CHARACTERIZATION OF THE INHIBITION OF THE HEPATOCYTE RECEPTOR-ACTIVATED CA2+ INFLOW SYSTEM BY GADOLINIUM AND SK-AND-F-96365

The inhibition of agonist-stimulated divalent cation inflow in hepatocytes by Gd3+ and compound SK&F 96365 (1-{beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl}-1H-imidazole hydrochloride) was investigated. Gd3+ and SK&F 96365 inhibited Ca2+ and Mn2+ inflow stimulated by vasopressin, angiotensin II or phenylephrine. The concentrations of Gd3+ and SK&F 96365 which gave half-maximal inhibition of vasopressin-stimulated Ca2+ inflow were 2.10(-7) M and 16.10(-6) M, respectively. The action of Gd3+ on vasopressin-stimulated Ca2+ inflow was rapid (less than 10 s in onset) and reversible. Gd3+ had no effect on Mn2+ inflow in the absence of an agonist and no effect on the ability of vasopressin to release Ca2+ from intracellular stores. SK&F 96365 inhibited Mn2+ inflow in the absence of agonists and vasopressin-induced release of Ca2+ from intracellular stores, but at approximately a 5-fold higher concentration than that which inhibited vasopressin-stimulated divalent cation inflow. It is concluded that Gd3+ and SK&F 96365 (at concentrations below 20 mu M) inhibit, in a selective manner, divalent cation movement through the putative cation channel of the hepatocyte receptor-activated Ca2+ inflow system. Gd3+ appears to be the most potent inhibitor of this Ca2+ inflow system so far described.