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PubMed1985

Use of cardiac glycosides in Finland.

The prevalence and number of persons receiving cardiac glycosides were estimated in connection with a general health survey. A population sample (n = 8000) representative of the adult Finnish population was studied. According to a questionnaire and an interview, about 10% of men and 11% of women were receiving cardiac glycosides. The total number of glycoside users in Finland was estimated at 311 000 (95% confidence limits 289 000-333 000). A significant serum digitalis concentration definitely indicating digitalis use was observed in about 9% of men and 10% of women. By this method the minimum number of persons receiving digitalis therapy was estimated at 248 000 (95% confidence limits 227 000-269 000). About 90% of all glycoside consumption appeared to take place outside institutions. The prevalence of glycoside use increased greatly with advancing age and tended to be higher in women than in men. The prevalence varied significantly between regions within the country. Further research is required to explain the unusually prevalent and geographically variable use of cardiac glycosides in Finland.

Adult↗

PubMed1981

High-performance liquid chromatography of cardiac glycosides.

Highly efficient, short columns have been prepared for the separation of mixtures of cardiac glycosides at relatively small pressure drops. The selectivities of silica adsorbents with different chemically modified surface layers for cardiac glycosides were determined. The influence of the structure of cardiac glycoside molecules on their retention characteristics in liquid chromatography was investigated. The relative number of hydrophobic and hydrophilic groups in the glycoside molecules as well as the configurations are very important for the separation.

Animals↗

PubMed1980

Hypotensive effects of cardiac glycosides in spontaneously hypertensive rats.

The effects of cardiac glycosides on systolic arterial pressure (SAP) and heart rate (HR) were studied in spontaneously hypertensive (SH) and normotensive (NT) Wistar rats. Ouabain (2 mg/kg), given by i.p. injection to unanesthetized rats, produced a significant decrease in SAP in both SH and NT rats with little concomitant HR change. Baroreceptor denervation abolished the response. To analyze the effects more completely, experiments were done on acutely anesthetized rats. Ouabain was administered i.p. 30 min after induction of anesthesia with alpha-chloralose (60 mg/kg i.p.). alpha-Chloralose alone produced a significant SAP decrease in both SH and NT rats and bradycardia in SH but no significant HR change in NT rats. Ouabain i.p. further reduced SAP in SH but had no effect on NT rats. When given by i.a. bolus injection (250 microgram in 0.1 mg of heparin-saline) to anesthetized (pentobarbital, 40 mg/kg i.p.) rats with intact left carotid sinus nerves, ouabain produced a transient but significant reduction in SAP of SH but NT rats or SH rats with sinoaortic denervation. Digitoxin, given by stomach tube (4--5 mg/kg) for 1 week, decreased SAP in SH but not NT rats. Digitoxin produced significant SAP increases in SH rats with sinoaortic denervation. Arterial baroreceptor discharge is increased by cardiac glycosides. The present results suggest that the reflex hypotensive effects of digitalis drugs are due, at least in part, to sensitization of baroreceptors and that SH rats may be more sensitive to these drugs possibly because of altered intrinsic baroreceptor properties.

Animals↗

PubMed1986

A dual effect of cardiac glycosides on Ca current in single cells of frog heart.

The effects of cardiac glycosides (1 microM ouabain, 50 microM dihydrooubain, 1 microM strophanthidin) on Ca current (ICa) were investigated on Cs-loaded single frog ventricular cells using the whole-cell patch-clamp technique (9). Cardiac glycosides exert both inhibitory and stimulatory effects on ICa in 20 Cs Ringer solution, but have only a stimulatory effect in 0 Cs, when the Na,K pump is blocked. The inhibitory response seems related to the inhibition of the Na,K pump by glycosides. The stimulatory effect on ICa may contribute to the positive inotropic effect of cardiac glycosides.

Animals↗

PubMed1997

A case of nondigitalis cardiac glycoside toxicity.

A case is presented of cardiac glycoside poisoning in a 1-year-old patient from the plant Nerium oleander (common oleander). The patient had bradycardia, vomiting, altered level of consciousness, and no history of ingestion. Antibody-based digoxin assays may cross-react with other cardiac glycosides nonquantitatively. Chromatographic techniques can be used in the specific diagnosis.

Animals↗

PubMed1992

A multispecific uptake system for taurocholate, cardiac glycosides and cationic drugs in the liver.

To test the hypothesis of multiplicity in carrier-mediated uptake mechanisms for organic cations in the liver and to study the possible relation with bile acid and cardiac glycoside uptake mechanisms, mutual interaction during uptake of various radiolabeled quaternary amines has been studied in isolated rat hepatocytes. Inhibition patterns at low concentrations (1 microM) of the presumed type I monovalent organic cation tri-n-butylmethylammonium were markedly different from those at relatively high concentrations (25 microM). Both the cardiac glycoside K-strophantoside and the bile acid taurocholate clearly reduced the uptake rate of tri-n-butylmethylammonium at 25 microM whereas these agents completely failed to reduce the uptake at low concentrations of the cation. Subsequently, inhibition of uptake of some multivalent amphipathic organic cations (muscle relaxants) for the type II uptake system was investigated. It was found that the uptake of these muscle relaxants both at tracer concentrations (< 1 microM) and at relatively high concentrations (25 microM) was decreased in the presence of low concentrations of the cardiac glycoside K-strophantoside, while taurocholate only inhibited the uptake at the concentration range > 25 microM of the muscle relaxants. Procainamide ethobromide, a typical type I organic cation, did not affect the uptake either at the low or high concentration range of the muscle relaxants. It is concluded that for each of the type I-like compounds and type II-like compounds tested at least two systems are involved in uptake into hepatocytes: tri-n-butylmethylammonium in a concentration range < or = 1 microM is mainly taken up by the type I uptake system and at concentrations > or = 25 microM also by system(s) that can be inhibited by taurocholate and K-strophantoside. Bulky amphipathic organic (type II) cations at concentrations < 1 microM are also transported by an uptake system that is inhibitable by cardiac glycosides but not by bile salts. At concentrations > 25 microM these compounds are predominantly accommodated by an uptake system that possibly mediates uptake of both cardiac glycosides and bile acids. This concept was supported by the observation that both type II organic cations and bile salts can inhibit ouabain uptake, while type II organic cations as well as the cardiac glycosides reduce taurocholate uptake rate. The present data support the idea that the liver seems to be equipped with a "multispecific" uptake system that transports hydrophobic compounds irrespective of charge, including some type I and type II organic cations at relatively high substrate concentrations.

Androstanols↗

PubMed1984

Cardiac glycosides and sodium/potassium-ATPase.

The sodium/potassium-ATPase complex is, according to modern research, the binding site for cardiac glycosides on the outer surface of the cell membrane and their receptor. Inhibition of this enzyme by cardiac glycosides leads for instance in the heart to a decrease or a delay in membrane sodium/potassium-ion transport, and indirectly to an increase in the intracellular ionized calcium-concentration and an increase in cardiac contractile force. According to recent observations the activity of the sodium/potassium-ATPase or its concentration, and therefore the concentration of binding sites can increase in some tissues after long term treatment with cardiac glycosides. This might explain the occasionally observed tolerance to digitalis glycosides.

Animals↗

PubMed1998

Identification of a model cardiac glycoside receptor: comparisons with Na+,K+-ATPase.

The availability of high-affinity anti-digoxin monoclonal antibodies (mAbs) offers the potential for their use as models for the characterization of the relationship between receptor structure and cardiac glycoside binding. We have characterized the binding of anthroylouabain (AO), a fluorescent derivative of the cardiac glycoside ouabain, to mAbs 26-10, 45-20, and 40-50 [Mudgett-Hunter, M., et al. (1995) Mol. Immunol. 22, 477] and lamb kidney Na+, K+-ATPase by monitoring the resultant AO fluorescence emission spectra, anisotropy, lifetime values, and Förster resonance energy transfer (FRET) from protein tryptophan(s) (Trp) to AO. These data suggest that the structural environment in the vicinity of the AO-binding site of Na+,K+-ATPase is similar to that of mAb 26-10 but not mAbs 45-20 and 40-50. A model of AO complexed to the antigen binding fragment (Fab) of mAb 26-10 which was generated using known X-ray crystal structural data [Jeffrey, P. D., et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 10310] shows a heavy chain Trp residue (Trp-H100) that is close ( approximately 3 A) to the anthroyl moiety. This is consistent with the energy transfer seen upon AO binding to mAb 26-10 and suggests that Trp-H100, which is part of the antibody's cardiac glycoside binding site, is a major determinant of the fluorescence properties of bound AO. In contrast, the generated model of AO complexed to Fab 40-50 [Jeffrey, P. D., et al. (1995) J. Mol. Biol. 248, 344] shows a heavy chain Tyr residue (Tyr-H100) which is part of the cardiac glycoside binding site, located approximately 10 A from the anthroyl moiety. The closest Trp residues (H52 and L35) are located approximately 17 A from the anthroyl moiety, and no FRET is observed despite the fact that these Trp residues are close enough for significant FRET to occur. The energy transfer seen upon AO binding to Na+,K+-ATPase suggests the presence of one completely quenched or two highly quenched enzyme Trp residues approximately 10 and approximately 17 A, respectively, from the anthroyl moiety. These data suggest that the Na+,K+-ATPase Trp residue(s) involved in fluorescence energy transfer to AO is likely to be part of the cardiac glycoside binding site.

Animals↗

PubMed1985

Suppression of positive inotropic and toxic effects of cardiac glycosides by amiloride.

Effects of amiloride on the inotropic and toxic actions of cardiac glycosides were examined using left atrial muscle isolated from guinea pig heart. Preincubation of atrial muscle with amiloride significantly decreased the maximum positive inotropic effect of dihydrodigoxin but failed to reduce that of isoproterenol. Amiloride prevented the contracture and significantly reduced the incidence of arrhythmias induced by 2 microM digoxin. Similar experiments examining 5 microM digoxin-induced arrhythmias showed that amiloride increased both the time required to produce arrhythmias and the fractional occupancy of sarcolemmal Na,K-ATPase by digoxin at the onset of arrhythmias. The antagonism of cardiac glycoside actions was best observed during the decline in developed tension elicited by amiloride subsequent to its initial positive inotropic effect. Amiloride had no effect on binding site concentration for ATP-dependent [3H]ouabain binding but decreased affinity of the binding sites for ouabain in membrane preparations obtained from guinea pig heart. Furthermore, amiloride inhibited Na,K-ATPase activity and increased the IC50 value for ouabain inhibition of the enzyme. These results indicate that amiloride antagonizes the positive inotropic and toxic effects of cardiac glycosides. Possible mechanisms for the antagonism include inhibition of sarcolemmal Na+/Ca2+ or Na+/H+ exchange.

Amiloride↗

PubMed2001

Biphasic effect of cardiac glycosides on action potential duration in isolated Purkinje fibers.

Despite the historical use of cardiac glycosides, the data describing the electrophysiological characteristics of this class of drug are not fully clear. The present study reported the biphasic effect of cardiac glycosides, digoxin (1.25 microM) and acetylstrophanthidin (0.15 microM), on action potential duration in isolated Purkinje fibers by the conventional glass microelectrode technique. At the cycle lengths of 990, 690 and 490 msec., action potential duration lengthened within 10 min. and shortened after 10 min. of digoxin and acetylstrophanthidin administration. The biphasic effect was observed at a concentration of 4.0 mM [K(+)]o. However, at a higher [K(+)]o concentration of 5.4 mM, only the shortening effect on action potential duration was recorded. These results suggest that the biphasic effect of cardiac glycosides on action potential duration is related to the concentration of extracellular potassium and is not related to the stimulating cycle lengths.

Action Potentials↗

PubMed2000

Effect of dietary cardiac glycosides on blood pressure regulation in rats.

To investigate the possible physiological significance of dietary cardiac glycosides in blood pressure regulation, the blood pressure of normal Sprague Dawley rats raised on a regular diet, which naturally contains large amounts of Na+-pump inhibitors, was compared with that of rats on a purified synthetic diet, which contains no Na+-pump specific inhibitors, and with that of rats on a synthetic diet supplemented with 10 microg x mL(-1) ouabain or 10 microg x mL- convallatoxin in the drinking water. After 6 weeks on the synthetic diet, the systolic blood pressure in the synthetic diet group was significantly elevated (145 +/- 5 vs. 128 +/- 4 mmHg, P < 0.05). At 10 weeks it reached a plateau (154 +/- 3 vs. 122 +/- 3 mmHg, P < 0.05). Plasma renin activity and Na+ level were significantly higher in animals fed synthetic diets than in the regular diet group (P < 0.01). Administration of either losartan or lisinopril or a switch to a low salt synthetic diet (0.03% sodium) normalized the synthetic diet-induced high blood pressure. Supplementation of the synthetic diet with the cardiac glycosides delayed the onset of the increase in blood pressure for 4 weeks. Plasma aldosterone levels were approximately doubled in the cardiac glycoside-treated groups. Higher plasma Na+ levels and hematocrit values present in the synthetic diet group were normalized by the glycoside supplements. These results suggest that supplemental dietary cardiac glycosides exert bidirectional effects on blood pressure regulation through actions that modulate extracellular fluid and electrolyte balance.

Animals↗

PubMedDate not supplied

Contribution of clinical pharmacology to a rational use of cardiac glycosides in Czechoslovakia.

In Czechoslovakia, drug utilization studies showed that oral forms of digoxin and lanatoside C are traditionally the most prescribed cardiac glycosides. Our study of the relative bioavailability of the oral form of lanatoside C revealed that the drug has a low and irregular bioavailability making use of this frequently prescribed drug non-rational. The above data definitely contributed to a sharp decrease in the use of the oral form of lanatoside C in our country, which is in agreement with consumption trends in other European countries. However, the use of only drug forms with a good bioavailability is one aspect of new approaches applied in pharmacotherapy with cardiac glycosides resulting in gradual decrease of their consumption as a pharmacological group. Clinical pharmacological evaluation of individual drug forms and postgraduate education in clinical pharmacology of cardiac glycosides contribute significantly--apart from other regulatory measures--to a more rational use of cardiac glycosides in Czechoslovakia.

Biological Availability↗

PubMed1991

[The current concepts of the effect of cardiac glycosides on sinus node function and atrioventricular conductivity].

The clinical aspects of the influence of cardiac glycosides on the sinus node and atrioventricular junction in health and dysfunction are reviewed. It has been shown that digitalis drugs do not produce any effect on sinus node automatism including that in dysfunction. Cardiac glycosides suppress enhanced atrioventricular conduction and do not affect it provided it remains within normal. The mechanisms by which cardiac glycosides may act are discussed: extracardiac, cholinomimetic (in the acute test and direct one) and influencing heart conduction components (when used continuously).

Cardiac Glycosides↗

PubMed1989

Specific binding of cardiac glycoside drugs and endogenous digitalis-like substances to particulate membrane fractions from human placenta.

We studied the characteristics of binding of cardiac glycosides to particulate membrane fractions from human placenta, to demonstrate that placental tissue is a suitable source of receptors for digitalis drugs. Moreover, we performed preliminary experiments with 125I-labeled digoxin and placental particulates to develop a radioreceptor assay for measurement of endogenous substances with activity similar to cardiac glycoside drugs (EDLS). Placental membrane fractions were incubated with [3H]ouabain (10 nmol/L) or 125I-labeled digoxin (50 pmol/L). With both ligands, binding followed a pseudo-first-order reaction kinetics and was saturable. Scatchard analysis revealed a single class of sites [for ouabain, KD = 20.2 +/- 5.8 nmol/L (mean +/- SEM), Bmax = 3.1 +/- 0.9 nmol per gram of protein; for digoxin, KD = 29.7 +/- 1.9 nmol/L, Bmax = 24.3 +/- 1.1 nmol per gram of protein]. As expected, digoxin was less potent than ouabain in displacing both tracers from digitalis drugs receptors; progesterone, cortisone, digitoxose, furosemide, bumetanide, and propranolol had no or little effect. Specific 125I-labeled digoxin binding was competitively inhibited by plasma and (or) urine extracts from newborns, adults, pregnant women, and patients with renal insufficiency. Inhibition of binding and volume of plasma and urine assayed were linearly related. These findings support the hypothesis that cardiac glycosides and EDLS can interact with the human placenta and suggest placental tissue to be a suitable source of receptors for cardiac glycosides.

Binding Sites↗

PubMed1996

Role of endogenous cardiac glycosides in the spontaneously hypertensive rat--antagonism by active immunization.

The effects of simultaneous active immunization against two cardiac glycoside drugs, digoxin and proscillaridin, have been examined in young spontaneously hypertensive and Wistar-Kyoto rats. Control animals were immunized with protein carrier only. Animals were studied from 5 weeks to 13 weeks of age. Effectiveness of immunization to produce antibody responses was assessed at the end of the study by estimating the titer of antibodies in plasma against both of the antigens. Robust antibody responses were obtained. Immunization had no effect on the normal growth of these animals. Further, immunization against cardiac glycosides did not change blood pressure in either strain of animals. Blood pressure in the SHR increased as anticipated as the weanling animals grew to maturity. These studies indicate that active immunization against cardiac glycosides does not alter blood pressure in the SHR in spite of strong evidence for increased levels of endogenous cardiac glycosides in this strain.

Animals↗

PubMed2006

Cardiac glycosides initiate Apo2L/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulation of death receptors 4 and 5.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) belongs to the TNF family known to transduce their death signals via cell membrane receptors. Because it has been shown that Apo2L/TRAIL induces apoptosis in tumor cells without or little toxicity to normal cells, this cytokine became of special interest for cancer research. Unfortunately, cancer cells are often resistant to Apo2L/TRAIL-induced apoptosis; however, this can be at least partially negotiated by parallel treatment with other substances, such as chemotherapeutic agents. Here, we report that cardiac glycosides, which have been used for the treatment of cardiac failure for many years, sensitize lung cancer cells but not normal human peripheral blood mononuclear cells to Apo2L/TRAIL-induced apoptosis. Sensitization to Apo2L/TRAIL mediated by cardiac glycosides was accompanied by up-regulation of death receptors 4 (DR4) and 5 (DR5) on both RNA and protein levels. The use of small interfering RNA revealed that up-regulation of death receptors is essential for the demonstrated augmentation of apoptosis. Blocking of up-regulation of DR4 and DR5 alone significantly reduced cell death after combined treatment with cardiac glycosides and Apo2L/TRAIL. Combined silencing of DR4 and DR5 abrogated the ability of cardiac glycosides and Apo2L/TRAIL to induce apoptosis in an additive manner. To our knowledge, this is the first demonstration that glycosides up-regulate DR4 and DR5, thereby reverting the resistance of lung cancer cells to Apo2/TRAIL-induced apoptosis. Our data suggest that the combination of Apo2L/TRAIL and cardiac glycosides may be a new interesting anticancer treatment strategy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1978

Current drug therapy: cardiac glycosides.

The following aspects of the cardiac glycosides are reviewed: chemistry; pharmacology; absorption, distribution, metabolism and excretion; uses; toxicity; cautions; drug interactions and laboratory test interferences; and dosage.

Absorption↗

PubMed1989

Biodistribution of two 99mTc-cardiac glycosides with end glucose unit: effect of lipophilicity on their relative myocardial accumulation.

In biodistribution experiments with tritium labelled cardiac glycoside it was observed that compounds of low lipophilicity showed a considerably higher affinity towards myocardium with respect to other tissues and organs. A similar trend was also observed with 99mTc-cardiac glycosides except for one compound with glucose residue, which in spite of its lower lipophilicity exhibited an unexpectedly low heart to non-target concentration ratio, thereby indicating a possible influence of carbohydrate residue on biodistribution. To confirm this, in this article we radiolabelled two glucose containing cardiac glycosides (K-strophanthin-beta and K-strophanthoside) with 99mTc and, in biodistribution experiments, less lipophilic 99mTc-K-strophanthoside showed a much better heart to non-target ratio over 99mTc-K-strophanthin-beta. It is thus concluded that, in addition to lipophilicity, the affinity of the carbohydrate residue for non-target organs is also an important consideration in determining the structure-distribution relationship of 99mTc-cardiac glycosides.

Animals↗