FLUFENAMIC AND TOLFENAMIC ACIDS AND LEMAKALIM RELAX GUINEA-PIG ISOLATED TRACHEA BY DIFFERENT MECHANISMS

The effects of K+ channel inhibitors on the relaxations induced by flu fenamic and tolfenamic acids and lemakalim were examined in guinea-pig isolated trachea precontracted with prostaglandin F-2 alpha (PGF(2 al pha), 1 mu M). Flufenamic and tolfenamic acids (0.1-33 mu M) and lemak alim (0.01-33 mu M) relaxed guinea-pig trachea in a concentration-depe ndent manner. Tetraethylammonium (0.5-2 mM), a nonspecific inhibitor o f K- channels, inhibited the relaxations induced by flufenamic and tol fenamic acids without affecting lemakalim-induced relaxation. Charybdo toxin (ChTX, 33-100 nM), an inhibitor of the large Ca2+-activated K- c hannels (BKCa, also inhibited the relaxations induced by flufenamic an d tolfenamic acids without affecting lemakalim-induced relaxation. Gli pizide (3.3-33 mu M), an inhibitor of the ATP-sensitive K+ channels (K -ATP) inhibited lemakalim-induced relaxation without affecting those i nduced by flufenamic and tolfenamic acids. Our results indicate that t he relaxations of guinea-pig isolated trachea by flufenamic and tolfen amic acids are due to activation of BKCa. The relaxant mechanism of fl ufenamic and tolfenamic acids thus differs from that of lemakalim, an activator of K-ATP. (C) 1998 Elsevier Science Inc.