Potassium Reuptake Research Articles

SYNAPTIC MECHANISMS OF EPILEPSY: CONTEMPORARY VIEW

The purpose of the paper is to analyze possible mechanisms of ictal activity at the synaptic level in epilepsy. Materials and Methods. The search for literature sources was carried out in Pubmed, CyberLeninka, and Google Scholar. Results. The diversity of pathophysiological mechanisms of epilepsy makes it difficult to treat approximately one third of patients, whose ictal activity is not suppressed by traditional pharmacological agents. The increased glutamate effect may be a consequence of its increased concentration in the intercellular space due to impaired reuptake caused by dysfunction of the EAATs transporters. Excitatory influences can also be enhanced by reduced connexin 43 (Cx43) expression in the synaptic cleft and downregulation of Kir4.1 inward rectifying potassium channel, which increases the extracellular concentration of K+ and glutamate causing neuron hyperexcitability. Disturbances in neuronal, glial or neuronal-glial interactions have a similar effect. This is caused by malfunctioning of ionotropic or metabotropic receptors due to abnormal expression of astrocytic glutamate transporters and/or malfunction of neuronal or astrocytic enzymes. One of the proteins involved in epileptogenesis is aquaporin (AQP4). Altered AQP4 expression potentially affects potassium reuptake by Kir 4.1 and glutamate reuptake and reduces glutamate transporter EAAT2 expression. AQP4 can also interact with glutamate receptor mGluR5. Decreased GABAergic signaling may result from decreased numbers of GABAergic neurons in glial diseases and tumors. Besides, due to a decrease in plasmalemmal expression of the chloride cotransporter KCC2 and an increase in the expression of NKCC1 (Na-K-2Cl cotransporter), the intracellular concentration of CI– ions increases. As a result, GABA performs a depolarizing, excitatory role. Conclusion. The pathophysiological mechanisms of epilepsy may become a target in the development of new drugs with anticonvulsant effects.

The renal channelopathies

Specific channels permit movement of selected ions through cellular membranes, and are of vital importance in a number of physiological processes, particularly in excitable tissues such as nerve and muscle, but also in endocrine organs and in epithelial biology. Disorders of channel proteins are termed channelopathies, and their importance is increasingly recognised within medicine. In the kidney, ion channels have critical roles enabling sodium and potassium reuptake or excretion along the nephron, in magnesium homeostasis, in the control of water reabsorption in the collecting duct, and in determining glomerular permeability. In this review, we assess the channelopathies encountered in each nephron segment, and see how their molecular and genetic characterisation in the past 20-30 years has furthered our understanding of normal kidney physiology and disease processes, aids correct diagnosis and promises future therapeutic opportunities.

Effects of high-intensity intermittent training on potassium kinetics and performance in human skeletal muscle.

A rise in extracellular potassium concentration in human skeletal muscle may play an important role in development of fatigue during intense exercise. The aim of the present study was to examine the effect of intense intermittent training on muscle interstitial potassium kinetics and its relationship to the density of Na(+),K(+)-ATPase subunits and K(ATP) channels, as well as exercise performance, in human skeletal muscle. Six male subjects performed intense one-legged knee-extensor training for 7 weeks. On separate days the trained leg (TL) and the control leg (CL) performed a 30 min exercise period of 30 W and an incremental test to exhaustion. At frequent intervals during the exercise periods interstitial potassium ([K(+)](I)) was determined by microdialysis, femoral arterial and venous blood samples were drawn and thigh blood flow was measured. Time to fatigue for TL was 28% longer (P < 0.05) than for CL (10.6 +/- 0.7 (mean +/-s.e.m.) versus 8.2 +/- 0.7 min). The amounts of Na(+),K(+)-ATPase alpha(1) and alpha(2) subunits were, respectively, 29.0 +/- 8.4 and 15.1 +/- 2.7% higher (P < 0.05) in TL than in CL, while the amounts of beta(1) subunits and ATP-dependent K(+) (K(ATP)) channels were the same. In CL [K(+)](I) increased more rapidly and was higher (P < 0.05) throughout the 30 W exercise bout, as well at 60 and 70 W, compared to TL, whereas [K(+)](I) was similar at the point of fatigue (9.9 +/- 0.7 and 9.1 +/- 0.5 mmol l(-1), respectively). During the 30 W exercise bouts and at 70 W during the incremental exercise femoral venous potassium concentration ([K(+)](v)) was higher (P < 0.05) in CL than in TL, but identical at exhaustion (6.2 +/- 0.2 mmol l(-1)). Release of potassium to the blood was not different in the two legs. The present data demonstrated that intense intermittent training reduce accumulation of potassium in human skeletal muscle interstitium during exercise, probably through a larger re-uptake of potassium due to greater activity of the muscle Na(+),K(+)-ATPase pumps. The lower accumulation of potassium in muscle interstitium in the trained leg was associated with delayed fatigue during intense exercise, supporting the hypothesis that interstitial potassium accumulation is involved in the development of fatigue.

A maize defense-inducible gene is a major facilitator superfamily member related to bacterial multidrug resistance efflux antiporters.

A defense-inducible maize gene was discovered through global mRNA profiling analysis. Its mRNA expression is induced by pathogens and defense-related conditions in various tissues involving both resistant and susceptible interactions. These include Cochliobolus heterostrophus and Cochliobolus carbonum infection, ultraviolet light treatment, the Les9 disease lesion mimic background, and plant tissues engineered to express flavonoids or the avirulence gene avrRxv. The gene was named Zm-mfs1 after it was found to encode a protein related to the major facilitator superfamily (MFS) of intregral membrane permeases. It is most closely related to the bacterial multidrug efflux protein family, typified by the Escherichia coli TetA, which are proton motive force antiporters that export antimicrobial drugs and other compounds, but which can be also involved in potassium export/proton import or potassium re-uptake. Other related plant gene sequences in maize, rice, and Arabidopsis were identified, three of which are introduced here. Among this new plant MFS subfamily, the characteristic MFS motif in cytoplasmic TM2-TM3 loop, and the antiporter family motif in transmembrane domain TM5 are both conserved, however the TM7 and the cytoplasmic TM8-TM9 loop are divergent from those of the bacterial multidrug transporters. We hypothesize that Zm-Mfs1 is a prototype of a new class of plant defense-related proteins that could be involved in either of three nonexclusive roles: (1) export of antimicrobial compounds produced by plant pathogens; (2) export of plant-generated antimicrobial compounds; and (3) potassium export and/or re-uptake, as can occur in plant defense reactions.

Spreading depression in focal ischemia: a computational study.

When a cerebral infarction occurs, surrounding the core of dying tissue there usually is an ischemic penumbra of nonfunctional but still viable tissue. One current but controversial hypothesis is that this penumbra tissue often eventually dies because of the metabolic stress imposed by multiple cortical spreading depression (CSD) waves, that is, by ischemic depolarizations. We describe here a computational model of CSD developed to study the implications of this hypothesis. After simulated infarction, the model displays the linear relation between final infarct size and the number of CSD waves traversing the penumbra that has been reported experimentally, although damage with each individual wave progresses nonlinearly with time. It successfully reproduces the experimental dependency of final infarct size on midpenumbra cerebral blood flow and potassium reuptake rates, and predicts a critical penumbra blood flow rate beyond which damage does not occur. The model reproduces the dependency of CSD wave propagation on N-methyl-D-aspartate activation. It also makes testable predictions about the number, velocity, and duration of ischemic CSD waves and predicts a positive correlation between the duration of elevated potassium in the infarct core and the number of CSD waves. These findings support the hypothesis that CSD waves play an important causal role in the death of ischemic penumbra tissue.

Reduced levels of skeletal muscle Na+K+ -ATPase in McArdle disease.

We evaluated the hypothesis that impaired sarcolemmal function associated with exaggerated potassium release, impaired potassium uptake, or both may contribute to exertional fatigue and abnormal circulatory responses to exercise in McArdle disease (MD). The cellular mechanism of exertional fatigue and muscle injury in MD is unknown but likely involves impaired function of the ATPases that couple ATP hydrolysis to cellular work, including the muscle sodium potassium pump (Na+K+-ATPase). However, the concentration of muscle Na+K+ pumps in MD is not known, and no studies have related exercise increases in blood potassium concentrations to muscle Na+K+ pump levels. We measured muscle Na+K+ pumps (3H-ouabain binding) and plasma K+ in response to 20 minutes of cycle exercise in six patients with MD and in six sex-, age-, and weight-matched sedentary individuals. MD patients had lower levels of 3H-ouabain binding (231 +/- 18 pmol/g w.w., mean +/- SD, range, 210 to 251) than control subjects (317 +/- 37, range, 266 to 371, p < 0.0004), higher peak increases in plasma potassium in response to 45 +/- 7 W cycle exercise (MD, 1.00 +/- 0.15 mmol/L; control subjects, 0.48 +/- 0.09; p < 0.0001), and mean exercise heart rate responses to exercise that were 45 +/- 12 bpm greater than control subjects. Our results indicate that Na+K+ pump levels are low in MD patients compared with healthy subjects and identify a limitation of potassium reuptake that could result in sarcolemmal failure during peak rates of membrane activation and may promote exaggerated potassium-activated circulatory responses to submaximal exercise. The mechanism of the low Na+K+ pump concentrations in MD is unknown but may relate to deconditioning or to disruption of a close functional relationship between membrane ion transport and glycolysis.

Effect of Aging on Changes in Plasma Potassium During Exercise

Exercising skeletal muscle releases large amounts of potassium into plasma. beta-adrenergic receptors enhance reuptake of potassium into muscle. Since beta-adrenergic responses decline with aging in many tissues, the elderly might be predisposed to hyperkalemia during exercise. Venous plasma potassium (K+) was measured during graded bicycle exercise (30 W initial workload with 3-minute 30 W increments) in 18 healthy young men (24.0 +/- 2.9 yrs; mean +/- SD), 18 healthy untrained elderly men (70.0 +/- 3.6 yrs), and 7 elderly master athletes (70.0 +/- 4.6 yrs). Subjects exercised to exhaustion. Exercise times and maximal oxygen uptake were: young (N = 14; 19.6 +/- 4.4 min, 42.1 +/- 3.8 ml/kg/min), elderly (N = 13; 11.7 +/- 1.9 min, 26.6 +/- 8.0 ml/kg/min), elderly master athletes (N = 6; 16.8 +/- 2.4 min, 40.2 +/- 10.2 ml/kg/min). The rate of increase in K+ was greater in both elderly (89 +/- 59 mumol/l/min) and elderly master athletes (88 +/- 26) compared with healthy young men (60 +/- 30), p < .05. Despite this greater rate of increase, the elderly group did not achieve higher maximal K+ concentrations than the young because of the much shorter duration of exercise in the elderly group. For subjects performing a maximal exercise test, the maximal increase in K+ was similar in the elderly (1.15 +/- 0.91), but significantly greater in elderly master athletes (1.70 +/- 0.31), compared with healthy young men (1.31 +/- 0.45). Changes in K+ during short-lasting exercise are similar in untrained healthy elderly men compared with healthy young men, but elderly master athletes have greater changes in K+ during exercise. The greater rate of increase in potassium in healthy and athletic subjects supports the hypothesis of an age-related impairment of the beta 2-adrenergic process that mediates potassium flux into skeletal muscle.

Plasma potassium and lactate concentrations in thoroughbred horses during exercise of varying intensity.

To investigate the effect of moderate to high intensity exercise of up to 6 min duration on plasma potassium and lactate concentrations, 6 Thoroughbred horses were studied using a treadmill at a 5 degree incline. Each test consisted of an 8-min standardised warm-up followed by an exercise bout at 8, 9, 10 or 12 m/sec. The horses were galloped at each speed for up to a maximum of 6 min or until signs of fatigue were present. The horses were then walked at 0 degree incline. Carotid arterial blood samples were taken during and after the exercise. At 8, 9 and 10 m/sec there was a general pattern of an initial rise in potassium to a peak around 1.5 min of exercise with the concentration then slowly decreasing. At 12 m/sec there was a continuous rise to a peak at the end of exercise in all horses. Immediately after exercise there was a rapid return (within 3-4 min) to the potassium concentrations recorded at the end of the warm-up period. Plasma lactate peaked around the end of exercise at all speeds. At the highest intensity of exercise the mechanisms for the re-uptake of potassium did not appear to be able to match the rate of efflux. In contrast, at less intense work loads, the rate of re-uptake appeared to be similar to or slightly greater than the rate of efflux. It is possible that a disturbance in this balance between efflux and re-uptake could result in a disturbance in normal neuromuscular function during exercise.

Volume Regulation in Liver: Further Characterization by Inhibitors and Ionic Substitutions

The present study has been performed to elucidate the mechanisms of volume regulation in isolated perfused liver. Reduction of extracellular osmolarity by 80 mOsm/L leads to a release of potassium and a sustained alkalinization of effluent. Reexposure to isotonic perfusate leads to reuptake of potassium by the liver and acidification of effluent. Part of the alkalinization could be due to release of bicarbonate parallel to potassium release. Carboanhydrase inhibition and replacement of bicarbonate/CO2 by HEPES buffer, however, do not significantly modify volume regulatory potassium release or reuptake. Reduction of perfusate chloride to 37 mmol/L by replacement of NaCl with raffinose leads to a decrease of liver weight indicative of shrinkage of liver cells. Subsequent omission of 180 mmol/L raffinose leads to potassium and chloride release and to alkalinization of effluent. Volume regulatory release of potassium is impaired in 1 mmol/L quinidine, 1 mmol/L SITS and 5 mmol/L barium. Volume regulatory reuptake of potassium is impaired by 1 mmol/L amiloride. Volume regulatory release of potassium is not appreciably affected by either; 1 mmol/L furosemide, 1 mumol/L verapamil, 1 mmol/L amiloride or 1 mmol/L barium and volume regulatory potassium reuptake proved insensitive to 1 mmol/L furosemide or 1 mmol/L barium. The data suggest that the cells release potassium and chloride during regulatory volume decrease by quinidine, SITS and weakly barium-sensitive transport systems and that regulatory volume increase is accomplished by activation of Na/H exchange.

Effects of hemodynamic variables on myocardial K + balance during and after shortlasting ischemia

Ischemia-induced myocardial potassium loss and post-ischemic potassium reuptake was quantitated in 8 open chest pigs during control conditions and during hemodynamic alterations which have been shown to increase steady state sarcolemmal potassium fluxes. Myocardial K + balance was continuously computed before, during and after a 90 s occlusion of a branch of the circumflex artery during control (CTR), during pacing tachycardia (PACE: 34% increase in heart rate), during proximal aortic constriction (AC; 28% increase in LVSP), and during isoprenaline infusion (ISO; 135% increase in LVdP dt and 35% increase in heart rate). Ischemia-induced potassium loss increased significantly (40%) during ISO only. Higher basal metabolic rate, increased sarcolemmal K + conductance, or ischemia-induced depression of a more active Na K -pump during ISO are possible explanations to why increased K + loss appeared in this situation. The maximal rate of post-ischemic potassium reuptake was not different from CTR during PACE and ISO, but it was reduced during AC, which might be due to persisting subendocardial ischemia in early reperfusion when ventricular wall stress is high. The extent of potassium restoration was not different from CTR during AC, PACE and ISO.

Calcium-activated potassium channels from rat parotid acinar cells.

Introduction Rat parotid acinar cells possess a calcium-activated potassium channel located at the bast-lateral plasma membrane. This channel is sensitive to voltage and is opened by calcium concentrations in the micromolar range. The stimulation of parotid cells by muscarinic agents or substance P or alpha-adrenergic agents increases the intracellular concentration of calcium to such levels. In response to these three classes of agonist, a massive efflux of potassium from the cells is obesrved. This is the starting point for secondary potassium reuptake by a Na+/K+/Cl'cotransport system and by the Na-K ATPase. The result of these ionic movements is a net uptake of chloride at the basal pole of the cell. This anion leaves the cell by a calcium-sensitive channel located at the apical pole of the cell. These negative charges in the lumen of the gland are responsible for the efflux of a counteraction, mostly sodium, and for the efflux of water. This explains why the saliva in response to parasympathetic stimulation is copious and very dilute (Petersen 1986). The potassium channels of parotid cells have been thoroughly studied by electrophysiologists but from a biochemical and pharmacological point of view, little is known about these channels. The purpose of this work was to test the sensitivity of these channels to various agonists and antagonists.

Insulin and the resting potential of hypoxic substrate-deprived myocardium.

Insulin stimulates ionic transport by the sodium pump and induces hyperpolarization in skeletal and cardiac muscle among other cells. The insulin-induced hyperpolarization in most cases can be inhibited by exposure to cardiac glycosides or metabolic inhibition. However, extracellular accumulation of K ions leaking from hypoxic cells in superfused preparations may distort the effects of insulin on the resting potential. We used standard microelectrode techniques and perfused rabbit hearts submitted to hypoxia and substrate deprivation to reinvestigate the effects of insulin (6.4 nM) on the membrane potential. The membrane depolarized by about 6 mV and the action potential was reduced to a sharp spike without overshoot. Insulin restored the resting potential to control values but did not change the action potential configuration substantially. The insulin-induced repolarization was not due to reuptake of potassium as revealed by spectrophotometric determinations of myocardial K content. In addition, the diffusion component of the resting potential measured after inhibition of the sodium pump with 10(-4) M ouabain was not modified by insulin. Our results suggest that an increase in the contribution of electrogenic Na extrusion to the resting potential underlies the repolarizing effect of insulin of hypoxic substrate-deprived myocardium.

Lack of influence of beta adrenergic blockade on serum potassium during an infusion of potassium.

The extent to which the serum potassium rose in a group of six healthy volunteers during an intra-venous infusion of potassium was identical following pretreatment with placebo, low or high dose propranolol and low or high dose metoprolol. Thus in this acute study, we were unable to demonstrate any influence of either selective or non-selective beta adrenergic blockade upon potassium uptake mechanisms. This is in contrast to the effects of beta blockers on potassium reuptake rates noted after exercise and during cardiac surgery.

Potassium reaccumulation by isolated frog epidermis

The involvement of potassium in transepithelial sodium transport was tested by studying net potassium reuptake by potassium-depleted frog skin epidermis. Normal potassium content in half-strength Ringer's (0.244 μequiv/mg dry weight) fell 43% after 16 h in K-free medium at 5°C. Reaccumulation, against an electrochemical potential gradient, to 83% of the initial tissue potassium content occurred following incubation for 4 h at 22°C in K-containing medium. Sodium was required in the solution bathing the inside, but not the outside surface of the skin, for net potassium reaccumulation. Ouabain caused an additional potassium loss from potassium-depleted epidermis, but did not have the same effect on potassium-depleted isolatedcells. Procaine, lithium and caffeine completely inhibited, antidiuretic hormone and cyclic AMP may partially inhibit and amiloride had no effect on potassium reaccumulation. In many cases decreases in sodium and water content were found to occur even in the absence of net potassium reaccumulation. The results suggest (1) potassium is actively transported into the epidermis, (2) this transport is not rigidly coupled to sodium extrusion or water loss, (3) potassium uptake is not rigidly coupled to transepithelial sodium transport, or only a small fraction is involved, (4) potassium diffusion is restricted in the extracellular space.

Two phases of chorda-lingual induced vasodilatation in the cat's submandibular gland during prolonged perfusion with Locke solution.

The effect of stimulation of the chorda-lingual nerve on the venous flow has been studied in cat submandibular glands perfused with Locke solution for 2-4 hr. When trains of pulses at 25 Hz were given for 1-5 sec, two distinct phases of vasodilatation were observed: a rapid initial phase of high amplitude and a slower developing more prolonged phase of smaller amplitude. Repeated stimulations did not lead to a reduction of the vasodilatory response. A close relationship was found between the duration and magnitude of the second phase of vasodilatation and the duration and magnitude of the post-stimulatory, active reuptake of potassium. When the active reuptake of potassium was prevented either by ouabain (which inhibits active transport) or by atropine (which abolishes the stimulation induced loss of potassium) the second phase of vasodilatation was severely reduced, while the initial phase remained virtually normal. It is concluded that the initial phase of vasodilatation probably is mediated by vasodilator nerve fibres. The second phase is perhaps causally related to the post-stimulatory, active transport of cations. An involvement of bradykinin formation is highly unlikely under the given experimental conditions.

Undershoots following stimulus-induced rises of extracellular potassium concentration in cerebral cortex of cat

Extracellular potassium activity (a K) was recorded with potassium-sensitive electrodes in the sensorimotor cortex of cats. Resting activity was 2.8–3.4 mEquiv./l. Electrical stimulation of the cortical surface and the nucleus ventroposterolateralis of the thalamus brough about an increase in a K followed by an undershoot and return to normal value. The lowest observed value of a K was 2.1 mEquiv./l. Size and duration (range 0.5–4 min) of the undershoots of a K increased with increasing peak amplitudes of the preceding rise in a K. Following the rise in a K, a period reduced neuronal activity was observed which was usually shorter lasting than the decrease in extracellular a K. An undershoot of a K and a concomitant reduction of neuronal discharge frequency can also occur in immediate response to antidromic stimulation of the pyramidal tract. To compare the K + redistribution at normal and reduced levels of a K electrophoretic K + signals were produced with constant current pulses from a proximate KCl-filled capillary. Both amplitudes and half times of decay of these K + signals were found to decrease during the phase of poststimulatory undershoot in a K (19 and 23% respectively). It is suggested that an activated reuptake of potassium contributes to the decrease in extracellular a K in addition to inhibitory processes.

NADH fluorescence and [K+]o changes during hippocampal electrical stimulation

1. Short (2 s) trains of stimuli were applied to the dorsal hippocampal surface of cats, producing an increase in [K+]o and a decrease in NADH fluorescence (the latter being indicative of an increase in tissue oxygen utilization). 2. The [K+]o rose rapidly during stimulation (delta[K+]o values from 1 to 6 mM) with larger stimulus currents producing larger changes. The time course of the poststimulus decline of [K+]o was an exponential decay function, with T 1/2 values varying from 1.3 to 6.9s, and independent of the magnitude of the delta[K+]o. Consistent undershoots of [K+]o occurred following stimuli causing less than 1 mM change in [K+]o. 3. The maximum depression of fluorescence and the time integral of the fluorescence changes following each stimulus train were both highly correlated with the total increase of [K+]o occurring during the stimulus train. 4. Application of several stimulus trains in close succession resulted in more rapid potassium reuptake following the later trains and an unusually large undershoot after the last train. Concomitantly, there was a progressive decrease in the fluorescence level. 5. When afterdischarges were induced by prolonged (less than 2 s) stimulation, larger and more sustained increases in [K+]o and decreases of fluorescence were observed, and there was some indication that afterdischarges were followed by accelerated reuptake of extracellular potassium.

Prevention of phaloidin poisoning in vitro by 4,7-phenanthroline

1. In the presence of 4,7-phenanthroline (30 mg/80 ml), phalloidin has no effect on the potassium content or the weight of the isolated rat liver. 2. Application of 4,7-phenanthroline to the poisoned liver, which has lost most of its potassium, causes a re-uptake of 83±9% of the released potassium. 3. When the perfusion medium was exchanged after the phenanthroline induced potassium re-uptake, the greater part of this amount of potassium is released again. A second application of 4,7-phenanthroline causes a complete re-uptake of the potassium. 4. Dipyridamol and hexobendin show similar effects on the phalloidin poisoned liver as 4,7-phenanthroline.