Mechanism of action of H2-antagonists on histamine- or dimaprit-stimulated H2-receptors of spontaneously beating guinea-pig atrium.

Cimetidine, ranitidine and famotidine are antagonists of the histamine H2-receptors on the spontaneously beating right atrium of the guinea pig. When analyzed by the classical Schild method their pA2-values are respectively: 6.3, 6.8 and 7.7 with dimaprit as agonist and 5.8, 6.5 and 7.7 with histamine as agonist. Radioligand-displacement studies with [3H]-tiotidine as radioligand resulted in pKd values for cimetidine, ranitidine and famotidine of 6.3; 6.9 and 8.2 respectively. In dimaprit-stimulated atria all antagonists added at concentrations above their Kd values depressed the maximal increase in frequency. In the presence of histamine this effect was much less pronounced and only visible at concentrations of ranitidine and famotidine around 10.Kd. The rightward shift of the curves as well as the decrease in Emax are reversible but the dissociation constants of the antagonists are small (less than 10(-3) s-1). The spontaneously beating right atrium showed receptor reserve for histamine and virtually no receptor reserve for dimaprit. The results have been interpreted in a model in which H2-antagonists act mainly by competing with the agonist for the histamine receptor site but have in addition a distinct affinity for a secondary site on the receptor. Occupation of this site by the antagonist prevents building up of the stimulus elicited by the agonist and thus decreases the Emax. In systems with receptor reserve (histamine) the effect of antagonist binding to the secondary binding site is seen only at high concentration of antagonist while in absence of receptor reserve (dimaprit) the depression of Emax is directly visible. Simulations of the model show that the affinity of this secondary binding site is 50-(famotidine) to 100-(cimetidine and ranitidine) fold lower than for the agonist binding site.