Mirabegron induces relaxant effects via cAMP signaling-dependent and -independent pathways in detrusor smooth muscle

Tomoko Maki, Shunichi Kajioka, Momoe Itsumi, Eljamal Kareman, Ken Lee, masaki shiota, Masatoshi Eto

Research output: Contribution to journalArticle

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Abstract

Objective: We previously found that mirabegron exerts a relaxant effect in the presence of the β 3 -adrenoceptor antagonist SR58894A during carbachol-induced contraction in human and pig detrusor. The aim of this study was to explore the possible mechanism underlying the relaxant effects of mirabegron using detrusor smooth muscle. Methods: Human tissue was obtained from urinary bladders of patients undergoing radical cystectomy at Kyushu University and Harasanshin Hospital. Pig tissue was obtained from an abattoir. Tension force (organ bath experiments) was measured in intact or permeabilised (α-toxin or β-escin) detrusor smooth muscle strips. The contribution of cAMP-dependent signaling and the inhibition of Ca 2+ sensitization to the relaxant effects of mirabegron were characterized using 1 μM SR58894A, 100 μM SQ22536 (an adenylyl cyclase inhibitor), 10 μM H-89 (a protein kinase [PK] A inhibitor), 10 μM Y-27632 (a selective Rho kinase inhibitor), and 10 μM GF-109203X (a selective PKC inhibitor). Results: 30 μM Mirabegron impaired carbachol (0.03-1 μM)-induced contraction in human detrusor smooth muscle. SR58894A only partially attenuated the relaxant effects of mirabegron in human and pig detrusor strips precontracted with 1 μM carbachol. In α-toxin-permeabilized detrusor strips, tension force at 1 μM [Ca 2+ ] i was decreased by mirabegron in a concentration-dependent manner. The relaxant effect of mirabegron was only slightly attenuated by H-89 and not significantly affected by SQ22536. Y-27632 potentiated the relaxation response to mirabegron, but attenuated responses to cAMP; GF-109203X had little effect. Mirabegron but not cAMP had a notable relaxant effect in the pig detrusor smooth muscle permeabilized with β-escin. Conclusions: Mirabegron-induced relaxation of pig and human detrusor smooth muscle occurs via both a β 3 -adrenoceptor/cAMP-dependent and -independent pathway.

Original languageEnglish
Pages (from-to)O209-O217
JournalLUTS: Lower Urinary Tract Symptoms
Volume11
Issue number2
DOIs
Publication statusPublished - Apr 1 2019

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Smooth Muscle
Swine
Carbachol
Escin
Adrenergic Receptors
mirabegron
rho-Associated Kinases
Abattoirs
Cystectomy
Protein Kinase Inhibitors
Cyclic AMP-Dependent Protein Kinases
Baths
Urinary Bladder

All Science Journal Classification (ASJC) codes

  • Neurology
  • Urology

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Mirabegron induces relaxant effects via cAMP signaling-dependent and -independent pathways in detrusor smooth muscle. / Maki, Tomoko; Kajioka, Shunichi; Itsumi, Momoe; Kareman, Eljamal; Lee, Ken; shiota, masaki; Eto, Masatoshi.

In: LUTS: Lower Urinary Tract Symptoms, Vol. 11, No. 2, 01.04.2019, p. O209-O217.

Research output: Contribution to journalArticle

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title = "Mirabegron induces relaxant effects via cAMP signaling-dependent and -independent pathways in detrusor smooth muscle",
abstract = "Objective: We previously found that mirabegron exerts a relaxant effect in the presence of the β 3 -adrenoceptor antagonist SR58894A during carbachol-induced contraction in human and pig detrusor. The aim of this study was to explore the possible mechanism underlying the relaxant effects of mirabegron using detrusor smooth muscle. Methods: Human tissue was obtained from urinary bladders of patients undergoing radical cystectomy at Kyushu University and Harasanshin Hospital. Pig tissue was obtained from an abattoir. Tension force (organ bath experiments) was measured in intact or permeabilised (α-toxin or β-escin) detrusor smooth muscle strips. The contribution of cAMP-dependent signaling and the inhibition of Ca 2+ sensitization to the relaxant effects of mirabegron were characterized using 1 μM SR58894A, 100 μM SQ22536 (an adenylyl cyclase inhibitor), 10 μM H-89 (a protein kinase [PK] A inhibitor), 10 μM Y-27632 (a selective Rho kinase inhibitor), and 10 μM GF-109203X (a selective PKC inhibitor). Results: 30 μM Mirabegron impaired carbachol (0.03-1 μM)-induced contraction in human detrusor smooth muscle. SR58894A only partially attenuated the relaxant effects of mirabegron in human and pig detrusor strips precontracted with 1 μM carbachol. In α-toxin-permeabilized detrusor strips, tension force at 1 μM [Ca 2+ ] i was decreased by mirabegron in a concentration-dependent manner. The relaxant effect of mirabegron was only slightly attenuated by H-89 and not significantly affected by SQ22536. Y-27632 potentiated the relaxation response to mirabegron, but attenuated responses to cAMP; GF-109203X had little effect. Mirabegron but not cAMP had a notable relaxant effect in the pig detrusor smooth muscle permeabilized with β-escin. Conclusions: Mirabegron-induced relaxation of pig and human detrusor smooth muscle occurs via both a β 3 -adrenoceptor/cAMP-dependent and -independent pathway.",
author = "Tomoko Maki and Shunichi Kajioka and Momoe Itsumi and Eljamal Kareman and Ken Lee and masaki shiota and Masatoshi Eto",
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T1 - Mirabegron induces relaxant effects via cAMP signaling-dependent and -independent pathways in detrusor smooth muscle

AU - Maki, Tomoko

AU - Kajioka, Shunichi

AU - Itsumi, Momoe

AU - Kareman, Eljamal

AU - Lee, Ken

AU - shiota, masaki

AU - Eto, Masatoshi

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Objective: We previously found that mirabegron exerts a relaxant effect in the presence of the β 3 -adrenoceptor antagonist SR58894A during carbachol-induced contraction in human and pig detrusor. The aim of this study was to explore the possible mechanism underlying the relaxant effects of mirabegron using detrusor smooth muscle. Methods: Human tissue was obtained from urinary bladders of patients undergoing radical cystectomy at Kyushu University and Harasanshin Hospital. Pig tissue was obtained from an abattoir. Tension force (organ bath experiments) was measured in intact or permeabilised (α-toxin or β-escin) detrusor smooth muscle strips. The contribution of cAMP-dependent signaling and the inhibition of Ca 2+ sensitization to the relaxant effects of mirabegron were characterized using 1 μM SR58894A, 100 μM SQ22536 (an adenylyl cyclase inhibitor), 10 μM H-89 (a protein kinase [PK] A inhibitor), 10 μM Y-27632 (a selective Rho kinase inhibitor), and 10 μM GF-109203X (a selective PKC inhibitor). Results: 30 μM Mirabegron impaired carbachol (0.03-1 μM)-induced contraction in human detrusor smooth muscle. SR58894A only partially attenuated the relaxant effects of mirabegron in human and pig detrusor strips precontracted with 1 μM carbachol. In α-toxin-permeabilized detrusor strips, tension force at 1 μM [Ca 2+ ] i was decreased by mirabegron in a concentration-dependent manner. The relaxant effect of mirabegron was only slightly attenuated by H-89 and not significantly affected by SQ22536. Y-27632 potentiated the relaxation response to mirabegron, but attenuated responses to cAMP; GF-109203X had little effect. Mirabegron but not cAMP had a notable relaxant effect in the pig detrusor smooth muscle permeabilized with β-escin. Conclusions: Mirabegron-induced relaxation of pig and human detrusor smooth muscle occurs via both a β 3 -adrenoceptor/cAMP-dependent and -independent pathway.

AB - Objective: We previously found that mirabegron exerts a relaxant effect in the presence of the β 3 -adrenoceptor antagonist SR58894A during carbachol-induced contraction in human and pig detrusor. The aim of this study was to explore the possible mechanism underlying the relaxant effects of mirabegron using detrusor smooth muscle. Methods: Human tissue was obtained from urinary bladders of patients undergoing radical cystectomy at Kyushu University and Harasanshin Hospital. Pig tissue was obtained from an abattoir. Tension force (organ bath experiments) was measured in intact or permeabilised (α-toxin or β-escin) detrusor smooth muscle strips. The contribution of cAMP-dependent signaling and the inhibition of Ca 2+ sensitization to the relaxant effects of mirabegron were characterized using 1 μM SR58894A, 100 μM SQ22536 (an adenylyl cyclase inhibitor), 10 μM H-89 (a protein kinase [PK] A inhibitor), 10 μM Y-27632 (a selective Rho kinase inhibitor), and 10 μM GF-109203X (a selective PKC inhibitor). Results: 30 μM Mirabegron impaired carbachol (0.03-1 μM)-induced contraction in human detrusor smooth muscle. SR58894A only partially attenuated the relaxant effects of mirabegron in human and pig detrusor strips precontracted with 1 μM carbachol. In α-toxin-permeabilized detrusor strips, tension force at 1 μM [Ca 2+ ] i was decreased by mirabegron in a concentration-dependent manner. The relaxant effect of mirabegron was only slightly attenuated by H-89 and not significantly affected by SQ22536. Y-27632 potentiated the relaxation response to mirabegron, but attenuated responses to cAMP; GF-109203X had little effect. Mirabegron but not cAMP had a notable relaxant effect in the pig detrusor smooth muscle permeabilized with β-escin. Conclusions: Mirabegron-induced relaxation of pig and human detrusor smooth muscle occurs via both a β 3 -adrenoceptor/cAMP-dependent and -independent pathway.

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