Actions of a new Ca2+ channel antagonist, CD832, on two 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 ICa) 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 microM for T-type ICa. The IC50 of nifedipine was 36 nM for L-type and 2.7 microM for T-type ICa. CD832 blocked both types of ICa 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 ICa less potently than does nifedipine, (2) CD832 blocks T-type ICa 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 ICa as compared with nifedipine.
Hirakawa
Y
Y
Research Institute of Angiocardiology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Kuga
T
T
Kanaide
H
H
Takeshita
A
A
D000818:Animals; D001011:Aorta / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
C082828:CD 832; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D009536:Niacinamide; D009543:Nifedipine