Effects of verapamil on activation of arachidonic acid metabolism in guinea-pig lungs.
The effects of (+/-)-verapamil and its optical isomers on the activation of arachidonic acid (AA) in guinea-pig isolated perfused lungs were investigated. The calcium ionophore A23187 (6-15 nmol), histamine (20-50 nmol) and leukotriene E4 (1-2 nmol) induced the release of thromboxane A2 (TxA2), which was detected by bioassay and by radioimmunoassay of the stable metabolite TxB2. Racemic (+/-)-verapamil (0.4-40 microM) caused concentration-dependent inhibition of A23187-induced release of TxA2 without affecting the conversion of exogenous AA to TxA2. Both (+)-verapamil and (-)-verapamil (1-10 microM) caused concentration-dependent inhibition of histamine-induced release of TxA2. In contrast, racemic (+/-)-verapamil did not inhibit leukotriene E4 (LTE4)-induced release of TxB2. Calcium depletion (with 2 mM ethylenediamine tetra acetate) significantly reduced both histamine-induced release of TxB2 from 8.6 +/- 2.6 to 1.8 +/- 0.8 ng/min (P less than 0.05) and LTE4-induced release of TxB2 from 4.9 +/- 0.9 to 0.5 +/- 0.2 ng/min (mean +/- S.E.M.) (P less than 0.05). Since histamine stimulates phospholipase A2 in guinea-pig lungs, these results suggest that (+/-)-verapamil inhibits phospholipase A2 and that A23187 activates AA metabolism by stimulating phospholipase A2. Although all three agents activate AA metabolism by calcium-dependent processes, LTE4 may stimulate calcium entry via separate mechanisms because it is not inhibited by (+/-)-verapamil.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001711:Biotransformation / Q000187:drug effects; D002118:Calcium / Q000502:physiology; D004492:Edetic Acid / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D017999:Leukotriene E4; D008168:Lung / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D013189:SRS-A / Q000031:analogs & derivatives / Q000494:pharmacology; D013237:Stereoisomerism; D013928:Thromboxane A2 / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology*
D001095:Arachidonic Acids; D013189:SRS-A; D016718:Arachidonic Acid; D013928:Thromboxane A2; D017999:Leukotriene E4; D006632:Histamine; D004492:Edetic Acid; D014700:Verapamil; D002118:Calcium