Effect of the K+ channel openers NIP-121 and cromakalim on melittin-induced relaxation of guinea-pig isolated trachea

We have investigated the effect of the K+ channel openers (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(2-oxo-piperidin-1-yl)-6H-pyrano[2,3-f]benz-e, 1,3-oxadiazole (NIP-121) and cromakalim on the relaxation induced by the phospholipase A2 activator melittin in guinea-pig isolated trachea. Melittin (0.1 to 3.0 mu g/ml) caused concentration-dependent relaxation of tracheal spirals precontracted with LTD(4). The magnitude of relaxation was about 40% of that obtained by 1 mM aminophylline. Melittin-induced relaxation was also observed in tracheas precontracted with histamine or the thromboxane A(2) mimetic U46619. The relaxation to melittin was prevented by the cyclooxygenase inhibitor indomethacin (5 mu M) or by removal of the tracheal epithelium, suggesting that cyclooxygenase products, possibly dependent on the epithelium, may be implicated in the response to melittin. Pretreatment of tracheas with NIP-121 (0.03 mu M) or cromakalim (0.4 mu M) did nor affect the contraction to LTD(4) but enhanced the relaxation to melittin. This enhancement to melittin was completely inhibited by the ATP-dependent K+ channel blocker glibenclamide (1 mu M). Higher concentrations of NIP-121 (0.1 mu M) or cromakalim (1 mu M) did nor enhance the response to melittin. In the presence of indomethacin, NIP-121 (0.03 mu M) or cromakalim (0.4 mu M) enhanced PGE(2)-induced relaxation of tracheas precontracted with LTD(4). These results suggest that cyclooxygenase products, possibly dependent on the epithelium, may be involved in melittin-induced relaxation. The enhancement of relaxation to melittin by IK+ channel activation might be due, at least in part, to an increased (sic).