The Ca2+-dependent actions of the alpha-adrenergic agonist phenylephrine on hepatic glycogenolysis differ from those of vasopressin and angiotensin

Abstract

The stimulation of hepatic glycogenolysis by the Ca2+-dependent hormones phenylephrine, vasopressin and angiotensin II was studied as a function of intracellular and extracellular Ca2+. In the isolated perfused rat liver the decline in glucose formation was monophasic ('half-life' approximately equal to 3 min) with vasopressin (1 nM) or angiotensin II (0.05 microM), but biphasic (half-life of 4.8 min and 17.6 min) in the presence of the alpha-agonist phenylephrine (0.01 mM), indicating either a different mode of mobilization or the mobilization of additional intracellular calcium stores. Under comparable conditions an elevated [Ca2+] level was maintained in the cytosol of hepatocytes for at least 10 min in the presence of phenylephrine, but not vasopressin. Titration experiments performed in the isolated perfused liver to restore cellular calcium revealed differences in the hormone-mediated uptake of Ca2+. The onset in glucose formation above that seen in the absence of exogenous calcium occurred at approximately 30 microM or 70-80 microM Ca2+ in the presence of phenylephrine or vasopressin respectively. The shape of the response curve was sigmoidal for vasopressin and angiotensin II, but showed a distinct plateau between 0.09 mM and 0.18 mM in the presence of phenylephrine. The plateau was also observed at phenylephrine concentrations as low as 0.5 microM. The formation of plateaus observed after treatment of the liver with A 23187, but not after EGTA, is taken as an indication that intracellular calcium stores are replenished. A participation of the mitochondrial compartment could be excluded by pretreatment of the liver with the uncoupler 2,4-dinitrophenol. Differences in the Ca2+ dependence of the glycogenolytic effects of these hormones were also revealed by kinetic analysis. It is concluded that phenylephrine differs from vasopressin and angiotensin II in that, in addition to a more common, non-mitochondrial pool, which is also responsive to the vasoactive peptides, the agonist mobilizes Ca2+ from a second, non-mitochondrial pool. The results are consistent with the proposal that Ca2+ transport across subcellular membranes may be subject to different hormonal control.