Mechanisms underlying the slow onset of action of a new dihydropyridine, NZ-105, on a cultured smooth muscle cell line.
The inhibitory effect of a new dihydropyridine derivative, (+/-)-2-[benzyl(phenyl)amino]ethyl-1,4-dihydro-2,6-dimethyl-5- (5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl )-3- pyridinecarboxylate hydrochloride (NZ-105), on whole cell Ca2+ current (ICa) in cultured vascular smooth muscle cells was investigated with the patch clamp technique. NZ-105 blocked ICa in a concentration-dependent manner when the command pulse ranged from +10 mV to -50 mV. The inhibitory effect of NZ-105 appeared at concentrations higher than 10 pmol/l and it blocked ICa completely at a concentration of 1 nmol/l. The concentration which produced the half-maximal inhibitory effect was estimated to be around 20 pmol/l. NZ-105 (500 pmol/l) completely blocked ICa elicited by depolarization to +10 mV at a holding potential of -40 mV, whereas it blocked ICa by only 67% at a holding potential of -90 mV. NZ-105 (100 pmol/l) shifted the steady-state inactivation curve by 40 mV to more negative potentials without affecting its slope factor. The blocking time constant of 500 pmol/l NZ-105 was 57.6 +/- 9.9 s at a holding potential of -70 mV. These results indicate that NZ-105 has characteristics typical of dihydropyridines and binds to Ca2+ channels of vascular smooth muscle cells with a high affinity. They also suggested that the slow onset of its action is due to the slow binding of the drug to Ca2+ channels.
Tamura
T
T
Department of Physiology, Jikei University, School of Medicine, Tokyo, Japan.
Saigusa
A
A
Kokubun
S
S
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D002460:Cell Line; D004095:Dihydropyridines / Q000494:pharmacology*; D004558:Electric Stimulation; D004594:Electrophysiology; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009596:Nitrophenols; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D051381:Rats
D000959:Antihypertensive Agents; D015220:Calcium Channels; D004095:Dihydropyridines; D009596:Nitrophenols; D009943:Organophosphorus Compounds; C066425:efonidipine