Inhibitory effect on calcium channel blockers on alpha -adrenergic activation of glycogenolysis and calcium efflux in perfused rat liver.

In an attempt to verify the importance of calcium ions in mediating alpha -adrenergic stimulation, the effects of a calcium channel blocker, verapamil, on phenylephrine-induced glycogenolysis and calcium efflux in perfused livers prepared from fed rats were determined. The blocker inhibited phenylephrine-induced glycogenolysis in a noncompetitive and dose-dependent manner between 50 micro M and 500 micro M. However, it did not affect 2, 4-dinitrophenol-induced glycogenolysis. It had no significant effect on 45 Ca uptake by the perfused liver, but inhibited basal as well as phenylephrine-induced efflux of 45Ca from 45Ca-loaded liver. The inhibitory effects on basal 45Ca release and phenylephrine-induced glycogenolysis and 45Ca released correlated very well. All the the effects of verapamil were reproduced by another calcium channel blocker, diltiazem, suggesting that these effects are common to a variety of calcium channel blockers. These results indicate that the process of calcium influx and the function of phosphorylase per se are not directly involved in the inhibitory action of the blocker. Although it is possible that verapamil interferes with binding of the alpha -adrenergic agonist to the plasma membrane, the good correlation between the inhibitory effects of verapamil on basal 45Ca released and on phenylephrine-induced release of 45Ca suggests another mechanism, involving calcium ions. The blocker appears to inhibit the glycogen phosphorylase activity induced by phenylephrine via a cell-membrane mechanism in which calcium ion flux changes are intimately involved.