Comparative studies of AJG049, a novel Ca 2+ channel antagonist, on voltage‐dependent L‐type Ca 2+ currents in intestinal and vascular smooth muscle

Background and purpose: Antagonists of Ca 2+ 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+ channels, in vascular and intestinal smooth muscle, comparing AJG049 with two other Ca 2+ channel antagonists, verapamil and diltiazem. Experimental approach: Affinities of AJG049 for various types of voltage‐dependent Ca 2+ channels were examined by binding studies. Effects of AJG049 on voltage‐dependent inward Ca 2+ (or Ba 2+ ) 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+ channels. In whole‐cell 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 AJG049>verapamil>diltiazem. 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 AJG049>verapamil>diltiazem. For the relative ratio of K i values between ileal and mesenteric arterial myocytes, the order was AJG049>diltiazem≫verapamil. Conclusions and implications: These results show that AJG049 inhibits L‐type Ca 2+ channels mainly through the diltiazem‐binding site(s). From our results, AJG049 showed a little selectivity for these Ca 2+ channels in intestinal smooth muscle. British Journal of Pharmacology (2006) 149 , 155–162. doi: 10.1038/sj.bjp.0706861