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PubMed2001

Direct inhibitory effect of digitalis on progesterone release from rat granulosa cells.

Digoxin (10(-7) - 10(-5) M) or digitoxin (10(-7) - 10(-5) M) decreased the basal and human chorionic gonadotropin (hCG)-stimulated release of progesterone from rat granulosa cells. Digoxin (10(-5) M) or digitoxin (10(-5) M) attenuated the stimulatory effects of forskolin and 8-bromo-cyclic 3' : 5'-adenosine monophosphate (8-Br-cAMP) on progesterone release from rat granulosa cells. Digoxin (10(-5) M) or digitoxin (10(-5) M) inhibited cytochrome P450 side chain cleavage enzyme (cytochrome P450(scc)) activity (conversion of 25-hydroxyl cholesterol to pregnenolone) in rat granulosa cells but did not influence the activity of 3beta-hydroxysteroid dehydrogenase (3beta-HSD). Neither progesterone production nor P450scc activity in rat granulosa cells was altered by the administration of ouabain. Digoxin (10(-5) M) or digitoxin (10(-5) M), but not ouabain, decreased the expression of P450scc and steroidogenic acute regulatory (StAR) protein in rat granulosa cells. The present results suggest that digoxin and digitoxin decrease the progesterone release by granulosa cells via a Na(+),K(+)-ATPase-independent mechanism involving the inhibition of post-cyclic AMP pathway, cytochrome P450scc and StAR protein functions.

Adenylyl Cyclases↗
PubMed1975

Studies on cardioactive steroids. III. Characterization of different cardiac glycosides by their effects on contractility and rhythmicity at different extracellular potassium concentrations.

In the present paper, the naturally occurring glycosides digitoxin, gitoxin, 16-acetyl-gitoxin, digoxin, cymarol, ouabain, and proscillaridin, and the semi-synthetic 16-epi-gitoxin and 16-acetyl-16-epi-gitoxin are investigated as to their inotropic action and their effects on rhythmicity at isolated spontaneously beating atria of the guinea-pig heart in dependence on the variation of the potassium concentration of the nutritive fluid ([K+]0: 1.34, 2.68, and 5.36 mM resp.). The major results are as follows. 1. Effects of raising [K+]0 from 1.34 to 2.68 mM: The range of the inotropically effective concentrations as well as the size of the maximum inotropic action are more or less strongly improved with all glycosides. The glycoside concentrations required to get inotropic maximum had to be increased to a high degree with proscillaridin and digoxin. The mean arrhythmia percentage occurring at the inotropic maximum is either decreased (gitoxin, 16-epi-gitoxin, digoxin, proscillaridin), unchanged (digitoxin, 16-acetyl-16-epi-gitoxin) or even increased (16-acetyl-gitoxin, cymarol, ouabain). The inotropic value is improved to a high extent with gitoxin only. 2. Effect of raising [K+]0 from 2.68 to 5.36 mM: The range of the inotropically effective concentrations is extended (digitoxin and cymarol) or diminished (proscillaridin), but remains essentially unchanged with most glycosides. The size of the maximum inotropic effect is increased with digoxin, ouabain and 16-epi-gitoxin, but decreased significantly with digitoxin and proscillaridin. The glycoside concentrations required to produce the inotropic maximum are essentially unchanged with the exception of 16-epi-gitoxin, 16-acetyl-gitoxin and ouabain. The mean arrhythmia percentage at the maximum inotropic effect is dramatically reduced with digoxin, cymarol and proscillaridin. The inotropic value is improved with all glycosides except digitoxin. 3. Evaluation of the various glycosides: When judged on the basis of the range of inotropically effective concentrations, the maximum inotropic effect, the mean arrhythmia percentage at the inotropic maximum and the inotropic value, the best first three glycosides include 16-epi-gitoxin and digoxin. 16-Epi-gitoxin and its 16-acetate show that most favourable relationship between the effect on contractility and rhythmicity. The cause of the differential actions of the structurally-different glycosides on contractility and rhythmicity is hypothesized to be due to divergences in structure and/or conformation of the receptor areas of (Na+ + K+)-ATPase of contractile and excitable cells.

Animals↗
PubMed1981

[Prospective examinations of digitalis poisoning].

Despite many years of using digitalis to treat congestive heart failure, the problem of intoxication has remained unchanged. In nine prospective studies on patients under a maintenance treatment with digoxin the intoxication rate ranged from 15.2% to 27.5%. Other studies have also shown that renal insufficiency was present in 70% of intoxicated patients. In contrast the digitoxin toxicity rate, as shown in two prospective studies from Norway and France on 649 and 2120 patients respectively, resulted in an intoxication rate of 5.8% and 3.2% respectively. The explanation for the discrepancy between the two glycosides seems to be predominantly the influence of renal function on drug elimination. Digoxin is mainly excreted through the kidneys; an impairment of the renal function will therefore lead to a reduced elimination of this drug. In these cases a dose reduction of digoxin is necessary. Digitoxin on the other hand is excreted both through the kidneys and the bile. Impairment of the renal function does, therefore, not lead to any decrease in digitoxin elimination whether in renal disease, during heart failure or in old age. In contrast to digoxin, no dose reduction is necessary with digitoxin when renal function is reduced. Digitoxin is therefore easier to handle in the long term management of cardiac patients with and without renal impairment.

Digitalis Glycosides↗
PubMed1986

The rate of uptake of cardiac glycosides into human cultured cells and the effects of chloroquine on it.

HeLa cells grown on Petri dishes were either pulse labelled with various cardiac glycosides or grown in low concentrations of them for up to 2 days; either in the presence of chloroquine or not. The cells were then homogenised and the cell free homogenate layered on a continuous sucrose gradient; and the glycoside content and that of various markers measured. In another series of experiments HeLa cells were grown on plastic beads under the above conditions and then the content of glycosides and of some marker enzymes measured. The rate of internalisation of ouabain, digoxin and digitoxin from the plasma membrane preparation produced by the bead method is at 9% hr-1, similar to the rate of loss of digoxin and digitoxin from whole cells but much faster than that of ouabain. In the sucrose gradient experiments it was found that [3H]ouabain, digoxin and digitoxin all initially co-distribute with the plasma membrane marker, 5'-nucleotidase, and then leave this fraction of the homogenate at a fast rate when kept at 37 degrees, to co-distribute with the lysosomal marker, beta-hexosaminidase. At 2 degrees the ouabain remains co-distributed with the plasma membrane marker. The rate of transfer is estimated to be some 90% hr-1, much faster than previously thought. Chloroquine causes an increased retention of digoxin and digitoxin in the lysosomal fraction of the homogenate. These results are best explained by supposing that the sodium pump-glycoside complex rapidly enters a region of the peripheral cytoplasm, and that this region then controls the subsequent exit of digoxin and digitoxin from the cell. The main barrier for ouabain occurs at a stage later than this. The consequences of this model on other aspects of pump activity is discussed.

Cardiac Glycosides↗
PubMed1981

Cardiac glycosides and their metabolites levels in plasma and heart of guinea-pigs after I. V. administration.

One hr, 3 hr and 6 hr after i.v. injection of tritiated gitoxin, digoxin and digitoxin to the guinea-pig, the chloroform-insoluble metabolites, mainly conjugates known to be cardio-inactive, represent two thirds of the cardiac glycoside and metabolites content of plasma for gitoxin, half for digitoxin and one quarter for digoxin. Most of the compounds taken up by the myocardium are chloroform-soluble and may be considered as cardio-active. Considering the nature and proportions of the unchanged cardiac glycoside and its cardio-active metabolites in the myocardium of the guinea-pig, the cardiac effects that would be measured after administration of digoxin ar due to unchanged digoxin only; after administration of digitoxin, these effects are partly due to unchanged digitoxin but also to 12 beta-hydroxylated metabolites; after administration of gitoxin, besides unchanged gitoxin, the hydrolysis products of the sugar chain of gitoxin may contribute to the cardiac effects. The data obtained in plasma and in myocardium between 1 and 6 hr after administration of digoxin or gitoxin show that the distribution of the unchanged cardiac glycoside and each chloroform-soluble metabolite, from plasma to myocardium, is achieved 1 hr after administration. This situation does not occur with digitoxin and its metabolites.

Animals↗
PubMed1999

Non-absorption of ingested lipophilic and amphiphilic allelochemicals by generalist grasshoppers: the role of extractive ultrafiltration by the peritrophic envelope.

The role of the peritrophic envelope in the non-absorption of three allelochemicals ingested by generalist grasshoppers was examined. This study tested the hypothesis that the association of lipophilic and amphiphilic allelochemicals with lipid aggregates (mixed micelles) reduces their permeability through the peritrophic envelope, a process similar to extractive ultrafiltration. Each of three allelochemicals (digitoxin, ouabain, and xanthotoxin) were solubilized in a lysolecithin suspension and injected separately into the midgut lumens of adult Melanoplus sanguinipes (Orthoptera: Acrididae). The low permeability of digitoxin through the peritrophic envelope was consistent with the extractive ultrafiltration of this compound. By comparison, ouabain and xanthotoxin permeability coefficients were 7- and 12-fold higher, respectively, than those of digitoxin. The results of extractive ultrafiltration assays confirmed that digitoxin is effectively extracted in lysolecithin micelles, but that neither ouabain nor xanthotoxin aggregates efficiently with these micelles.

Animals↗
PubMed1968

The binding of 3H-digitoxigenin by guinea-pig atrial tissue.

1. The uptake and release of (3)H-digitoxigenin by electrically driven, guinea-pig isolated atria (frequency 180/min) has been determined for two different medium concentrations of the genin. Both concentrations-1 x 10(-7) and 5 x 10(-7) g/ml.-caused a pronounced increase in contractile force.2. The uptake of (3)H-digitoxigenin reached equilibrium after approximately 2 hr of incubation. At equilibrium, the tissue/medium radioactivity ratio reached a value of about 8 for both concentrations studied. After initial saturation of the atria with (3)H-digitoxigenin, approximately 60% of the accumulated genin was released on wash-out in genin-free Tyrode solution for 2 hr.3. After presaturation of the atria with equimolar concentrations of either digitoxigenin or digitoxin (both non-radioactive) the uptake of (3)H-digitoxigenin occurred more slowly. After 2 hr of incubation approximately 60-70% of the tissue bound digitoxigenin or digitoxin had exchanged against (3)H-digitoxigenin from the medium. Presaturation of the atria with ouabain in equimolar concentration did not significantly affect the uptake of (3)H-digitoxigenin.4. The release process of (3)H-digitoxigenin was not affected by the same concentration of non-radioactive digitoxigenin as used for the accumulation of the genin.5. The kinetic properties of (3)H-digitoxigenin, determined by means of isotope techniques, are very similar to those of (3)H-digitoxin. The discrepancy between kinetic and pharmacological behaviour is, however, much larger for digitoxigenin than for digitoxin. Obviously, the presence or absence of the sugar moieties considerably influences the behaviour of the molecule towards the specific receptors, without particularly affecting the binding to unspecific, cellular structures.

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↗
PubMed1977

Accumulation of radioactive cardiac glycosides by various brain regions in relation to the dysrhythmogenic effect.

Ouabain was administered at a loading dose of 3 mug/kg followed by an infusion at a rate of 1 mug/kg-1 min-1 in order to produce severe dysrhythmia in dogs within 60 minutes. Similarly, digitoxin at a loading dose of 9 mug/kg followed by an infusion at a rate of 3 mug kg-1 min-1 was administered to compare its effect with that of ouabain. 2 During the 60 min experimental period, the plasma concentrations gradually rose with the continuous infusion of these drugs. However, in comparison to the 60 min plasma value of 119+/-20 pmol/ml for ouabain and 177+/-68 pmol/ml for digitoxin, the cerebrospinal fluid (CSF) concentrations for these drugs at this time were less than 5 pmol/ml. 3 Upon termination of the experiment at 60 min it was found that kidney, liver, heart, adrenal, and the non-neural tissue in the brain such as pituitary and choroid plexus concentrated ouabain and digitoxin to give high tissue to plasma ratios. However, various neural areas of the brain (cerebellum, mesencephalon, hypothalamus, pons, and medulla) showed no preferential localization or uptake of these two glycosides. 4 Concentration of ouabain and digitoxin by the choroid plexus does not seem to affect the ionic composition of the CSF. 5 It was concluded that sampling the large areas of neural tissue above could provide no evidence for local accumulation of digitalis glycosides that might account for a central nervous system origin of digitalis-induced cardiac arrhythmias.

Animals↗
PubMed1977

Effect of prophylactic digitalization on the development of myocardial hypertrophy.

The effect of prophylactic digitalization on the development of left ventricular hypertrophy was studied in adult rats. Digitoxin, 0.1 mg/100 g body wt or solvent was given daily for 1 wk prior to either aortic constriction or sham operation and was continued until the animals were killed, either 1 or 4 wk after surgery. A hemodynamic study was done in those animals killed 1 wk after surgery; hearts of all animals were examined for evidence of myocardial hypertrophy. Constriction of the ascending aorta had no significant effect on cardiac output but did reduce peak flow velocity and flow acceleration. An increase in left ventricular mass, RNA, and hydroxyproline was found in the animals with aortic constriction. Digitoxin treatment did not alter peak flow velocity or flow acceleration, but did significantly increase isovolumic (dP/dt)P-1. Digitoxin had no effect on body weight, heart weight, RNA, or hydroxyproline in either the sham-operated animals or in the animals with aortic constriction. Therefore, despite plasma digitoxin levels sufficient to affect myocardial contractility, left ventricular hypertrophy still developed after aortic constriction.

Animals↗
PubMed2004

Pharmaceutical-grade albumin: impaired drug-binding capacity in vitro.

BACKGROUND: Albumin is the most abundant protein in blood plasma, and due to its ligand binding properties, serves as a circulating depot for endogenous and exogenous (e.g. drugs) compounds. Hence, the unbound drug is the pharmacologically active drug. Commercial human albumin preparations are frequently used during surgery and in critically ill patients. Recent studies have indicated that the use of pharmaceutical-grade albumin is controversial in critically ill patients. In this in vitro study we investigated the drug binding properties of pharmaceutical-grade albumins (Baxter/Immuno, Octapharma, and Pharmacia & Upjohn), native human serum, and commercially available human serum albumin from Sigma Chemical Company. METHODS: The binding properties of the various albumin solutions were tested in vitro by means of ultrafiltration. Naproxen, warfarin, and digitoxin were used as ligands. HPLC was used to quantitate the total and free drug concentrations. The data were fitted to a model of two classes of binding sites for naproxen and warfarin and one class for digitoxin, using Microsoft Excel and Graphpad Prism. RESULTS: The drugs were highly bound to albumin (95-99.5%). The highest affinity (lowest K1) was found with naproxen. Pharmaceutical-grade albumin solutions displayed significantly lower drug-binding capacity compared to native human serum and Sigma albumin. Thus, the free fraction was considerably higher, approximately 40 times for naproxen and 5 and 2 times for warfarin and digitoxin, respectively. The stabilizers caprylic acid and N-acetyl-DL-tryptophan used in the manufacturing procedure seem to be of importance. Adding the stabilizers to human serum and Sigma albumin reduced the binding affinity whereas charcoal treatment of the pharmaceutical-grade albumin from Octapharma almost restored the specific binding capacity. CONCLUSION: This in vitro study demonstrates that the specific binding for warfarin and digitoxin is significantly reduced and for naproxen no longer detectable in pharmaceutical-grade albumin. It further shows that the addition of stabilizers may be of major importance for this effect.

Albumins↗
PubMed1976

Cardiac glycosides: relationship among active 86Rb uptake, (Na+,K+)-ATPase activity, and inotropy in guinea pig heart.

Relationships among positive inotropic responses, (Na+,K+)-ATPase inhibition, and sodium pump activities were studied using paced Langendorff preparations of guinea pig heart. (Na+,K+)-ATPase activity was estimated from the initial velocity of [3H] ouabain binding in ventricular homogenates, and sodium pump activity from ouabain-sensitive 86Rb uptake of ventricular slices. These parameters were measured in control, or in ouabain-or digitoxin-treated hearts either at the time of inotropic response or during the course of drug washout and compared with inotropy in the same heart. Perfusion of ouabain or digitoxin caused an increase in contractile force and a decrease in the initial velocity of ATP-dependent [3H] ouabain binding. The levels of [3H] ouabain binding in homogenates observed after a long incubation period were not different in ouabain-perfused and control homogenates, indicating that the nonlabeled ouabain bound to (Na+,K+)-ATPase during Langendorff perfusion was exchangeable with [3H] ouabain. Perfusion of drug-free solution after a 20-min perfusion of the isolated heart with either ouabain or digitoxin resulted in a loss of inotropic response and a recovery of the inhibition of the initial velocity of ATP-dependent [3H] ouabain binding. Inotropic responses to digitoxin during perfusion and subsequent loss during washout were accompanied by a reduction and subsequent recovery of ouabain-sensitive 86Rb uptake. Thus, it would appear that with cardiac glycosides, a relationship exists among cardiac contractile force, the inhibition of cardiac (Na+,K+)-ATPase, and the inhibition of the sodium pump activity. The inhibition of (Na+,K+)-ATPase and sodium pump because of cardiac glycoside perfusion of the isolated beating heart was reversible.

Adenosine Triphosphatases↗
PubMed1987

[Acute electrophysiological effects of cardiac glycosides on sinus node function and ventricular repolarization under clinical conditions].

The influence of digoxin, digitoxin and g-strophanthin (ouabain) on the sinus node function (recovery time, sinoatrial conduction time, PP-interval) and on ventricular repolarisation (corrected QT interval and QT during permanent atrial stimulation) was studied in 101 patients (36 with sick sinus syndrome-SSS, 34 with ischaemic heart disease-IHD, and 31 control patients without cardiac disease). Digoxin caused marked prolongation of sinoatrial conduction time (in SSS and in control patients), digitoxin prolonged the PP interval (in IHD and SSS patients); digitoxin and ouabain shortened the QTcorr in SSS patients, ouabain shortened also QT during atrial pacing. The results do not point to specific indication of individual glycosides in sinus node function disturbances. Under certain clinical prerequisites, however, digitoxin can be recommended in ventricular ectopic contractions caused by prolonged or inhomogeneous repolarisation, and also the capacity of ouabain to shorten the repolarisation time deserves attention.

Cardiac Pacing, Artificial↗
PubMed1977

[Treatment of the experimental chronic digitalisintoxication by hemoperfusion (author's transl)].

In 5 adult dogs experimental chronic digitalis intoxication was produced by oral administration of different digitalis-types (digoxin, beta-methyl-, beta-acetyl-digoxin, digitoxin). 18 to 24 hours after the last application of digitalis, charcoal hemoperfusion was performed in Dipidolor-N2O-anesthesia and serum digitalis-concentrations in the arterial and venous lines of the hemoperfusion system were determined by RIA J125. The Ecg was registered continuously as a simple clinical parameter of cardiac digitalis intoxication. Initial multiple cardiac arrhythmias (AVII degree, SAII degree, tachycardia of the atrium) subsided in the dogs with digoxin, beta-methyl- and beta-acetyl-digoxin during hemocolperfusion within 130 to 160 min. The disturbances of rhythm persisted up to 200 min after onset of hemoperfusion in the dog intoxicated by digitoxin. The clearances of digoxin and derivatives (35.8--43.1 ml/min) are higher than the digitoxin clearance (17--23.2 ml/min) which is supposed to be the reason for cardiac detoxication in the digoxin-intoxicated dogs. Hemoperfusion using polymer coated charcoal appears to be effective for the elimination of digoxin leading to a marked improvement of cardiac arrhythmias. By contrast digitoxin induced cardiac arrhythmias are not influenced during hemoperfusion.

Animals↗
PubMed1983

[Color perception disorders in therapeutic glycoside serum concentrations].

Vision deficiencies are dominant symptoms from digitalis intoxication. Twenty-nine and twenty-eight patients have been examined by the Farnsworth-Munsell-100-Hue-test under common maintenance therapy with digitoxin respectively digoxin or beta-acetyldigoxin. This was done to prove how glycosides may create colour vision disturbances even in "therapeutic" glycoside serum concentrations, and in which degree the lipophile digitoxin differs in its effect from the less lipophile digoxin. To exclude any congenital colour vision deficiencies the study was restricted to females. No definite difference in the total error score has been found among patients treated with digitoxin and digoxin. Our results and further new investigations have pointed out that colour vision in digitalized patients is influenced even under common maintenance therapy. It can also be stated that digitoxin does not influence colour vision other than digoxin.

Aged↗
PubMed1996

Endocytosis inhibition protects the isolated guinea pig heart against ouabain toxicity.

We have tested whether toxicity and uptake of ouabain are linked phenomena in isolated guinea-pig heart. We perfused toxic dose of either ouabain, dihydroouabain (hydrophilic cardiac steroids), ouabagenin or digitoxin (hydrophobic steroids) in conditions of endocytosis inhibited. We used two schemes of inhibition of endocytosis. First, we cooled the heart at 0-4 degrees C and exposed it 60 min to either 1 X 10(-6) M ouabain or 3 X 10(-7)M digitoxin. Upon rewarming, the heart exposed to ouabain relaxed with a shorter time constant than those exposed to digitoxin. Second, we perfused four receptor mediated endocytosis (RME) inhibitors at the same time that the cardiac glycosides. RME inhibitors significantly delayed the cardiac arrest caused by ouabain and dihydroouabain but they did not modify the toxicity of 3 X 10(-7)M digitoxin or 5 X 10(-6)M ouabagenin. None of RME inhibitors modified the toxicity of 0.5 mM K+ or zero Na+ saline solution. We suggest that the protection against ouabain toxicity brought by endocytosis inhibition, is related to the Na-pump recycling. We infer that besides the sarcolemmal exposed Na-pumps, the intracellular Na-pumps pool may be of importance for the pharmacological effects of digitalis steroids.

Animals↗
PubMed1983

The effects of chloroquine and other weak bases on the accumulation and efflux of digoxin and ouabain in HeLa cells.

We have studied the effects of the weak bases chloroquine, NH4Cl and amantadine on the handling of certain cardiac glycosides by HeLa cells. When these weak bases are applied acutely to HeLa cells they have only minor effects on the binding of cardiac glycosides to the sodium pumps and on the recovery of pump function following block. When cells are grown in these weak bases there is a variable (10-30%) reduction in pump numbers. This effect is additive to that of chronic treatment with cardiac glycosides. If all sodium pumps are blocked with ouabain, digoxin or digitoxin then recovery of function recovers with a T1/2 of about 7 h (10% h-1); digoxin and digitoxin molecules are excreted at a similar rate but ouabain excretion occurs at a much slower rate (3% h-1). These weak bases greatly slow (x 3) the rate of excretion of digoxin and digitoxin but do not alter that of ouabain. The process affected by chloroquine was estimated to have a T1/2 of 8 h. Cells grown in the presence of cardiac glycosides accumulate large numbers of glycoside molecules; chloroquine, NH4Cl and amantadine increase the accumulation of digoxin and digitoxin and may decrease that of ouabain. Quantitatively these results fit a model whereby cardiac glycosides are accumulated by HeLa cells bound to the sodium pumps, are processed by the lysosomes and then excreted. The results are consistent with a process of internalisation and renewal of sodium pumps by HeLa cells.

Amantadine↗
PubMed2006

Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking.

Direct block of the cardiac potassium channel human ether-a-go-go-related gene (hERG) by a large, structurally diverse group of therapeutic compounds causes drug-induced QT prolongation and torsades de pointes arrhythmias. In addition, several therapeutic compounds have been identified more recently that prolong the QT interval by inhibition of hERG trafficking to the cell surface. We used a surface expression assay to identify novel compounds that interfere with hERG trafficking and found that cardiac glycosides are potent inhibitors of hERG expression at the cell surface. Further investigation of digitoxin, ouabain, and digoxin revealed that all three cardiac glycosides reduced expression of the fully glycosylated cell surface form of hERG on Western blots, indicating that channel exit from the endoplasmic reticulum is blocked. Likewise, hERG currents were reduced with nanomolar affinity on long-term exposure. hERG trafficking inhibition was initiated by cardiac glycosides through direct block of Na(+)/K(+) pumps and not via off-target interactions with hERG or another closely associated protein in its processing or export pathway. In isolated guinea pig myocytes, long-term exposure to 30 nM of the clinically used drugs digoxin or digitoxin reduced hERG/rapidly activating delayed rectifier K(+) current (I(Kr)) currents by approximately 50%, whereas three other cardiac membrane currents--inward rectifier current, slowly activating delayed rectifier K(+) current, and calcium current--were not affected. Importantly, 100 nM digitoxin prolonged action potential duration on long-term exposure consistent with a reduction in hERG/I(Kr) channel number. Thus, cardiac glycosides are able to delay cardiac repolarization at nanomolar concentrations via hERG trafficking inhibition, and this may contribute to the complex electrocardiographic changes seen with compounds such as digitoxin.

Action Potentials↗