Potassium Regulation During Exercise and Recovery

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Potassium Regulation During Exercise And Recovery

Michael I. Lindinger

School of Human Biology

University of Guelph

Guelph, ON

Canada

Potassium (K+) is a monovalent cation which is fully dissociated from anions such as chloride (Cl-) in physiological solutions such as body fluids. Chemically, K+ is not very reactive in solution however its small size allows it to easily cross membranes and move between body fluid compartments. Potassium is abundantly distributed in all body fluids and because K+ itself is a regulator or modulator of many tissue and cellular functions the regulation of extracellular and intracellular K+ concentrations ([K+]) is very important and essential for the health and well being of the individual.

Some of the cellular and tissue activities affected by changes in muscle and plasma [K+] include: (a) a role as a chemical messenger stimulating cardiac and ventilatory drive during exercise; (b) role as a chemical messenger inducing vasodilatation of the vascular bed of contracting muscle during exercise; (c) an important role in determining the resting membrane potential and hence cellular excitability of skeletal muscle and other cells; (d) interstitial and intracellular [K+], as determinants of the membrane potential, will influence the magnitude and duration of the action potential and hence the force and duration of muscle contraction; (e) it is a modulator of the plasma membrane sodium/potassium ATPase (Na+,K+ pump) activity; (f) it is a modulator of the activities of several metabolic enzymes important to the provision of energy during contraction in skeletal muscle; (g) it is involved in cell volume regulation of some tissues such as blood cells and perhaps skeletal muscle; and (h) it is an important determinant of acid-base status in skeletal muscle cells.

This chapter describes the movement of K+ between blood and muscle fluid compartments, and discusses the mechanisms responsible for changes in [K+] within these body fluids during exercise and recovery. In addition, some interesting new developments in the study of K+ regulation are introduced. These include the role of red blood cells (RBCs) in plasma [K+] regulation during intense exercise, the effects of training on skeletal muscle Na+,K+ pump number and activity, and the effects of caffeine ingestion on [K+] regulation during exercise.

K+ Distribution

Similar to other ions such as sodium (Na+), magnesium, calcium (Ca2+) and Cl-, K+ is found in all body fluids and ranges in concentration from a few millimoles per liter (mM) in blood plasma to 150 mM or more in skeletal muscle cells. Within the blood or vascular compartment, K+ is found in the cell free plasma portion and within the blood cells, of which the RBCs that transport oxygen and carbon dioxide are the most abundant. The intracellular (within cells) [K+]i of human RBCs is about 115 mM or about 30-fold greater than the plasma [K+] of about 4 mM in humans at rest.

The extracellular and intracellular distribution of K+ in other tissues is similar to that seen in blood. In skeletal muscle at rest, K+ is present in low concentrations (about 4 mM) in the interstitial fluids between cells and in the lymphatic vessels, but intracellular [K+]i ranges between 110 and 160 mM depending on muscle fiber type. In human and rat hindlimb skeletal muscle the slow twitch oxidative muscle fibers have a lower [K+]i than fast twitch oxidative glycolytic muscle fibers, with fast twitch glycolytic fibers having the highest [K+]i. Within human RBCs and skeletal muscle cells, the high [K+]i is maintained by the energy dependent Na+,K+ pump located on the plasma membrane and transverse tubular membrane. The low [K+] in the extracellular (plasma and interstitial) fluid compartments and high [K+]i are important determinants of the muscle resting membrane potential, such that increased extracellular [K+] and decreased [K+]i will result in a depolarized membrane (increased resting membrane potential). The magnitude and stability of the membrane potential are important determinants of skeletal muscle function and influence attributes such as strength or force of contraction and duration of force maintenance.

Within cells K+ is not uniformly distributed, but rather the various intracellular organelles such as the sarcoplasmic reticulum, vacuoles, mitochondria and nucleus have different [K+] than the cytoplasm. There is also some evidence that within the cytoplasm the [K+] may be different in the region of contractile filaments, plasma membrane, and free cytoplasm. In addition, a considerable amount (about 75% or more) of intracellular K+ is loosely bound or adsorbed to molecules such as myosin and glycogen, yet much of this K+ remains readily capable of being released from these molecules to participate in cellular reactions and tissue ion balance.

Changes in K+ Balance During Exercise and Recovery

Muscular contraction results in a transient net release of K+ from contracting muscle fibers into the interstitial fluids surrounding the fibers. The K+ diffuses easily and rapidly through the interstitial fluids into the small lymphatic vessels and venules perfusing the muscle. Since diffusion of K+ occurs from areas of high to lower [K+], it is believed that the interstitial [K+] in the regions adjacent to muscle fiber plasma membrane (sarcolemma) may exceed 15 mM during intense static contractions. The movement of K+ released from muscle into the venous circulation draining contracting muscle results in the characteristic rise in plasma [K+] seen during exercise, and often referred to as exercise-induced hyperkalemia (Fig. 1).

The renal response to the elevated plasma [K+] and lactacidosis incurred during repeated high intensity exercise has also been studied, and it differs from clinical cases of hyperkalemia. During exercise, reduced urine flow rate and glomerular filtration rate conserves body water and ions. This conservation is essential for maintained performance during exercise and for a rapid restoration of fluid and ion balance upon cessation of exercise.

Exercise may involve dynamic or isometric muscle contraction or a combination of the two. Also, the exercise may be of short duration but high intensity, or of longer term and lower intensity. Each exercise situation produces characteristic changes in muscle and plasma [K+] during muscle contraction and recovery (Fig. 1). Dynamic exercise and repetitive, short-term (less than 2s) isometric contractions may be considered synonymous when examining muscle and plasma responses to the contractions. With dynamic contractions, in contrast to isometric, there is a repeated, continuous cycle of net K+ release and uptake, but initially at least, K+ uptake does not match release and K+ enters venous blood to raise plasma [K+].

At the onset of exercise there is a time delay between net K+ release and the maximal activation of the Na+,K+ pump. As pump activity increases during repeated, low-intensity contractions the uptake rate may approach or even transiently exceed the release rate. When the elevated release rate is equaled by a faster influx rate then intracellular K+ balanced may be achieved. The concentration of K+ in plasma and red blood cells depends on the balance between the rates of release and uptake by nearly all cells in the body. Nearly all cells are many-fold higher in [K+] than plasma and interstitial fluid and therefore K+ leaks out of cells through K+ channels as they periodically open or, in the case of contracting skeletal muscle, K+ diffuses out at high rates when K+ channels open frequently or remain open for longer periods. Uptake of K+ in all cells primarily occurs the Na+,K+ pump, and secondarily in many cells including RBCs and perhaps skeletal muscle) by a Na+, K+, Cl- cotransport protein located on the plasma membrane. These mechanisms will now be discussed in more detail.

High Intensity Contractions

Generally, at high exercise or contraction intensities, i.e. greater than about 90% of peak O2, plasma [K+] will continue to increase until exercise stops (Fig. 1 & 2). Similarly high rates of K+ movement into plasma occurs at the onset of exercise, or with the transition from low to higher intensity workloads as occurs in many sports activities and exercise training protocols. The characteristic rapid increase in plasma [K+] is also accompanied by increases in the plasma catecholamines epinephrine and norepinephrine which, among other regulatory roles, stimulates Na+,K+ pump activity in skeletal muscle and other tissues.

At contraction intensities greater than 70-90% of peak O2 (depending on trained state) it appears that the time delay for achieving a K+ influx rate which matches efflux is increased, such that influx cannot keep pace with efflux. When this happens the increasing interstitial [K+] and decreasing [K+]i results in gradual depolarization of the cell membrane potential, producing a decrease in action potential amplitude and duration, a decreased frequency and force of contraction (fatigue), and a decreased rate of K+ release. The rise in plasma [K+] is thus proportional to exercise intensity (Fig. 1). Arterial plasma [K+] has been observed to increase to 9 mM or higher in some subjects performing 60 s of exercise at an intensity equal to about 200% of peak O2(8).

Such rapid and large increases in plasma [K+], together with associated increases in plasma catecholamines, stimulates both RBCs and inactive tissues, including resting skeletal muscle, to take up K+ from the plasma and interstitial fluids at higher rates than at rest (6). This effective removal of K+ from plasma serves to regulate plasma [K+] below the 8-10 mM range (except for rapid, transient excursions into this range with short-term, supramaximal exercise) which may cause cardiac arrhythmia and neuromuscular dysfunction. In contracting muscles a low plasma [K+] also serves to maintain the diffusion of K+ away from the exterior cell surface, through the interstitial fluids and into the venous circulation. This regulation of interstitial [K+] is instrumental in keeping accumulation of K+ in this compartment below the 10-12 mM at which occurs a substantial depolarization of the resting membrane potential and decreased amplitude of the action potential.

Cessation of exercise results in a rapid decrease in plasma [K+], particularly in venous blood draining recovering skeletal muscle where Na+,K+ pump activity is high. This serves to rapidly restore [K+]i in muscle recovering from contraction, but may reduce plasma [K+] to values significantly lower than before exercise. In extreme cases arterial plasma [K+] may fall below 3 mM, possibly resulting in membrane hyperpolarization and cell hyperexcitability.

If the contraction intensity is sufficient to decrease intracellular ATP concentrations to below 1 mM in the region of the sarcolemma, an opening of the ATP-dependent K+ channels will contribute to the K+ release and the decrease in [K+]i. While a role for the ATP-dependent K+ channels has yet to be demonstrated in contracting skeletal muscle, such a decrease in intracellular ATP does occur with prolonged ischemia or anoxia. Under these conditions it is conceivable that local depletions of ATP in the region of the plasma membrane would contribute to an increase in the open time of ATP-dependent K+ channels, resulting in a pronounced K+ release and membrane depolarization.

Moderate and Low Intensity Contractions

The onset of less intense, dynamic exercise produces results similar to high intensity contraction but of lower magnitude (Fig. 1). Also, instead of the progressive increase in plasma [K+] seen over time at higher intensities, increasing duration at lower intensity is characterized by a leveling off or a decrease in plasma [K+].

A maintained high plasma [K+] during moderately intense exercise is due to a balance between net release by contracting muscle and uptake throughout the body. Here, the increase in plasma [K+] from rest is a reflection of the initial imbalance between net rates of release and uptake. During low intensity exercise, the decline in plasma [K+] seen after the initial increase is explained by the whole body uptake rate exceeding the net rate of K+ release by contracting muscles.

Muscle K+ Release Versus Uptake

Two questions may be asked at this point. The first is why can contracting muscle fibers not transport K+ back into the cells fast enough with the Na+,K+ pump to prevent the net loss of K+ at the onset of exercise and during high intensity exercise? The second is, since other tissues also have Na+,K+ pumps, why do they not take up K+ from blood at a rate sufficient to keep plasma [K+] at pre-exercise levels? Prior to responding to these questions a brief review of the main events associated with K+ release and uptake in contracting skeletal muscle may be helpful.

Skeletal muscle contracts in response to neural discharge of acetylcholine from motoneurons at the neuromuscular junction. Acetylcholine binds to its receptors, and the transduction of this signal results in an opening of Na+ channels which are in high density in the region of the neuromuscular junction. The rapid influx of Na+ depolarizes the sarcolemma and produces an action potential which is propagated as a fast, moving wave of depolarization over the sarcolemma and extending into the transverse tubular system. Voltage changes associated with the action potential initiates the release of Ca2+ from the sarcoplasmic reticulum into the cytoplasm. Increased cytoplasmic [Ca2+] activates the interactions between contractile filaments (troponin, actin, myosin) responsible for producing force.

Following depolarization, the sarcolemma must be repolarized in order to allow for subsequent action potentials and contractions. Potassium is involved in the repolarization of the membrane potential. The opening of outwardly directed, delayed rectifier K+ channels in response to the depolarizing Na+ influx, and of Ca2+-activated K+ channels in response to increased cytoplasmic [Ca2+], allows for a rapid movement of K+ from the cells into the interstitial fluids. As the membrane repolarizes, the K+ channels close. Restoration of [Na+]i, [K+]i and interstitial [K+] occurs by the activity of the Na+,K+ pump which is stimulated to operate at elevated rates under conditions of high [Na+]i, high interstitial [K+] and low [K+]i. The Na+,K+ pump transports 2 K+ into the cell for 3 Na+ transported out. This serves to rapidly restore transmembrane K+ equilibrium and membrane potential when the contraction period is brief and of low intensity.

The net rate of K+ release by muscle is a function of the number of action potentials per unit time (stimulus intensity) and the rate of muscle K+ uptake by the Na+,K+ pump. High intensity muscle contraction and low Na+,K+ pump rate results in a release of K+ greater than the uptake rate, producing a decrease in [K+]i and increases in interstitial and plasma [K+] (Fig. 1).

However the activity of the Na+,K+ pump can be increased several fold by extracellular regulators such as epinephrine and norepinephrine, in addition to the contraction induced increases in [Na+]i and interstitial [K+] and decreases in [K+]i. Muscle contraction alone results in a direct, near maximal stimulation of Na+,K+ pump activity which does not appear to be further increased by increased plasma epinephrine and norepinephrine. Therefore in contracting muscle the contraction-induced changes in intracellular and interstitial [Na+] and [K+] appear to be the primary mechanism responsible for maximally activating Na+,K+ pump activity. However, in noncontracting tissues increases in plasma catecholamines have a profound effect on reducing plasma [K+] through stimulation of Na+,K+ pump activity in these tissues.

In response to the first question, in resting muscle (prior to contraction) the Na+,K+ pump activity is low. Also, the experimental evidence indicates that maximal in vivo activation of the Na+,K+ pump may require several minutes after the initiation of contraction. At the onset of exercise muscle K+ release therefore exceeds K+ uptake. But in time, muscle [Na+]i and interstitial [K+] rise to levels which may be sufficient to achieve maximal Na+,K+ pump activity. At low to moderate exercise intensities K+ uptake may match or exceed K+ release, however at high intensities K+ uptake cannot match K+ release.

In response to the second question, there is an initial delay in the increase in Na+,K+ pump activity in noncontracting tissues as plasma [K+] increases. With time, plasma catecholamines increase and may stimulate Na+,K+ pump activity in these tissues. As with plasma [K+], the rise in plasma catecholamines with exercise is proportional to exercise intensity. The experimental evidence suggests that at both low and high exercise intensities either the time delay in these increases and/or the absolute increase in plasma catecholamines is insufficient to stimulate an Na+,K+ pump rate in noncontracting tissues which will regulate plasma [K+] at pre-exercise levels. There may be an important reason for this. For example, regulation of plasma [K+] at resting levels (about 4 mM) by noncontracting tissues may be very beneficial to contracting muscle during the period of exercise by maintaining a rapid rate of removal of interstitial K+ thereby preventing its accumulation in the interstitium of contracting muscle. However, given the very high Na+,K+ pump rate in contracting and recovering skeletal muscle, the cessation of exercise would be associated with a marked decrease in plasma [K+]. Studies of moderately intense exercise typically show increases in arterial plasma [K+] of about 2 mM, raising plasma [K+] from about 3.7 to about 5.7 mM (6). Cessation of exercise produces a decrease in plasma [K+] to below resting (3.7 mM) which persists for several minutes of recovery. Therefore, if plasma [K+] were regulated at about 4 mM during moderately intense or high intensity exercise, it would be expected that plasma [K+] would fall to about 2 mM or lower, values which are incompatible with normal cardiac and skeletal muscle function. The increase in plasma [K+] during exercise is therefore justified because it allows a rapid rate of K+ uptake by recovering skeletal muscle while preventing catastrophic decreases in plasma [K+] upon cessation of exercise. The high blood flows through contracting and recovering skeletal muscle also prevents plasma [K+] from falling too low.

Potassium regulation during isometric contractions has received renewed research interest in the past few years and will be briefly considered. Isometric contractions greater than about 60% of the maximal voluntary contraction results in little or no blood flow to or from the muscle and therefore the K+ released from the cells remains in the interstitial fluids adjacent to the sarcolemma. While contributing to membrane depolarization, the accumulation of interstitial K+ may be advantageous for muscle recovery by providing a large and readily available pool of K+ for the Na+,K+ pump. Also, Na+,K+ pump activity is expected to be increased during the period of contraction due to net movement of Na+ into cells raising [Na+]i and an elevated interstitial [K+]. When contraction ceases, considerable K+ may pumped back into the cell through a highly activated Na,K+ pump, while some diffuses rapidly into venous blood and increases local venous plasma [K+] (Fig. 3).

Role of RBCs in K+ Transport

Recent experiments performed on humans bicycling at high intensity showed that the majority of K+ released to and transported by the blood is found within the RBCs (6,7). The general sequence of events involved in K+ transport during exercise and recovery is depicted in Fig. 3. Contracting skeletal muscle releases K+ into the interstitial fluids and K+ diffuses into the lymphatics and venous plasma. The rapid increases in plasma [K+] and [lactate], and decreases in plasma volume due to water movement into contracting muscle, raises plasma osmolality and alters the K+ equilibrium across the RBC plasma membrane. This results in the net movement of K+ (and lactate) into RBCs. It is likely that this K+ uptake is stimulated by increases in plasma catecholamines. At uptake sites elsewhere in the body, such as noncontracting skeletal muscle, K+ diffuses from plasma into the interstitial fluids and is transported into the cells. This establishes a gradient for the net release of K+ from RBCs into the plasma. Therefore in the venous circulation draining noncontracting tissues both the RBC and plasma [K+] are lower than in the arterial circulation. After cessation of exercise there is presumed to be a slow net release of K+ from noncontracting tissues back into the circulation and recovering skeletal muscle as whole body K+ homeostasis is approached.