The actions of azelnidipine, a dihydropyridine‐derivative Ca antagonist, on voltage‐dependent Ba²⁺ 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 þ channels, in smooth muscle have not been elucidated. Therefore, its effects on spontaneous contractions and voltagedependent L-type Ca 2 þ 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 þ 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 ¼ 153 nM; amlodipine, K i ¼ 16 nM; nifedipine, K i ¼ 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 ¼ 282 nM; À90 mV, K i ¼ 2 mM) and shifted the steady-state inactivation curve of I Ba to the left at À90 mV by 16 mV. The inhibitory effects of azelnidipine on I Ba persisted after 7 min washout at À60 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 þ channels in vascular smooth muscle.

Azelnidipine Inhibits Msx2-Dependent Osteogenic Differentiation and Matrix Mineralization of Vascular Smooth Muscle Cells

“…In fact, azel-nidipine is reported to cause longer relaxation of smooth muscle cells and more enhanced NO production in endothelial cells than other CCBs. 15,16) Furthermore, we have previously reported that azelnidipine down-regulates gene expression of molecular components of the renin-angiotensin-aldosterone system, 17) suggesting a novel mechanism for the vasoprotective and renoprotective effect of azelnidipine. Despite the potential beneficial effect of azelnidipine on vascular cells, it has not yet been determined whether azelnidipine inhibits the osteogenic differentiation of VSMCs and further development of vascular calcification.…”

Electrophysiological effect and the gating mechanism of astragaloside IV on l-type Ca2+ channels of guinea-pig ventricular myocytes

“…Similar mechanism has been reported in many dihydropyridine (DHP) agonists and antagonists and other types of Ca 2 þ entry-blocking agents (benzothiazepines and phenylakylamines). Zhu et al (2006) reported that the voltage-dependent inhibitory action of azelnidipine, a new DHP-deriivative calcium antagonist, occur at the inactivated state of L-type Ca 2 þ channels. Recently, structural model for DHP binding to L-type Ca 2 þ channels showed that preferential binding to the open/inactivated states was a characteristic feature of various ligands of P-loop channels, which have largely different chemical structures, access pathways to the binding sites within the pore-forming domain, and binding determinants within the sites (Tikhonov and Zhorov, 2009).…”

Effect of azelnidipine and amlodipine on single cell mechanics in mouse cardiomyocytes

“…Although third generation Ca 2+ channel blockers are well known as slow-acting drugs, it has been reported that direct effects of application of azelnidipine or amlodipine on L-type Ca 2+ channel in single cell preparation reach stable within a few minutes (Zhu et al, 2006). Therefore, after the measurement of ESFLR and EDFLR, cells were perfused with NT solution without any drugs (control), or NT solution containing either therapeutically relevant concentration (10 nM) (Kuramoto et al, 2003;Nakashima et al, 2000) or high concentration (100 nM) of one of the drugs for 5 min, and then, ESFLR and EDFLR were measured again to calculate rate of drug-induced changes in slopes of them.…”