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.
Background and purpose: Antagonists of Ca 2 þ channels reduce contraction of intestinal smooth muscle but also affect vascular smooth muscle. We have therefore examined the effects of AJG049, a newly synthesized antagonist for regulation of gut motility, on voltage-dependent L-type Ca 2 þ channels, in vascular and intestinal smooth muscle, comparing AJG049 with two other Ca 2 þ channel antagonists, verapamil and diltiazem. Experimental approach: Affinities of AJG049 for various types of voltage-dependent Ca 2 þ channels were examined by binding studies. Effects of AJG049 on voltage-dependent inward Ca 2 þ (or Ba 2 þ ) currents (I Ca or I Ba ) in dispersed smooth muscle cells from guinea-pig ileum, colon and mesenteric artery were measured using conventional whole-cell configurations. Key results: In binding studies, AJG049 showed a high affinity for the diltiazem-binding site of L-type Ca 2 þ channels. In wholecell configuration, AJG049 suppressed I Ca in ileal myocytes, with concentration-, voltage-and use-dependencies. AJG049 shifted the steady-state inactivation curve of I Ca to the left. The order of potency to inhibit I Ca in ileal myocytes was AJG0494verapamil4diltiazem. AJG049 also suppressed I Ba in guinea-pig mesenteric arterial myocytes, showing concentration-and voltage-dependencies and the potency order for this action was also AJG0494verapamil4diltiazem. For the relative ratio of K i values between ileal and mesenteric arterial myocytes, the order was AJG0494diltiazemcverapamil. Conclusions and implications:These results show that AJG049 inhibits L-type Ca 2 þ channels mainly through the diltiazembinding site(s). From our results, AJG049 showed a little selectivity for these Ca 2 þ channels in intestinal smooth muscle.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.