Comparative studies of AJG049, a novel Ca²⁺ channel antagonist, on voltage‐dependent L‐type Ca²⁺ currents in intestinal and vascular smooth muscle

<jats:sec><jats:title>Background and purpose:</jats:title><jats:p>Antagonists of Ca<jats:sup>2+</jats:sup> 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<jats:sup>2+</jats:sup> channels, in vascular and intestinal smooth muscle, comparing AJG049 with two other Ca<jats:sup>2+</jats:sup> channel antagonists, verapamil and diltiazem.</jats:p></jats:sec><jats:sec><jats:title>Experimental approach:</jats:title><jats:p>Affinities of AJG049 for various types of voltage‐dependent Ca<jats:sup>2+</jats:sup> channels were examined by binding studies. Effects of AJG049 on voltage‐dependent inward Ca<jats:sup>2+</jats:sup> (or Ba<jats:sup>2+</jats:sup>) currents (<jats:italic>I</jats:italic><jats:sub><jats:italic>Ca</jats:italic></jats:sub> or <jats:italic>I</jats:italic><jats:sub><jats:italic>Ba</jats:italic></jats:sub>) in dispersed smooth muscle cells from guinea‐pig ileum, colon and mesenteric artery were measured using conventional whole‐cell configurations.</jats:p></jats:sec><jats:sec><jats:title>Key results:</jats:title><jats:p>In binding studies, AJG049 showed a high affinity for the diltiazem‐binding site of L‐type Ca<jats:sup>2+</jats:sup> channels. In whole‐cell configuration, AJG049 suppressed <jats:italic>I</jats:italic><jats:sub><jats:italic>Ca</jats:italic></jats:sub> in ileal myocytes, with concentration‐, voltage‐and use‐dependencies. AJG049 shifted the steady‐state inactivation curve of <jats:italic>I</jats:italic><jats:sub><jats:italic>Ca</jats:italic></jats:sub> to the left. The order of potency to inhibit <jats:italic>I</jats:italic><jats:sub><jats:italic>Ca</jats:italic></jats:sub> in ileal myocytes was AJG049>verapamil>diltiazem. AJG049 also suppressed <jats:italic>I</jats:italic><jats:sub><jats:italic>Ba</jats:italic></jats:sub> 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 <jats:italic>K</jats:italic><jats:sub><jats:italic>i</jats:italic></jats:sub> values between ileal and mesenteric arterial myocytes, the order was AJG049>diltiazem≫verapamil.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and implications:</jats:title><jats:p>These results show that AJG049 inhibits L‐type Ca<jats:sup>2+</jats:sup> channels mainly through the diltiazem‐binding site(s). From our results, AJG049 showed a little selectivity for these Ca<jats:sup>2+</jats:sup> channels in intestinal smooth muscle.</jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2006) <jats:bold>149</jats:bold>, 155–162. doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0706861">10.1038/sj.bjp.0706861</jats:ext-link></jats:p></jats:sec>