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PubMed1986

Factors of importance for valid digitalis assays particularly for the determination of digoxin in plasma and urine.

Four commercial radioimmunoassay (RIA) kits for digoxin varied in precision (coefficient of variation, CV within-assays 5-14%) and accuracy (up to 40%). Thus it seems that such commercial RIA-kits can reach at best a CV within-assay of 5% and a similar variation between assays. Without a good control of the performance, the variation can increase 5-6 times. We found that the precision of digoxin RIA as performed at 27 Swedish laboratories using 10 different methods varied from 0.05 to 0.61 nmol/L in between-assay SD for a pool of 2.60 nmol/L. Up to 100% deviations between the highest and lowest reported concentration of a spiked plasma pool may occasionally occur. Such deviations mostly depend on the laboratory, but there are contributions from the kit and effects of the matrix as well. Matrix effects were observed in plasma samples from patients with uremia, acute myocardial infarction and treated with spironolactone to which digoxin was added to a concentration of 2.50 nmol/L. We found 10% underestimation by one method, 10% overestimation by two methods and 5% overestimation by a fourth method, respectively, with the above described samples. For a good judgement of a found plasma concentration value, calculation of a confidence interval is useful. This can be done by computer fitting of the standard curve after duplicate runs of standards and samples in random order. One source of error in RIA appears to be the use of inaccurate standards. We found that standards provided with different RIA-kits for digoxin varied up to 30%. Various physicochemical properties of cardiac glycosides, which could influence the assays were studied. Both digitoxin and digoxin are sparsely soluble in water (5.1 and 36 mumol/L, respectively). Methanol is a much better solvent, which dissolves 6.9 mmol/L of digoxin and 20-24 mmol/L of digitoxin. Chloroform is a good solvent for digitoxin (29-34 mmol/L) but not for digoxin (0.42 mmol/L). Partition of cardenolides between chloroform and water reflected their lipophilic or hydrophilic character. Thus, digitoxin had a high affinity to the organic phase (distribution constant KD = 10(3.65)), while the hydrophilic deslanoside was preferentially found in the aqueous phase (KD = 10(-3.08). Interestingly, the sugar moiety digitoxose in the digoxin molecule turned out to be a substituent that increased lipophilicity. Adsorption of cardiac glycosides occurs to plastics and glass from aqueous solutions. To overcome losses at low concentrations, the solutions must contain plasma, albumin, alcohol or similar solubility-increasing ingredients.(ABSTRACT TRUNCATED AT 400 WORDS)

Chromatography, High Pressure Liquid↗
PubMed1982

On the glucuronidation of digitalis compounds in different species.

Experiments were undertaken to evaluate for various species the activity and specificity of the glucuronyltransferase(s) which are responsible for the conjugation of digitoxin or its metabolites formed by oxidative cleavage of the sugar chain. As shown for rats the glucuronide of digitoxigenin monodigitoxoside is the main polar digitoxin metabolite in vivo. However, it cannot be decided whether this digitoxoside or another metabolite is the best substrate for the glucuronyltransferase. Therefore, in vitro measurements were made with possible cleavage products of digitoxin using detergent activated liver microsomes. Digitoxigenin monodigitoxoside is by far the best substrate for the microsomal glucuronyltransferase of rats (120 pmoles/mg/min). Ten-fold lower values were found with digitoxigenin bisdigitoxoside and only traces of glucuronides were formed with digitoxin, digitoxigenin or its 3-epimer. With liver microsomes of other species the glucuronidation rates for digitoxigenin monodigitoxoside decreased in the following order: rat greater than rabbit greater than guinea-pig greater than cat (1:0.3:0.2:0.05). For rabbit liver microsomes, however, the best substrate was the 3-epi-digitoxigenin instead of the monodigitoxoside (145 pmoles/mg/min). Experiments with tissue slices of liver and small intestine revealed further differences between rats and rabbits. Whereas rat intestine was nearly inactive the activity of rabbit intestine attained about 50% of that found in the liver. It can be concluded that various species show remarkable differences in the activity, stereospecificity and organ distribution of the glucuronyltransferase(s) conjugating cardenolide derivatives.

Animals↗
PubMed1976

Effects of colestipol hydrochloride on drug absorption in the rat II.

The effects of colestipol hydrochloride, a hypocholesterolemic bile acid-binding anion-exchange polymer, on the GI absorption of drugs commonly used in humans were studied in the rat. Colestipol hydrochloride was given by gavage in single doses of 71.5 or 214.5 mg/kg, equivalent to 5 or 15 g, respectively, in a 70-kg human; controls received equivalent amounts of microcrystalline cellulose. Single oral doses of labeled drugs were given concurrently with colestipol hydrochloride or microcrystalline cellulose at the human therapeutic dose range on a milligrams per kilogram basis. Subsequent changes in serum drug levels were measured at several time periods, and absorption was evaluated as the total area under the time-concentration curve. Colestipol hydrochloride at either dose did not significantly alter the absorption of 6-14C-nicotinic acid, 7-3H-tetracycline, 35S-chlorpromazine, 12alpha-3H-digoxin, warfarin (alpha-14C-benzyl), or clofibrate (14C-carboxyl). In addition, the effects of 214.5 mg/kg of colestipol hydrochloride were compared with the same dose of cholestyramine with respect to the absorption of 3-14C-hydrochlorothiazide, 2-14C-phenobarbital, and 3H-digitoxin. Cholestyramine reduced absorption of hydrochlorothiazide by 42%, but colestipol hydrochloride had no significant effect. Neither resin altered phenobarbital or digitoxin absorption when compared with the the control, but a significant difference occurred between the two resins with digitoxin; areas under the time-concentration curve [in (dpm/0.1 ml serum) x hr] were: colestipol hydrochloride, 2001; cholestyramine, 16,300; and cellulose, 17, 067. These results indicate that colestipol hydrochloride and cholestyramine can differ in their effects on the absorption of certain drugs from the GI tract of the rat.

Animals↗
PubMedDate not supplied

Functional antagonism by a monoclonal antibody to digoxin in a test system of cultured rat heart myocytes.

A monoclonal antibody with a high affinity for digitoxin (KA = 0.50 nM) and digoxin (KA = 0.55 nM) was produced by somatic cell fusion. This antibody, designated 2A3(47), displayed little cross reactivity with other glycosides. In cultured rat heart myocytes, 2A3(47), antagonized the positive chronotropic effect exerted by digitoxin but did not alter that of ouabain. Our results suggest that this monoclonal antibody may prove to be useful in treating digoxin and digitoxin intoxication.

Animals↗
PubMed1977

Influence of acute renal failure on the protein binding of drugs in animals and in man.

Serum protein binding of phenylbutazone has been measured in the rat, guinea pig, cat, rabbit and dog, and the influence on it of renal failure induced by uranyl nitrate injection has been studied. In all speciies a clearcut decrease in binding was observed after the occurrence of renal failure; the time course of the fall in binding correlated well with development of renal failure. In further experiments, serum protein binding of two acidic drugs (phenylbutazone, warfarin), two basic drugs (papaverine, quinidine) and one neutral drug (digitoxin) was studied in rabbits with experimental renal failure, and the results compared with those obtained in patients with acute renal failure. In the rabbits, a decrease in the binding of phenylbutazone, warfarin, papaverine and quinidine was found, whereas protein binding of digitoxin was unchanged. In man, there was a definite fall in protein binding of phenylbutazone and digitoxin, a small decrease for warfarin and papaverine, and a slight increase for quinidine.

Acute Kidney Injury↗
PubMed1977

Digitalis pharmacokinetics and therapy with respect to impaired renal function.

The various cardiac glycosides differ significantly in their retention as a result of renal failure. In the case of digoxin, digitoxin, and strophanthin the retention is directly related to the normal renal clearance of these cardiac glycosides: Strophanthin has the highest clearance and the most marked prolongation of pharmacological action in renal failure, whereas digitoxin shows the lowest renal clearance and even in uremic patients a total elimination comparable to normal subjects as a result of increased hepatic clearance; digoxin takes an intermediate position. The quantity of a cardiac glycoside and its metabolites excreted by the kidneys depends, besides the renal clearance, on the plasma concentration which increases considerably during the first days after onset of treatment. From the daily dose approximately 90% of strophanthin, 70% of digoxin, 50% of digitoxin plus metabolites are excreted by normal kidneys under steady-state conditions. The efficiency of hemodialysis in the elimination of cardiac glycosides is low (3-5%) if estimated in relation to a single dose injected before dialysis and high (30-50%) if estimated in relation to the excretory capacity of normal kidneys during a period corresponding to the duration of a dialysis. During hemodialysis the plasma concentration of digoxin decreases as rapidly as in patients with normal renal function. Beside the efficiency of dialysis this finding may be explained by the decrease in the apparent volume of distribution of cardiac glycosides in patients with advanced renal failure; a reduced tissue protein binding seems likely to be the main reason for these changes in chronic renal insufficiency. A reduced volume of distribution and a reduced myocardial sensitivity are the main reasons for a very low predictability of the necessary individual maintenance dose of cardiac glycosides from the creatinine clearance. In patients with advanced renal insufficiency the tolerance to cardiac glycosides is reduced with respect to the daily dose, but it is rather increased in relation to the plasma concentration required to maintain the positive inotropic effect. The combination of hyperkalemia, hypermagnesemia, bypocalcemia and acidosis which is found almost exclusively with chronic renal failure, may explain the reduced myocardial sensitivity. Dosage regimens based on the measurement of creatinine-clearance are of little help in "effective digitalisation". Serial measurements of steady-state plasma concentration of cardiac glycosides may be the only way to reduce the risk of under- and overtreatment in patients with impaired renal function.

Cardiac Glycosides↗
PubMed1975

Digitalis pharmacokinetics and metabolism.

The pharmacokinetics of the cardiac glycofides have been elucidated as a result of the development of assays of sufficient sensitivity to measure the concentration of digitalis compounds in biological fluids. Digoxin can accumulate in the body without the administration of a loading dose, and a steady state blood concentration will be reached in 5 to 7 days. Digitoxin requires 35 days to accumulate to a plateau. If a loading dose of digoxin is used, it should be approximately three times the estimated daily maintenance dose. Factors that determine the selection of the appropriate maintenance dose of digoxin include renal function and lean body mass. Digitoxin is less dependent on renal function for its elimination than is digoxin. Knowledge of the pharmacokinetics of digitalis preparations is useful in determining how to change from one cardiac glycoside to another, each with different half-lives. One should wait 3 days before starting digoxin therapy when changing from maintenance digitoxin to digoxin (assuming normal renal function). The pharmacokinetics of changing from ouabain to digoxin without loss of digitalis effect are described. The metabolism of the commonly used digitalis preparations are summarized.

Atrial Fibrillation↗
PubMed1983

Digitalis structure-activity relationship analyses. Conclusions from indirect binding studies with cardiac (Na+ + K+)-ATPase.

We have performed direct and indirect binding studies with [3H]ouabain or [3H]digitoxin on beef or guinea pig cardiac (Na+ + K+)-ATPase to measure the potencies of a broad range of cardiotonic steroids for structure-activity relationship (SAR) studies for comparison with previously determined positive inotropic potencies. The positive inotropic potencies of twelve compounds on contracting guinea pig left atria correlated well with the equilibrium dissociation constants (KD values) from the inhibition of [3H]ouabain binding to guinea pig cardiac (Na+ + K+)-ATPase (r = 0.98 for seven 5 beta-compounds, r = 0.95 for five 5 alpha-compounds). Further we calculated KD values from the inhibition of [3H]ouabain binding data for a total of 33 digitalis derivatives on the digitalis-sensitive beef cardiac (Na+ + K+)-ATPase. For the 27 compounds tested on both beef cardiac (Na+ + K+)-ATPase and guinea pig left atria, the potencies showed a significant correlation (r = 0.92 for 22 5 beta-compounds, r = 0.96 for five 5 alpha-compounds. For seven compounds, KD values were measured on beef cardiac (Na+ + K+)-ATPase using inhibition of binding of [3H]digitoxin. These values correlated well (r = 0.99) with the KD values from the [3H]ouabain studies. These results show that: (1) The significant correlation observed between KD values on guinea pig cardiac (Na+ + K+)-ATPase and positive inotropic potency in guinea pig left atria is further evidence that the pharmacological receptor for inotropy is part of the enzyme, (2) Inhibition of the binding of [3H]ouabain or [3H]digitoxin can be used to determine the relative potencies of unlabelled digitalis derivatives. The similar relative potencies on beef and guinea pig cardiac (Na+ + K+)-ATPase of a broad range of digitalis derivatives indicate that the binding site is similar for both species; and (3) SAR studies indicate that functional groups on these steroids have the same influence on potency on either the positive inotropy or cardiac (Na+ + K+)-ATPase studies.

Animals↗
PubMed1975

Dependence of the cardiac uptake of digitalis glycosides on the extracellular calcium concentration in guinea pig isolated hearts.

The purpose of the present study was to investigate, at the myocardial level, the divergent influences of Ca2+ on the action of various cardiotonic steroids. Therefore, the cardiac uptake of 3-H-digitoxin and 3-H-digitoxin was studied in experiments on guinea pig isolated hearts. The following results were obtained: with digitoxin the increase of the extracellular calcium concentration from 0.45 upto 7.2 mM resulted in a concomitant decrease of the myocardial glycoside uptake from about 1.8 nmoles/g wet weight down to about 1.2 nmoles/g wet weight. Similar results were obtained when digoxin uptake was studied under the same conditions: with 0.45 mM Ca2+ about 0.6 nmoles/g wet weight were bound, increasing the calcium concentration upto 7.2 mM lead to a concomitant decrease of the cardiac digoxin uptake down to about 0.45 nmoles/g wet weight. Despite the different physicochemical behaviour of these two drugs and the different amounts of drug present in the hearts the influence of Ca2+ was almost identical if calculated on a relative basis. So far, no experimental based explanation can be given for the above discrepancies. Other possible interpretations are discussed.

Animals↗
PubMed1985

Pharmacokinetics, bioavailability and serum levels of cardiac glycosides.

Digoxin, the cardiac glycoside most frequently used in clinical practice in the United States, can be given orally or intravenously and has an excretory half-life of 36 to 48 hours in patients with serum creatinine and blood urea nitrogen values in the normal range. Since the drug is excreted predominantly by the kidney, the half-life is prolonged progressively with diminishing renal function, reaching about 5 days on average in patients who are essentially anephric. Serum protein binding of digoxin is only about 20%, and differs markedly in this regard from that of digitoxin, which is 97% bound by serum albumin at usual therapeutic levels. Digitoxin is nearly completely absorbed from the normal gastrointestinal tract and has a half-life averaging 5 to 6 days in patients receiving usual doses irrespective of renal function. The bioavailability of digoxin is appreciably less than that of digitoxin, averaging about two-thirds to three-fourths of the equivalent dose given intravenously in the case of currently available tablet formulations. Recent studies have shown that gut flora of about 10% of patients reduce digoxin to a less bioactive dihydro derivative. This process is sensitive to antibiotic administration, creating the potential for important interactions among drugs. Serum or plasma concentrations of digitalis glycosides can be measured by radioimmunoassay methods that are now widely available, but knowledge of serum levels does not substitute for a sound working knowledge of the clinical pharmacology of the preparation used and careful patient follow-up.

Absorption↗
PubMed1988

Specific binding characteristics of high affinity monoclonal antidigitoxin antibodies.

The specificity of various monoclonal antidigitoxin antibodies was characterized using 6 cardiac glycoside analogs. Spleen cells from BALB/c mice, immunized with BSA- or KLH-digitoxin conjugates, were fused with NS1 myeloma cells, and antibody-producing hybrids were identified by radioimmunoassay. Twenty-one monoclonal antidigitoxin-specific antibodies were obtained, 10 of which were cloned and characterized for affinity and specificity. All the antibodies had a high affinity constant, ranging from 8.10(8) to 2.5.10(10) 1/M. On the basis of their binding specificities, the antibodies could be classified into 3 groups: the first contained 7 antibodies exhibiting high cross reactivity (42-100%) with digitoxigenin, whereas the second and third groups did not recognize this analog (cross-reactivity of 1%). In the former group, the absence of the sugar moiety only slightly affected the binding reaction, although for the two other groups, this structure did appear to be involved in antibody recognition. Changes in the functional groups of the hapten molecule led to considerable changes in the antibody-antigen reaction. For all the antibodies except one, saturation of the lactone ring considerably affected binding. These results demonstrated that monoclonal antibodies of different specificities with respect to both the steroid backbone and the sugar moiety of digitoxin can be induced using a digitoxin-protein conjugate.

Animals↗
PubMed1998

Unexpected suppression of total digoxin concentrations by cross-reactants in the microparticle enzyme immunoassay: elimination of interference by monitoring free digoxin concentration.

The microparticle enzyme immunoassay (MEIA for digoxin (Abbott Laboratories, Abbott Park, Ill) requires no sample pretreatment and is widely used in clinical toxicology laboratories for monitoring serum digoxin concentrations. One advantage of the new MEIA is the lower cross-reactivities with such cross-reactants as digitoxin, oleandrin, and bufalin compared with the fluorescence polarization immunoassay (FPIA)for digoxin. Digitoxin, oleandrin, and bufalin showed positive cross-reactivity with MEIA and FPIAs for digoxin in the absence of the primary analyte, digoxin. A surprising finding was that digoxin concentrations were falsely decreased by these cross-reactants when serum pools containing digoxin were supplemented with various concentrations of these cross-reactants and when digoxin concentrations were measured by the MEIA. In contrast, digoxin concentrations were falsely elevated when measured by the FPIA. For example, when a serum pool containing 2.15 nmol/L of digoxin was supplemented with 129.5 nmol/L of bufalin, the apparent digoxin concentrations were 1.45 nmol/L with the MEIA and 3.00 nmol/L with the FPIA. Taking the advantage of only 25% protein binding of digoxin and more than 95% protein binding of digitoxin and bufalin, we demonstrated that monitoring free digoxin instead of total digoxin eliminated negative interference of digoxin by these cross-reactants in the MEIA and positive interference in the FPIA. Although oleandrin is also strongly bound to serum protein, high concentrations of oleandrin still modestly affect the free digoxin assay for both MEIA and FPIAs.

Bufanolides↗
PubMed1984

Variable cross-reactivity of digoxin metabolites in digoxin immunoassays.

The authors investigated the cross-reactivity of the major known digoxin metabolites--digoxigenin, digoxigenin monodigitoxoside, digoxigenin bisdigitoxoside, and dihydrodigoxin--and of digitoxin in three 125I-radioimmunoassays and one enzyme immunoassay for digoxin. Digitoxin and dihydrodigoxin exhibit low cross-reactivity and nonparallel dilution responses for these assays. The cross-reactivities of the other three substances are significant for all assays studied with digoxigenin and monodigitoxoside having nonparallel and enhanced tracer displacement compared with digoxin itself. The authors demonstrate that because of nonparallel tracer displacement estimates of cross-reactivity calculated by the 50% displacement method fail to adequately predict the error induced in digoxin assays by digitoxin. They conclude that digoxin metabolites in serum are measured to various extents as the parent digoxin compound by all of the immunoassays they studied. In view of the varying biologic activity of digoxin metabolites and the large patient to patient variations in digoxin metabolism, the cross-reactivities the authors observe may help to explain the discrepancies in correlation of clinical response to measured serum digoxin values reported in other studies.

Cross Reactions↗
PubMedDate not supplied

A novel inexpensive murine model of oral chronic digitalization.

A novel inexpensive murine model of oral administration of digitoxin (100 micro g/kg per day) added to routine chow is described. Serum digitoxin levels achieved after oral (n = 5; 116 +/- 14 ng/mL) and subcutaneous (n = 5; 124 +/- 11 ng/mL) administration were similar. A significant increase in the maximal left ventricular pressure rise of treated (n = 9) compared with control (n = 6) rats (dP/dt: 8956 +/- 233 vs 7980 +/- 234 mmHg/s, respectively; P = 0.01) characterized the positive inotropic action of digitoxin. In addition, no differences were observed in treated compared with control rats with regard to the electrocardiogram and systolic and diastolic left ventricular pressures.

Administration, Oral↗
PubMed1969

The distribution of 3H-labelled cardenolides between isolated guinea-pig atrial tissue and circulating, oxygenated whole blood.

1. An experimental method was developed that allowed the incubation of isolated organs in circulating whole blood. The circulating blood was oxygenated with a specially designed disc-oxygenator and drawn through the system by means of a roller pump.2. The method proved suitable for guinea-pig isolated atria, rabbit duodenum and to a lesser extent for chronically denervated rat diaphragm. Isolated atria could be kept for several hours. Various parameters of the circulating blood (haemolysis, pH, O(2) saturation, concentration of electrolytes) remained satisfactory for at least 5 hr. The method proved convenient for pharmacological and kinetic studies on isolated organs, suspended in whole blood of the corresponding species. The organs showed normal spontaneous mechanical activity and also responded to electrical stimuli and various drugs.3. The uptake of (3)H-labelled ouabain, digoxin, digitoxin and digitoxigenin was studied in guinea-pig isolated atria, suspended in circulating blood. The uptake reached equilibrium after 60-90 min. With respect to the total serum radio-activity the "apparent" tissue/medium (T/M) ratios obtained for the four drugs were within the range 0.4-1.1. If, however, the amount of free, non protein bound drug was taken as a base for the calculations, the following "true" T/M ratios were obtained: (3)H-ouabain 0.45; (3)H-digoxin 1.6; digitoxin 8.8; digitoxigenin 8.4. These values are virtually the same as those obtained with atria, suspended in an aqueous medium. Obviously, the uptake of (3)H-cardenolides from whole blood is determined by the amount of free non-protein-bound drug.4. (3)H-digitoxin and (3)H-digitoxigenin were taken up by guinea-pig erythrocytes to a small extent. No measurable amounts of (3)H-ouabain and (3)H-digoxin were taken up by erythrocytes.

Animals↗
PubMed1972

Species and ionic influences on the accumulation of digitalis glycosides by isolated perfused hearts.

1. The ability of isolated perfused guinea-pig (digitalis-sensitive species) and rat (digitalis-resistant species) hearts to accumulate radio-labelled digitalis glycosides was studied in relation to the ionic composition of the perfusion medium.2. It was observed that in both species much less digoxin was accumulated than was digitoxin or proscillaridin.3. The accumulation of digoxin was markedly inhibited in a low sodium or in high potassium medium. These effects were similar, but relatively less marked, with digitoxin and proscillaridin. Calcium and magnesium removal had relatively smaller effects on the accumulation of both polar and non-polar glycosides.4. The low accumulation of all digitaloids by the rat heart in comparison to the guinea-pig heart may be due to the formation of unstable complexes between the cellular membranes in the rat heart and the various digitaloids used in this study. Although digitaloids have a reduced affinity for rat hearts and rat heart membranes in comparison to guinea-pigs, the order of the accumulation of different glycosides in both species is the same, i.e. much less with polar glycosides than with non-polar glycosides.5. It was concluded that non-polar glycosides such as digitoxin and proscillaridin demonstrate the same ion-dependent accumulation mechanism as do the more polar glycosides such as digoxin and ouabain. In addition, the non-polar glycosides possess high capacity for ion-independent binding presumably due to lipophilic interactions with membranes.

Animals↗
PubMed1983

Electrophysiological studies of some semisynthetic cardiac glycoside derivatives in isolated papillary muscle of the guinea-pig.

The effects of digitoxin, 3 alpha-methyl-digitoxigenin-3 beta-monoglucoside (3 alpha-MDM), 3 alpha-methyl-digitoxigenin (3 alpha-MD), proscillaridin, 4, 5-methylene-procillaridin (4, 5-MP), and 3 beta-hydroxy-4, 5-methylene-A, B-trans-scillarenin (3 beta-HMTS) on force of contraction and on the transmembrane action potentials were examined in isolated papillary muscles of guinea-pigs. All derivatives exhibited the typical cardiac glycoside effects: i.e. they increased the force of contraction and shortened the action potential duration at 20% (plateau phase) and 90% of repolarization. With digitoxin, 3 beta-HMTS and 4, 5-MP a transient prolongation in action potential duration was observed at the lower concentrations. The action potential amplitude and the resting membrane potential were reduced consistently only with the higher concentrations used. The onset of the positive inotropic effects of 3 alpha-MDM, 3 alpha-MD and 3 beta-HMTS was more rapid than that of digitoxin and proscillaridin. The increment in contractile force reached a maximum well before the full shortening effect on the action potential duration had developed. The shortening of the action potential is thought to be responsible for the biphasic nature of the positive inotropic effect. With 3 alpha-MD and 3 alpha-MDM even toxic effects, e.g. increase in baseline tension, were completely reversible after washing in drug-free solution. The dose-response curves for the positive inotropism can only be compared reliably once the equilibrium of drug action has been established. This steady state is probably reflected by the development of the full shortening in action potential duration.

Action Potentials↗
PubMed1976

Effect of taurine on responses to noradrenaline, acetylcholine and ouabain in isolated auricles from digitalized guinea pigs.

Responses of the isolated heart from the guinea pig treated chronically with digitoxin until the T wave had disappeared were studied. The development of the abnormal ECG pattern was abolished by a simultaneous injection of taurine and digitoxin. Taurine also inhibited the change by digitoxin of the responses to acetylcholine and ouabain but not to noradrenaline. The causal relationship between the inhibitory effect of taurine and prevention of the development of arrhythmias remains obscure.

Acetylcholine↗