Thyroid hormones increase the contractility but suppress the effects of β-adrenergic agonist by decreasing phospholamban expression in rat atria

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Abstract
Objective: The aim of the present study was to characterize the relationships between the thyroid-hormone-dependent changes in sarcoplasmic reticulum (SR) Ca2+ handling and contractile performance in atria. Methods: Hypothyroidism in rats was induced by adding 0.05% 6-n-propyl-2-thiouracil to their drinking water for 6 weeks. Hyperthyroidism was induced by daily subcutaneous injections of l-thyroxine (1 μg/g body weight) to euthyroid rats for 1 week. Left atria from the hearts with different thyroid states were examined by means of contractile measurements, SR oxalate-supported Ca2+-uptake, and Western blot of SR proteins. Results: The tissue level of SR Ca2+-pump protein decreased in hypothyroid (46±6%) atria, but remained unchanged in hyperthyroid (110±8%) atria as compared with euthyroid atria. Hypothyroidism was associated with increased phospholamban expression (141±25%), whereas it was drastically downregulated under hyperthyroidism (21±4%). The rate of SR Ca2+-uptake, measured in the presence of the protein kinase A inhibitor, H-89, was higher in hyperthyroid atria and lower in hypothyroid atria than in euthyroid atria (397±40, 55±6 and 194±17 nmol Ca2+/g protein/min, respectively). However, the stimulation of SR Ca2+-uptake by the catalytic subunit of protein kinase A was relatively weaker in hyperthyroid (130±20% over control level without catalytic subunit) and stronger in hypothyroid (640±60%) than in euthyroid atria (280±40%). The rates of inotropic contraction (+dT/dt) were higher in the hyperthyroid atria (133±10 mN/s), but lower in hypothyroid atria (15±3 mN/s) than in their euthyroid counterparts (95±13 mN/s). Inversely, hypothyroid atria responded to isoproterenol with much larger increases in contractility (883±164% over the control values for the same muscle before addition of isoproterenol) and hyperthyroid with smaller increases (25±9%) than euthyroid preparations (207±17%). Conclusions: Thyroid hormones increase the contractility, but decrease the inotropic response to isoproterenol through decreasing the phospholamban/SR Ca2+-pump ratio in rat atria.

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