Positive Inotropic Effect Of Digoxin Research Articles

Interactions between Verapamil and Digoxin in Langendorff‐Perfused Rat Hearts: The Role of Inhibition of P‐glycoprotein in the Heart

P-glycoprotein (P-gp) is expressed in tumour cells as well as normal tissues including heart. Modulation of P-gp transport in vivo may lead to increased drug penetrance to tissues with resulting increases in toxicity. We aimed to investigate the effects of P-gp on the isolated heart by digoxin infusion in the absence and presence of verapamil. The study was performed in Langendorff isolated perfused rat hearts. After a 20 min. stabilisation period with Tyrode Buffer, digoxin (125 μg/5 mL) was infused for 10 min. in the control group (n = 7). The same dose of digoxin was infused during perfusion with verapamil (1 nm) containing Tyrode Buffer (n = 8) in the study group. Outflow concentration and cardiac parameters of digoxin were measured at frequent intervals for 40 min. AUEC((0-40 min)) for left ventricular developed pressure was significantly increased in the presence of verapamil (4260 ± 39.37 mmHg min versus 4607 ± 98.09 mmHg min; 95% CI -587.7 to -105.8; p = 0.0083). The significant increases in left ventricular developed pressure were at 20, 25, 30, 35 and 40 min. AUC((0-40 min)) value for outflow digoxin concentration-time curve was significantly lower in the presence of verapamil. Verapamil increased the positive inotropic effect of digoxin, probably through the inhibition of P-gp, which effluxes digoxin out of cardiac cells.

Mechanism-based modeling of reduced inotropic responsiveness to digoxin in endotoxemic rat hearts

The mechanisms by which endotoxemia affects myocardial contractility and responsiveness to inotropic drugs are not well understood. We examined the positive inotropic effect of digoxin in single-pass Langendorff-perfused hearts from rats after in vivo pretreatment with lipopolysaccharide (LPS, 4 mg/kg, i.p., 4 h before heart isolation). Using a mathematical modeling approach that allows differentiation between effects elicited at the receptor and postreceptor level, we studied uptake, receptor binding and effectuation kinetics after three consecutive digoxin doses (15, 30, and 45 μg) in the absence and presence of the reverse mode Na +/Ca 2+ exchange (NCX) inhibitor KB-R7943 (0.1 μM) in perfusate. LPS significantly depressed baseline contractility and the inotropic response to digoxin without affecting its uptake mechanism. Compared with the control group, the slope of the functional receptor occupancy (stimulus)-to-response relationship was reduced by 44% in the LPS group. Model analysis revealed a significant correlation between changes in digoxin action and LPS-induced febrile response: digoxin receptor affinity increased and the response/stimulus ratio decreased with rise in body temperature, respectively. In contrast, the diminished responsiveness to digoxin observed after NCX inhibition in the control group was not further attenuated in the LPS group. These results support the hypothesis that postreceptor events may be responsible for the diminished contractile response to digoxin during endotoxemia.

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.

Digoxin- and monensin-induced changes of intracellular Ca2+ concentration in isolated guinea-pig ventricular myocyte.

This study was undertaken to determine the possible mechanisms of actions of monensin and digoxin by using isolated guinea-pig ventricular myocytes. Since Ca2+ is the major signal for triggering contraction of cardiac muscle, the objective of this study was to determine whether monensin and digoxin affect the [Ca2+]i of cardiac myocytes and if so is this effect due to an increase in [Na+]i. Three different concentrations of digoxin (0.3, 1 and 3 micromol/l) and three different concentrations of monensin (0.3, 1 and 3 micromol/l) were used. Each treatment was monitored for two hours by using computerized fluoroscopy. Both digoxin and monensin increased the [Ca2+]i and accelerated the onset time of [Ca2+]i increase in a dose-dependent manner. Normal myocytes (loaded with fura-2 for 30 min before the treatment) were also compared with 'weakened' myocytes (loaded with fura-2 for 3 h before the treatment to create a 'weakened' condition). It was found that although 0.3 micromol/l monensin and digoxin did not change the [Ca2+]i in normal myocytes, they increased the [Ca2 +]i in 'weakened' myocytes. Finally, a Na+-free medium was used to demonstrate the effect of [Na+]o on both monensin- and digoxin-induced increases in [Ca2+]i. It was found that digoxin did not increase the [Ca2+]i in the Na+-free medium. Although monensin increased the [Ca2+]i in the Na+-free solution, this increase was not as large as in the Na+-containing medium. The results of the study led to the conclusion that the positive inotropic effect of digoxin depends on [Na+]o. However, monensin increases [Ca2+]i in Na+-dependent and -independent ways. An addition conclusion was that 'weakened' myocytes are more sensitive to the monensin and digoxin treatment than normal myocytes.

Modulation of the contractility of guinea pig papillary muscle by the activation of ATP-sensitive K + channels

The influence of activation of ATP-sensitive K + channels on the positive inotropic action of l-isoproterenol d-bitartrate (isoprenaline), 12b-hydroxydigitoxin (digoxin), 5-amino-[3,4′-bipyridin]-6[1 H]-one (amrinone), 1,6-dihydro-2-methyl-6-oxo 3,4-bipyridine-5-carbonitrile (milrinone) and UD-CG 115 BS; 4,5-dihydro-6[2-(4-methoxyphenyl)-1 H-benzimidazol-5-yl]-5-methyl-3(2 H)pyridazinone (pimobendan) was investigated in guinea pig papillary muscle. The force of contraction (d F) and the rate of rise of force of contraction ( dF dt ) were measured. After activation of ATP-sensitive K + channels by 1 μM of (3 S,4 R)-3-hydroxy-2,2-dimethyl-4-(oxo-1 pyrrolidinyl)-6-phenyl-sulfonylchroman hemihydrate (HOE 234) the dose-response curves for isoprenaline were shifted to the right (about 9-fold). The positive inotropic action of digoxin and milrinone was significantly enhanced (about 5-fold). The inotropic action of amrinone and pimobendan before and after pretreament with HOE 234 was not significantly different. HOE 234 pretreatment decreased irreversibly the maximum effect ( E max) of isoprenaline only for the amplitude of force of contraction, but not for the rate of rise of force. Opposite to this, activation of ATP-sensitive K + channels evidently enhanced the positive inotropic effects of digoxin and milrinone. In the case of milrinone, the E max for both parameters (d F and dF dt ) was greater after HOE 234 pretreatment. Only the E max of digoxin for the amplitude of the force of contraction was significantly increased in the presence of HOE 234. The above mentioned results indicate that activation of ATP-sensitive K + channels by HOE 234 modulates the positive inotropic action of cardiotonic drugs. This change may be expressed as potentiation (digoxin, milrinone) or attenuation (isoprenaline) of the positive inotropic effects, depending on the mechanism of action.

Amiloride improves hemodynamics in patients with chronic congestive heart failure treated with chronic digoxin and diuretics

Potassium-sparing diuretics have been reported to decrease the positive inotropic effect of digoxin. We studied the hemodynamic effects of amiloride in patients taking digoxin for chronic heart failure. Eleven men with a history of congestive heart failure were studied in a double blind, cross-over, placebo controlled trial with the patients on digoxin alternating placebo with amiloride. After 7 days on the trial drug, a Swan-Ganz catheter was placed in the pulmonary artery and measurements made at rest and with increasing degrees of supine bicycle exercise. Right-sided and pulmonary artery wedge pressures and systemic arterial pressures, as well as cardiac outputs, were measured. After a 7 day washout period, placebo (P) and Amiloride (A) were switched and after 7 days on the therapy, a second hemodynamic study at rest and varying degrees of supine bicycle exercise was repeated. At rest there were no significant differences in the right-sided, pulmonary arterial wedge pressure or cardiac outputs between the patients on Amiloride (A) versus placebo (P). During exercise there were significant differences between (P) and (A) at the 50 watt-second stage of exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional antagonism by monoclonal antibody to digoxin in the guinea-pig atria

A monoclonal antibody with a high affinity for digoxin (K a = 1.14 × 10 9 M) was produced by somatic cell fusion. This antibody, designated 35 6.1 , displayed little or no cross reactivity with other steroids. In the guinea-pig atria, 35 6.1 antagonized functionally the positive inotropic effect of digoxin but did not alter that of isoproterenol. Our results suggest that this monoclonal antibody may represent a useful probe for studying the physiological role of the putative endogenous digoxin-like factor in various pathophysiological conditions.

Prazosin alters free and total plasma digoxin levels in dogs

Digoxin has been associated with a variety of drug interactions. Studies in our laboratory indicate that single doses of prazosin may alter plasma steady-state digoxin levels. Adult mongrel dogs were given digoxin tablets orally (0.008 mg/kg, twice daily) until steady-state levels of digoxin were reached. Dogs were then tested in a cross-over study with prazosin and saline. Plasma samples were assayed for both free and total plasma digoxin via radioimmunoassay. Free drug was separated from protein bound drug utilizing a micropartition system. Plasma binding of digoxin as well as nonspecific tissue binding was reduced by prazosin and resulted in an increased fraction of free digoxin in plasma. The increase in free digoxin leads to an increase in the pool of digoxin available for pharmacologic activity. Acute experiments demonstrated such an increased pharmacologic effect of digoxin in the presence of prazosin. Prazosin pretreatment prior to a continuous digoxin infusion significantly increased the positive inotropic effect of digoxin compared to dogs receiving only digoxin.

Reduction of digoxin-induced inotropism during quinidine administration

A kinetic and dynamic study of digoxin was performed in 6 healthy subjects, and repeated in the same subjects after administration of quinidine for 1 wk. Myocardial performance evaluated by systolic time intervals increased in parallel with plasma digoxin concentration, whereas left ventricular end-diastolic diameter on echocardiography and arterial blood pressure remained constant. The positive inotropic effect of digoxin was abolished during concomitant treatment with quinidine. Quinidine has been reported to increase the risk of digitoxicity, and therefore the treatment with digoxin and quinidine in combination should be reconsidered.

Positive inotropic effects of digoxin on left ventricular performance at rest and during exercise in normal subjects.

Positive inotropic effects of digoxin on left ventricular performance at rest and during exercise in normal subjects.

Positive Inotropic Effects of Digoxin on Left Ventricular Performance at Rest and During Exercise in Normal Subjects.

The effect of digitalis preparation on the normal heart has been the subject of controversy. Most of the studies using acute intravenous administration of digitalis or oral administration of its full dose demonstrated no positive effect on the normal heart. In subjects without congestive heart failure the positive inotropic action was probably masked by the increased peripheral vasoconstriction. In this study left ventricular performance was assessed mechanocardiographically and echocardiographically in ten normal non-trained subjects before and after oral administration of small dose of digoxin. Subjects and Methods Out of 100 non-trained healthy young males, ten subjects aged from 22 to 33 years were selected in whom a clear left ventricular echocardiograms could be contineously recorded at rest and during exercise. Echocardiogram (UCG), electrocardiogram (ECG), phonocardiogram (PCG) and blood pressure readings were obtained in the basal state and every one minute during 120 Watt steady state exercise of three minutes' duration in recumbent position before and after oral administration of digoxin, 0.5 mg on the first day and 1.0 mg on the subsequent day. The experimental procedures after digoxin treatment were done 4 hours after the second administration of digoxin. Blood pressure, the ratio of preejection period to ejection time (PEP/ET), percent shortening of left ventricular minor dimension (ΔD), ejection fraction (EF) and mean velocity of circumferential fiber shortening of the left ventricle (mVcf) were analyzed by the paired student's test comparing the control measures to the digoxin measures in the basal state, during and after exercise. Results Systolic and diastolic pressures were not affected by digoxin treatment. After digoxin administration, despite a decrease in heart rate from 67 ± 4 to 60 ± 5 in the basal state, PEP/ET decreased from 0.42 ± 0.05 to 0.38 ± 0.03 (p < 0.01), ΔD increased from 33 ± 4 to 38 ± 3% (p < 0.001), EF increased from 69 ± 6 to 76 ± 4% (p < 0.001) and mVcf increased from 1.20 ± 0.13 to 1.35 ± 0.11 (p < 0.01). During exercise, while a decrease in mean heart rate by digoxin treatment was as much as that of basal state, effects of digoxin therapy on ΔD and EF were augmented during exercise: ΔD increased from 34 ±4 to 44 ± 4% and EF increased form 71 ± 5 to 83 ± 4% at three minutes after initation of exercise. An increase in ΔD after digoxin treatment was mainly caused by a change in endsystolic dimension.

The inotropic effects of digoxin in hyperkalemia. Relation to (Na+,K+)-ATPase inhibition in the intact animal.

The effects of hyperkalemia on the inotropic properties of digoxin were studied in anesthetized mongrel dogs. With preload, afterload and heart rate maintained constant in dogs who received atropine and practolol to block cardiac reflexes, 0.08 mg/kg digoxin increased the first derivative of the left ventricular pressure curve (LV dp/dt) 53.1 ± 8.3% (SEM) in normokalemic animals but only 9.5 ± 2.5% in hyperkalemic animals at 60 min. This decrease in the inotropic effects of digoxin by hyperkalemia was accompanied by significant decreases in both total left ventricular digoxin concentration and microsomal-bound digoxin. (Na + , K + )-ATPase was inhibited 43.3 ± 2.4% in normokalemic animals but only 27.4 ± 2.5% in hyperkalemic animals ( P &lt; 0.01), while (Mg ++ )-ATPase levels were similar in normokalemia and hyperkalemia. In animals not given digoxin, hyperkalemia had no effect on either LV dp/dt or (Na + , K + )-ATPase. There was a good correlation between the positive inotropic effects of digoxin and percent inhibition of (Na + , K + )-ATPase. These studies provide further support for the importance of (Na + , K + )-ATPase inhibition and microsomal-bound digoxin in determining the inotropic effects of digoxin. Hyperkalemia alters the inotropic effects of digoxin by decreasing binding of digoxin to a microsomal cell fraction containing (Na + , K + )-ATPase activity. These studies also provide support for the importance of reflex withdrawal of sympathetic tone in modifying the inotropic properties of digoxin in normokalemic and hyperkalemic animals.

Some aspects of interaction between diphenylhydantoin and digoxin by simultaneous administration to dogs

Diphenylhydantoin, 1.1 mg/kg/min, and digoxin, 2.78 μg/kg/min, were infused separately and simultaneously in anesthetized dogs. Diphenylhydantoin lowered mean arterial pressure and heart rate after 30–40 min of infusion. Its average lethal dose was 127 mg/kg. All animals died in cardiac arrest. The hypotensive effect of diphenylhydantoin was associated with a decrease in cardiac output, stroke volume, peripheral vascular resistance, and maximum left ventricular dp dt . Diphenylhydantoin increased mean right atrial and left ventricular end-diastolic pressures. Digoxin, 2.78 μg/kg/min, infused for 40 min, increased mean aortic pressure, peripheral vascular resistance, and maximum left ventricular dp dt . It decreased cardiac output and heart rate. After 20–30 min of infusion, digoxin caused the usual ECG effects of digitalis: A-V block, premature beats, and paroxysmal ventricular tachycardia. The average lethal dose of digoxin was 0.26 mg/kg. All animals died in ventricular fibrillation. Digoxin given simultaneously with diphenylhydantoin protected animals from diphenylhydantoin-induced hypotension and myocardial depression. The decrease in mean aortic pressure, cardiac output, stroke volume, total peripheral vascular resistance, and maximum left ventricular dp dt as well as the increase in the left ventricular end-diastolic pressure after diphenylhydantoin and digoxin were less pronounced than after diphenylhydantoin alone. Digoxin did not antagonize diphenylhydantoin-induced cardiac slowing. The peripheral vasoconstrictor as well as the positive inotropic effects of digoxin are thought to be responsible for the protection of animals from the diphenylhydantoin-induced hypotension. Diphenylhydantoin, in the doses employed, prevented digoxin-induced elevation of mean arterial pressure, peripheral vascular resistance and maximum left ventricular dp dt ; it increased the dose of digoxin which caused ventricular arrhythmias but had no significant effect on the lethal dose of digoxin. Most animals which received both drugs, died in sudden cardiac arrest, which occurred at a time when the mean arterial pressure was only slightly decreased.