Effect of verapamil on prostaglandin E₂ synthesis by hydronephrotic rabbit cortical interstitial cells in primary culture

The effect of the calcium channel blocker verapamil on prostaglandin (PG) E₂ production by hydronephrotic cortical interstitial cells in primary culture was investigated. Verapamil displayed a dual action, maximally enhancing PGE₂ production from 1.2 ± 0.2 to 30.7 ± 4.3 ng/ml at 30 μM, whereas at higher concentrations the effect tapered down to base line. Stimulation of PGE₂ synthesis by verapamil required extracellular calcium, but was unaffected by the intracellular calcium inhibitor 8-(Diethylamino)octyl 3,4,5-trimethoxy-benzoate or the calmodulin inhibitor trifluoperazine. Other calcium channel blockers, nifedipine and diltiazem, failed to stimulate PGE₂ synthesis, implying that this effect of verapamil was unrelated to its commonly recognized action to inhibit calcium channels. However, stimulation by verapamil was inhibited by quinacrine (mepacrine), suggesting a mechanism involving activation of a phospholipase. In addition, verapamil attenuated the bradykinin- or ionophore A23187-stimulated PGE₂ production, but it did not alter arachidonic acid-induced PGE₂ synthesis. These observations indicate that, in addition to phospholipase activation, verapamil may also act to inhibit phospholipase activity. Inhibition was concentration-dependent over the range 3 to 300 μM, was reversible. It is concluded that verapamil, at different concentrations, exerts a dual action on cellular phospholipase activity, thereby stimulating, and in turn inhibiting, PGE₂ synthesis by hydronephrotic interstitial cells.