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

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 mu g/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.