filtered by the glomerulus and then undergo little to no reabsorption by the tubules. These agents disrupt the osmotic gradient which

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