An adenylate cyclase that is stimulated by low concentrations of histamine (ka, 6 µM) has been studied in cell-free preparations of guinea pig cardiac ventricular muscle. The characteristics of activation of this adenylate cyclase by histamine receptor agonists, and of inhibition of this enzyme by H2-receptor antagonists (e.g., metiamide, cimetidine), indicate that this histamine-sensitive adenylate cyclase possesses pharmacological properties similar to those of an H2-receptor as defined by physiological experiments in peripheral tissues. Thus, the activation of this adenylate cyclase by histamine may be an early step in the sequence of biochemical events through which histamine acting at H2-receptors exerts its positive inotropic effects on cardiac ventricular muscle. The stimulation of adenylate cyclase activity by histamine was also competitively inhibited by several H1-receptor antagonists (e.g., mepyramine, diphenhydramine, promethazine) and by several imidazole-N-methyl transferase (INMT) inhibitors (e.g., quinacrine, etoprine). The results indicate that many structurally diverse compounds known to interact with various histamine binding proteins (i.e., the H2-receptor, as well as the H1-receptor and the histamine catabolic enzyme INMT) are capable of interacting with H2-receptors coupled to adenylate cyclase in heart. Furthermore, quantitative differences in the inhibition constants of H2-receptor antagonists, H1-receptor antagonists, and INMT inhibitors for the histamine-sensitive adenylate cyclases from guinea pig heart and brain suggest the existence of tissue heterogeneity in the pharmacological properties of H2-receptors.
- Copyright © 1979 by Academic Press, Inc.