Inhibition by cations of antagonist binding to histamine H1-receptors: differential effect of sodium ions on the binding of two radioligands.
1. Measurements have been made of the inhibition by mono- and divalent cations of the binding of [3H]-(+)-N-methyl-4-methyldiphenhydramine ([3H]-QMDP) to histamine H1-receptors in homogenates of guinea-pig cerebellum. 2. The binding of [3H]-QMDP was inhibited by monovalent cations with an order of potency Li+ = Na+ greater than K+ greater than Cs+ = Rb+. The IC50 for Li+ was 39 mM, but that for K+ was 132 mM. Hill coefficients for inhibition curves for Li+ and Na+ were less than 1. 3. Divalent cations also inhibited the binding of [3H]-QMDP. The most potent cations examined were Hg2+, Cd2+ and Zn2+, with IC50 values of 5, 17 and 41 microM, respectively. Ca2+ and Mg2+ were relatively weak inhibitors (IC50 12 and 34 mM, respectively). The potency of Ni2+, Co2+ and Mn2+ was intermediate between these groups. Hill coefficients for inhibition curves for Hg2+, Cd2+ and Zn2+ were greater than 1, but Hill coefficients for the other cations were less than 1. 4. Both mono- and divalent cations also inhibited the binding of [3H]-mepyramine. The divalent cations were approximately equipotent in inhibiting the binding of [3H]-QMDP and [3H]-mepyramine. The same was true for Li+. However, Na+ was markedly more effective against [3H]-QMDP binding than against the binding of [3H]-mepyramine. 5. The effect of 40 mM Li+ on the parameters of binding of [3H]-mepyramine was to increase the best-fit value of the concentration giving half-maximal binding EC50, by approximately 2 fold without having any significant effect on the maximum amount of binding. Cd2+ (15 microM) caused both an increase in EC 0 and a decrease in Bmax (32 +/- 4% inhibition). Na+, 100 mm, had no significant effect on either EC50 or Bmax for [3H]-mepyramine binding.
Department of Pharmacology, University of Cambridge.
J M
JM
Treherne
J S
JS
Stern
W J
WJ
Flack
J M
JM
Young
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002104:Cadmium / Q000494:pharmacology; D002412:Cations / Q000494:pharmacology*; D002413:Cations, Divalent / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002586:Cesium / Q000494:pharmacology; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008094:Lithium / Q000494:pharmacology; D008297:Male; D009966:Orphenadrine / Q000031:analogs & derivatives / Q000494:pharmacology; D011738:Pyrilamine / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000187:drug effects*; D012413:Rubidium / Q000494:pharmacology; D012964:Sodium / Q000494:pharmacology*
D002412:Cations; D002413:Cations, Divalent; D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D002104:Cadmium; C057530:N-methyl-4-methyldiphenhydramine; D002586:Cesium; D008094:Lithium; D012964:Sodium; D009966:Orphenadrine; D011738:Pyrilamine; D012413:Rubidium