Intracellular Sodium Concentration Research Articles

The mechanism of ranolazine action to reduce ischemia-induced diastolic dysfunction

Ischaemia of myocardium is associated with increases in the late sodium current (INa), intracellular sodium and calcium concentrations, calcium overload, and impairment of contractile relaxation (i.e. increased diastolic wall tension). An increase in diastolic wall tension compresses the vasculature and reduces nutritive blood flow, creating a positive feedback system that further impairs myocardial oxygenation and contractile function. Ranolazine reduces the late INa and, is expected to decrease sodium entry into ischaemic myocardial cells. As a consequence, ranolazine is proposed to reduce calcium uptake indirectly via the sodium/calcium exchanger and to preserve ionic homeostasis and reverse ischaemia-induced contractile dysfunction.

The Activity of Erythrocyte Sodium-Proton Exchanger in Women with Pregnancy- Induced Hypertension

Background: Hypertension that develops after 20 gestational weeks and is defined as pregnancy-induced hypertension (PIH). The main cause of PIH is vasoconstriction and the thickening of vascular media, which decreases vascular capacity and increases peripheral resistance. One of the theories postulated to explain this phenomenon is that a transmembrane sodium transport disorder causes an increase in intracellular sodium concentration. In the latest literature, special attention is paid to the role of the increased intracellular sodium concentration in the pathogenesis of essential hypertension (EH). One of the best documented phenotypes for EH is the increased activity of the sodium-proton exchanger (NHE). The aim of this study was to assess if increased NHE activity could be the mechanism responsible for the development of PIH. Subjects and methods: The study included 30 women: 10 pregnant women with PIH after gestational week 30, 10 women with physiological pregnancy after 30 gestational weeks, and 10 healthy non-pregnant women. NHE activity was determined according to Orlov’s method as amiloride-sensitive H+ efflux from acid-loaded cells. Results: The NHE activity in the group of women with PIH was significantly higher than that in women with physiological pregnancy: 10.09 ± 1.65 vs. 6.81 ± 2.3 mmol/L RBC/h (p < 0.049) and in the group of non-pregnant women: 10.09 ± 1.65 vs. 7.56 ± 1.66 mmol/L RBC/h (p < 0.029). Erythrocyte NHE activity did not differ in the group of women with physiological pregnancy and in the group of non-pregnant women. Conclusion: These results seem to suggest that erythrocyte NHE activity is elevated in PIH pregnancies.

A DIFFERENTIAL MODEL OF CONTROLLED CARDIAC PACEMAKER CELL

A differential model of a cardiac pacemaker cell with only ten state variables is proposed. It is intended for 0D or 3D simulation of the heart under the vagal control of the autonomous nervous system. Three variables are used to describe the membrane (membrane potential and two gate variables of ionic channels), taking into account the dynamics of the main ionic currents (inward sodium, L-type calcium and outward potassium), Na+/Ca2+ exchangers and Na+/K+ pumps. The remaining seven variables are associated with the fluid compartment model that includes Ca2+ binding by myoplasmic proteins, and the intracellular concentrations of free Calcium, Sodium and Potassium. Despite its moderate number of state variables, this model includes the main processes thought to be important in pacemaking on the cell scale and predicts the experimentally observed ionic concentration of calcium, sodium and potassium, action potential and membrane currents. The control by the calcium of the pacemaking activity is also considered.

Stomatocytosis of Standard Schnauzers is not associated with stomatin deficiency

Stomatocytosis resembles human overhydrated hereditary stomatocytosis (OHSt), a disease characterised by a reduced or absent stomatin expression. The objective of this report was to investigate the expression level of stomatin in erythrocytes from Standard Schnauzers with stomatocytosis. Routine haematology, intraerythrocytic Na +/K + concentration and stomatin expression were evaluated in blood from twelve Standard Schnauzers and from three controls. SDS–PAGE and Western blotting on isolated integral membrane proteins were used to investigate stomatin expression. Circulating stomatocytes, macrocytosis, anisocytosis, increased erythrocyte fragility and high intracellular sodium and potassium concentrations were found in 10/12 dogs from the same breeding line although stomatin levels were similar to those of controls. In spite of the clinico-pathological similarities between human and canine stomatocytosis, erythrocytes from affected dogs do not lack stomatin and the expression level of this protein cannot therefore be used to diagnose hereditary stomatocytosis in Standard Schnauzers.

Glial Intercellular Waves

Glial cells have long been assigned a supporting role in the nervous system, in which they help maintain and modulate neuronal metabolism. However, recent attention has focused on the ability of astrocytes to propagate long-range calcium signals and actively communicate with each other, as well as with neurons and vascular cells. Synaptic activity in neurons triggers an increase in the intracellular calcium concentration ([Ca2+]i) of neighboring astrocytes, stimulating the release of ATP and glutamate. The released ATP stimulates an increase in [Ca2+]i in neighboring astrocytes so that a "calcium wave" is propagated from cell to cell. Released glutamate is cotransported with Na+ into neighboring cells; thus, glutamate uptake leads to an increase in astrocyte intracellular sodium concentration ([Na+]i) that is also propagated from cell to cell. This increase in [Na+]i stimulates an increase in glucose uptake and metabolism that leads to the formation of lactate, which is delivered to nearby--and perhaps distant--neurons as an energy substrate. Thus, long-range intercellular calcium signaling in astrocytes may enable them to spatially coordinate their function in supporting neuronal metabolism.

Hyperforin activates nonselective cation channels (NSCCs)

A large body of evidence supports the preclinical antidepressant profile of hyperforin including inhibition of the synaptosomal uptake of several neurotransmitters by hyperforin and studies in behavioural models. In contrast to other antidepressants, hyperforin does not directly inhibit neurotransmitter transporters, but instead uptake inhibition seems to be the consequence of an elevated intracellular sodium concentration ([Na+]i). The mechanism of hyperforin-induced elevation of [Na+]i was investigated using two different cell types: human platelets and rat pheochromocytoma cells (PC12 cells). In both cell systems, hyperforin increased both [Na+]i and free intracellular Ca2+ concentration ([Ca2+]i). One pathway for Na+ and Ca2+ entry is mediated by nonselective cation channels (NSCCs), which can be blocked by SK&F 96365 and LOE 908. LOE 908 is a blocker of both NSCC1 and NSCC2 subclasses, while SK&F 96365 blocks NSCC2 only. Both SK&F 96365 and LOE 908 completely inhibited the hyperforin-induced influx of Na+ and Ca2+ into platelets and PC12 cells. This indicates that hyperforin is mainly active upon NSCC2. The effect of hyperforin is inhibited by La3+ and Gd3+, indicating that there is a potential homology with canonical transient receptor potential protein channels (TRPC channels). Moreover, La3+ and Gd3+ attenuate the effect of hyperforin on serotonin uptake in human platelets. Additionally, hyperforin induces barium influx in PC12 cells and this influx can be inhibited by SK&F 96365, LOE 908, Gd3+ and La3+. In summary, these findings suggest that hyperforin represents a new principle for preclinical antidepressant activity, modulating brain neurotransmission by inhibition of neurotransmitter uptake via activation of NSCCs.British Journal of Pharmacology (2005) 145, 75-83. doi:10.1038/sj.bjp.0706155.

Changes in intracellular sodium, chlorine, and potassium concentrations in staurosporine‐induced apoptosis

Ion gradients across the plasma membrane, fundamentally K(+), play a pivotal role in the execution phase of apoptosis. However, little is known about other monovalent anions (Cl(-)) or cations (Na(+)) in apoptosis. In addition, the relationship between changes in total ion composition and morphological and biochemical events are poorly understood. We investigated simultaneous changes in sodium (Na), chlorine (Cl), and potassium (K) concentrations in stauroporine-induced apoptosis by quantitative electron probe X-ray microanalysis (EPXMA) in single cells. Apoptotic cells identified unequivocally from the presence of chromatin condensation in backscattered electron images were characterized by an increase in intracellular Na, a decrease in intracellular Cl and K concentrations, and a decrease in K/Na ratio. The ouabain-sensitive Rb-uptake assay demonstrated a net decrease in Na(+)/K(+)-ATPase activity, suggesting that increases in Na and decreases in K and the K/Na ratio in apoptotic cells were related with inhibition of the Na(+)/K(+)-ATPase pump. These changes in diffusible elements were associated with externalization of phosphatidyl serine and oligonucleosomal fragmentation of DNA. This alteration in ion homeostasis and morphological hallmarks of apoptosis occur in cells that have lost their inner mitochondrial transmembrane potential and before the plasma membrane becomes permeable.

P.4.038 The influence of hypotonic swellingand hyportonic shrinking on intracellular sodium concentration in rat brain synaptosomes

P.4.038 The influence of hypotonic swellingand hyportonic shrinking on intracellular sodium concentration in rat brain synaptosomes

Effects of Aldosterone and Mineralocorticoid Receptor Blockade on Intracellular Electrolytes

Genomic mechanisms of mineralocorticoid action have been increasingly elucidated over the past four decades. In renal epithelia, the main effect is an increase in sodium transport through activation and de novo synthesis of epithelial sodium channels. This leads to increased concentrations of intracellular sodium activating sodium-potassium-ATPase molecules mainly at the basolateral membrane which extrude sodium back into the blood stream. In contrast, rapid steroid actions have been widely recognized only recently. The present article summarizes both traditional and rapid effects of mineralocorticoid hormones on intracellular electrolytes, e.g. free intracellular calcium in vascular smooth muscle cells as determined by fura 2 spectrofluorometry in single cultured cells from rat aorta. Latter effects are almost immediate, reach a plateau after only 3 to 5 minutes and are characterized by high specificity for mineralocorticoids versus glucocorticoids. The effect of aldosterone is blocked by neomycin and short-term treatment with phorbol esters but augmented by staurosporine, indicating an involvement of phospholipase C and protein kinase C. The Ca(2+) effect appears to involve the release of intracellular Ca(2+), as shown by the inhibitory effect of thapsigargin. This mechanism operates at physiological subnanomolar aldosterone concentrations and appears to result in rapid fine tuning of cardiovascular responsivity. As a landmark feature of these rapid effects, insensitivity to classic antimineralocorticosteroids, e.g. spironolactone or canrenone has been found in the majority of observations. In an integrated view, mineralocorticoids seem to mainly effect intracellular electrolytes genomically to induce transepithelial transport, and induce nongenomically mediated alterations of cell function (e.g. vasoconstriction) by rapid effects on intracellular electrolytes such as free intracellular calcium.

More on the sodium saga.

The relationship between sodium (salt) intake and blood pressure has been convincingly established by epidemiological, observational, interventional, physiological, and some genetic evidence for some time. Yet the interaction remains the subject of passionate and heated debate. Even among those who are convinced of the salt–blood pressure interaction, some advocate a population-wide attempt to reduce dietary salt intake, arguing on the basis of epidemiological and interventional evidence, and others who suggest that such interventions should be targeted toward those most likely to benefit: the “salt-sensitive” subpopulation. Studies have characterized such subgroups on the basis of higher blood pressure, increased age or African-American ethnicity.1 The issue is rendered even more compelling by the findings that salt sensitivity can be identified among “normotensive” subjects (ie, those with blood pressure <140/90) as well as those with hypertension1 and the designation of those with blood pressure levels between 120 and 139 mm Hg systolic and 80 and 89 diastolic as prehypertensive2 and at increased risk for development of fixed hypertension and for cardiovascular events compared with those with lower blood pressure.3 Observational data have provided a starting point for the quantitative considerations of dietary salt intake. The most recent (1999–2000) NHANES survey provides an estimated dietary sodium intake based on food records, excluding discretionary sodium, of 135 to 204 mmol per day for men and 100 to 135 mmol per day for women in the United States.4 Questionnaires are acknowledged to underestimate actual intake, and urinary sodium excretion has been shown to provide a more accurate index of total sodium intake because it represents ≈93% of intake at steady-state conditions.5 A recent British survey reported that urinary sodium excretion averaged 187 mmol per day for men and 139 mmol per day for women.5 This was very similar to …

Cardiac sarcolemmal ion channels and transporters as possible targets for antiarrhythmic and positive inotropic drugs: strategies of the past--perspectives of the future.

In this article we overview the most important antiarrhythmic and positive inotropic mechanisms based on pharmacological modification of an ion channel or a transport protein in the surface membrane of cardiac myocytes. First we briefly characterize the ion currents mediated by these proteins in atrial and ventricular cells. Since the level of expression of ion channels is markedly altered in various types of chronic heart diseases, such as atrial fibrillation or heart failure, cardiac remodelling characteristic of these cases is also discussed. The paper gives evaluation of the currently applied most important antiarrhythmic strategies and some insight into the perspectives of the future by reviewing a few but promising mechanisms and drugs that are currently investigated. Positive inotropic agents and mechanisms are similarly treated, focusing primarily on proarrhythmic risks or potential antiarrhythmic effects of these compounds. Based on the backgrounds and aims above, modification of the followings factors is discussed in details: I(Na), I(Ca), I(Kr), I(Ks), I(Kl), I(to), I(Kur), I(K,Ach), I(K,ATP), I(f), gap-junction channel, Na(+)/K(+) pump, Na(+)/Ca(2+) exchanger, Na(+)/H(+) exchanger, as well as the intracellular concentrations of sodium and calcium ions. In addition to the critical evaluation of each manipulation, the following general conclusions can be drawn. (1) Since large modifications in action potential parameters are usually disadvantageous at long time scale, combination of the various mechanisms, each represented at a moderate degree, appears to be better. (2) Regarding Class III. antiarrhythmic action, selective potassium channel blockers free of reverse rate-dependent properties should be preferred. (3) Partial inhibition of the Na(+)/Ca(2+) exchanger may result-paradoxically in an antiarrhythmic action under specific conditions, in addition to its positive inotropic effect. We believe that investigation of new antiarrhythmic mechanisms, rather than new compounds of the old families, might be most beneficial in order to effectively treat life threatening cardiac arrhythmias in the future.

Lidocaine increases intracellular sodium concentration through voltage-dependent sodium channels in an identified lymnaea neuron.

The local anesthetic lidocaine affects neuronal excitability in the central nervous system; however, the mechanisms of such action remain unclear. The intracellular sodium concentration ([Na]i) and sodium currents (INa) are related to membrane potential and excitability. Using an identifiable respiratory pacemaker neuron from Lymnaea stagnalis, the authors sought to determine whether lidocaine changes [Na]i and membrane potential and whether INa is related to these changes. Intracellular recording and sodium imaging were used simultaneously to measure membrane potentials and [Na]i, respectively. Measurements for [Na]i were made in normal, high-Na, and Na-free salines, with membrane hyperpolarization, and with tetrodotoxin pretreatment trials. Furthermore, changes of INa were measured by whole cell patch clamp configuration. Lidocaine increased [Na]i in a dose-dependent manner concurrent with a depolarization of the membrane potential. In the presence of high-Na saline, [Na]i increased and the membrane potential was depolarized; the addition of lidocaine further increased [Na]i, and the membrane potential was further depolarized. In Na-free saline or in the presence of tetrodotoxin, lidocaine did not change [Na]i. Similarly, hyperpolarization of the membrane by current injections also prevented the lidocaine-induced increase of [Na]i. In the patch clamp configuration, membrane depolarization by lidocaine led to an inward sodium influx. A persistent reduction in membrane potential, resulting from lidocaine, brings the cell within the window current of INa where sodium channel activation occurs. Lidocaine increases intracellular sodium concentration and promotes excitation through voltage-dependent sodium channels by altering membrane potential in the respiratory pacemaker neuron.

Marinobufagenin may mediate the adverse impact of salty diets on renal calcium retention by impairing the efficiency of renal tubular sodium–calcium exchange

For reasons yet to be clarified, salt loading and plasma volume expansion decrease renal calcium retention; consequently, high-salt diets are thought to increase risk for osteoporosis and renal stones. These measures also can evoke increased adrenal production of the natriuretic factor marinobufagenin (MBG), recently implicated in the genesis of essential hypertension. MBG achieves natriuresis via potent selective inhibition of the alpha-1-type sodium pump, expressed throughout the nephron. In as much as renal calcium retention is largely dependent on efficient activity of calcium-sodium exchangers situated in the basolateral membranes of tubular epithelium, it is evident that an increased intracellular sodium concentration consequent to sodium pump inhibition could blunt the activity of these exchangers. Thus, it is postulated that MBG mediates the impact of salt loading on renal calcium retention.

Angiotensin II directly stimulates activity and alters the phosphorylation of Na-K-ATPase in rat proximal tubule with a rapid time course.

We present evidence that Na-K-ATPase in the rat proximal tubule is directly activated by ANG II much faster than previously observed. Specifically, we show that a 2-min exposure to 0.1 and 1 nM ANG II slowed the rate of intracellular sodium accumulation in response to an increase in extracellular sodium added in the presence of gramicidin D. From these data, we show that ANG II directly stimulates Na-K-ATPase activity at rate-limiting concentrations of intracellular sodium. Under these same conditions, exposing proximal tubules to ANG II altered the amount of 32P incorporated into multiple phosphopeptides generated from a tryptic digest of the alpha-subunit of Na-K-ATPase. Na-K-ATPase was isolated from whole cell lysates by means of a ouabain-affinity column and then separated into its individual subunits by SDS-PAGE. Na-K-ATPase bound to the column in its E2 conformation and was eluted by altering its conformation to E1 using Na+ATP. Na-K-ATPase isolated from cells treated with ANG II eluted more easily from the ouabain-affinity column than Na-K-ATPase isolated from control cells, suggesting that ANG II decreased the affinity of Na-K-ATPase for ouabain. Thus ANG II rapidly stimulated the activity of Na-K-ATPase in 2 min or less by a mechanism that could involve changes in phosphorylation and conformation of Na-K-ATPase. We suggest that the physiological role for rapid direct activation of Na-K-ATPase is greater control of intracellular sodium during sodium reabsorption.

Phospholipase D Is a Negative Regulator of Proline Biosynthesis in Arabidopsis thaliana

Accumulation of proline has been observed in a large number of plant species in response to drought and salt stresses, suggesting a key role of this amino acid in plant stress adaptation. Upstream components of the proline biosynthesis signal transduction pathways are still poorly defined. We provide experimental evidence that phospholipase D (PLD) is involved in the regulation of proline metabolism in Arabidopsis thaliana. The application of primary butyl alcohols, which divert part of PLD-derived phosphatidic acid by transphosphatidylation, stimulated proline biosynthesis even without hyperosmotic constraints. Moreover, application of primary butyl alcohols enhanced the proline responsiveness of seedlings to mild hyperosmotic stress. These data indicate that some PLDs are negative regulators of proline biosynthesis and that plants present a higher proline responsiveness to hyperosmotic stress when this regulator is abolished. We clearly demonstrate that PLD signaling for proline biosynthesis is similar to RD29A gene expression and different from the abscisic acid-dependent RAB18 gene expression. Our data reveal that PLDs play positive and negative roles in hyperosmotic stress signal transduction in plants, contributing to a precise regulation of ion homeostasis and plant salt tolerance.

Pathophysiology of Focal Cerebral Ischemia: a Therapeutic Perspective

The pathophysiology of cerebral ischemia is best understood in animal models of stroke. Within minutes of interrupted blood flow, mitochondria are deprived of substrate, which prevents adenosine triphosphate generation and results in membrane depolarization. This leads to increased intracellular calcium and sodium concentration followed by generation of free radicals and initiation of apoptosis. Glutamate release from ischemic neurons contributes to cellular damage. Each step in this complex, interdependent series of events offers a potential point to intervene and prevent neuronal death. Although many human trials in acute stroke therapy have had disappointing results, many promising therapies are in the pipeline, including hypothermia and free-radical inhibitors. Herein, the author discusses the pathophysiology of focal cerebral ischemia as has been revealed in rodent models and reviews the major human trials according to treatment mechanism.

Genotypic difference in salinity tolerance of green gram cultivars

Responses of two green gram ( Phaseolus aureus) cultivars differing in salt tolerance ability were compared for seed germination efficiency, seedling vigor (root and shoot length), plant growth (dry weight (DW) and fresh weight (FW)), water uptake and intracellular Na +/K + contents during germination under the conditions of absence as well as presence of various levels of salinity. In cultivar SML-32 increasing levels of salinity remarkably decreased seed germination and caused pronounced decrease in seedling vigor, plant growth and water uptake in shoot and root compared to cultivar T-44. Intracellular sodium content of the root and shoot tissues of the cultivar SML-32 was found to be increased several folds in presence of salinity while that of the cultivar T-44 exhibited only moderate increase even at high salinity level (200 mM NaCl). However intracellular K + content of the root and shoot tissues of both the cultivars did not much increased in presence of salinity. Results suggest possible different behaviors of cultivars differing in salt tolerance with respect to germination, seedling vigor, plant growth, water content (WC) and Na +/K + contents. Based on these criteria, cultivar T-44 was considered as salt tolerant while that of SML-32 salt sensitive.

Cell Signaling Microdomain with Na,K-ATPase and Inositol 1,4,5-Trisphosphate Receptor Generates Calcium Oscillations

Recent studies indicate novel roles for the ubiquitous ion pump, Na,K-ATPase, in addition to its function as a key regulator of intracellular sodium and potassium concentration. We have previously demonstrated that ouabain, the endogenous ligand of Na,K-ATPase, can trigger intracellular Ca2+ oscillations, a versatile intracellular signal controlling a diverse range of cellular processes. Here we report that Na,K-ATPase and inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) form a cell signaling microdomain that, in the presence of ouabain, generates slow Ca2+ oscillations in renal cells. Using fluorescent resonance energy transfer (FRET) measurements, we detected a close spatial proximity between Na,K-ATPase and InsP3R. Ouabain significantly enhanced FRET between Na,K-ATPase and InsP3R. The FRET effect and ouabain-induced Ca2+ oscillations were not observed following disruption of the actin cytoskeleton. Partial truncation of the NH2 terminus of Na,K-ATPase catalytic alpha1-subunit abolished Ca2+ oscillations and downstream activation of NF-kappaB. Ouabain-induced Ca2+ oscillations occurred in cells expressing an InsP3 sponge and were hence independent of InsP3 generation. Thus, we present a novel principle for a cell signaling microdomain where an ion pump serves as a receptor.

Myocardial inflammatory responses to sepsis complicated by previous burn injury.

It is generally accepted that an initial injury such as burn trauma alters immune function such that a second insult increases the morbidity and mortality over that observed with each individual insult. We have shown previously that either burn trauma or sepsis promotes cardiomyocyte secretion of TNF-alpha and IL-1beta, cytokines that have been shown to produce myocardial contractile dysfunction. This study determined whether a previous burn injury (given eight days prior to sepsis) (1) provides a preconditioning phenomenon, decreasing inflammatory responses to a second insult or (2) exacerbates inflammatory response observed with either injury alone. Anesthetized Sprague-Dawley rats were given either burn injury over 40% total body surface area, sepsis alone (intratracheal S. pneumoniae, 4 x 10(6) colony forming units) or sepsis eight days after burn; all rats received lactated Ringer's solution. Hearts harvested 24 h after onset of sepsis alone or sepsis plus eight-day burn were used to (1) isolate cardiomyocytes (collagenase) or (2) assess contractile function (Langendorff). Cardiomyocytes loaded with 2 microg/mL Fura-2AM or sodium-binding benzofuran isophthalate were used to measure intracellular calcium and sodium concentrations (Nikon inverted microscope, Grooney optics, InCyt Im2 Fluorescence Imaging System). Additional cardiomyocytes were used to measure myocyte-secreted TNFalpha, IL-1, IL-6, IL-10 (pg/ml, ELISA). Either burn trauma alone or sepsis alone promoted TNF-alpha, IL-1beta, nitric oxide, IL6 and IL-10 secretion by cardiomyocytes (p < 0.05). Producing aspiration-related pneumonia eight days postburn produced myocardial pro- and anti-inflammatory responses and increased myocyte Ca2+/Na+ concentrations to a significantly greater degree than the responses observed after either insult alone. A previous burn injury alters myocardial inflammatory responses, predisposing the burn-injured subject to exaggerated inflammation, which correlates with greater myocardial dysfunction.

Gadolinium reduces short-term stretch-induced muscle damage in isolated mdx mouse muscle fibres.

Duchenne muscular dystrophy is a lethal muscle disease caused by absence of the protein dystrophin which is part of a glycoprotein complex located on the intracellular surface of the surface membrane. The precise function of dystrophin and the reason why its absence causes severe muscle damage are unclear. Stretch-induced muscle damage is well recognised in normal muscle and is more severe in muscles from animals lacking dystrophin (mdx mice). It has been proposed that stretch-induced damage underlies the progression of damage in muscular dystrophy. In the present study we confirm that single fibres from mdx muscle are more susceptible to stretch-induced damage and show that there is an associated rise in intracellular sodium concentration ([Na+]i) which is greater than in wild-type mice. We show that this rise in [Na+]i can be prevented by Gd3+, which is an established blocker of stretch-activated channels. mdx fibres have a higher than normal resting [Na+]i and this is also reduced by Gd3+. If Gd3+ is applied over the period in which [Na+]i rises following stretched contraction, it prevents one component of the reduced force. The other component of reduced force is caused by inhomogeneity of sarcomeres and can be minimised by stretching the muscle to its new optimum length. These experiments show that part of the short-term damage caused by stretch in mdx fibres can be prevented by blocking stretch-activated channels.