Airway smooth muscle relaxation.

Knox, Alan J.; Tattersfield, A. E.

doi:10.1136/thx.50.8.894

Cited by 49 publications

(31 citation statements)

References 86 publications

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“…In that study, we also found that salbutamol as well as a cell-permeant cAMP analog increase the rate of decline in [Ca 2ϩ ] i within each oscillation, suggesting accelerated SR Ca 2ϩ reuptake. Other studies in non-ASM cell types have found that cAMP activates plasma membrane K ϩ channels, leading to membrane hyperpolarization (15), thus leading to inhibition of Ca 2ϩ influx via L-type Ca 2ϩ channels (16,17). Thus there is considerable previous evidence Fig.…”

Section: Effect Of Cyclic Nucleotides On [Ca 2ϩ ] I In Asmmentioning

confidence: 97%

Cyclic nucleotide regulation of store-operated Ca²⁺influx in airway smooth muscle

Iyanoye

Sieck³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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([Ca 2ϩ ]o), nifedipine, and KCl (preventing Ca 2ϩ influx through L-type and SOCC channels). SOCC was then activated by reintroduction of [Ca 2ϩ ]o and characterized by several techniques. We examined cAMP effects on SOCC by activating SOCC in the presence of 1 M isoproterenol or 100 M dibutryl cAMP (cell-permeant cAMP analog), whereas we examined cGMP effects using 1,2-diolate (DETA-NO nitric oxide donor) or 100 M 8-bromoguanosine 3',5'-cyclic monophosphate (cell-permeant cGMP analog). The role of protein kinases A and G was examined by preexposure to 100 nM KT-5720 and 500 nM KT-5823, respectively. SOCC-mediated Ca 2ϩ influx was dependent on the extent of SR Ca 2ϩ depletion, sensitive to Ni 2ϩ and La 3ϩ , but not inhibitors of voltage-gated influx channels. cAMP as well as cGMP potently inhibited Ca 2ϩ influx, predominantly via their respective protein kinases. Additionally, cAMP cross-activation of protein kinase G contributed to SOCC inhibition. These data demonstrate that a Ni 2ϩ /La 3ϩ -sensitive Ca 2ϩ influx in ASM triggered by SR Ca 2ϩ depletion is inhibited by cAMP and cGMP via a protein kinase mechanism. Such inhibition may play a role in the bronchodilatory response of ASM to clinically relevant drugs (e.g., ␤-agonists vs. nitric oxide).capacitative calcium entry; trachea; adenosine 3Ј,5Ј-cyclic monophosphate; guanosine 3Ј,5Ј-cyclic monophosphate; nitric oxide; isoproterenol AIRWAY SMOOTH MUSCLE (ASM) tone represents a balance between bronchoconstriction and bronchodilation. The goal of clinical therapy for pathophysiological states such as asthma, allergy, and inflammation is to prevent excessive bronchoconstriction, both in the acute and chronic setting, and to restore a balance by producing bronchodilation. Cytosolic (intracellular) Ca 2ϩ concentration ([Ca 2ϩ ] i ) is a key determinant of ASM tone (12,23,33 The cyclic nucleotides cyclic adenosine 3Ј,5Ј-cyclic monophosphate (cAMP) and cyclic guanosine 3Ј,5Ј-cyclic monophosphate (cGMP) mediate the effects of a variety of endogenous substances as well as clinically relevant drugs, e.g., ␤ 2 -agonists and nitric oxide (NO), used to produce relaxation of ASM (13,25,28). Cyclic nucleotide effects are mediated in part by downregulation of mechanisms that would normally elevate [Ca 2ϩ ] i in ASM. Previously, we demonstrated that salbutamol, a ␤ 2 -agonist (28), as well as NO donors (26) inhibit ACh-induced [Ca 2ϩ ] i oscillations in ASM that occur via repetitive SR Ca 2ϩ release and reuptake. Both cAMP and cGMP also influence the plasma membrane via membrane hyperpolarization (9, 15) and inhibition of Ca 2ϩ influx via L-type Ca 2ϩ channels (16,17). Given the relative novelty but somewhat ubiquitous expression of SOCC, there is currently limited and sometimes inconsistent data on cyclic nucleotide modulation of Ca 2ϩ influx via this mechanism in tissues other than ASM. In rat aorta, cAMP inhibits SOCC (34) but enhances it in astrocytes (37). We hypothesize that cyclic nucleotides inhibit SOCC, preventing [Ca 2ϩ ] i elevation as well as S...

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Section: Effect Of Cyclic Nucleotides On [Ca 2ϩ ] I In Asmmentioning

confidence: 97%

Cyclic nucleotide regulation of store-operated Ca²⁺influx in airway smooth muscle

Iyanoye

Sieck³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…ϩ, p Ͻ 0.01 compared with the saline group without methacholine aerosol. (Knox and Tattersfield, 1995). It is noteworthy that in epithelium-intact trachea rings, 7-epiclusianone dose-dependently inhibited Ca 2ϩ -induced contractions in K ϩ (60 mM)-depolarized preparations, suggesting that 7-epiclusianone could inhibit Ca 2ϩ influx via blockade of voltage-dependent Ca 2ϩ channels (Neves et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

7-Epiclusianone, a Tetraprenylated Benzophenone, Relaxes Airway Smooth Muscle through Activation of the Nitric Oxide-cGMP Pathway

Coelho¹,

Serra²,

Pires³

et al. 2008

J Pharmacol Exp Ther

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This study was undertaken to investigate the putative mechanism(s) underlying the antispasmodic effect of 7-epiclusianone, a naturally occurring compound isolated from the plant Garcinia brasiliensis. Guinea pig tracheal rings were mounted in tissue baths filled with Krebs' solution, and the contractile response to distinct stimuli was measured in the presence or absence of 7-epiclusianone. We also tested the effect of 7-epiclusianone on methacholine-evoked airways obstruction in BALB/c mice using barometric plethysmography. 7-Epiclusianone (10 M) inhibited epithelium-intact tracheal ring contraction induced by allergen, histamine, 5-hydroxytryptamine, or carbachol challenge. The relaxation effect was abrogated by epithelium removal, the presence of nitric-oxide synthase inhibitor N -nitro-L-arginine methyl ester (L-NAME) (100 M), or soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 M). 7-Epiclusianone (1-100 M) induced a dosedependent increase in the intracellular cGMP levels of cultured tracheal rings. The relaxation effect of 7-epiclusianone was also inhibited by K ϩ channel blockers tetraethylammonium (10 M), glibenclamide (1 M), or apamin (1 M), but not by 9-(tetrahydro-2Ј-furyl)adenine (SQ22,536) (100 M), an adenylate cyclase inhibitor. In epithelium-intact tracheal rings, 7-epiclusianone also inhibited Ca 2ϩ -induced contractions in K ϩ (60 mM)-depolarized preparations, but it seemed ineffective in assays in which epithelium-denuded tracheal ring preparations were used. Oral administration of 7-epiclusinone (25-100 mg/kg) dose-dependently inhibited airway obstruction triggered by aerosolized methacholine (6 -25 mg/ml), in a mechanism sensitive to L-NAME (20 mg/kg). In conclusion, the relaxation effect of 7-epiclusinone seems to be mediated by epithelium-, nitric oxide-, and cGMP-dependent mechanisms. Furthermore, oral administration of 7-epiclusianone reduces episodes of bronchial obstruction, warranting further research on this compound regarding a putative application in asthma therapy.Ginkgo biloba, Artocarpus heterophyllus, Allium sativum, Glycyrrhiza glabra, and Panax ginseng ginseng are examples of plant species that have been used in the so-called complementary and alternative medicine as herbal formulations,

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“…1,3,4 The b 2 AR is a seven-transmembrane G-protein coupled receptor whose activation increases the intracellular level of adenylyl cyclase, resulting in the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) 1 Increased cAMP upregulates protein kinases A and G, which modulate the intracellular release of calcium eventually resulting in relaxation of the airway smooth muscle. 5,6 In the late 1960's, salbutamol (also known as albuterol in the United States), was the first selective b 2 -agonist to be identified. …”

Section: Physiology Of B 2 -Adrenergic Receptors and B 2 -Agonistsmentioning

confidence: 99%

Tolerance & resistance to β2-agonist bronchodilators

Yim

Koumbourlis

2013

Paediatric Respiratory Reviews

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Airway smooth muscle relaxation.

Cited by 49 publications

References 86 publications

Cyclic nucleotide regulation of store-operated Ca²⁺influx in airway smooth muscle

Cyclic nucleotide regulation of store-operated Ca²⁺influx in airway smooth muscle

7-Epiclusianone, a Tetraprenylated Benzophenone, Relaxes Airway Smooth Muscle through Activation of the Nitric Oxide-cGMP Pathway

Tolerance & resistance to β2-agonist bronchodilators

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Airway smooth muscle relaxation.

Cited by 49 publications

References 86 publications

Cyclic nucleotide regulation of store-operated Ca2+influx in airway smooth muscle

Cyclic nucleotide regulation of store-operated Ca2+influx in airway smooth muscle

7-Epiclusianone, a Tetraprenylated Benzophenone, Relaxes Airway Smooth Muscle through Activation of the Nitric Oxide-cGMP Pathway

Tolerance & resistance to β2-agonist bronchodilators

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Cyclic nucleotide regulation of store-operated Ca²⁺influx in airway smooth muscle

Cyclic nucleotide regulation of store-operated Ca²⁺influx in airway smooth muscle