Characterisation of the inhibition of the hepatocyte receptor-activated Ca²⁺ inflow system by gadolinium and SK&F 96365

The inhibition of agonist-stimulated divalent cation inflow in hepatocytes by Gd³⁺ and compound SK&F 96365 (1-{β-[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 μM) 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.