THE CA-CHANNEL BLOCKER RO-40-5967 BLOCKS DIFFERENTLY T-TYPE AND L-TYPE CA++ CHANNELS(+)

The effects of Ro 40-5967, a nondihydropyridine Ca++ channel blocker, on low-voltage activated (T-type) and high-voltage activated (L-type) Ca++ channels were compared. L-type barium currents were measured in C hinese hamster ovary cells stably transfected with the alpha(1) subuni t of the class Cb Ca++ channel. T-type barium currents were investigat ed in human medullary thyroid carcinoma cells. The Ba++ currents of hu man medullary thyroid carcinoma cells were transient, activated at a t hreshold potential of -50 mV with the maximum at -14 +/- 3.2 mV and bl ocked by micromolar Ni++. The T- and L-type current inactivated with t ime constants of 33.4 +/- 4.1 and 416 +/- 26 msec at maximum barium cu rrents, respectively. Ro 40-5967 inhibited reversibly the T- and L-typ e currents with IC50 values of 2.7 and 18.6 mu M, respectively. The in hibition of the L-type current was voltage-dependent, whereas that of the T-type current was not. Ro 40-5967 blocked T-type current already at a holding potential of -100 mV. The different types of block, i.e., voltage-dependent vs, tonic block, may contribute to the pharmacologi cal profile of Ro 40-5967 in intact animals.