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At least 1,261 records · Page 70Linked to original sources
PubMed2004

Modulation of sarcoplasmic reticulum function by Na+/K+ pump inhibitors with different toxicity: digoxin and PST2744 [(E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride].

OBJECTIVE: To gain some insight on the lesser arrhythmogenic properties of PST2744 [(E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride] compared with digoxin, we compared modulation of intracellular Ca2+ dynamics by the two agents. METHODS: SERCA (sarcoplasmic reticulum Ca2+-ATPase) activity and Ca2+ leak rate were measured in sarcoplasmic reticulum (SR) vesicles from guinea pig ventricles. Membrane current, intracellular Ca2+, and twitch amplitude were evaluated in guinea pig ventricular myocytes with or without blockade of the Na+/Ca2+ exchanger. RESULTS: In SR vesicles, PST2744 (30-300 nM), but not digoxin, increased SERCA activity; digoxin only (> or =0.1 nM) increased SR Ca2+ leak. In myocytes with blocked Na+/Ca2+ exchanger, Ca2+ reloading of caffeine-depleted SR was enhanced by PST2744 and slightly inhibited by digoxin. In myocytes with functioning Na+/Ca2+ exchanger, both agents increased diastolic Ca2+, SR Ca2+ content, the gain of Ca2+-induced Ca2+ release, the rate of cytosolic Ca2+ decay, twitch amplitude, and relaxation rate. Consistent with the observations in SR vesicles, the effects on SR Ca2+ content and Ca2+ decay rate were significantly larger for PST2744 than for digoxin. CONCLUSIONS: In isolated SR vesicles, PST2744 and digoxin directly affected SR function in opposite ways; this could be reproduced in myocytes during Na+/Ca2+ exchanger blockade. Under physiological conditions (functioning Na+/Ca2+ exchanger), the two agents affected Ca2+ dynamics in the same direction, as expected by their Na+/K+ pump inhibition; however, differential SR modulation was still expressed by quantitative differences. Thus, the more favorable inotropy-to-toxicity ratio previously described for PST2744 appears to be associated with direct SERCA stimulation and/or lack of enhancement of Ca2+ leak.

Animals↗
PubMed2005

Down-regulation of Na+ pump alpha 2 isoform in isoprenaline-induced cardiac hypertrophy in rat: evidence for increased receptor binding affinity but reduced inotropic potency of digoxin.

Cardiac hypertrophy in rats induces a down-regulation of Na(+),K(+)-ATPase alpha(2) isoform, although its functional consequences are poorly understood. Using a mathematical modeling approach that allows differentiation between effects elicited at the receptor and postreceptor level, we studied uptake, receptor binding kinetics, and positive inotropism of digoxin in single-pass Langendorff-perfused hearts of vehicle- and isoprenaline-pretreated rats (2.4 mg/kg per day over 4 days). Digoxin outflow concentration and left ventricular developed pressure data were measured for three consecutive doses (15, 30, and 45 microg) in the absence and presence of the reverse mode Na(+)/Ca(2+) exchange inhibitor 2-[2-[4-(4-nitrobenzyloxyl-)phenyl]ethyl isothiourea methansulfonate] (KB-R7943) (0.1 microM) in perfusate. In hypertrophied hearts, 1) the amount of alpha(2) receptors was reduced to 52% of control levels; 2) the digoxin binding affinity was increased 12-fold due to a decrease in dissociation rate constants of alpha(1) and alpha(2) receptors, and 3) inotropic responsiveness to digoxin the was attenuated on the stimulus-response level, where the coupling ratio of stimulus to response was reduced to 38% of control values. Only in the lowest dose level (15 microg) was this decrease in inotropic potency counterbalanced by the increase in receptor affinity. The Na(+),K(+)-ATPase isoform shift was not responsible for the diminished inotropic effect of digoxin. Coadministration of KB-R7943 significantly reduced cellular response generation at higher digoxin doses to the same limiting stimulus-response relationship in both the vehicle and isoprenaline group.

Animals↗
PubMed2005

Vascular binding, blood flow, transporter, and enzyme interactions on the processing of digoxin in rat liver.

The roles of vascular binding, flow, transporters, and enzymes as determinants of the clearance of digoxin were examined in the rat liver. Digoxin is metabolized by Cyp3a and utilizes the organic anion transporting polypeptide 2 (Oatp2) and P-glycoprotein (Pgp) for influx and excretion, respectively. Uptake of digoxin was found to be similar among rat periportal (PP) and perivenous (PV) hepatocytes isolated by the digitonin-collagenase method. The Km values for uptake were 180 +/- 112 and 390 +/- 406 nM, Vmax values were 13 +/- 8 and 18 +/- 4.9 pmol/min/mg protein, and nonsaturable components were 9.2 +/- 1.3 and 10.7 +/- 2.5 microl/min/mg for PP and PV, respectively. The evenness of distribution of Oatp2 and Pgp was confirmed by Western blotting and confocal immunofluorescent microscopy. When digoxin was recirculated to the rat liver preparation in Krebs-Henseleit bicarbonate (KHB) for 3 h in absence or presence of 1% bovine serum albumin (BSA) and 20% red blood cell (rbc) at flow rates of 40 and 10 ml/min, respectively, biexponential decays were observed. Fitted results based on compartmental analyses revealed a higher clearance (0.244 +/- 0.082 ml/min/g) for KHB-perfused livers over the rbc-albumin-perfused livers (0.114 +/- 0.057 ml/min/g) (P < 0.05). We further found that binding of digoxin to 1% BSA was modest (unbound fraction = 0.64), whereas binding to rbc was associated with slow on (0.468 +/- 0.021 min(-1)) and off (1.81 +/- 0.12 min(-1)) rate constants. We then used a zonal, physiologically based pharmacokinetic model to show that the difference in digoxin clearance was attributed to binding to BSA and rbc and not to the difference in flow rate and that clearance was unaffected by transporter or enzyme heterogeneity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Induction of rat intestinal P-glycoprotein by spironolactone and its effect on absorption of orally administered digoxin.

The effect of the diuretic spironolactone (SL) on expression and function of intestinal P-glycoprotein (P-gp), as well as its impact on intestinal absorption of digoxin, was explored. Rats were treated with daily doses of 200 micromol/kg b.wt. of SL intraperitoneally for 3 consecutive days. The small intestine was divided into four equal segments of approximately 25 cm, with segment I being the most proximal. Brush-border membranes were isolated and used in analysis of P-gp expression by Western blot analysis. P-gp content increased in the SL group by 526, 292, 210, and 622% over controls for segments I, II, III, and IV, respectively. Up-regulation of apical P-gp was confirmed by immunofluorescence microscopy. P-gp transport activity was explored in intestinal sacs prepared from segment IV using two different model substrates. Serosal to mucosal transport (efflux) of rhodamine 123 was 140% higher, and mucosal to serosal transport (absorption) of digoxin was 40% lower in the SL group, both indicating increased P-gp function. In vivo experiments showed that intestinal absorption of a single dose of digoxin administered p.o. was attenuated by SL pretreatment. Thus, concentration of digoxin in portal and peripheral blood was lower in SL versus control groups, as well as its accumulation in kidney and liver. Urinary excretion of digoxin was significantly decreased in the SL group, probably reflecting decreased systemic availability of digoxin for subsequent urinary elimination. We conclude that SL induces P-gp expression with potential impact on intestinal absorption of substrates with therapeutic application.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1983

Digoxin-inactivating bacteria: identification in human gut flora.

Digoxin, the most widely used cardiac glycoside, undergoes significant metabolic conversion in many patients to cardioinactive metabolites in which the lactone ring is reduced. This appears to occur within the gastrointestinal tract. An attempt was made to isolate and identify the organisms capable of reducing digoxin from stool cultures obtained from human volunteers. Of hundreds of isolates studied, only Eubacterium lentum, a common anaerobe of the human colonic flora, converted digoxin to reduced derivatives. Such organisms were also isolated in high concentrations from the stools of individuals who did not excrete these metabolites when given digoxin in vivo. When the growth of E. lentum was stimulated by arginine, inactivation of digoxin was inhibited. Neither the presence of these organisms alone nor their concentration within the gut flora appeared to determine whether digoxin would be inactivated by this pathway in vivo.

Arginine↗
PubMed1975

Serum digoxin in patients with thyroid disease.

Serum digoxin concentrations were measured by radioimmunoassay in 17 hyperthyroid and 16 hypothyroid patients after a seven-day course of oral digoxin. The significantly higher levels of serum digoxin in patients with hypothyroidism and lower levels in those with hyperthyroidism were closely related to the measured changes of glomerular filtration rate and digoxin serum half time in these two groups. Differences in serum digoxin concentration contribute to the altered sensitivity to digoxin shown by patients with thyroid disease.

Administration, Oral↗
PubMed1973

Pharmacokinetics of digoxin: interpreting bioavailability.

Three subjects were first given a digoxin tablet in the fasting state and subsequently received the same formulation in the fed state, to simulate a spurious oral bioavailability difference. As expected, when measured by peak serum digoxin concentration as well as by area under the serum digoxin concentration-time curve the bioavailability of digoxin appeared to be higher in the fasting state than in the fed state. However, when measured by cumulative five-day urinary excretion of digoxin bioavailability was identical in both conditions.This simple experiment illustrates the fact that the estimation of bioavailability is subject to considerable methodological error, of which the clinician must be aware when evaluating reports on drug bioavailability in general and of digoxin in particular.

Administration, Oral↗
PubMed1985

Rapid plasma digoxin assay in outpatients--a useful routine technique?

In 25 outpatients taking digoxin for chronic atrial fibrillation (established for at least six months) a prospective study identified only one case in which rapid availability of the results of a plasma digoxin assay altered the dose which had already been selected on the basis of simple clinical assessment. No patient received more than 375 micrograms digoxin per day and none showed clinical evidence of toxicity even though seven had renal impairment. Six other patients had poorly controlled ventricular rates requiring larger doses of digoxin, but even in these patients the dose could be selected on clinical grounds alone. Despite the availability of a very rapid fluorescence polarisation immunoassay for digoxin, simple but careful clinical monitoring is an adequate basis for the selection of a suitable dose in most patients taking digoxin for atrial fibrillation.

Aged↗
PubMed1990

Time of occurrence, duration, and ventricular rate of paroxysmal atrial fibrillation: the effect of digoxin.

One hundred and thirty nine episodes of atrial fibrillation were identified from Holter recordings in 72 patients with paroxysmal atrial fibrillation. Paroxysms occurred more often by day than by night, suggesting that attacks are more closely associated with sympathetic than with vagal activity. In 41 patients who were not taking digoxin there were 79 episodes, and in 31 patients who were taking digoxin there were 60 episodes. Significantly more of the episodes that lasted for 30 minutes or more occurred in patients taking digoxin (13/17); the relative risk of a prolonged paroxysm associated with taking digoxin was 4.3 (95% confidence intervals 1.6-11.9). The mean (SD) ventricular rate at the onset of the paroxysms was not significantly different in those taking digoxin (140 (25) beats/min) and in those who were not (134 (22) beats/min). In paroxysmal atrial fibrillation, pretreatment with digoxin does not seem to reduce the frequency of paroxysms, or the ventricular rate when paroxysms occur, but it is associated with longer attacks.

Adult↗
PubMed1980

Myocardial effects and pharmacokinetics of digoxin and ouabain in protein-deficient guinea pigs.

Myocardial effects and pharmacokinetics of digoxin and ouabain were studied in male albino guinea pigs fed ad libitum either a 21% (control) or a 5% (low) protein diet for 4 weeks. Dietary protein deficiency was associated with a decrease in body weight gain, ventricular weight, total plasma proteins and plasma albumin, hepatic total and microsomal proteins, cytochrome P-450, and protein:DNA ratios; serum potassium was slightly but insignificantly decreased. No significant differences were found in the following experiments with digoxin and ouabain in control and protein-deficient animals: inotropic effects of ouabain on isolated papillary muscles and left atria; uptake of [3H]ouabain by isolated papillary muscles; ventricular fibrillatory doses of digoxin and ouabain in anesthetized animals and the concentrations of digoxin in plasma and papillary muscles at the onset of ventricular fibrillation in these animals; plasma half-life of digoxin in unanesthetized guinea pigs. It is concluded that although dietary protein deficiency influences several physiological and biochemical parameters it does not alter the myocardial effects and pharmacokinetics of digoxin and ouabain in guinea pigs.

Animals↗
PubMed1985

In vitro effects of hypoxia and (or) hypercapnic acidosis on the myocardial uptake of digoxin.

A recent study has shown in the conscious dog that hypoxia associated with respiratory acidosis could increase the in vivo distribution of digoxin in the myocardium. The aim of the present study was to evaluate in vitro the effects of hypoxia and (or) hypercapnic acidosis on the digoxin uptake. For this purpose, rat myocardium was incubated for 180 min with radiolabelled [3H]digoxin. The uptake of digoxin which was expressed in nanograms of digoxin bound per 100 mg of myocardium was decreased by hypoxia and increased by hypercapnic acidosis. The association of hypoxia and hypercapnic acidosis had no effect on the digoxin uptake, suggesting that in vitro hypoxia acts in an opposite way to hypercapnia.

Acidosis↗
PubMed1993

Energy-dependent transport of digoxin across renal tubular cell monolayers (LLC-PK1).

Digoxin secretory transport across renal tubular cell monolayers (LLC-PK1) grown on permeable filters was characterized. Metabolic inhibitors reduced total and specific basolateral to apical (B-A) flux of digoxin and conversely increased the apical to basolateral (A-B) flux. The specific transport of digoxin from the basolateral to the apical compartment was saturable, with a maximum velocity of transport of 184.5 +/- 38.0 pmol.cm-2.h-1 and a Michaelis-Menten constant (Km) of 14.1 +/- 1.6 microM. In addition, B-A flux of digoxin resulted in accumulation of digoxin in the apical compartment against the concentration gradient. P-Glycoprotein inhibitors such as quinidine, verapamil, vincristine, and cyclosporine increased the net A-B flux and inhibited the total B-A flux without affecting the nonspecific flux significantly. Tetraethylammonium, a prototype substrate for an organic cation transport system, had no such effect. Our results suggest that digoxin undergoes transepithelial secretion by an energy-dependent, carrier-mediated process in renal tubules, a process that seems to be distinct from the tetraethylammonium transport system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Systems analysis of digoxin kinetics and inotropic response in the rat heart: effects of calcium and KB-R7943.

To gain more insight into the mechanistic processes controlling the kinetics of inotropic response of digoxin in the perfused whole heart, an integrated kinetic model was developed incorporating digoxin uptake, receptor binding (Na(+)-K(+)-ATPase inhibition), and cellular events linking receptor occupation and response. The model was applied to data obtained in the single-pass Langendorff-perfused rat heart for external [Ca(2+)] of 0.5 and 1.5 mM under control conditions and in the presence of the reverse-mode Na(+)/Ca(2+) exchange inhibitor KB-R7943 (0.1 microM) in perfusate. Outflow concentration and left ventricular developed pressure data measured for three consecutive doses (15, 30, and 45 microg) in each heart were analyzed simultaneously. While disposition kinetics of digoxin was determined by interaction with a heterogeneous receptor population consisting of a high-affinity/low-capacity and a low-affinity/high- capacity binding site, response generation was >80% mediated by binding to the high-affinity receptor. Digoxin sensitivity increased at lower external [Ca(2+)] due to higher stimulus amplification. Coadministration of KB-R7943 significantly reduced the positive inotropic effect of digoxin at higher doses (30 and 45 microg) and led to a saturated and delayed receptor occupancy-response relationship in the cellular effectuation model. The results provide further evidence for the functional heterogeneity of the Na(+)-K(+)-ATPase and suggest that in the presence of KB-R7943 a reduction of the Ca(2+) influx rate via the reverse mode Na(+)/Ca(2+) exchanger might become the limiting factor in digoxin response generation.

Animals↗
PubMed1979

Digoxin-norepinephrine response and calcium blocker effects in vascular smooth muscle.

The mechanism of potentiation by digoxin of the response of vascular smooth muscle to norepinephrine was investigated in 5-cm intact segments of rabbit carotid artery. Segments were mounted in a chamber and perfused at constant pressure while flow and upstream and downstream pressures were recorded and resistance was calculated. Each vessel was perfused with a submaximal vasoconstricting concentration of norepinephrine (6 x 10(-6)M) alone, in the presence of digoxin (6 x 10(-5)M), and during exposure to both digoxin and one of the following calcium antagonists: lanthanum chloride (5 x 10(-4)M procaine hydrochloride (5 x 10(-3)M), or verapamil (5 x 10(-5)M). Digoxin potentiated the response to norepinephrine alone by 20% (P less than 0.01), to norepinephrine plus lanthanum chloride by 10% (P less than 0.001), and to norepinephrine plus procaine hydrochloride by 17% (P less than 0.001). Digoxin did not potentiate the norepinephrine response in the presence of verapamil. These data suggest that the mechanism of digoxin potentiation of the norepinephrine response in vascular smooth muscle may involve an alteration in a cellular calcium sequestration or release process. The potential cellular sites that may contribute to this phenomenon are discussed.

Animals↗
PubMed1986

Effects of digoxin on diaphragmatic strength generation.

Contrary to hindlimb muscle, extracellular calcium plays an important role in diaphragmatic strength generation (J. Appl. Physiol. 58: 2054-61, 1985). Since the inotropic effect of digitalis appears to be related to cell membrane transport of calcium, we studied the effect of digoxin on diaphragmatic contractility in 20 anesthetized dogs. The diaphragm was electrically stimulated with intramuscular electrodes. The transdiaphragmatic pressure (Pdi) during supramaximal (50 V) 2-s stimulations applied over a frequency range of 10-100 Hz was measured with balloon catheters at functional residual capacity. Cardiac output was measured with a Swan-Ganz catheter and diaphragmatic blood flow (Qdi) by timed volume collections of left inferior venous effluent. The force generated by the sartorius muscle during electrical stimulations was studied concomitantly to Pdi. In 10 dogs (group A) 0.04 mg/kg of digoxin was infused in 10 min. In 10 other dogs (group B) 0.2 mg/kg was administered. All measurements were performed during control and 30, 60, 90, and 120 min after digoxin administration. In group A, digoxin plasmatic level at 60 min reached a therapeutic range in all dogs (1.8 +/- 0.3 ng/ml), whereas in group B, digoxin plasmatic level was higher (8 +/- 1.3 ng/ml). No significant change in cardiac output and Qdi was noted after administration of digoxin, either in the dogs of group A or those of group B.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

The effects of acute focal cerebral ischemia on digoxin toxicity and pharmacokinetics.

24 h after ligation of the left middle cerebral artery in cats (sham operation in the control group), a constant intravenous infusion of digoxin was begun and continued to toxicity (ventricular rhythm) and death. We found that the lethal dose of digoxin was significantly less in the stroke group than in the control group, but the lethal plasma digoxin concentration was significantly greater in the stroke group than in the control group. In a subsequent study, we demonstrated that ischemic stroke caused a significant prolongation in the elimination half-life of digoxin and an increase in the volume of distribution. The mean plasma clearance of the stroke group was approximately three fourths of that of the control group. We concluded that the decreased tolerance to digoxin after ischemic stroke was due to the prolonged half-life and decreased clearance of digoxin.

Animals↗
PubMed1982

Digoxin-quinidine interaction in unanesthetized guinea pigs.

The clinically relevant interaction between quinidine (3 mg/kg) and digoxin (0.6 mg/kg plus 20 microCi 3H-digoxin) was investigated using unanesthetized and unrestrained guinea pigs for in vivo pharmacokinetic and tissue disposition studies. Quinidine caused a significant elevation of plasma levels of digoxin as early as 5 min after injection, and the increase persisted for at least 8 h. A significant decrease in the volume of distribution for digoxin from 3.6 to 2.7 liters/kg (20%) was observed in quinidine-treated animals. No change was noted in the dominant elimination half-life of digoxin in quinidine-treated animals. The decreased volume of distribution appeared to be due to displacement of digoxin from tissue stores by quinidine as evidenced by decreased tissue to plasma ratios for kidney (41%), intestine (41%), fat (33%), lung (31%), left ventricle (27%), liver (24%), left atrium (22%), right ventricle (21%), right atrium (18%), pancreas (12%), and bladder (-4%) samples.

Animals↗
PubMed1981

Localization of digoxin in sheep myocardium by immunofluorescent microscopy.

6 newborn and 6 adult sheep were treated intravenously with digoxin for 2 weeks prior to sacrifice. Plasma and myocardial concentrations of digoxin were determined at steady state; the myocardial/plasma digoxin ratio was similar for the newborn and adult sheep. An immunofluorescent technique was used to localize digoxin within the myocardium. The pattern of fluorescence also did not vary with age. These studies show no age-related differences in the penetration or localization of digoxin within the heart. A simple immunofluorescent technique for the localization of digoxin within the heart is described.

Aging↗