In this study, we determined the pharmacological activities of MJ-451 (6-cyano-3S,4R-dihydro-2,2-dimethyl-2H-3-hydroxy-4-[2-oxo-5S-1-hydroxmethyl)-1-pyrrolidinyl]-1-benzopyran) in guinea pig isolated trachea and compared its effects with those of cromakalim. MJ-451 (0.1–10 µmol/l) and cromakalim (0.01–1 µmol/l) produced concentration-dependent relaxation of guinea pig isolated trachea precontracted with carbachol (0.5 µmol/l) or histamine (1 µmol/l). MJ-451 (0.03–30 µmol/l), as well as cromakalim (0.03–30 µmol/l), caused a complete and concentration-dependent relaxation of guinea pig isolated trachea precontracted with 20 mmol/l KCl, but did not inhibit the spasmogenic effect of 80 mmol/l KCl. However, theophylline (30–3,000 µmol/l) caused a complete and concentration-dependent relaxation of guinea pig isolated trachea precontracted with either 20 or 80 mmol/l KCl. Propranolol (0.1 µmol/l) markedly antagonized the relaxant action of isoprenaline, but not that of MJ-451 in carbachol-contracted isolated trachea. 8-(p)-sulfophenyltheophylline (150 µmol/l), a selective P1 purinoceptor antagonist, had no effect against the tracheal relaxation induced by MJ-451, but markedly depressed the concentration-response curve of 5′-N-ethylcarboxamidoadenosine. Charybdotoxin (10 µmol/l), a large-conductance Ca2+-activated K+ channel blocker, failed to modify the relaxant activity of MJ-451 in carbachol-contracted isolated trachea. The ATP-sensitive K+ channel blocker, glibenclamide (0.1, 1 and 10 µmol/l) concentration-dependently antagonized the relaxant activity of MJ-451 in carbachol-contracted isolated trachea. It is concluded that MJ-451 is a selective ATP-sensitive K+ channel opener in the tracheal smooth muscle of the guinea pig.

Keywords:
MJ-451, Cromakalim, Trachea, guinea pig
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1998
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