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PubMed1989

Interaction of DPI 201-106 with cardiac glycosides.

The interaction of the cardiotonic agent DPI 201-106 (4-[3-(4-diphenylmethyl-1-piperazinyl(-2-hydroxypropoxy]-1H-indole -2- carbonitrile) with cardiac glycosides was investigated. In rabbit papillary muscles, all effects were normalized by using potentiating paired stimulation (PPS) as the 100% reference standard. Ouabain 1 microM alone increased the force of contraction (FC) by 66% +/- 6% (SEM) of PPS; 0.1 microM was ineffective. In the presence of 0.1 microM S-(-)-DPI 201-106, the active enantiomer of DPI 201-106, ouabain 0.1 and 1 microM increased FC by 41% +/- 11% and 119% +/- 19% of PPS, respectively. In anesthetized dogs, left ventricular dP/dtmax was increased by racemic DPI 201-106 0.2 mg/kg i.v. (+1987 +/- 660 mm Hg/s) and by ouabain 35 micrograms/kg i.v. (+560 +/- 40 mm Hg/s). The combined effect of DPI 201-106 and ouabain in similar doses was +2827 +/- 942 mm Hg/s. In digoxin-pretreated anesthetized cats, racemic DPI 201-106 was infused up to an accumulated dose of 12.22 mg/kg i.v. No signs of cardiotoxicity were observed in combination. In conclusion, the concomitant administration of DPI 201-106 and cardiac glycosides leads to enhanced positive inotropic effects in vitro and in vivo. The cardiotoxicity of glycosides was not increased by DPI 201-106.

Anesthesia↗
PubMed1988

Wall mannoproteins of the yeast and mycelial cells of Candida albicans: nature of the glycosidic bonds and polydispersity of their mannan moieties.

Zymolyase released between 20 and 25% of the total protein from purified walls of yeast (Y) and mycelial (M) cells of Candida albicans. The material released contained 92% carbohydrate (86% mannose and 6% glucose) and 7% protein. Over 85% of the carbohydrate was N-glycosidically linked to the protein and the rest (less than 15%) was linked O-glycosidically. Highly polydisperse, high molecular mass mannoproteins, resolved by electrophoresis as four defined bands in Y cells and two bands in M cells, had both types of sugar chains. A 34 kDa species found in both types of cells had a single 2.5 kDa N-glycosidically linked sugar chain and a 31.5 kDa protein moiety. Polydispersity in the high molecular mass mannoproteins was due to the N-linked sugar chains (mannan) with a molecular mass between 500 kDa and 20 kDa (average 100 kDa) in Y cells and between 400 kDa and 20 kDa (average 50 kDa) in M cells. Three mannoproteins of 34, 30 and 29 kDa secreted by protoplasts were associated with the high molecular mass mannoproteins, suggesting that this type of interaction might be related to the regeneration of the cell wall.

Candida albicans↗
PubMed2004

Molecular modeling of family GH16 glycoside hydrolases: potential roles for xyloglucan transglucosylases/hydrolases in cell wall modification in the poaceae.

Family GH16 glycoside hydrolases can be assigned to five subgroups according to their substrate specificities, including xyloglucan transglucosylases/hydrolases (XTHs), (1,3)-beta-galactanases, (1,4)-beta-galactanases/kappa-carrageenases, "nonspecific" (1,3/1,3;1,4)-beta-D-glucan endohydrolases, and (1,3;1,4)-beta-D-glucan endohydrolases. A structured family GH16 glycoside hydrolase database has been constructed (http://www.ghdb.uni-stuttgart.de) and provides multiple sequence alignments with functionally annotated amino acid residues and phylogenetic trees. The database has been used for homology modeling of seven glycoside hydrolases from the GH16 family with various substrate specificities, based on structural coordinates for (1,3;1,4)-beta-D-glucan endohydrolases and a kappa-carrageenase. In combination with multiple sequence alignments, the models predict the three-dimensional (3D) dispositions of amino acid residues in the substrate-binding and catalytic sites of XTHs and (1,3/1,3;1,4)-beta-d-glucan endohydrolases; there is no structural information available in the databases for the latter group of enzymes. Models of the XTHs, compared with the recently determined structure of a Populus tremulos x tremuloides XTH, reveal similarities with the active sites of family GH11 (1,4)-beta-D-xylan endohydrolases. From a biological viewpoint, the classification, molecular modeling and a new 3D structure of the P. tremulos x tremuloides XTH establish structural and evolutionary connections between XTHs, (1,3;1,4)-beta-D-glucan endohydrolases and xylan endohydrolases. These findings raise the possibility that XTHs from higher plants could be active not only on cell wall xyloglucans, but also on (1,3;1,4)-beta-D-glucans and arabinoxylans, which are major components of walls in grasses. A role for XTHs in (1,3;1,4)-beta-D-glucan and arabinoxylan modification would be consistent with the apparent overrepresentation of XTH sequences in cereal expressed sequence tags databases.

Amino Acid Sequence↗
PubMed1985

Interaction of palytoxin and cardiac glycosides on erythrocyte membrane and (Na+ + K+) ATPase.

Palytoxin (PTX), at extremely low concentrations (0.01-1 nM), caused K+ release from rabbit erythrocytes. Among the various chemical compounds tested, cardiac glycosides potently inhibited the PTX-induced K+ release. The order of inhibitory potency (IC50) was cymarin (0.42 microM) greater than convallatoxin (0.9 microM) greater than ouabain (2.3 microM) greater than digitoxin (88 microM) greater than digoxin (90 microM). Their corresponding aglycones, even at 10 microM, did not inhibit the K+ release, but competitively antagonized the inhibitory effect of the glycosides. All these cardiotonic steroids inhibited the activity of (Na+ + K+)-ATPase prepared from hog cerebral cortex in narrow concentration ranges (IC50 = 0.15-2.4 microM), suggesting that the inhibition of K+ release is not related to their inhibitory potency on the (Na+ + K+)-ATPase activity, and the sugar moiety of cardiac glycosides is involved in the inhibition. On the other hand PTX, at higher concentrations (greater than 0.1 microM), inhibited the (Na+ + K+)-ATPase activity. However, this inhibitory effect of PTX was not antagonized by ouabain. It is suggested that, compared with ouabain, PTX has additional binding site(s) on the (Na+ + K+)-ATPase.

Acrylamides↗
PubMed1990

Cleavage of zearalenone-glycoside, a "masked" mycotoxin, during digestion in swine.

Comparative analyses of cereal samples pretreated with or without beta-glucosidase indicate the presence of zearalenone-glycoside. To examine the stability of zearalenone-glycoside during digestion, mixed feed was artificially contaminated with synthesized zearalenone-4-beta-D-glucopyranoside (395 micrograms/kg) and fed to a pig over a period of 14 days. The metabolites detected in feces and urine samples were zearalenone and alpha-zearalenol. These results demonstrate that zearalenone-4-beta-D-glucopyranoside is decomposed during digestion and the aglucone, zearalenone, is released. Since zearalenone-glycoside is not detected during routine analysis, but hydrolysed during digestion, it seems likely that such "masked mycotoxins" are involved in cases of mycotoxicoses.

Animal Feed↗
PubMedDate not supplied

Glycosidic activities of Candida albicans after action of vegetable latex saps (natural antifungals) and isoconazole (synthetic antifungal).

Glycosidic activities have been examined in Candida albicans grown on medium culture containing latex sap (natural antifungal) or isoconazole (synthetic antifungal). The different types of utilized latex sap were those of Lactuca sativa (latex exuded from articulated laticifers) and Asclepias curassavica (latex flowing from non-articulated laticifers). The same enzyme assays were performed on C. albicans grown without antifungal compounds. Except for alpha-arabinosidase, all glycosidase activities were increased when C. albicans was grown in medium supplemented with L. sativa latex sap. The most stimulated activities were those of beta-fucosidase, alpha-galactosidase, alpha- and beta-glucosidase, alpha- and beta-mannosidase, acetyl-beta-glucosaminidase. The presence of A. curassavica latex sap in culture medium produced similar results: the most stimulated activities were those of alpha-mannosidase, alpha-galactosidase, acetyl-beta-glucosaminidase and beta-fucosidase. Electron microscope observations suggested a correlation between this stimulation of glycosidic activities and the fungal cell wall breakdown. For comparison the presence of isoconazole in culture medium yields no increase in glycosidic activities and no ultrastructural modification of fungal cell wall. The mode of action of latex saps in cell wall breakdown is discussed.

Antifungal Agents↗
PubMed2001

Charge movements in intact amphibian skeletal muscle fibres in the presence of cardiac glycosides.

1. Intramembrane charge movements were examined in intact voltage-clamped amphibian muscle fibres following treatment with cardiac glycosides in the hypertonic gluconate-containing solutions hitherto reported to emphasise the features of q(gamma) at the expense of q(beta) charge. 2. The application of chlormadinone acetate (CMA) at concentrations known selectively to block Na(+)-K(+)-ATPase conserved the steady-state voltage dependence of intramembrane charge, contributions from delayed (q(gamma)) charging transients, and their inactivation characteristics brought about by shifts in holding potential. 3. The addition of either ouabain (125, 250 or 500 nM) or digoxin (5 nM) at concentrations previously reported additionally to influence excitation-contraction coupling similarly conserved the steady-state charge-voltage relationships, Q(V), in fully polarised fibres to give values of maximum charge, Q(max), transition voltage, V*, and steepness factor, k, that were consistent with a persistent q component as reported on earlier occasions (Q(max) approximately = 25-27 nC F-1, V* approximately = -45 to -50 mV, k approximately = 7-9 mV). 4. In both cases shifts in holding potential from -90 to -50 mV produced a partial inactivation that separated steeply and more gradually voltage-dependent charge components in agreement with previous characterisations. 5. However, charge movements that were observed in the presence of either digoxin or ouabain were monotonic decays in which delayed (q(gamma)) transients could not be distinguished from the early charging records. These features persisted despite the further addition of chlormadinone acetate over a 10-fold concentration range (5-50 microM) known to displace ouabain from the Na(+)-K(+)-ATPase. 6. Ouabain (500 nM) restored the steady-state charge movement that was previously abolished by the addition of 2.0 mM tetracaine in common with previous results of using ryanodine receptor (RyR)-specific agents. 7. Perchlorate (8.0 mM) restored the delayed 'on' relaxations and increased the prominence of the 'off' decays produced by q(gamma) charge following treatment with cardiac glycosides. This was accompanied by a negative (approximately 10-15 mV) shift in the steady-state charge-voltage relationship but an otherwise conserved maximum charge, Q(max), and steepness factor, k, in parallel with previously reported effects of perchlorate following treatments with RyR-specific agents. 8. The features of cardiac glycoside action thus parallel those of other agents that act on RyR-Ca(2+) release channels yet influence the kinetics but spare the steady-state properties of intramembrane charge.

Animals↗
PubMed1971

Metabolism of cardiac glycosides studied in the isolated perfused guinea-pig liver.

1. Metabolic degradation of tritiated ouabain, digoxin, and digitoxin has been investigated quantitatively using the isolated perfused guinea-pig liver. The cardiac glycosides and their metabolites have been extracted from the plasma, liver, and bile by different solvents and identified as far as possible by radio-chromatographic analysis.2. The total metabolic activity in the experimental system was localized in the liver.3. The hydrophilic glycoside ouabain could not penetrate into the metabolically active compartment of the liver and was, therefore, not degraded. The more lipophilic compound digitoxin, however, was completely degraded due to its high affinity for the metabolically active sites. The unchanged digitoxin cannot enter the aqueous bile fluid in contrast to its more hydrophilic metabolites.4. The only detectable metabolic degradation of digoxin was a conjugation with glucuronic and/or sulphuric acid, but a cleavage of sugar molecules seemed not to occur.5. In the case of digitoxin the metabolic processes are more complicated: sugar cleavage, conjugation, and C-12 hydroxylation take place simultaneously. An immediate hydroxylation of digitoxin leading to digoxin was not observed. After administration of digitoxin conjugation products as well as digoxigenin-bis-and digoxigenin-mono-digitoxosides were present in each of the compartments investigated, but the digitoxosides of digitoxigenin were intermediates in concentrations too low to be determined indicating a very high rate of conjugation and/or C-12 hydroxylation as compared with the cleavage of the digitoxoses.6. A scheme for the metabolic pathways of the cardiac glycosides based on experimental results is presented. The metabolic behaviour of each of the three compounds involved is closely related to their physicochemical properties, especially the lipid solubility.

Animals↗
PubMed1972

The uptake of cardiac glycosides in relation to their actions in isolated cardiac muscle.

1. The uptake of (3)H-digitoxin, (3)H-ouabain and (3)H-dihydro-ouabain by isolated guinea-pig atria has been studied and compared with the inhibition of the sodium pump and with the inotropic effect.2. Analysis of the curve relating the uptake of digitoxin and ouabain at equilibrium to the bath concentration enabled a non-saturable and a saturable binding site to be distinguished.3. The uptake of inactive doses of dihydro-ouabain was only by a non-saturable mechanism.4. The uptake of labelled digitoxin and ouabain was reduced in the presence of another glycoside. The amount of bound glycoside was nearly equivalent to the estimated non-saturable uptake.5. The uptake was reduced at 4 degrees C to the clearance of the non-saturable site.6. ED50 of digitoxin and of ouabain for inhibition of the sodium pump were measured and compared to the ED50 for inotropic effect and to the concentrations producing a half-saturation of the saturable binding site.7. It is concluded that binding to the saturable site may be responsible for the cardiac actions of the glycosides.

Animals↗
PubMed1978

Sodium-dependent cardiac glycoside binding: experimental evidence and hypothesis.

1 The influence of increasing Na+ concentrations on the binding of digitoxin, digoxin and ouabain was examined in a Na+-K+-ATPase preparation of guinea-pig hearts. 2 Two distinct processes seem to be involved in this interaction: one binding process was activated at low Na+ concentrations. The maximum binding capacities were different and the K0.5 values were nearly identical for the cardiac glycosides studied. 3 In contrast, the second binding process was activated at appreciably higher Na+ concentrations, the maximum binding capacities were almost identical and the K0.5 values were different for the cardiac glycosides studied. 4 On the basis of these results attempts are made to explain the well known differences in the myocardial accumulation of cardiac glycosides.

Adenosine Triphosphatases↗
PubMed1985

Potassium changes the relationship between receptor occupancy and the inotropic effect of cardiac glycosides in guinea-pig myocardium.

K+ (2.4-15.6 mmol l-1) antagonized the positive inotropic effect of dihydro-ouabain. The concentration-effect curves became steeper with the shift to higher concentrations of the glycoside. At 1.2 mmol l-1 Ca2+, an increase in K+ from 2.4 to 12 mmol l-1 required tenfold higher concentrations of dihydro-ouabain to produce equal inotropic effects. This factor was reduced to four at 3.2 mmol l-1 Ca2+. The same change in K+ concentration, at 1.2 mmol l-1 Ca2+, diminished the inotropic effect of ouabain on rested-state contractions by a factor of six. The positive inotropic effect of Ca2+ was also antagonized by K+ (1.2-12 mmol l-1). Reduction of Na+ from 140 to 70 mmol l-1 abolished the antagonistic action of K+ (1.2-8.0 mmol l-1). Moreover the inotropic effect of Ca2+ was enhanced. Reduction of Na+, from 140 to 70 mmol l-1, antagonized the positive inotropic effect of dihydro-ouabain more at low (2.4 mmol l-1) than at high (8.0 mmol l-1) K+. Accordingly, the extent of the dihydro-ouabain-K+ antagonism was reduced. When the K+ concentration was increased from 2.4 to 12 mmol l-1, [3H]-ouabain binding was reduced by a factor of three. This is less than the reduction in the inotropic effectiveness of ouabain or dihydro-ouabain. Reduction of stimulation frequency from 1 to 0.1215 Hz did not significantly alter the antagonistic effect of K+. Diminution of Vmax of the action potential was observed only at K+ concentrations greater than 5.9 mmol l-1, whereas the resting membrane potential was continuously depolarized over the entire range of K+ concentrations. The results support the view that the reduction in receptor affinity cannot be the sole cause of the antagonism between the glycoside and K+. Impairment of passive Na+ influx during diastole, due to the K+-dependent depolarization of the resting membrane potential, contributed to about one half of the glycoside-K+ antagonism.

Animals↗
PubMed1987

Influence of derivation on the lipophilicity and inhibitory actions of cardiac glycosides on myocardial Na+-K+-ATPase.

Lipophilicity and inhibitory actions on guinea-pig heart Na+-K+-ATPase of twenty-six digitalis and six strophanthus glycosides comprising the aglycones, mono-, bis-, tris-sugar, alkylated (acylated) tris-sugar, acyl steroid derivatives and three cardanolides were investigated. Their octanol/water partition coefficients (P), reversed phase thin layer (r.t.l.c.) and reversed phase high performance liquid chromatography (r.h.p.l.c.) were determined and the viability of these methods as a measure of the lipophilicity of the cardiotonic steroids evaluated. The influence of lipophilicity and so also structural changes on the inhibitory effects of the cardiac glycosides on myocardial Na+-K+-ATPase was then examined. It is concluded that (a) r.t.l.c. and r.h.p.l.c. are just as effective as the conventional shake-flask method for estimation of the lipophilicity of cardiac glycosides and (b) the inhibitory potencies of cardiotonic steroids on the myocardial Na+-K+-ATPase increase with growing lipophilicity. The relationship between these two parameters is, however, governed by the influence of substitution or derivation of structural components on their inhibitory potencies on the myocardial Na+-K+-ATPase.

Animals↗
PubMed1987

Alpha 2-adrenoceptor blockade prevents cardiac glycoside-evoked neurotransmitter release from sympathetic nerves in dog saphenous vein.

1 The effect of alpha-adrenoceptor antagonists upon neurotransmitter release evoked by cardiac glycosides from sympathetic nerve terminals has been investigated in dog saphenous vein. 2 In rings of saphenous vein preloaded with [3H]-noradrenaline, acetylstrophanthidin (ACS) caused a concentration-dependent efflux of 3H (EC50 ca. 4.4 microM) that was attenuated by phentolamine and yohimbine but not by prazosin. 3 In helical strips of saphenous vein superfused with ACS at EC50 the efflux of 3H-compounds in general, and of [3H]-noradrenaline in particular, occurred after a short delay and increased with time to a maximum reached at 75 min. Phentolamine and phenoxybenzamine, but not prazosin reduced the efflux of [3H]-noradrenaline and of total 3H-compounds throughout the time-course of the ACS-evoked effect. 4 In helical strips of saphenous vein the glycoside ouabain also caused an increase in [3H]-noradrenaline and in total 3H-efflux that was attenuated by phentolamine. 5 By contrast with the above, in bovine adrenal medullary chromaffin cells, which appear to have no functional alpha-adrenoceptors, ACS caused a small, but significant increase in 3H-efflux which was not prevented by phentolamine. 6 Phentolamine, at concentrations that attenuate markedly the ouabain- or ACS-evoked increase in 3H-efflux from dog saphenous vein, did not cause significant inhibition of cocaine-sensitive [3H]-noradrenaline uptake nor did it reduce the extent of the 3H-efflux evoked either by tyramine or by reduced extracellular Na+. These findings imply that phentolamine does not affect ACS-evoked neurotransmitter release by an action on the catecholamine uptake mechanism. 7. It is concluded that the cardiac glycoside-evoked increase in neurotransmitter release from noradrenergic nerve terminals ofdog saphenous vein is modulated by a mechanism that involves an alpha2- adrenoceptor.

Adrenergic alpha-Agonists↗
PubMed2003

Effect of cardiac glycosides on action potential characteristics and contractility in cat ventricular myocytes: role of calcium overload.

There is increasing evidence that cardiac glycosides act through mechanisms distinct from inhibition of the sodium pump but which may contribute to their cardiac actions. To more fully define differences between agents indicative of multiple sites of action, we studied changes in contractility and action potential (AP) configuration in cat ventricular myocytes produced by six cardiac glycosides (ouabain, ouabagenin, dihydroouabain, actodigin, digoxin, and resibufogenin). AP shortening was observed only with ouabain and actodigin. There was extensive inotropic variability between agents, with some giving full inotropic effects before automaticity occurred whereas others produced minimal inotropy before toxicity. AP shortening was not a result of alterations in calcium current or the inward rectifier potassium current, but correlated with an increase in steady-state outward current (Iss), which was sensitive to KB-R7943, a Na+-Ca2+ exchange (NCX) inhibitor. Interestingly, Iss was observed following exposure to ouabain and dihydroouabain, suggesting that an additional mechanism is operative with dihydroouabain that prevents AP shortening. Further investigation into differences in inotropy between ouabagenin, dihydroouabain and ouabain revealed almost identical responses under AP voltage clamp. Thus all agents appear to act on the sodium pump and thereby secondarily increase the outward reverse mode NCX current, but the extent of AP duration shortening and positive inotropy elicited by each agent is limited by development of their toxic actions. The quantitative differences between cardiac glycosides suggest that mechanisms independent of sodium pump inhibition may result from an altered threshold for calcium overload possibly involving direct or indirect effects on calcium release from the sarcoplasmic reticulum.

Action Potentials↗
PubMed1972

Variation in cardiac glycoside content of monarch butterflies from natural populations in eastern North America.

A new spectrophotometric assay has been used to determine the gross concentration of cardiac glycoside in individual monarch butterflies. Adults sampled during the fall migration in four areas of eastern North America exhibited a wide variation in cardiac glycoside concentration. The correlation between spectrophotometrically measured concentrations and emetic dose determinations supports the existence of a broad palatability spectrum in wild monarch butterflies. The cardiac gylcoside concentration is greater in females than in males and is independent of the dry weight of the butterflies; contrary to prediction, both the concentration mean and variance decrease southward. The defensive advantage of incorporating cardiac glycosides may be balanced by detrimental effects on individual viability.

Analysis of Variance↗
PubMed1998

Nutritional Properties and significance of vitamin glycosides.

Glycosylated forms of pyridoxine, vitamin D, niacin, pantothenate, and riboflavin exist in nature, whereas glycosides of retinol and ascorbic acid are products of in vitro transglycosidation. Beta-Glucosides of pyridoxine (a) are prevalent in plant-derived foods, (b) contribute to human nutrition as partially available sources of vitamin B6, (c) undergo partial hydrolysis by a novel mammalian cytosolic beta-glucosidase, and (d) exert a weak antagonistic effect on the utilization of free pyridoxine. Niacin exists in grains as complexed forms with low bioavailability, whereas vitamin D glycosides are toxic components of certain calcinogenic plants of importance in animal health. Glycosides of pantothenate and riboflavin appear to be minor products of mammalian metabolism. Glycosylation of retinol or other hydrophobic alcohols may facilitate glycolipid turnover, whereas a stable ascorbyl glucoside may have nutritional applications. Glycosylation of vitamins exerts widely ranging chemical and biological effects, with great nutritional and metabolic significance.

Animals↗
PubMed1981

Changes in cellular Na+, K+, and Ca2+ contents, monovalent cation transport rate, and contractile state during washout of cardiac glycosides from cultured chick heart cells.

To delineate more clearly the importance of altered monovalent cation transport rate in the mediation of the positive inotropic effects of cardiac glycosides, we studied changes in the contractile state and rate of uptake of K+ and Rb+ by monolayer cultures of chick embryo ventricular cells during exposure to and washout of ouabain and dihydro-ouabain. These cardiac glycosides produced a positive inotropic effect in this system, accompanied by a significant reduction in monovalent cation transport rate, by increases in cellular contents of Na+ and Ca2+, and by a decrease in cellular content of K+ as judged by radioisotopic tracer studies. Following removal of glycosides from media bathing the cultures, monovalent cation transport rate returned to normal within 1 minute, followed by a loss of inotropy which was complete by 7 minutes, a time at which cellular [Ca2+] had returned to normal. The bulk cellular concentration of Na+ remained increased, however, and that of K+ depressed for longer periods. Veratrine (1 microgram/ml) induced a positive inotropic effect, but caused a less marked increase in cellular [Na+] than did equipotent concentrations of ouabain and dihydroouabain. These results indicate that there is not a simple relationship between bulk cellular [Na+] and magnitude of inotropic effect in these cells, and are consistent with the proposal that there is a subsarcolemmal space in which [Na+] regulates Ca2+ fluxes and contractility, and in which [Na+] is regulated primarily by the balance between transsarcolemmal influx and Na+ pump rate and, to a lesser degree, by bulk [Na+].

Animals↗
PubMed2002

The Na+-Ca2+ exchanger is essential for the action of cardiac glycosides.

The widely accepted model to explain the positive inotropic effect of cardiac glycosides invokes altered Na+-Ca2+ exchange activity secondary to Na+ pump inhibition. However, proof of this model is lacking and alternative mechanisms have been proposed. We directly tested the role of the Na+-Ca2+ exchanger in the action of the glycoside ouabain using Na+-Ca2+ exchanger knockout mice. Ablation of the exchanger is embryonic lethal, but contractility can be studied in embryonic heart tubes at day 9.5 postcoitum. Heart tubes isolated from homozygous Na+-Ca2+ exchanger knockout mice (NCX-/-) display surprisingly normal Ca2+ transients. Removal of extracellular Na+ induces Ca2+ overload in wild-type heart tubes but does not alter the Ca2+ transients of NCX-/- heart tubes. Similarly, ouabain, at levels causing Ca2+ overload in wild-type heart tubes, has no effect on NCX-/- heart tubes. We conclude that in embryonic mouse myocytes the Na+-Ca2+ exchanger is absolutely required for the effect of cardiac glycosides on Ca2+(i).

Animals↗