Y-27632 potentiates relaxant effects of β2-adrenoceptor agonists in bovine tracheal smooth muscle

Nakahara, Tsutomu; Moriuchi, Hiroshi; Yunoki, Motonari; Sakamato, Kenji; Ishii, Kunio

doi:10.1016/s0014-2999(99)00891-2

Cited by 28 publications

(11 citation statements)

References 11 publications

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“…In separate studies, Boterman and colleagues (41) found potentiation of b-AR function in tracheal smooth muscle by inhibiting PKC, whereas Nakahara and colleagues (42) found similar potentiation with Rho kinase inhibition. CPI-17 is a downstream target of both PKC and Rho kinase in ASM (43).…”

Section: Mlck/mlcp In Contraction and Relaxation-role For Accessory Pmentioning

confidence: 98%

Active Components of Ginger Potentiate β-Agonist–Induced Relaxation of Airway Smooth Muscle by Modulating Cytoskeletal Regulatory Proteins

Townsend

Zhang

et al. 2014

Am J Respir Cell Mol Biol

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b-Agonists are the first-line therapy to alleviate asthma symptoms by acutely relaxing the airway. Purified components of ginger relax airway smooth muscle (ASM), but the mechanisms are unclear. By elucidating these mechanisms, we can explore the use of phytotherapeutics in combination with traditional asthma therapies. The objectives of this study were to: (1) determine if 6-gingerol, 8-gingerol, or 6-shogaol potentiate b-agonist-induced ASM relaxation; and (2) define the mechanism(s) of action responsible for this potentiation. Human ASM was contracted in organ baths. Tissues were relaxed dose dependently with b-agonist, isoproterenol, in the presence of vehicle, 6-gingerol, 8-gingerol, or 6-shogaol (100 mM). Primary human ASM cells were used for cellular experiments. Purified phosphodiesterase (PDE) 4D or phospholipase C b enzyme was used to assess inhibitory activity of ginger components using fluorescent assays. A G-LISA assay was used to determine the effects of ginger constituents on Ras homolog gene family member A activation. Significant potentiation of isoproterenol-induced relaxation was observed with each of the ginger constituents. 6-Shogaol showed the largest shift in isoproterenol half-maximal effective concentration. 6-Gingerol, 8-gingerol, or 6-shogaol significantly inhibited PDE4D, whereas 8-gingerol and 6-shogaol also inhibited phospholipase C b activity. 6-Shogaol alone inhibited Ras homolog gene family member A activation. In human ASM cells, these constituents decreased phosphorylation of 17-kD protein kinase C-potentiated inhibitory protein of type 1 protein phosphatase and 8-gingerol decreased myosin light chain phosphorylation. Isolated components of ginger potentiate b-agonist-induced relaxation in human ASM. This potentiation involves PDE4D inhibition and cytoskeletal regulatory proteins. Together with b-agonists, 6-gingerol, 8-gingerol, or 6-shogaol may augment existing asthma therapy, resulting in relief of symptoms through complementary intracellular pathways.Keywords: asthma; adrenergic receptor; myosin light chain; lung; bronchodilation Clinical RelevanceNatural herbal remedies, including ginger, have long been used to treat respiratory conditions. Many individuals with asthma use herbal therapies to self-treat their asthma symptoms; however, little is known regarding how these compounds work in the airway. In the current work, we show that 6-gingerol, 8-gingerol, and 6-shogaol potentiate b-agonist-induced relaxation of airway smooth muscle by inhibiting both phosphodiesterase 4D and phosphatidylinositol-specific phospholipase C, leading to downstream regulation of contractile proteins. These data suggest that natural compounds can work in combination with traditional asthma therapies to relieve asthma symptoms.

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Section: Mlck/mlcp In Contraction and Relaxation-role For Accessory Pmentioning

confidence: 98%

Active Components of Ginger Potentiate β-Agonist–Induced Relaxation of Airway Smooth Muscle by Modulating Cytoskeletal Regulatory Proteins

Townsend

Zhang

et al. 2014

Am J Respir Cell Mol Biol

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“…Y-27632, {(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride, monohydrate}, selectively inhibits Rho-associated protein kinases (ROCKs) which are downstream effectors for RhoA [3]. Recent studies demonstrated that Y-27632 induced a relaxation of contracted tracheal and bronchial smooth muscle [4], potentiated relaxant effects of beta 2-adrenoceptor agonists in tracheal smooth muscle [5], and inhibited chemotaxis of eosinophils activated by eotaxin [6], suggesting that this compound might be useful for the clinical management of bronchial asthma in the range of 0.1 -10.0 AM. The RhoA system is also involved in the activation and function including cytokine production of T cells through T cell receptor (TCR) [7 -9].…”

Section: Introductionmentioning

confidence: 99%

Effect of Y-27632 on release of cytokines from peripheral T cells in asthmatic patients and normal subjects

Aihara

Dobashi

Iizuka

et al. 2004

International Immunopharmacology

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“…11 -13 ( þ )-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide (Y-27632), a selective Rhokinase inhibitor, enhanced relaxation occurring in the penile and bronchial smooth muscle. 8,9 It was reported that the increase of blood pressure and the decrease of cavernosum pressure were potently inhibited by Y-27632. 8,14 However, little is known about the role of Rho-kinase in ANG II-induced smooth muscle contraction in the clitoris.…”

Section: Introductionmentioning

confidence: 99%

“…8,9 It was reported that the increase of blood pressure and the decrease of cavernosum pressure were potently inhibited by Y-27632. 8,14 However, little is known about the role of Rho-kinase in ANG II-induced smooth muscle contraction in the clitoris. We evaluated the effect of Y-27632 in relation to ANG II in the clitoral CSM.…”

Section: Introductionmentioning

confidence: 99%

Role of rho-kinase activity in angiotensin II-induced contraction of rabbit clitoral cavernosum smooth muscle

et al. 2002

Int J Impot Res

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Isometric tension measurement using a selective Rho-kinase inhibitor ( þ )-(R)-trans4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide (Y-27632) and a selective myosin light chain kinase (MLCK) inhibitor 1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride (ML7) were used in rabbit clitoral cavernosum smooth muscle (CSM). N G -nitro-L-arginine methyl ester (L-NAME) was used to evaluate the relationship between NO release and Rho-kinase. Y-27632 significantly attenuated contractions induced by ANG II, dose-dependently. However, ML7 did not affect the contractile response to ANG II except in the high concentrations of ML7. Y-27632 inhibited contraction with phenylephrine (PhE), but ML7 did not inhibit contraction with PhE. Nitric oxide synthase inhibitor (NAME) did not affect the Y-27632-induced relaxation in the pre-contracted strip with PhE. The present study demonstrates that G-protein-coupled increase in myofilament Ca 2þ sensitivity mediated through the RhoA=Rho-kinase signal pathway is involved in the control by ANG II of the clitoral CSM tone. RhoA=Rho-kinase pathway acts in the ANG IIinduced contraction independently of the NO pathway.

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Y-27632 potentiates relaxant effects of β2-adrenoceptor agonists in bovine tracheal smooth muscle

Cited by 28 publications

References 11 publications

Active Components of Ginger Potentiate β-Agonist–Induced Relaxation of Airway Smooth Muscle by Modulating Cytoskeletal Regulatory Proteins

Active Components of Ginger Potentiate β-Agonist–Induced Relaxation of Airway Smooth Muscle by Modulating Cytoskeletal Regulatory Proteins

Effect of Y-27632 on release of cytokines from peripheral T cells in asthmatic patients and normal subjects

Role of rho-kinase activity in angiotensin II-induced contraction of rabbit clitoral cavernosum smooth muscle

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