Inhibitory Effect of Calcium Channel Blockers on α-Adrenergic Activation of Glycogenolysis and Calcium Efflux in Perfused Rat Liver

Abstract

In an attempt to verify the importance of calcium ions in mediating α-adrenergic stimulation, the effects of a calcium channel blocker, verapamil, on phenylehrineinduced 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 50μM and 50μM. 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 release correlated very well. All of 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 α-adrenergic agonist to the plasma membrane, the good correlation between the inhibitory effects of verapamil on basal ⁴⁵Ca release 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.