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Extrarenal Potassium Metabolism
Internal potassium homeostasis is defined as the regulation of potassium distribution between the intracellular and extracellular fluid compartments, as distinct from the net gain or loss of potassium from the body. While the kidney plays the predominant role in maintaining external potassium balance, nonrenal tissues, especially muscle and liver, are quantitatively the most important organs involved in the regulation of internal potassium balance.
The ratio of potassium between intracellular and extracellular fluids is critically important, not only to the behavior of electrically excitable cells, such as muscle and nerve, but also to the vital processes of all living cells. The reason for this is that a major regulator of cell function is the transmembrane potential. The determinants of this membrane potential are described by the Goldman–Hodgkin–Katz equation, the most important term of which is the logarithm of the ratio of internal to external ionic activity of potassium.
Of the 3500 mEq of potassium found in the body of a 70 kg human, about 98% is confined to intracellular water ( Figure 48.1 ). Of this, 80% is contained in muscle cells, at a concentration of about 150 mEq/liter. The remaining 2% of total body potassium (about 70 mEq) is located in the extracellular fluid (about 14 liters), where the normal concentration is 3.5–5.5 mEq/liter. The chief biological mechanism responsible for maintaining this 30-fold potassium gradient between cell water and extracellular fluid is the Na,K-ATPase pump, situated in the plasma membrane of all animal cells. A minor role is played by the inward transport of potassium coupled with sodium and chloride, via the Na K 2Cl transporter in the plasma membrane of some cells. Transcellular distribution of potassium is also modulated by hormonal factors, such as insulin and catecholamines, by hydrogen ion balance, plasma osmolality, intracellular potassium content, and by factors that affect the passive movement of potassium through membrane channels, such as the level of intracellular calcium and pH ( Table 48.1 ). Some of these factors, such as the activity of Na,K-ATPase and the distribution of hydrogen ions, may concurrently affect the potassium content of cells of the distal nephron, and thereby influence the external balance of potassium.
Internal potassium homeostasis in a 70 kg person.
The potassium concentration in the extracellular fluid (ECF) depends on both the external balance (intake and output) and the internal balance (distribution between extracellular and intracellular fluid, ICF). Factors affecting internal balance are listed in Table 48.1 . Note that the large ICF pool exists at a far greater K concentration than the small ECF pool; the ECF pool will therefore change more dramatically with changes in total body K or K distribution.
Table 48.1
Factors Affecting Internal Potassium Homeostasis
| Factor | Effect on Potassium |
|---|---|
| Insulin | Enhanced cell uptake |
| β-Catecholamines | Enhanced cell uptake |
| α-Catecholamines | Impaired cell uptake |
| Acidosis | Impaired cell uptake and enhanced efflux a |
| Alkalosis | Enhanced cell uptake and reduced efflux a |
| External potassium balance | Loose correlation |
| Drugs | See text |
| Hyperosmolality | Enhance cell efflux |
From a practical standpoint, a key determinant of transmembrane potential is the plasma potassium. Since the concentration of potassium inside cells far exceeds extracellular concentration, percentile changes in intracellular potassium are relatively small, even during extreme degrees of total body potassium surfeit, deficit or internal redistribution. The changes in extracellular potassium seen in diseased states are therefore much more likely to alter the membrane potential of cells than are concomitant changes in intracellular potassium. For this reason, a variety of mechanisms have evolved to preserve the extracellular concentration of potassium within the normal range.
If a moderate load of potassium (0.5 mEq/kg) is administered intravenously over 1 hour, about 40% of it is excreted into the urine at the end of that time. Within 3 hours, renal excretion is complete and the serum potassium, which initially increases by about 0.6 mEq/liter, returns to baseline. The ability of the normal human kidney to excrete all of an oral load of potassium is more sluggish; while potassium excretion increases 6-10-fold within a few hours, only about half of the load is excreted during the first 3–6 hours after it is ingested. Of considerable interest, however, is recent evidence that is consistent with the existence of an unidentified “gut” and/or “hepatoportal factor” that senses potassium ingestion, and rapidly initiates the process of renal potassium excretion in the absence of a significant change in plasma potassium concentration.
Consumption of only 35 mEq of potassium by a 70 kg adult during an average meal (an amount equivalent to 1% of total body potassium) would, if confined exclusively to the extracellular space, raise the plasma potassium by 2.5 mEq/liter – enough to have pronounced effects on neuromuscular function. It is well-established, however, that a potassium load given to a normal human or dog has an apparent volume of distribution of 70–80% of body weight, somewhat greater than total body water, instead of the 20% that represents extracellular fluid. In other words, only a small portion (about one quarter) of the 35 mEq of ingested potassium will normally remain in the extracellular compartment, raising the concentration of potassium in plasma by only about 0.6 mEq/liter. In contrast, a similar load of potassium administered to patients with deranged extrarenal potassium homeostasis may produce serious hyperkalemia.
The cells also buffer plasma potassium during potassium depletion. In states of progressive potassium deficiency, as depletion worsens, a greater amount of potassium is lost from within cells to lessen the fall in external concentration, and to minimize the alteration in its intracellular to extracellular ratio.
These examples of potassium surfeit or deficit emphasize the critical role of internal potassium homeostasis in mitigating potentially dangerous changes in the plasma potassium. Disorders of the factors that mediate this adjustment thus may have substantial clinical importance and are the primary topic of this chapter.
Potassium Depletion and Repletion
In many conditions, such as vomiting, diabetic ketoacidosis, and chronic renal failure, abnormalities of internal and external potassium homeostasis coexist. Just as internal potassium homeostasis can affect potassium uptake and excretion by the kidney, so changes in external potassium balance, by altering cellular potassium content, can independently influence internal potassium homeostasis.
Potassium Depletion
The idealized curvilinear relationship between total body potassium and the serum potassium concentration illustrated in Figure 48.2 is derived from several measurements in hypokalemic patients with positive potassium balance during replacement therapy, and from unpublished data on hyperkalemic humans and animals. In the early stages of depletion, extracellular potassium loss is proportionately greater than the loss of cellular potassium. Nonetheless, since only a small fraction of total body potassium is extracellular, the quantity of potassium lost from the extracellular compartment is much smaller than that lost from inside cells.
In the early phases of hypokalemia (>2.5 mEq/liter), patients tend to display an almost linear relationship between total body potassium and the serum potassium concentration. It has been observed that a change of 100–200 mEq in total body potassium (about 5%) is required to lower the serum potassium by 1.0 mEq/liter. In such a situation, the extracellular potassium concentration would be expected to fall proportionately more (e.g., 4.0 to 3.0 mEq/liter) than the intracellular concentration (e.g., 140 to 133 mEq/liter). Because of the relationship of cell membrane potentials to the ratio of internal to external ionic activity of potassium, excessive extracellular potassium loss would be expected to hyperpolarize cells (resting membrane potential is increased). This expectation has been confirmed in studies of early potassium deficiency in both dogs and humans.
When potassium depletion becomes more severe, so that serum levels fall below about 2.5 mEq/liter, a further 1.0 mEq/liter fall will represent a much larger 200–400 mEq decrement in total body potassium (greater than 10%), reflecting a greater degree of potassium loss from within the cells than occurred in the early phases of depletion. Decreased cell potassium content has, in fact, been observed in several tissues during severe hypokalemia.
In severe potassium depletion cells tend to depolarize (resting membrane potential is decreased), at least in dogs which, like humans, then develop weakness and muscle paralysis. Under conditions of chronic hypokalemia, however, there is also upregulation of the colonic form of H,K-ATPase (HKα2), which leads to enhanced potassium reabsorption from the gut.
Potassium Repletion
During potassium repletion for severe hypokalemia, cellular potassium uptake is enhanced both in animals and in humans ; that is, the administered potassium has an increased volume of distribution; as potassium is gained by the body and the stores become higher, the cellular uptake of potassium decreases. In anuric humans, for example, the cellular uptake of a potassium-load decreases as total body potassium increases. Extracellular potassium then tends to rise and membrane potential decreases. The important therapeutic caveat in the late phases of correction of potassium depletion is that less potassium administration is required than in earlier phases to increase serum potassium, which may rise suddenly to unexpected, dangerously hyperkalemic levels.
As reviewed extensively by Sterns et al., the serum potassium alone is, at best, an extremely rough guide for estimating potassium replacement therapy, presumably because other factors, such as acid–base status, influence it. A low serum potassium value (e.g., 3.0 mEq/liter) may be associated with a range of total body deficits spanning a few hundred millequivalents ( Figure 48.2 ).
The exact mechanisms that produce this curvilinear relationship are uncertain. They may stem in part from impairment of the electrogenic sodium pump. During potassium depletion in rats, skeletal muscle potassium loss is associated with a reduced capacity for Na-K pumping and a reversible decrease in the number of [ 3 H] ouabain-binding sites. A possible mechanism for suppression of the Na-K pump during potassium depletion is enhanced stimulation of alpha-adrenoreceptors (see “Catecholamines”). In addition, even modest dietary potassium restriction provokes resistance to insulin-mediated cellular potassium uptake (see “Insulin”).
Insulin
The effect of insulin on potassium homeostasis was first demonstrated two years after its purification by Banting and Best. Harrop and Benedict, and Briggs and Koechig described the fall in serum potassium coincident with lowering of blood sugar when insulin was administered to diabetic patients, as well as in the non-diabetic human, dog, and rabbit. Later, there were reports of severe hypokalemia in insulin-treated patients with ketoacidosis who developed paralysis.
Cellular Mechanism
The hypokalemic action of insulin derives from its capacity to cause net potassium uptake in skeletal muscle, adipose tissue, and hepatic cells, as well as other extrarenal sites. This effect was formerly assumed to occur to preserve electrical neutrality when insulin-mediated glucose uptake produced intracellular anionic sugars and deposited potassium as an accompaniment of glycogen in the liver.
This classical hypothesis did not explain the clinical observation that sudden lowering of serum potassium could precede the fall in blood sugar in insulin-treated diabetic coma. Zierler first noted that insulin’s effect on potassium movement in rat muscle occurred even in the absence of glucose; its known effect to increase sodium efflux in vitro also occurred without glucose. Furthermore, enhancement of potassium disposal in the intact animal was separable temporally from glucose uptake and occurred at plasma insulin concentrations having no measurable influence on uptake of glucose in vivo . Different receptor mechanisms for potassium and glucose transport appear to exist.
In vitro , insulin is known to stimulate both potassium uptake and sodium efflux in frog and rat muscle preparations. Similar effects have been reported in rat adipose tissue, hepatocytes, and other cells. Considerable evidence suggests that following binding to cell surface receptors, insulin accelerates monovalent cation transport by stimulating Na,K-ATPase, the sodium-potassium pump. Most convincing is the fact that both insulin-stimulated net sodium efflux and potassium influx are blocked by ouabain. In vitro , addition of insulin to purified plasma membrane of skeletal muscle increases the activity of the Na,K-ATPase. Little evidence is currently available on whether insulin affects potassium permeability or potassium channels in skeletal muscle cells. Insulin activation of sodium–hydrogen exchange sensitive to amiloride does not appear to be important to sodium-pump-mediated potassium uptake. In adipocytes, insulin-stimulated uptake of K + and Rb + is inhibited by bumetanide and by removal of Cl − from the extracellular fluid, suggesting a primary action of insulin on the Na K 2Cl co-transporter. On the other hand, in skeletal muscle, insulin does not appear to activate the co-transport of K + with Na + and Cl − . There is evidence, however, that the serum and glucocorticoid-inducible kinase SGK1 participates in the different signaling pathways that mediate the hypokalemic effect of insulin.
Stimulation of active sodium–potassium transport by Na,K-ATPase could be due to a de novo increase in the number of sodium pump sites or to allosteric activation of existing sites. The latter theory is consistent with the rapid activation of transport that occurs, as well as with the lack of new ouabain-binding sites after exposure to insulin in vitro .
At least three molecular forms of the Na,K-ATPase catalytic subunit have been identified, designated alpha1, alpha2, and alpha3. In both rat and human skeletal muscles, insulin mediates the Na,K-ATPase alpha1- and alpha2-subunit translocation into the plasma membrane via a phosphatidylinositol 3-kinase-dependent mechanism. In liver, the effect of insulin can be accounted for by increased intracellular sodium concentration. Insulin also activates a KCl co-transporter uptake system in a cultured cell line resembling skeletal muscle.
It should be noted that insulin is known to produce hyperpolarization of cellular membranes, not only in skeletal muscle, but in a variety of other tissues. This rapid effect appears to precede measurable increases in intracellular potassium. Although stimulation of Na,K-ATPase could account for insulin’s hyperpolarizing effect, failure of ouabain to block it, at least in some studies, suggests that changes in ion permeability may be responsible. The role of hyperpolarization in mediating insulin effects on cation transport is uncertain. The effect of insulin to stimulate active sodium and potassium transport in skeletal muscle is mimicked by insulin-like growth factor I (IGF-I).
In Vivo Effects
Abundant evidence therefore exists that insulin increases net uptake of potassium ions by several tissues in vitro . Since skeletal muscle is well-documented to respond to insulin and is the major body reservoir for potassium, it is most likely the dominant site for insulin-stimulated extrarenal potassium disposal in vivo . Human forearm muscle (and adipose tissue) increases potassium uptake during arterial infusion of insulin.
Wilde noted over half-a-century ago that injected potassium rapidly disappeared from the blood of cats, but was followed by a secondary rise in serum potassium. Recent investigation suggests that, at least during insulin infusion, hepatic disposal plays an important role in potassium homeostasis in the first hour of exposure to insulin in humans. Splanchnic uptake accounted for two-thirds of the fall in plasma potassium during euglycemic hyperinsulinemia. In the second hour, net splanchnic uptake reversed, and peripheral tissues became the dominant site of potassium disposal.
That the effect of insulin on extrarenal potassium homeostasis is dose related is well-established ( Figure 48.3 ). In normal subjects, neither intramuscular nor subcutaneous administration of insulin, which achieved plasma insulin levels of about 50 µU/ml, decreased the plasma potassium. Intravenous insulin injection, by comparison, produced 40-fold greater insulin levels, which were accompanied by a steady-state reduction in plasma potassium, with a maximal effect of about 30% occurring 50 minutes after insulin injection. On the other hand, much smaller increments of insulin, about three-fold above basal values, either during constant venous or intra-arterial infusion also appear capable of augmenting potassium uptake in vivo . Under conditions of prolonged potassium depletion, however, the expression of skeletal muscle Na,K-ATPase α2 isoform is decreased, which allows for enhanced efflux of potassium from muscle to the extracellular space. Of particular interest is the observation that even modest dietary potassium restriction leads to a decrease in insulin-mediated cellular potassium uptake in rats in the absence of a fall in plasma potassium concentration.
Clinical Implications
The relevance of these findings to a given clinical situation of exogenous potassium challenge will depend on the magnitude of potassium-load requiring disposal, and the elevation of insulin accompanying it. Following carbohydrate feeding, for example, increased liver uptake of potassium occurs. Since peripheral venous insulin levels for 2 hours following oral glucose loading are elevated five-fold, well within the range capable of augmenting potassium uptake, it seems likely that insulin contributes to the transient decrease in potassium that occurs after feeding. Even basal circulating insulin levels may be essential to disposal of an acute potassium-load, since disposal is impaired when basal levels are decreased 50% by somatostatin. The effect of carbohydrate meals to blunt or prevent hyperkalemia may be particularly important in anuric patients dependent on extracorporeal dialysis.
During exogenous potassium challenge, the importance of insulin to potassium disposal by the intact organism deprived of endogenous insulin or resistant to the actions of insulin is well-established. As expected, supraphysiologic doses of exogenous insulin are capable of improving potassium tolerance. Thus, for emergency treatment of hyperkalemia, the intravenous administration of insulin together with glucose is indicated, unless the patient is already hyperglycemic from diabetes in which case additional glucose is not warranted.
The ability of potassium-loading to stimulate the release of pancreatic insulin directly, in amounts sufficient to contribute to disposal of that potassium, is less clear. In pancreatic B-cells, ATP-sensitive K channels link cellular membrane potential to hormone secretion. These channels control the transmembrane potential, and thereby the calcium channels that trigger glucose-induced insulin secretion. Depolarization of the cell membrane (as expected with hyperkalemia) induces an increase in insulin secretion. In humans and intact dogs, minor increments in blood potassium appear capable of triggering pancreatic insulin secretion. Since elevations in portal venous insulin far exceed those in the peripheral circulation when insulin release is stimulated, it seems reasonable to conclude that, under conditions of significant hyperkalemia, induction of insulin release to promote potassium uptake does constitute a homeostatic feedback control system.
Glucagon
The effect of glucagon on extrarenal potassium disposal has been difficult to isolate, because the hormone also influences the secretion of insulin, epinephrine, and aldosterone. Administration of glucagon to cats does appear to mobilize potassium from the liver and produce a transient rise in arterial potassium levels. In humans, the hyperkalemic response to the hormone appears to be only partly due to an epinephrine-like effect of glucagon to increase liver glycogenolysis.
For example, aortic injection of glucagon in humans, which results in hepatic vein glucagon levels within the pathophysiologic range, causes a transient increment in hepatic vein potassium concentrations, but this precedes the slow rise in glucose in hepatic venous blood. The specific source of the modest rise in hepatic venous potassium under these conditions has not been determined. Previous in vitro investigations using perfused rat liver suggest that glucagon releases potassium directly from the liver. The effect would not appear to be due to diminished Na K pump-mediated potassium uptake, since isolated rat hepatocytes exposed to glucagon actually undergo stimulation of this cation pump.
Systemic infusion of glucagon to physiologic levels tends to elevate plasma potassium slightly by an extrarenal mechanism, at least when glucagon-induced insulin secretion is suppressed by somatostatin, both in normal subjects and in diabetic subjects. It is unclear whether hyperglucagonemia, which occurs in decompensated diabetes mellitus, uremia, and exhausting exercise affect potassium homeostasis. In the dog, potassium-stimulated insulin release appears to be accompanied by a modest rise in circulating glucagon.
Catecholamines
The observation of D’Silva in 1934 that epinephrine lowers the serum potassium in cats has since acquired important physiologic and clinical relevance. Although D’Silva emphasized the rapid rise in the serum potassium that followed a bolus injection of epinephrine (now felt to be a consequence of transient hepatic discharge of potassium by alpha-adrenergic stimulation), of greater significance was the sustained “after-fall” in serum potassium that he observed. This secondary decrease in potassium was found to persist throughout a 1 hour infusion of epinephrine.
Since epinephrine inhibited the renal excretion of potassium, its late hypokalemic action was attributed to net uptake of potassium by extrarenal tissues. Indeed, in vivo limb studies in dogs and humans, as well as tissue analysis and ion flux studies, supported accelerated uptake of potassium, primarily in skeletal muscle, but also in liver and heart, in response to epinephrine. In vitro , epinephrine was demonstrated to stimulate potassium uptake, as well as sodium efflux, by isolated skeletal muscle in both rats and humans. A similar effect was present in rat diaphragm, cat cardiac muscle, and frog sartorius muscle.
Because epinephrine may influence insulin secretion, it was necessary to show that its hypokalemic effect was independent of insulin. Independence from renin-mediated aldosterone release was established by the lowering of potassium despite nephrectomy. Since extrarenal potassium disposal was impaired when nephrectomized rats were subjected to adrenalectomy or to chemical sympathectomy, both circulating adrenomedullary epinephrine, as well as peripheral sympathetic nervous activity, appeared to be important sources of sympathetic influence on potassium.
Beta-Adrenergic Effects
Epinephrine stimulates both alpha- and beta-adrenergic receptors. The conclusion that its hypokalemic action was a result of beta-adrenergic stimulation derived from experiments many years later employing beta-agonists and beta-antagonists. Isoproterenol, a nonspecific beta-agonist, reproduced the prolonged hypokalemia earlier observed by D’Silva, and this effect was reversed by the beta-adrenergic-antagonist propranolol; likewise, epinephrine’s effects on cation flux were blocked by beta-antagonists.
Beta-agonists and -antagonists have been used to establish that the stimulating effect of catecholamines on potassium uptake is mediated by the beta2-receptor subtype. Epinephrine’s effect on potassium is prevented by the presence of nonselective beta-antagonists such as propranolol and timolol, as well as by the nonspecific alpha-beta blocker labetalol. Less reversal occurs with the partially beta1-selective-antagonists metoprolol and atenolol. No effect on potassium appears to be produced by the more specific beta1-antagonist practolol. In addition, the selective beta2-antagonists butoxamine and ICI-118551 are able to block the hypokalemic action of beta-agonists.
Numerous studies of beta-agonists have revealed that several beta2-agonists, including salbutamol, terbutaline, fenoterol, and ritodrine lower potassium levels, unlike the beta1-agonist ITP, which has no effect. These pharmacologic studies therefore provide strong support for beta2 mediation of adrenergic effects to enhance potassium disposal.
Mechanism of Action
The specific cellular mechanism by which cell surface beta2-receptor stimulation augments transcellular potassium uptake in affected tissues has been evaluated in detail. Compelling evidence exists to support the proposal of Clausen that beta2-stimulation initiates cyclic AMP formation, which leads to activation of the sodium pump (Na,K-ATPase), and therefore electrogenic sodium efflux accompanied by potassium uptake. Beta receptors are known to stimulate adenylate cyclase, enhancing conversion of intracellular ATP to cyclic AMP. Linkage of beta receptors and cyclic AMP is supported by the ability of theophylline to potentiate the effect of epinephrine on cation transport and membrane potential, as well as by the increase in membrane potential that dibutyryl cyclic AMP and theophylline produce in rat diaphragm muscle. Epinephrine, in stimulating cation transport, is well known to produce hyperpolarization of membranes in skeletal muscle.
The sodium pump of muscle cells and lipocytes is activated by cyclic AMP. For example, Na,K-ATPase activity in smooth muscle membrane fragments is enhanced by exposure to cyclic AMP. The most compelling evidence that catecholamine-mediated potassium influx involves the beta-adrenergic system through activation of the sodium pump, however, are the demonstrations in a series of experiments that potassium influx occurs as active movement of the cation against its electrochemical gradient ; ouabain blocks the ability of epinephrine to promote potassium influx in rat soleus muscle ; epinephrine markedly increases the ouabain-sensitive 22Na efflux by stimulating the Na K pump in frog skeletal muscle, and this effect is blocked by propranolol ; epinephrine produces membrane hyperpolarization and transient decreases in extracellular potassium and intracellular sodium, which is blocked by ouabain, in isolated rat soleus muscle and human intercostal muscle ; and isoproterenol directly stimulates the Na K pump in isolated rabbit myocytes. While the specific sequence of events linking beta-adrenergic stimulation to sodium pump activity has not been delineated, phosphorylation of some portion of the sodium pump after beta2-receptor stimulation is presumably involved. Beta-adrenergic agents also stimulate the cellular uptake of potassium via the Na K 2Cl transporter in the skeletal muscle membrane of rats.
There are numerous clinical examples showing that enhanced exogenous or endogenous beta-adrenergic stimulation augments extrarenal potassium uptake in humans. Whether high potassium levels can stimulate secretion of endogenous adrenomedullary epinephrine, and thereby form a homeostatic feedback loop, remains unresolved. Supraphysiologic levels of potassium in vitro can cause the release of catecholamines from isolated chromaffin cells and perfused adrenal glands, possibly related to the membrane depolarizing effect of a high potassium level. Induction of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, by extremely high levels of potassium has also been observed. Reports that intra-arterial injections of KCl augment catecholamine release in cats and in the dogfish shark suggest a potential role for potassium as a catecholamine secretagogue in vivo .
Although specific stimulation of catecholamine release by potassium is not yet established, it is clear that physiologic elevations of endogenous catecholamines do enhance potassium uptake. Similar to the pharmacologic doses of epinephrine used in earlier animal reports of its protective effect during potassium-loading, as well as its ability to lower basal potassium, relatively small doses have also been shown to enhance extrarenal disposal of an acute potassium-load. It has also been established that ambient potassium may be lowered when sustained epinephrine infusions ( Figure 48.4 ) elevate plasma concentrations of epinephrine to levels no higher than those observed in stressful conditions, such as myocardial infarction, surgical stress, and diabetic ketoacidosis. By comparison, acute beta blockade does not appear to elevate fasting potassium levels, suggesting that basal beta-adrenergic tone plays a limited role in potassium homeostasis in normal fasted individuals at rest.
It has recently been appreciated, however, that there are two common physiologic circumstances in which endogenous catecholamines could act to defend against increments in extracellular potassium concentration. The first of these is postprandial disposal of dietary potassium. Feeding is now known to be associated with stimulation of the sympathetic nervous system. Since only half of the potassium ingested in a meal is normally excreted within 6 hours, enhanced beta-adrenergic-mediated extrarenal potassium disposal may help to limit elevations of serum potassium in the immediate postprandial period. In conjunction with enhanced potassium uptake due to insulin release, this mechanism would be particularly important in subjects at risk for hyperkalemia for any reason.
The second circumstance is the dramatic effect of catecholamine release during vigorous exertion to moderate the acute physiological hyperkalemia of exercise. Catecholamines circulate at high levels during vigorous exercise, and the associated short-term elevation of potassium that is released into the circulation from working muscles is exaggerated by beta blockade ( Figure 48.5 ), suggesting that endogenous beta-adrenergic activity does protect against extreme hyperkalemia during exhaustive exercise. In this context, it is of particular interest that training leads to upregulation of the content of the Na,K-ATPase, which serves to mitigate the rise in extracellular potassium concentration relative to the work performed. Another mechanism that might mitigate the rise in extracellular potassium seen during exercise is AMP-activated protein kinase. This cellular enzyme, which is normally stimulated by exercise or ischemia, has been demonstrated to produce a decrease in plasma potassium when stimulated chemically in the rat. This decrease does not appear, however, to be mediated by the Na,K-ATPase, and may instead be secondary to diminished efflux of potassium from the intracellular compartment.
Alpha-Adrenergic Effects
The fact that opposing alpha- and beta-adrenergic influences have in the past been reported on smooth muscle tone, glucoregulatory hormones, presynaptic membrane receptors, and changes in intracellular second messengers suggests the role of alpha-adrenergic agonists in potassium homeostasis. As noted previously, the early rise in extracellular potassium emphasized by D’Silva in 1934 was later attributed to alpha-mediated hepatic potassium release by the mixed alpha- and beta-agonist epinephrine. This initial rise in potassium could be prevented by alpha blockade. In addition, phenylephrine, a pure alpha-agonist, was observed to cause a sustained increase in potassium in dogs.
When phenylephrine was infused into normal human subjects who were challenged with an intravenous potassium-load, the overall rise in plasma potassium was augmented by about 50%, despite no change in insulin, renin, aldosterone or urinary potassium. In separate studies, addition of the alpha-antagonist phentolamine blocked the phenylephrine effect on potassium disposal. Neither alpha stimulation nor blockade appeared to affect the concentration of potassium in the absence of potassium-loading.
Other evidence suggests that the alpha effect might directly contribute to potassium homeostasis in certain circumstances. Alpha-receptor stimulation during vigorous exercise contributes to the acute rise in potassium that is maximal at peak exercise, and limits the dramatic fall due to potassium re-uptake during recovery. Furthermore, during potassium depletion in rats, the sodium–potassium pump of skeletal muscle is suppressed by an increase in alpha-adrenergic activity mediated by nerves, an action that would mitigate the expected fall in plasma potassium concentration. It is therefore speculated that enhanced alpha-agonist activity might act to preserve potassium similarly during a variety of acute illnesses, such as myocardial infarction or delirium tremens, where catecholamine stimulation of both beta- and alpha-receptors may coexist. Unopposed stimulation of alpha receptors may contribute to the impairment of potassium disposal caused by beta-receptor blockade.
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