Ca²⁺ channel activators reveal differential L-type Ca²⁺ channel pharmacology between native and stem cell-derived...

Human stem cell-derived cardiomyocytes provide new models for studying the ion channel pharmacology of human cardiac cells for both drug discovery and safety pharmacology purposes. However, detailed pharmacological characterization of ion channels in stem cell-derived cardiomyocytes is lacking. Therefore, we used patch-clamp electrophysiology to perform a pharmacological survey of the L-type Ca²⁺ channel in induced pluripotent and embryonic stem cell-derived cardiomyocytes and compared the results with native guinea pig ventricular cells. Six structurally distinct antagonists [nifedipine, verapamil, diltiazem, lidoflazine, bepridil, and 2-[(cis-2-phenylcyclopentyl)imino]-azacyclotridecane hydrochloride (MDL 12330)] and two structurally distinct activators [methyl 2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate (Bay K8644) and 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylic acid methyl ester (FPL 64176)] were used. The IC₅₀ values for the six antagonists showed little variability between the three cell types. However, whereas Bay K8644 produced robust increases in Ca²⁺ channel current in guinea pig myocytes, it failed to enhance current in the two stem cell lines. Furthermore, Ca²⁺ channel current kinetics after addition of Bay K8644 differed in the stem cell-derived cardiomyocytes compared with native cells. FPL 64176 produced consistently large increases in Ca²⁺ channel current in guinea pig myocytes but had a variable effect on current amplitude in the stem cell-derived myocytes. The effects of FPL 64176 on current kinetics were similar in all three cell types. We conclude that, in the stem cell-derived myocytes tested, L-type Ca²⁺ channel antagonist pharmacology is preserved, but the pharmacology of activators is altered. The results highlight the need for extensive pharmacological characterization of ion channels in stem cell-derived cardiomyocytes because these complex proteins contain multiple sites of drug action.