Pharmacological characteristics of MJ-451, a new benzopyran-derived ATP-sensitive potassium channel opener, in guinea pig isolated trachea

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 (30-3000 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-45 1 in carbachol-contracted isolated trachea. The ATP-sensitive KC 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.