Mechanism of glycogenolytic action of histamine in rat hepatocytes

Abstract

The mechanism by which histamine induces glycogenolysis was investigated in rat hepatocytes. Histamine induced stimulation of glucose output in hepatocytes in a dose-dependent manner. The maximal effect of the glycogenolytic action of histamine, which was approximately 60% of the maximal glucagon action, was obtained at 10(-6) M. These effects were inhibited by H1 receptor antagonists triprolidine hydrochloride and tripelennamine but not by a H2 receptor antagonist cimetidine. Histamine also increased the activity of phosphorylase a. When 10(-6) M histamine and 5 x 10(-9) M glucagon were added simultaneously, the actions of these two agents were additive. In contrast, there was no additivity when 10(-6) M histamine and 10(-8) M angiotensin II were added. Histamine did not increase adenosine 3',5'-cyclic monophosphate at any doses tested but induced a rapid increase in the cytoplasmic free calcium concentration ([Ca2+]c). Histamine increased [Ca2+]c even in the presence of 1 microM extracellular calcium, an observation suggesting that histamine caused calcium release from an intracellular calcium pool(s). When [3H]inositol-labeled hepatocytes were incubated with histamine, radioactivity in the D-myo-inositol trisphosphate fraction was rapidly increased. These results indicate that histamine acts on rat hepatocytes mainly via H1 receptors and stimulates glycogenolysis by activating the calcium messenger system.