Zhu H-L, Tomoda T, Aishima M, Ito Y, Teramoto N
Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Br J Pharmacol. 2006 Nov;149(6):786-96. doi: 10.1038/sj.bjp.0706919. Epub 2006 Oct 3.
Although azelnidipine is used clinically to treat hypertension its effects on its target cells, Ca2+ channels, in smooth muscle have not been elucidated. Therefore, its effects on spontaneous contractions and voltage-dependent L-type Ca2+ channels were investigated in guinea-pig portal vein.
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 Ba2+ currents (IBa) in smooth muscle cells dispersed from guinea-pig portal vein were investigated by use of a conventional whole-cell patch-clamp technique.
Spontaneous contractions in guinea-pig portal vein were reduced by all of the Ca antagonists (azelnidipine, Ki = 153 nM; amlodipine, Ki = 16 nM; nifedipine, Ki = 7 nM). In the whole-cell experiments, azelnidipine inhibited the peak amplitude of IBa in a concentration- and voltage-dependent manner (-60 mV, Ki = 282 nM; -90 mV, Ki = 2 microM) and shifted the steady-state inactivation curve of IBa to the left at -90 mV by 16 mV. The inhibitory effects of azelnidipine on IBa persisted after 7 min washout at -60 mV. In contrast, IBa gradually recovered after being inhibited by amlodipine, but did not return to control levels. Both azelnidipine and amlodipine caused a resting block of IBa at -90 mV. Only nifedipine appeared to interact competitively with S(-)-Bay K 8644.
These results suggest that azelnidipine induces long-lasting vascular relaxation by inhibiting voltage-dependent L-type Ca2+ channels in vascular smooth muscle.
尽管阿折地平在临床上用于治疗高血压，但其对平滑肌中靶细胞钙通道的作用尚未阐明。因此，在豚鼠门静脉中研究了其对自发收缩和电压依赖性L型钙通道的影响。
通过记录张力，比较阿折地平与其他二氢吡啶（DHP）类钙拮抗剂（氨氯地平和硝苯地平）对豚鼠门静脉自发收缩的抑制效力。此外，使用传统的全细胞膜片钳技术研究了其对从豚鼠门静脉分离的平滑肌细胞中电压依赖性硝苯地平敏感内向Ba2+电流（IBa）的影响。
所有钙拮抗剂（阿折地平，Ki = 153 nM；氨氯地平，Ki = 16 nM；硝苯地平，Ki = 7 nM）均降低了豚鼠门静脉的自发收缩。在全细胞实验中，阿折地平以浓度和电压依赖性方式抑制IBa的峰值幅度（-60 mV时，Ki = 282 nM；-90 mV时，Ki = 2 μM），并在-90 mV时将IBa的稳态失活曲线向左移动16 mV。在-60 mV洗脱7分钟后，阿折地平对IBa的抑制作用仍然存在。相比之下，氨氯地平抑制后IBa逐渐恢复，但未恢复到对照水平。阿折地平和氨氯地平在-90 mV时均引起IBa的静息阻断。只有硝苯地平似乎与S(-)-Bay K 8644竞争性相互作用。
这些结果表明，阿折地平通过抑制血管平滑肌中的电压依赖性L型钙通道诱导持久的血管舒张。
