The actions of azelnidipine, a dihydropyridine-derivative Ca antagonist, on voltage-dependent Ba 2+ currents in guinea-pig vascular smooth muscle

Abstract

Background and purpose: Although azelnidipine is used clinically to treat hypertension its effects on its target cells, Ca 2+ channels, in smooth muscle have not been elucidated. Therefore, its effects on spontaneous contractions and voltage-dependent L-type Ca 2+ channels were investigated in guinea-pig portal vein.Experimental approach:The inhibitory potency of azelnidipine on spontaneous contractions in guinea-pig portal vein was compared with those of other dihydropyridine (DHP)-derived Ca antagonists (amlodipine and nifedipine) by recording tension. Also its effects on voltage-dependent nifedipine-sensitive inward Ba 2+ currents (I Ba) in smooth muscle cells dispersed from guinea-pig portal vein were investigated by use of a conventional whole-cell patch-clamp technique. Key results: Spontaneous contractions in guinea-pig portal vein were reduced by all of the Ca antagonists (azelnidipine, K i = 153 nM; amlodipine, K i = 16 nM; nifedipine, K i = 7 nM). In the whole-cell experiments, azelnidipine inhibited the peak amplitude of I Ba in a concentration- and voltage-dependent manner (-60 mV, K i = 282 nM; -90 mV, K i = 2 μM) and shifted the steady-state inactivation curve of I Ba to the left at -90 mV by 16 mV. The inhibitory effects of azelnidipine on I Ba persisted after 7 min washout at -60 mV. In contrast, I Ba gradually recovered after being inhibited by amlodipine, but did not return to control levels. Both azelnidipine and amlodipine caused a resting block of I Ba at -90 mV. Only nifedipine appeared to interact competitively with S(-)-Bay K 8644. Conclusions and implications: These results suggest that azelnidipine induces long-lasting vascular relaxation by inhibiting voltage-dependent L-type Ca 2+ channels in vascular smooth muscle. © 2006 Nature Publishing Group. All rights reserved.