Effects of Amiodarone and Desethylamiodarone on Rabbit Myocardial β-Adrenoceptors and Serum Thyroid Hormones—Absence of Relationship to Serum and Myocardial Drug Concentrations

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Abstract
The antiadrenergic actions of amiodarone (Am) are well known but its effect and that of its metabolite, desethylamiodarone (DAm), on .beta.-receptor density (Bmax) and affinity (KD) are poorly defined. Thus, the acute and chronic effects of Am and DAm on myocardial .beta.-receptors in rabbits were determined relative to changes in thyroid hormones and serum and tissue drug concentrations. Bmax and KD were measured by radio-ligand binding, thyroid hormones by RIA, and drug levels by HPLC. Compared with controls, intravenous Am (20 mg/kg) reduced Bmax by 23% (p < 0.05) and DAm (20 mg/kg) by 32% (p < 0.05). After 3 weeks of chronic drug, the corresponding value for Am was 24% (p < 0.05) versus 45% (p < 0.05) for DAm. The effect of DAm was significantly greater (p < 0.05) than that of Am, being comparable to that of Am (-44%) after 6 weeks. In the case of Am, doubling the dose (and myocardial level) led to no further decrease in Bmax. DAm also reduced Bmax more following chronic treatment than after acute administration (-45 versus -32%), a difference of borderline significance. Following 3 weeks of p.o. Am, T3 decreased 3% (NS) and reverse T3 (rT3) increased 90% (p < 0.05); after 6 weeks, the corresponding values were 25% (p < 0.05) and 181% (p < 0.01). After 1 week of p.o. DAm, T3 did not change but rT3 increased by 34% (p < 0.05); after 3 weeks the corresponding values were 21% (p < 0.01) and 64% (p < 0.01). Neither compound affected serum T4 levels. Thus, Am and DAm reduce Bmax acutely with a trend for further reduction after chronic therapy as a function of time but not of serum and myocardial drug levels.