EFFECTS OF A NEWLY SYNTHESIZED K+ CHANNEL OPENER, Y-26763, ON NORADRENALINE-INDUCED CA2+ MOBILIZATION IN SMOOTH-MUSCLE OF THE RABBIT MESENTERIC-ARTERY

1 The mechanisms underlying the vasodilatation induced by (-)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2, 2-dimethyl-2H-1-benzopyran-3-ol (Y-26763) were investigated by measuring membrane potential, intracellular Ca2+ concentration ([Ca2+](i)) and isometric force in smooth muscle cells of the rabbit mesenteric artery. 2 Y-26763 (0.03-1 mu M) concentration-dependently hyperpolarized the membrane and glibenclamide (1-10 mu M) inhibited this hyperpolarization. Noradrenaline (NA, 10 mu M) depolarized the membrane and generated spike potentials. Y-26763 (1 mu M) inhibited these NA-induced electrical responses. 3 In thin Smooth muscle strips in 2.6 mM Ca2+ containing (Krebs) solution, 10 mu M NA produced a large phasic, followed by a small tonic increase in [Ca2+](i) and force with associated oscillations. In Ca2+-free solution (containing 2 mM EGTA), NA produced only phasic increases in [Ca2+](i) and force. In ryanodine-treated strips, NA could not produce the phasic increases in [Ca2+](i) and force even in the presence of 2.6 mM Ca2+, suggesting that ryanodine functionally removes the NA-sensitive intracellular storage sites. 4 Nicardipine (1 mu M) partly inhibited the NA-induced tonic increases in [Ca2+](i) and force but had no effect on either the resting [Ca2+](i) or the NA-activated phasic increases in [Ca2+](i) and force. By contrast, Y-26763 (10 mu M) lowered the resting [Ca2+](i) and also inhibited both the phasic and the tonic increases in [Ca2+](i) and force induced by NA. All these actions of Y-26763 were inhibited by glibenclamide (10 mu M). 5 In ryanodine-treated strips, nicardipine partly, but Y-26763 completely inhibited the NA-induced increases in [Ca2+](i), suggesting that Y-26763 inhibits both the nicardipine-sensitive and -insensitive Ca2+ influxes activated by NA. Y-26763 attenuated the phasic increase in [Ca2+](i) and force in a Ca2+-free solution containing 5.9 mM K+, but not in one containing 50 mM K+, suggesting that Y-26763 inhibits NA-induced Ca2+ release, probably as a result of its membrane hyperpolarizing action. 6 In beta-escin-skinned strips, Y-26763 (10 mu M) had no effect on either the NA-induced Ca2+ release or the Ca2+-tension relationship in the presence and absence of NA (10 mu M) with guanosine 5'-triphosphate (GTP, 10 mu M), suggesting that Y-26763 has no direct action on either NA-induced Ca2+ release or the contractile proteins. 7 It is concluded that Y-26763 inhibits NA-activated Ca2+ release and Ca2+ influx and thus inhibits the NA-contraction. Y-26763 also lowers the resting [Ca2+](i) through an inhibition of the nicardipine-insensitive Ca2+ influx. These actions of Y-26763 may be linked with the membrane hyperpolarization it produces by activation of the ATP-sensitive K+ channels.