Because normal regulation of potassium excretion occurs mainly as a result of changes in potassium secretion by the principal cells of the late distal and collecting tubules, in this chapter we discuss the primary factors that influence secretion by these cells. The most important factors that stimulate potassium secretion by the principal cells include (1) increased extracellular fluid potassium con centration, (2) increased aldosterone, and (3) increased tubular flow rate.

One factor that decreases potassium secretion is increased hydrogen ion concentration (acidosis).

Increased Extracellular Fluid Potassium Concentration Stimulates Potassium Secretion. The rate of potassium secretion in the late distal and cortical collecting tubules is directly stimulated by increased extracellular fluid potassium concentration, leading to increases in potassium excretion, as shown in Figure 1. This effect is especially pronounced when extracellular fluid potassium concentration rises above about 4.1 mEq/L, slightly less than the normal concentration. Increased plasma potassium concentration, therefore, serves as one of the most important mechanisms for increasing potassium secretion and regulating extracellular fluid potassium ion concentration.

Fig1. Effect of plasma aldosterone concentration (red line)  and extracellular potassium ion concentration (black line) on the rate  of urinary potassium excretion. These factors stimulate potassium  secretion by the principal cells of the cortical collecting tubules. (Data from Young DB, Paulsen AW: Interrelated effects of aldosterone and plasma potassium on potassium excretion. Am J Physiol 244:F28, 1983.)

Increased dietary potassium intake and increased extracellular fluid potassium concentration stimulate potassium secretion by four mechanisms:

1. Increased extracellular fluid potassium concentration stimulates the sodium-potassium ATPase pump, thereby increasing potassium uptake across the basolateral membrane. This increased potassium uptake in turn increases intracellular potassium ion concentration, causing potassium to diffuse across the luminal membrane into the tubule.

2. Increased extracellular potassium concentration increases the potassium gradient from the renal interstitial fluid to the interior of the epithelial cell, which reduces backleakage of potassium ions from inside the cells through the basolateral membrane.

3. Increased potassium intake stimulates synthesis of potassium channels and their translocation from the cytosol to the luminal membrane, which, in turn, increases the ease of potassium diffusion through the membrane.

4. Increased potassium concentration stimulates aldosterone secretion by the adrenal cortex, which further stimulates potassium secretion, as discussed next.

Aldosterone Stimulates Potassium Secretion. Aldosterone stimulates active reabsorption of sodium ions by the principal cells of the late distal tubules and collecting ducts. This effect is mediated through a sodium-potassium ATPase pump that transports sodium outward through the basolateral membrane of the cell and into the renal interstitial fluid at the same time that it pumps potassium into the cell. Thus, aldosterone also has a powerful effect to control the rate at which the principal cells secrete potassium.

A second effect of aldosterone is to increase the number of potassium channels in the luminal membrane and therefore its permeability for potassium, further adding to the effectiveness of aldosterone in stimulating potassium secretion. Therefore, aldosterone has a powerful effect to increase potassium excretion, as shown in Figure 1.

Increased Extracellular Potassium Ion Concentration Stimulates Aldosterone Secretion. In negative feed back control systems, the factor that is controlled usually has a feedback effect on the controller. In the case of the aldosterone-potassium control system, the rate of aldosterone secretion by the adrenal gland is controlled strongly by extracellular fluid potassium ion concentration. Figure 2 shows that an increase in plasma potassium concentration of about 3 mEq/L can increase plasma aldosterone concentration from nearly 0 to as high as 60 ng/100 ml, a concentration almost 10 times normal.

Fig2.  Effect of extracellular fluid potassium ion concentration on plasma aldosterone concentration. Note that small changes  in potassium concentration cause large changes in aldosterone  concentration. 

The effect of potassium ion concentration to stimulate aldosterone secretion is part of a powerful feedback system for regulating potassium excretion, as shown in Figure 3. In this feedback system, an increase in plasma potassium concentration stimulates aldosterone secretion and, therefore, increases the blood level of aldosterone (block 1). The increase in blood aldosterone then causes a marked increase in potassium excretion by the kidneys (block 2). The increased potassium excretion then reduces the extracellular fluid potassium concentration back toward normal (circle 3 and block 4). Thus, this feedback mechanism acts synergistically with the direct effect of increased extracellular potassium concentration to elevate potassium excretion when potassium intake is raised (Figure 4).

Fig3.  Basic feedback mechanism for control of extracellular  fluid potassium concentration by aldosterone (Ald). 

Fig4. Primary mechanisms by which high potassium intake  raises potassium excretion. Note that increased plasma potassium  concentration directly raises potassium secretion by the cortical collecting tubules and indirectly increases potassium secretion by raising  plasma aldosterone concentration. 

Blockade of the Aldosterone Feedback System Greatly Impairs Control of Potassium Concentration. In the absence of aldosterone secretion, as occurs in patients with Addison’s disease, renal secretion of potassium is impaired, thus causing extracellular fluid potassium concentration to rise to dangerously high levels. Conversely, with excess aldosterone secretion (primary aldosteronism), potassium secretion becomes greatly increased, causing potassium loss by the kidneys and thus leading to hypokalemia.

In addition to its stimulatory effect on renal secretion of potassium, aldosterone also increases cellular uptake of potassium, which contributes to the powerful aldosterone-potassium feedback system, as discussed previously.

The special quantitative importance of the aldosterone feedback system in controlling potassium concentration is shown in Figure 5. In this experiment, potassium intake was increased almost sevenfold in dogs under two conditions: (1) under normal conditions and (2) after the aldosterone feedback system had been blocked by removing the adrenal glands and placing the animals on a fixed rate of aldosterone infusion so that plasma aldosterone concentration was maintained at a normal level but could neither increase nor decrease as potassium intake was altered.

Fig5. Effect of large changes in potassium intake on plasma  potassium concentration under normal conditions (red line) and after  the aldosterone feedback had been blocked (blue line). Note that  after blockade of the aldosterone system, regulation of potassium  concentration was greatly impaired. (Courtesy Dr. David B. Young.)

Note that in the normal animals, a sevenfold increase in potassium intake caused only a slight increase in plasma potassium concentration, from 4.2 to 4.3 mEq/L. Thus, when the aldosterone feedback system is functioning normally, potassium concentration is precisely controlled, despite large changes in potassium intake.

When the aldosterone feedback system was blocked, the same increases in potassium intake caused a much larger increase in plasma potassium concentration, from 3.8 to almost 4.7 mEq/L. Thus, control of potassium con centration is greatly impaired when the aldosterone feedback system is blocked. A similar impairment of potassium regulation is observed in humans with poorly functioning aldosterone feedback systems, such as occurs in patients with either primary aldosteronism (too much aldosterone) or Addison’s disease (too little aldosterone).

Increased Distal Tubular Flow Rate Stimulates Potassium Secretion. A rise in distal tubular flow rate, as occurs with volume expansion, high sodium intake, or treatment with some diuretics, stimulates potassium secretion (Figure 6). Conversely, a decrease in distal tubular flow rate, as caused by sodium depletion, reduces potassium secretion.

Fig6. Relationship between flow rate in the cortical collecting  tubules and potassium secretion and the effect of changes in potassium intake. Note that a high dietary potassium intake greatly  enhances the effect of increased tubular flow rate to increase potassium secretion. The shaded bar shows the approximate normal  tubular flow rate under most physiological conditions. (Data from Malnic G, Berliner RW, Giebisch G: Flow dependence of K+ secretion in cortical distal tubes of the rat. Am J Physiol 256:F932, 1989.)

The effect of tubular flow rate on potassium secretion in the distal and collecting tubules is strongly influenced by potassium intake. When potassium intake is high, increased tubular flow rate has a much greater effect to stimulate potassium secretion than when potassium intake is low (see Figure 6).

There are two effects of high-volume flow rate that increase potassium secretion:

1. When potassium is secreted into the tubular fluid, the luminal concentration of potassium increases, thereby reducing the driving force for potassium diffusion across the luminal membrane. With increased tubular flow rate, the secreted potassium is continuously flushed down the tubule, so the rise in tubular potassium concentration becomes minimized and net potassium secretion is increased.

2. A high tubular flow rate also increases the number of high conductance BK channels in the luminal membrane. Although the BK channels are normally quiescent, they become active in response to increases in flow rate, thereby greatly increasing conductance of potassium across the luminal membrane.

The effect of increased tubular flow rate is especially important in helping to preserve normal potassium excretion during changes in sodium intake. For example, with a high sodium intake, there is decreased aldosterone secretion, which by itself would tend to decrease the rate of potassium secretion and, therefore, reduce urinary excretion of potassium. However, the high distal tubular f low rate that occurs with a high sodium intake tends to increase potassium secretion (Figure 7), as dis cussed in the previous paragraph. Therefore, the two effects of a high sodium intake—decreased aldosterone secretion and the high tubular flow rate—counterbalance each other, so there is little change in potassium excretion. Likewise, with a low sodium intake, there is little change in potassium excretion because of the counterbalancing effects of increased aldosterone secretion and decreased tubular flow rate on potassium secretion.

Fig7.  Effect of high sodium intake on renal excretion of  potassium. Note that a highsodium diet decreases plasma aldosterone, which tends to decrease potassium secretion by the cortical  collecting tubules. However, the highsodium diet simultaneously  increases fluid delivery to the cortical collecting duct, which tends to  increase potassium secretion. The opposing effects of a highsodium  diet counterbalance each other, so there is little change in potassium  excretion.

Acute Acidosis Decreases Potassium Secretion. Acute increases in hydrogen ion concentration of the extra cellular fluid (acidosis) reduce potassium secretion, whereas decreased hydrogen ion concentration (alkalosis) increases potassium secretion. The primary mechanism by which increased hydrogen ion concentration inhibits potassium secretion is by reducing the activity of the sodium-potassium ATPase pump. This reduction in turn decreases intracellular potassium concentration and subsequent passive diffusion of potassium across the luminal membrane into the tubule. Acidosis may also reduce the number of potassium channels in the luminal membrane.

With more prolonged acidosis, lasting over a period of several days, there is an increase in urinary potassium excretion. The mechanism for this effect is due in part to an effect of chronic acidosis to inhibit proximal tubular sodium chloride and water reabsorption, which increases distal volume delivery, thereby stimulating potassium secretion. This effect overrides the inhibitory effect of hydrogen ions on the sodium-potassium ATPase pump. Thus, chronic acidosis leads to a loss of potassium, whereas acute acidosis leads to decreased potassium excretion. 

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