Differences in the interaction of histamine H2 receptor antagonists and tricyclic antidepressants with adenylate cyclase from guinea pig gastric mucosa.

The interaction of adenylate cyclase with histamine H2 receptor agents and with tricyclic antidepressants was studied in guinea pig gastric mucosal membranes. The H2 receptor antagonist tiotidine acted as a competitive inhibitor of histamine-stimulated adenylate cyclase. The tricyclic antidepressants imipramine and amitryptyline were also competitive inhibitors. The dissociation constant of imipramine was the same whether histamine or dimaprit was used to activate the enzyme. In membrane preparations that had been stored frozen, there was a marked increase in the concentration of histamine or dimaprit required to cause half-maximal enzyme stimulation, and the dissociation constants of some classical H2 receptor antagonists were greatly increased. In contrast, the dissociation constants of the antidepressants were either unchanged or decreased. These results suggest that antidepressants are potent blockers of H2 receptors in gastric mucosal membranes, but there are differences between antidepressants and classical H2 receptor antagonists in their interaction with H2 receptors.