The sensitivity of mast cells to H3-receptor modulation was studied in rat lung under various hormonal conditions. The heterogeneity of mast cell sub-populations in rat lung was assessed by the tissue content of rat mast cell protease I (RMCP I) and rat mast cell protease II (RMCP II). After 24 h fasting, concentrations of RMCP I were unchanged whereas the concentration of RMCP II was significantly reduced by 49%. The [3H]histamine (HA) synthesis was concomitantly decreased by 35%. In addition, the modulation of [3H]HA synthesis by the H3 receptor agonist, (R)alpha-methylHA and by the antagonist, thioperamide, observed in control rats, was lost in fasted rats. Single and repeated administrations of dexamethasone did not influence RMCPI concentrations, but decreased the concentrations of RMCP II with a parallel decrease in [3H]HA synthesis. The inhibitory effect of (R)alpha-methylHA on [3H]HA synthesis was also reduced. These results suggest that a subpopulation of RMCP II-containing mast cells, very sensitive to environmental factors, could be the mast cells synthesizing HA in an H3-receptor-dependent manner.