Effects of antidiabetic sulphonylureas, cromakalim and their interaction in guinea-pig isolated tracheal smooth muscle.

Glibenclamide, glipizide and glibornuride showed dual effects in guinea-pig isolated trachea. The drugs antagonized the relaxant response to the K+ channel opener cromakalim (order of effectiveness: glibenclamide > glipizide > glibornuride) and at concentrations of 1-1000 microM produced airway smooth muscle relaxation (order of potency: glibenclamide > glipizide = glibornuride). Gliclazide, tolbutamide and chlorpropamide did not antagonize cromakalim nor did the two latter drugs produce tracheal relaxation. The sulphonylureas and cromakalim were compared as airway relaxants against a panel of different spasmogens. The order of tissue responsiveness for the sulphonylureas was: spontaneous tone = LTD4 > PGF2 alpha = histamine = 30 mM K+ > carbachol and for cromakalim: spontaneous tone = LTD4 = PGF2 alpha = histamine > carbachol > 30 mM K+. Glibenclamide, but not cromakalim, relaxed contractions induced by 124 mM K+. Phentolamine and Ba2+, which are reported blockers of ATP-regulated K+ channels, failed to influence sulphonylurea-induced airway smooth muscle relaxation. Glibenclamide reversed tracheal relaxation produced by cromakalim, whereas cromakalim failed to reverse relaxation induced by glibenclamide. The mechanism for the additional property of sulphonylureas to relax airway smooth muscle is unclear, but the results do not support a role for involvement of cromakalim-sensitive K+ channels.