L-TRIIODOTHYRONINE ACUTELY INCREASES CA2+ UPTAKE IN THE ISOLATED, PERFUSED RAT-HEART - CHANGES IN L-TYPE CA2+ CHANNELS AND BETA-RECEPTORS DURING SHORT-TERM AND LONG-TERM HYPERTHYROIDISM AND HYPOTHYROIDISM

Acutely administered triiodothyronine (T-3) in supraphysiological doses has been shown to exert an acute positive inotropic effect in vivo a few minutes after intravenous administration. To investigate whether this effect could be explained by an acutely increased Ca2+ uptake in the myocardium, an isolated perfused rat heart model ad modum Langendorff was established. The acute stimulative effect of T-3 On myocardial Ca2+ uptake was determined indirectly by measuring changes in Ca2+ concentration in the perfusate following coronary perfusion with Ca-45(2+)-containing buffer. Perfusion with T-3 gave rise to dose-dependent reductions in perfusate Ca2+ within 20 s. Following 10(-9) and 10(-11) mol/l T-3, the effect was small and usually lasted less than 1 min. Perfusion with 10(-6) and 10(-7) mmol/l T-3 resulted in a decrease in perfusate Ca2+, which remained stable throughout 4-6 min of observation. Calcium channel blockade with nifedipine prevented the decrease in perfusate Ca2+, suggesting that voltage-operated Ca2+ channels are involved in the increased Ca2+ uptake. A washout period with T-3-free buffer re-established the Ca2+ concentration in the perfusate, suggesting that the effect is reversible. Calcium channels have been suggested to be regulated directly by T-3. Maximum binding capacities for myocardial Ca2+ channels and beta-receptors were determined by binding studies with [H-3]PN200-110 and [(125)]iodocyanopindolol in short-term and long-term hyper- and hypothyroid rats. After 2 and 8 weeks, Ca2+-channel maximum binding capacities were reduced by 25% and 23% in hyperthyroid rats (p<0.05) and increased by 33% and 23% in hypothyroid rats (p<0.05). beta-Receptor binding capacities were increased by 33% and 50% in hyperthyroid rats (p<0.05) and reduced by 28% and 47% (p<0.05) in hypothyroid rats. The reduced Ca2+-channel maximum binding capacity during chronic hyperthyroidism is hypothesized to be a secondary event to a T-3-induced increase in myocardial Ca2+ uptake in hyperthyroid rats, serving a protective role against Ca2+ overloading of the cell. The acute increase in Ca2+ uptake following Tg administration may explain the reported acute inotropic effect of T-3.