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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.
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The effect of intravenous digoxin (0.01 mg/kg) on ventricular function, coronary arterial haemodynamics and myocardial oxygen uptake was studied in 12 patients with essential hypertension but no heart failure, significant left ventricular hypertrophy and normal coronary arteriogram. There was a definite, velocity-related increase in the inotropic function of the left ventricle, by 19.4%, 50 min after digoxin injection, while ventricular pumping function decreased by between 6.5 and 11.2%. Coronary blood flow through the left ventricle decreased by 8.8%. On the other hand, coronary vascular resistance and coronary arteriovenous oxygen difference increased by 11 and 5.9%, respectively. Oxygen uptake remained essentially unchanged (-2.1%). These results indicate that the increase in inotropism caused by intravenous digoxin in essential hypertension without heart failure produces not only no therapeutically useful improvement in left ventricular pumping function: there is also a coronary constrictor and ischaemia-inducing effect on the coronary arterial system.
The effect of digoxin antibody fragments (Fab) on clearance of specifically bound digoxin from its specific receptor (Na, K-ATPase) was studied in human heart left ventricle (LV) and vastus lateralis skeletal muscle (SK) samples obtained postmortem. Initially, [3H]digoxin was bound to samples at conditions giving high relative occupancy of receptor. Half-life (t1/2) for its net release from LV in buffer was 32.2, 6.7, and 0.9 h at 0 degrees, 30 degrees, and 37 degrees C, respectively. For SK, t1/2 was 5.4 h in buffer at 30 degrees C. Inhibition of rebinding of digoxin by addition of specific digoxin Fab (5 x 10(-7) M) or excess unlabeled digoxin (1 x 10(-4) M) to buffer at 30 degrees C increased net release rate for specifically bound digoxin 2.5- to 3.0-fold in heart and SK. [3H]Digoxin was also bound to samples at conditions giving low relative occupancy. Samples were subsequently washed in buffer containing 5 x 10(-7) M specific digoxin Fab for 16 h at 30 degrees C. This wash reduced occupancy of receptors by digoxin from 10 to 0.5% in LV and from 9 to 0.3% in SK, respectively. At variance with wash at 37 degrees C, this procedure allowed subsequent vanadate-facilitated complete quantification of Na,K-ATPase by [3H]ouabain binding; values were 378 +/- 13 and 370 +/- 12 pmol/g wet weight (p greater than 0.6) in LV and 309 +/- 19 and 315 +/- 16 pmol/g wet weight (p greater than 0.7) in SK with and without previous wash, respectively (mean +/- SEM, n = 12).(ABSTRACT TRUNCATED AT 250 WORDS)
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The influences of hypoxia and of the interactions of hypoxia with digoxin and ouabain on myocardial stiffness were studied at two extracellular calcium concentrations (2.5 mM and 4.0 mM) in isolated, isometrically contracting cat papillary muscles. Stiffness (delta T/delta L), defined as a change in tension (delta T) in response to an imposed length change (delta L), was measured during contraction and during rest by use of a sinusoidal forcing function. Neither digoxin, ouabain, nor increased extracellular calcium altered contraction or resting stiffness in the well-oxygenated environment. Resting stiffness was increased at the end of hypoxia only in the presence of digoxin in both 2.5 mM and 4.0 mM Ca. Contraction stiffness was increased in 2.5 mM Ca by hypoxia alone and by hypoxia in the presence of digoxin or ouabain, but was not increased in experiments carried out in 4.0 mM Ca. Thus it appears that hypoxia per se increases contraction stiffness, but increasing extracellular calcium from 2.5 mM to 4.0 mM prevents the increase elicited by hypoxia; resting stiffness, however, is increased by hypoxia only in the presence of digoxin, and this occurs in both 2.5 mM and 4.0 mM Ca.
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