Effects of thyroid hormone on sodium pump sites, sodium content, and contractile responses to cardiac glycosides in cultured chick ventricular cells.

Abstract

Abstract. Sensitivity of cardiac muscle to digitalis glycosides depends on the thyroid state. The mechanism of this interaction was investigated at the cellular level using spontaneously beating monolayers of cultured chick embryo ventricular cells. Cells were grown for 48 h in serum-free medium containing concentrations of triiodothyronine (T3) from zero to 10-7 M, and the total number of sodium pump sites, sodium content, and contractile amplitude in the presence and absence of various concentrations of ouabain were determined. T3 caused a concentration-dependent increase in the number of specific ouabain binding sites; the maximal increase to 160% of control was observed in response to 10-8 M T3. T3 lowered steady-state cellular sodium content in a concentration-dependent manner, also. Ouabain (1 ,uM) exposure elevated cellular sodium content in all cells, but the increase was greatest in cells grown in T3-free medium and least in cells grown in 10-8 M T3. The positive inotropic and toxic effects of ouabain in cells grown in 10-8 M T3 were diminished at any given ouabain concentration, and thus, the dose-response curve was shifted to the right. These results indicate that T3 causes induction of additional sodium pump sites that are functional. The increased tolerance of hyperthyroid cells and reduced tolerance of hypothyroid cells to cardiac glycosides can be explained by these changes in the number of sodium pump sites and cellular sodium

Effect of thyroid hormone on slow calcium channel function in cultured chick ventricular cells.

“…Thus, Ca movements across the membranes of the sarcolemma and sarcoplasmic reticulum of heart muscle appear to be altered by exposure to elevated thyroid hormone levels. We have shown previously that in cultured chick ventricular cells, unidirectional Ca flux rates across the sarcolemmal membrane as well as the size of the rapidly exchangeable Ca pool are increased in cells grown in the presence ofT3 compared with cells grown in its absence (4 We have shown previously that in cultured chick heart cells, T3 increases the number of Na pump sites in the cell membrane by 1.6-fold (19). Whether such changes are functionally related to the increased Ca uptake rate reported here is not clear.…”

“…The available findings on the actions ofT3 do not suggest any specific relationship between an increased Ca uptake rate and the number of sodium pump sites. Because elevated numbers of Na pump sites were associated with reduced steady-state cellular Na content (19), the decreased [Na]i would be expected to be associated with reduced Ca influx via Na-Ca exchange. Because the 45Ca uptake rate was significantly increased in T3-treated cells despite the reduced [Na]j, Ca uptake via pathways other than Na-Ca exchange is likely increased.…”

“…These findings have led to the hypothesis that enhancement of myocardial contractility by thyroid hormones is the result of increased cardiac myosin ATPase ac-tivity. However, thyroid hormone has also been reported to alter Ca uptake by sarcoplasmic reticulum (9)(10)(11)(12)(13)(14), to stimulate plasma membrane Ca-ATPase activity (4,15,16), and also to increase the numbers of sarcolemmal sodium pump sites (17)(18)(19). Therefore, the mechanisms by which myocardial contractility is enhanced in response to thyroid hormone appear to include altered Ca handling by sarcoplasmic reticulum and also changes in sarcolemmal membrane function that would directly influence the excitation-contraction coupling process.…”

Thyroid Disease and the Heart

“…85 Although digitalis has been used in hyperthyroidism-associated atrial fibrillation, the increased rate of digitalis clearance as well as the decreased sensitivity of the hyperthyroid heart to this drug results in the need for higher doses of this medication with less predictable responses. 86 Treatment with calcium channel blockers, especially when administered parenterally, should be avoided because of the potential unwanted effects of blood pressure reduction through effects on the smooth muscle cells of the resistance arterioles. Such therapy has been linked to acute hypotension and cardiovascular collapse.…”

Thyrotoxic Cardiomyopathy

“…Thus, non-genomic actions of thyroid hormones include regulation of intracellular ion levels and their intracellular distribution. Changing transmembrane ion transport TH affect electrophysiologic features of cardiomyocytes (Kim & Smith, 1984). T3-induced expression of L-type calcium channels leads to the following: less calcium ions enter cardiomyocytes through L-type channels, and action potential gets shorter (Freedberg et al, 1970).…”