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-2, 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 micrograms/ml) caused concentration-dependent relaxation of tracheal spirals precontracted with LTD4. 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 A2 mimetic U46619. The relaxation to melittin was prevented by the cyclooxygenase inhibitor indomethacin (5 microM) 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 microM) or cromakalim (0.4 microM) did not affect the contraction to LTD4 but enhanced the relaxation to melittin. This enhancement to melittin was completely inhibited by the ATP-dependent K+ channel blocker glibenclamide (1 microM). Higher concentrations of NIP-121 (0.1 microM) or cromakalim (1 microM) did not enhance the response to melittin. In the presence of indomethacin, NIP-121 (0.03 microM) or cromakalim (0.4 microM) enhanced PGE2-induced relaxation of tracheas precontracted with LTD4. 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 K+ channel activation might be due, at least in part, to an increased inhibitory response to cyclooxygenase products [corrected].
Shikada
K
K
Shiraoka Research Station of Biological Science, Nissan Chemical Industries, Ltd., Saitama Japan.
Tanaka
S
S
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D019806:Cromakalim; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation; D004848:Epithelium / Q000187:drug effects; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D017998:Leukotriene D4 / Q000494:pharmacology; D008297:Male; D008555:Melitten / Q000494:pharmacology*; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D010069:Oxadiazoles / Q000494:pharmacology*; D010741:Phospholipases A; D054467:Phospholipases A2; D010880:Piperidines / Q000494:pharmacology*; D015221:Potassium Channels / Q000819:agonists*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects*
D001578:Benzopyrans; D016861:Cyclooxygenase Inhibitors; D010069:Oxadiazoles; D010880:Piperidines; D015221:Potassium Channels; D011450:Prostaglandin Endoperoxides, Synthetic; D011758:Pyrroles; D019806:Cromakalim; D008555:Melitten; D013928:Thromboxane A2; D017998:Leukotriene D4; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C070366:NIP 121; D006632:Histamine; D010741:Phospholipases A; D054467:Phospholipases A2; D007213:Indomethacin