NIP-121 AND CROMAKALIM, POTASSIUM CHANNEL OPENERS, PREFERENTIALLY SUPPRESS PROSTANOID-INDUCED CONTRACTION OF THE GUINEA-PIG ISOLATED TRACHEA

We have investigated the relaxant effect of the potassium channel openers, NIP-121 and cromakalim, on spontaneous and spasmogen-induced tone in the isolated guinea-pig trachea. NIP-121 and cromakalim fully suppressed the spontaneous tone in a concentration-dependent manner and the maximal response was 89 and 97% of that to 1 mM aminophylline. The suppressant effect of NIP-121 (pD2 7.39) was 5 times stronger than that of cromakalim (pD2 6.69). Spontaneous tone was completely inhibited by the cyclooxygenase inhibitor, indomethacin, and partially inhibited by the thromboxane A2 (TXA2) antagonist, BM13177. In the presence of indomethacin, the contraction induced by prostaglandin (PG) F(2-alpha) and PGD2 was reversed by BM13177 to the same extent. NIP-121 and cromakalim reversed the contraction induced by PGF(2-alpha), PGD2 and the TXA2 mimetic, U46619, and the effects were more potent than those observed on the contraction induced by leukotriene (LT) D4, LTC4, histamine and acetylcholine. The maximal relaxant responses (%) induced by NIP-121 and cromakalim were 97 and 96 for PGF(2-alpha), 94 and 87 for PGD2, 94 and 93 for U46619, 69 and 69 for LTD4, 75 and 58 for LTC4, 73 and 61 for histamine and 1 and 16 for acetylcholine, respectively. The relaxant effect of NIP-121 on responses to these spasmogens (pD2 7.35 for PGF(2-alpha), 7.40 for PGD2, 7.31 for U46619, 7.28 for LTD4, 7.09 for LTC4, and 7.15 for histamine) was about 10-20 times stronger than the effect of cromakalim (pD2 6.23 for PGF(2-alpha), 6.04 for PGD2, 6.20 for U46619, 6.01 for LTD4, 5.82 for LTC4 and 5.88 for histamine). The calcium antagonist, nifedipine, had no effect on prostanoid-induced tone. The NIP-121- and cromakalim-induced relaxation of tracheal contractions induced by PGF(2-alpha), PGD2 and U46619 was similarly antagonized by glibenclamide (0.1-mu-M). These results suggest that glibenclamide-sensitive potassium channel openers preferentially relax the prostanoid response, which may be mediated by TXA2 receptors in the guinea-pig trachea.