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-[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 x 10(-7) M and 16 x 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 microM) 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.
Department of Medical Biochemistry, School of Medicine, Flinders University, Adelaide, Australia.
K C
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Fernando
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Barritt
D000634:Aminoquinolines; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005682:Gadolinium / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008345:Manganese / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014667:Vasopressins / Q000494:pharmacology
D000634:Aminoquinolines; D007093:Imidazoles; D014667:Vasopressins; D008345:Manganese; D005682:Gadolinium; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; C035739:Quin2; D002118:Calcium