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 μM) 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 μM) 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 < 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<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.