Histamine H1-receptors in the brain of the guinea-pig and the rat: differences in ligand binding properties and regional distribution.

1 The equilibrium dissociation constant, K(d), for mepyramine binding to a particulate fraction from rat brain, 9.1 nM, determined from inhibition of the binding of 1 nM [(3)H]-mepyramine, was distinctly higher than that, 0.83 nM, measured on an equivalent preparation from guinea-pig brain.2 In rat brain the dissociation constant for mepyramine, determined from the binding of [(3)H]-mepyramine sensitive to inhibition by 2 x 10(-6) M promethazine, was higher than the constant obtained from the inhibition of the binding of 1 nM [(3)H]-mepyramine by non-radioactive mepyramine. This suggests that the promethazine-sensitive binding of [(3)H]-mepyramine includes a lower affinity non-receptor component, which becomes apparent at higher concentrations of [(3)H]-mepyramine.3 In the guinea-pig the dissociation constant for mepyramine determined from inhibition of [(3)H]-mepyramine binding was in good agreement with the value obtained from inhibition of the contractile response of intestinal smooth muscle to histamine. No similar comparison was possible in the rat. Rat ileum was much less sensitive to histamine and the contraction produced was not inhibited by 10(-6) M mepyramine, indicating that it is not mediated by H(1)-receptors.4 Low levels of promethazine-sensitive [(3)H]-mepyramine binding were present in membrane fractions prepared from the longitudinal muscle from rat small intestine, but the characteristics of this binding suggest that it may be largely to lower affinity, non-receptor sites.5 Promethazine was practically equipotent as an inhibitor of [(3)H]-mepyramine binding in rat and guinea-pig brain. Chlorpheniramine showed stereospecificity in the rat as in the guinea-pig, although the potency of the (+)-isomer in the rat was only a tenth of that in the guinea-pig. Histamine had nearly the same IC(50) in both species.6 The evidence suggests that the high-affinity [(3)H]-mepyramine binding sites in rat brain can be described as H(1)-receptors, but that these differ structurally from H(1)-receptors in the guinea-pig.7 The regional distribution of [(3)H]-mepyramine binding in rat brain was not the same as that in guinea-pig brain, the most notable difference being the very much lower level in rat cerebellum compared to guinea-pig cerebellum.