In Vivo Effect of 3,5,3‘-Triiodothyronine on Calcium Uptake in Several Tissues in the Rat: Evidence for a Physiological Role for Calcium as the First Messenger for the Prompt Action of Thyroid Hormone at the Level of the Plasma Membrane*

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Abstract
Calcium has been shown in vitro to serve as the first messenger for the rapid effect of thyroid hormone at the level of the plasma membrane. In the present study the physiological relevance of this mechanism is examined in the whole animal. To this end, the effect of T3 on 45calcium uptake and sugar [2-deoxyglucose (2-DG)] uptake, an effect that requires extracellular calcium, and the influence of calcium blockers thereon were measured in ventricles, atria, diaphragm, fat, and liver in the rat. In the first three tissues, T3 produced comparable changes in 45Ca uptake and 2-DG uptake (T3 increased 2-DG uptake in fat, where 45Ca uptake was undetected, and had no effect in liver); this activity was blocked by the calcium channel blocker cadmium. The effect of T3 on 45Ca uptake, like its effect on the in vivo uptake of 2-DG described previously, was biphasic and time related; at physiological doses of 0.01 and 0.1 .mu.g/100 g BW, T3 increased 45Ca uptake, whereas at greater (pharmacological) doses of 1 and 100 .mu.g/100 g BW, T3 was without effect or inhibited 45Ca uptake. In ventricles and atria, the stimulatory effect of T3 on 45Ca uptake was very rapid [within 2 min, at which time it was at or near maximum (50-90% above control] and then declined gradually and was not seen after 10-20 min. Of the several calcium blockers employed, verapamil (organic) and cadmium (inorganic) were found to be the most effective. Verapamil and cadmium produced a rapid, transient, and dose-related inhibition of 45Ca uptake in the tissues examined (except fat tissue where, under the experimental conditions employed, 45Ca uptake was undetected). Verapamil, given iv (200 .mu.g/100 g BW) or ip (1 mg/100 g BW), reduced tissue 45Ca uptake by 50-90% within 2 or 10 min, respectively, and then its inhibitory effect diminished rapidly and was not seen after 20-30 min. Cadmium, given iv (was ineffective when given ip) produced a rapid and dose-related decrease in 45Ca uptake, being most effective (40-90% inhibition) 1-10 min after its administration. Cadmium (1 mg/100 g BW) injected into the tail vein 2 min before T3 produced a comparable inhibition of the stimulatory effect of T3 on 45Ca uptake and 2-DG uptake. Verapamil did not change the T3 effect. The present study demonstrates that in several tissues the rapid effects of T3 in vivo and in vitro are comparable in that in both 45Ca uptake is the most rapid metabolic change observed, and a decrease in the stimulatory effect of T3 on 45Ca uptake is accompanied by a comparable decrease in the subsequent effect on sugar uptake. Thus, these findings lend credence to the physiological relevance of calcium being the first messenger for the direct action of thyroid hormone at the level of the plasma membrane.