ACTIONS OF A NEW CA2+ CHANNEL ANTAGONIST, CD832, ON 2 TYPES OF CA2+ CHANNELS IN SMOOTH-MUSCLE

The purpose of this study was to determine the characteristics of blockade of L- and T-type Ca2+ channels by a new Ca2+ channel antagonist, 3-(2-nicotinoylamino)ethyl 5-(3-nitrooxypropyl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (CD832), in comparison with those of nifedipine, in rat aortic smooth muscle cells in primary culture. In a whole-cell configuration under voltage-clamp, CD832 and nifedipine dose dependently blocked both L- and T-type Ca2+ currents (L- and T-type I-Ca) without shifting the axis of the current-voltage relations. The 50% inhibition concentration (IC50) of CD832 was 310 nM for L-type and 1.1 mu M for T-type I-Ca. The IC50 of nifedipine was 36 nM for L-type and 2.7 mu M for T-type I-Ca. CD832 blocked both types of I-Ca from the first step pulses after drug application, shifted their steady-state inactivation curves to the left, and did not significantly accelerate the current decay. The effect of CD832 reached its maximum within 6 min and was hardly washed out, while that of nifedipine reached a maximum within 30 s and could be washed out within 3 min. These results suggest that (1) CD832 blocks L-type I-Ca less potently than does nifedipine, (2) CD832 blocks T-type I-Ca more potently than does nifedipine, (3) CD832 blocks not only the resting state but, more preferentially, the inactivated state of L- and T-type Ca2+ channels, and (4) CD832 has a slow and long-acting activity in blocking both types of I-Ca as compared with nifedipine.