Effects of simple aromatic compounds and flavonoids on Ca2+ fluxes in rat pituitary GH4C1 cells

The biological activity of phenolic compounds from plants is well documented in vitro, but little is known about the possible effect of simple aromatic compounds and flavonoids on voltage-operated Ca(2+) channels (VOCCs). In pituitary cells, several intracellular pathways may regulate the activity of VOCCs. In this study, we investigated the effect of nine phenylpropanes and metanes, and 20 flavonoids on high K(+)-induced (45)Ca(2+) entry in clonal rat pituitary GH(4)C(1) cells. At the highest dose tested (20 mug/ml), flavone (a flavone) inhibited (45)Ca(2+) entry by 63.5%, naringenin (a flavanone) by 56.3% and genistein tan isoflavone) by 54.6%. The phenylmetane derivative octyl gallate was the most potent compound tested, with an IC(50) value of 15.0 mug/ml. The IC(50) value for the reference compound verapamil hydrochloride was 3.0 mug/ml. In sharp contrast to the above, the flavonols quercetin and morin potentiated (45)Ca(2+) entry. At 70 mug/ml. quercetin increased (45)Ca(2+) entry by 54.1% and morin by 48.0%. Quercetin increased the cellular cAMP content in a concentration-dependent manner. H 89. an inhibitor of protein kinase A, inhibited the effect of quercetin on (45)Ca(2+) entry. The results thus suggest that the effect of quercetin is the result of a protein kinase A-mediated activation of VOCCs. Quercetin induced a rapid and marked increase in both the transient (143.1 +/- 4.2%) and delayed (198.8 +/- 10.0%) Ca(2+) currents, measured by the whole cell patch clamp technique. The onset of the inhibitory effect of octyl gallate was slow, but resulted in an almost complete inhibition of both Ca(2+) currents. (C) 2001 Elsevier Science B.V. All rights reserved.