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

Takeo Itoh, Shinichi Ito, Jonaid Shafiq, Hikaru Suzuki

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)165-172
Number of pages8
JournalBritish Journal of Pharmacology
Volume111
Issue number1
DOIs
Publication statusPublished - Jan 1994

Fingerprint

Mesenteric Arteries
Smooth Muscle
Rabbits
Nicardipine
Membranes
Glyburide
Contractile Proteins
Ryanodine
Guanosine
Egtazic Acid
Guanosine Triphosphate
Vasodilation
Membrane Potentials
Action Potentials
Smooth Muscle Myocytes
Norepinephrine

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Effects of a newly synthesized K+ channel opener, Y‐26763, on noradrenaline‐induced Ca2+ mobilization in smooth muscle of the rabbit mesenteric artery. / Itoh, Takeo; Ito, Shinichi; Shafiq, Jonaid; Suzuki, Hikaru.

In: British Journal of Pharmacology, Vol. 111, No. 1, 01.1994, p. 165-172.

Research output: Contribution to journalArticle

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AU - Ito, Shinichi

AU - Shafiq, Jonaid

AU - Suzuki, Hikaru

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N2 - 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

AB - 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

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