Amiodarone inhibits the 3,5,3''-triiodothyronine-dependent increase of sodium/potassium adenosine triphosphatase activity and concentration in human atrial myocardial tissue

In animal models the function of the sodium pump (sodium/potassium-adenosine triphosphatase [Na /K - ATPase]) is enhanced by 3,5,3 -triiodothyronine (T3) and inhibited by the antiarrhythmic agent amiodarone. However, it is still unclear whether the effect of the drug on Na /K -ATPase depends on the interference with thyroid hormone action. We evaluated the interaction of T3 with amiodarone on Na /K -ATPase activity and site number in human myocardium. Right atrial slices were cultured with (T3 ) and without (T3 ) 3 nM T3 in presence and absence of amiodarone at therapeutical dose (1.5 M). When compared to T3 , T3 preparations showed decreased 3H-ouabain binding (p 0.004) and lower 20-minute and 45-minute 86Rb-uptake (p 0.004). Amiodarone caused an average 49% reduction of the T3 -dependent 3H-ouabain binding and decreased the Western blot signal for the Na /K -ATPase 1 subunit. The drug also inhibited T3-dependent increase in 86Rbinflux at 20 and 45 minutes by 66% and 42%, respectively, without affecting the affinity of the pump for K . No differences were found in the 3H-ouabain binding and 86Rb-uptake of T3 , T3 amio and T3 amiodarone. In conclusion, T3 stimulates the Na /K -ATPase in human atrial myocardium by increasing the number of ouabain-binding sites, whereas amiodarone decreases the sodium pump function secondarily to the antagonism with thyroid hormone. 491 Introduction THYROID HORMONES ARE KNOWN TO influence cardiac contractile and electrical activity. A possible mechanism for these effects might involve the control of sodium/potassiumadenosine triphosphatase (Na /K -ATPase), the key determinant of the plasma membrane electrochemical gradient (1). Indeed, several studies in animal models have suggested that the sodium pump units are regulated by the thyroid status (1). Low concentrations of the (Na /K -ATPase are associated with hypothyroidism, and the treatment of hypothyroid animals with the biologically active 3,5,3 -triiodothyronine (T3) increases Na /K -ATPase activity by directly upregulating the Na /K -ATPase gene expression (2,3). The sodium pump units are also influenced by the antiarrhythmic compound amiodarone. In the animal heart long-term treatment with the drug reduces Na /K -ATPase activity (4,5). The antiarrhythmic action of amiodarone involves use-dependent block of Na , Ca2 , and K channels (6). At the same time, because of its structural similarities to thyroid hormones, the drug is believed to cause in the heart several features that are characteristic of hypothyroidism (7,8). Amiodarone, or its active metabolite desethylamiodarone likely inhibits peripheral conversion of thyroxine (T4) to T3 and antagonizes the binding of T3 to its nuclear receptors (9-12). However, it is unclear whether, at least in part, amiodarone exerts its pharmacological effects by interfering with the action of thyroid hormone; the data regarding this issue are controversial (13,14). Moreover the regulatory effect of T3 on the sodium pump in the human heart is not as clear nor are the interactions of amiodarone and thyroid system on Na /K -ATPase function. Therefore, the aim of this study was to assess the influence of treatment with T3 and/or amiodarone on Na /K -ATPase activity and number of sodium pump sites in an ex vivo human myocardial model.