1. The mechanism of activation of liver phosphorylase after splanchnic nerve stimulation has been investigated in rabbits and compared with the effects of intraportal injections of noradrenaline.2. The increase in the activity of liver phosphorylase-a, the active form of this key glycogenolytic enzyme, in response to injections of noradrenaline was blocked by beta-adrenergic antagonists, but not by alpha-adrenergic antagonists, suggesting that the effect of noradrenaline is mediated mainly through beta-adrenoceptors in vivo. In contrast, the increase in phosphorylase activity in response to stimulation of the peripheral end of the splanchnic nerve was resistant to both alpha- and beta-adrenoceptor blockade.3. When diltiazem and verapamil, selective Ca(2+) antagonists that restrict calcium influx across the cell membrane, were infused intraportally, the phosphorylase response to splanchnic nerve stimulation was virtually abolished, while the response to noradrenaline was unaltered.4. Infusion of the prostaglandin-synthesis inhibitor indomethacin at a dose of 3.4 mug/min was found to block the activation of liver phosphorylase in response to stimulation of the splanchnic innervation.5. These results suggest that the mechanism whereby stimulation of the sympathetic innervation to the liver leads to activation of phosphorylase is not mediated by either alpha- or beta-adrenoceptors, but appears to depend upon prostaglandin formation and influx of Ca(2+) ions into the hepatocytes.