Effects of a newly synthesized K⁺ channel opener, Y‐26763, on noradrenaline‐induced Ca²⁺ mobilization in smooth muscle of the rabbit mesenteric artery

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. Y‐26763 (0.03–1 μm) concentration‐dependently hyperpolarized the membrane and glibenclamide (1–10 μm) inhibited this hyperpolarization. Noradrenaline (NA, 10 μm) depolarized the membrane and generated spike potentials. Y‐26763 (1 μm) inhibited these NA‐induced electrical responses. In thin smooth muscle strips in 2.6 mM Ca²⁺ containing (Krebs) solution, 10 μm 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. Nicardipine (1 μm) 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 μm) 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 μm). 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. In β‐escin‐skinned strips, Y‐26763 (10 μm) had no effect on either the NA‐induced Ca²⁺ release or the Ca²⁺‐tension relationship in the presence and absence of NA (10 μm) with guanosine 5′‐triphosphate (GTP, 10 μm), suggesting that Y‐26763 has no direct action on either NA‐induced Ca²⁺ release or the contractile proteins. 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. 1994 British Pharmacological Society