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 microM, 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 microM, and 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.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D004110:Diltiazem / Q000494:pharmacology; D015232:Dinoprostone; D004305:Dose-Response Relationship, Drug; D006869:Hydronephrosis / Q000378:metabolism*; D007672:Kidney Cortex / Q000166:cytology / Q000187:drug effects*; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D011458:Prostaglandins E / Q000096:biosynthesis*; D011796:Quinacrine / Q000494:pharmacology; D011817:Rabbits; D014268:Trifluoperazine / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology*
D001095:Arachidonic Acids; D011458:Prostaglandins E; D014268:Trifluoperazine; D016718:Arachidonic Acid; D000001:Calcimycin; D014700:Verapamil; D004110:Diltiazem; D011796:Quinacrine; D008274:Magnesium; D009543:Nifedipine; D015232:Dinoprostone; D001920:Bradykinin; D002118:Calcium