Inhibition by calcium channel blockers of the glycogenolytic effect of glucagon in perfused rat liver.

Verapamil and diltiazem, calcium channel blockers, inhibited significantly the glucagon-induced glucose output and 45Ca efflux from perfused rat liver at concentrations higher than 50 microM when the perfusate contained calcium. Although the blockers partially interfered with glucagon-induced elevation of cyclic AMP in the tissue, they also inhibited the effects of cyclic AMP. The blockers did not show the inhibitory effects in the absence of perfusate calcium. However, the inhibition of calcium influx into hepatocytes by omission of extracellular calcium or addition of EGTA did not interfere with these effects of glucagon and cyclic AMP. In the presence of extracellular calcium, the blockers did not inhibit cyanide-induced glucose output, indicating that the activity of glycogen phosphorylase and later processes leading to glucose output were not affected by the blockers. These data suggest that, in the presence of calcium, the blockers inhibit the effect of glucagon also at a step (or steps) subsequent to cyclic AMP production and before the activation of phosphorylase b, probably by inhibiting glucagon-induced mobilization of calcium from intracellular calcium pools rather than inhibiting calcium influx into hepatocytes.