PHARMACODYNAMIC BASIS FOR THE INTERACTION OF CIMETIDINE WITH THE BONE-MARROW STEM-CELLS (CFU-S)

Abstract

A histamine H2-receptor agonist, 4-methylhistamine, triggers the pluripotent stem cells of mouse bone marrow from a noncycling state into the DNA synthetic phase of the cell cycle. The histamine H2-receptor blocking agent cimetidine antagonized the action of 4-methylhistamine. The antagonism was reversed by increasing 4-methylhistamine concentrations. When compared at equimolar concentrations with another antagonist, metiamide, cimetidine was more effective than was metiamide at shifting the concentration-response curve of 4-methylhistamine to the right. The data give a pharmacodynamic basis for the interaction of histamine-H2-receptor antagonists with bone marrow cells. They also question the hypothesis that the bone marrow toxicity of metiamide was related to the thioureido group in its structure and that substitution of a cyanoguanidino group for the thioureido moiety represents a structural modification that would avoid bone marrow effects of histamine-H2-receptor antagonists. Hence, interaction with progenitor cells, e.g., CFUs may be a property of all histamine-H2-receptor antagonists. Pathophysiologic conditions that increase demand for functional hematopoietic cells may represent situations that make bone marrow growth and differentiation susceptible to inhibition by histamine-H2-receptor antagonists.