Studies on Digitalis

Abstract

The effects of triiodothyronine (T 3 ) administration on digitalis requirements was studied in a group of patients with atrial fibrillation. The ventricular rate was utilized to provide a quantitative expression of digitalis effect. In one patient the amount of acetylstrophanthidin, administered as a constant infusion, required to slow the ventricular rate to 70 beats per minute rose from an average of 0.58 mg. while he was myxedematous, to 1.50 mg. when he was euthyroid. When mild thyrotoxicosis was induced in three euthyroid patients the daily dose of digoxin had to be increased approximately four-fold in order to maintain the ventricular rate at a control level. In three patients it was observed that reserpine or syrosingopine administered intramuscularly abolished the increased requirements for digoxin induced by T 3 . In two patients syrosingopine was found to prevent partially the tachycardia resulting from large doses of intravenous T 3 . The possible mechanisms responsible for these effects and their therapeutic implications are discussed.

Role of Thyroid State in Age-Dependent Cardiac Effects of Ouabain in Guinea Pigs

“…However, such a shift from Vi to V3 has not yet been demonstrated in hypothyroid newborn guinea pigs and is worth investigating. In the present study we have confirmed that the positive inotropic and toxic effects of oua bain are age-related, namely the responsive ness increases with age [2,3,9], As pre viously reported, we also found that hypo thyroidism amplifies the myocardial re sponse to ouabain [6,7,17], A possible explanation for the inverse re lationship between the thyroid state and the (age-related) responsiveness to ouabain, is the modulation of Na+-K+,ATPase by thy roid hormones, which is brought about by increasing the number of enzyme molecules as well as their activity [10,11,13]. The involvement of Na+-K+,ATPase is further supported by studies demonstrating devel opmental changes in myocardial Na+-K+,ATPase activity, such that enzyme activ ity is larger in newborns than in adults [15,23].…”

“…We attempted to provide a plausible explanation by testing the hypothesis that the develop mental changes in ouabain responsiveness are modulated (at least partially) by differ ences in the 'thyroid state'. The hypothesis is based on 3 observations: (1) Thyroid hor mones modulate Na+,K+-ATPase, the recep tor for cardiac glycosides [1,10,11,16,22,23]; (2) thyroid hormone levels change with age [5,8] and (3) in adult animals, hyperthy roidism decreases while hypothyroidism in creases the responsiveness to cardiac glyco sides [7,17], The hypothesis was tested by comparing the inotropic and toxic effects of ouabain on right ventricular papillary mus cle of adult (3 months old), euthyroid new born and hypothyroid newborn (0-5 days old) guinea pigs. The study shows that while euthyroid newborns are less sensitive to oua bain than adults, hypothyroid newborns are as sensitive as adults, suggesting that the developmental differences in the thyroid state are contributing to the age-related changes in the responsiveness to cardiac gly cosides.…”

Determination of P-Glycoprotein ATPase Activity Using Luciferase

“…18) In general, the changes in the expression and function of duodenal P-gp were associated with alterations in the absorption of digoxin after oral administration. We hypothesised that thyroid hormones were involved directly in the regulation of P-gp expression, because the alterations in the pharmacokinetics of digoxin and other drugs in patients with hyperthyroidism could be explained by induction of P-gp.…”

“…18) Absorption of digoxin in humans is related to the expression and function of duodenal P-gp, which is modified by drug interactions. 27) To evaluate the Caco-2 cells were treated with 10 mM of all-trans-retinoic acid, dexamethasone or rifampicin for 48 h, 10 mM of levothyroxine for 24 h, or 1 mM of digoxin for 24 h. The compounds were dissolved in DMSO, which was added to the culture medium at a final concentration of 0.1%.…”