Influence of calmodulin antagonists and calcium channel blockers on triiodothyronine uptake by rat hepatoma and myoblast cell lines.

The influence of calcium-related mechanisms on cellular uptake of triiodothyronine (T3) has not yet been defined, although it is known that T3 can stimulate cellular entry of calcium. We therefore investigated the saturable uptake of [125I]-T3 (10(-11) mol/L) from serum-free medium in vitro by hepatoma (H4) cells and skeletal myoblast (L6) cells to establish the calcium-dependency of this process. We studied the effects of the following three structurally distinct types of calmodulin antagonists in H4 cells: the naphthalene sulfonamides W7, W12, and W13, calmidazolium, and trifluoperazine. Uptake of [125I]-T3 as a percentage of control values (n = 4, 10(-4) mol/L antagonist) was as follows: W7, 42.0% +/- 3.3% (P < .001); W12, 87.5% +/- 4.5% (NS); W13, 79.5% +/- 2.5% (P < .05); calmidazolium (10(-6) mol/L, n = 8), 55.1% +/- 2.2% (P < .001); and trifluoperazine (10(-5) mol/L, n = 6), 65.7% +/- 4.1% (P < .001). To investigate whether the calmodulin sensitivity of uptake was mediated via transmembrane calcium flux, we also studied the effects of three structurally distinct types of organic calcium channel blockers in both H4 and L6 cells. [125I]-T3 uptake as a percent of control values (10(-4) mol/L blocker, n = 4) was as follows: nifedipine, 8.6% +/- 0.9% (H4) and 16.7% +/- 7.2% (L6); verapamil, 24.6% +/- 3.2% (H4) and 61.9% +/- 4.2% (L6); diltiazem, 62.7% +/- 3.6% (H4) and 36.1% +/- 5.4% (L6); all P < .001. Eadie-Hofstee analysis indicated competitive inhibition of T3 uptake for both calmidazolium and nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)