Effects of amitriptyline, a tricyclic antidepressant, on smooth muscle reactivity in isolated rat trachea

Matsunaga, Shinobu; Shibata, Osamu; Nishioka, Kenji; Tsuda, Atsushi; Makita, Tetsuji; Sumikawa, Koji

doi:10.1007/s00540-009-0781-0

Cited by 4 publications

(4 citation statements)

References 26 publications

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“…Matsunaga et al . showed that smooth muscle reactivity in isolated tracheal rings from rats was attenuated by amitriptyline incubation [ 36 ]. However, the concentrations of amitriptyline used by these authors in their study (> 1 µM) were in the higher µM range and partially toxic.…”

Section: Discussionmentioning

confidence: 99%

Amitriptyline inhibits bronchoconstriction and directly promotes dilatation of the airways

Hempel,

Klein,

Michely

et al. 2023

Respir Res

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Introduction The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß2-sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ß2-sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological TH2-phenotype in asthma, acting—at least partially—through inhibition of acid sphingomyelinase (ASM), an enzyme involved in sphingolipid metabolism. Here, we investigated the non-immunological role of amitriptyline on acute bronchoconstriction, a main feature of airway hyperresponsiveness in asthmatic disease. Methods After stimulation of precision cut lung slices (PCLS) from mice (wildtype and ASM-knockout), rats, guinea pigs and human lungs with mediators of bronchoconstriction (endogenous and exogenous acetylcholine, methacholine, serotonin, endothelin, histamine, thromboxane-receptor agonist U46619 and leukotriene LTD4, airway area was monitored in the absence of or with rising concentrations of amitriptyline. Airway dilatation was also investigated in rat PCLS by prior contraction induced by methacholine. As bronchodilators for maximal relaxation, we used IBMX (PDE inhibitor) and salbutamol (ß2-adrenergic agonist) and compared these effects with the impact of amitriptyline treatment. Isolated perfused lungs (IPL) of wildtype mice were treated with amitriptyline, administered via the vascular system (perfusate) or intratracheally as an inhalation. To this end, amitriptyline was nebulized via pariboy in-vivo and mice were ventilated with the flexiVent setup immediately after inhalation of amitriptyline with monitoring of lung function. Results Our results show amitriptyline to be a potential inhibitor of bronchoconstriction, induced by exogenous or endogenous (EFS) acetylcholine, serotonin and histamine, in PCLS from various species. The effects of endothelin, thromboxane and leukotrienes could not be blocked. In acute bronchoconstriction, amitriptyline seems to act ASM-independent, because ASM-deficiency (Smdp1−/−) did not change the effect of acetylcholine on airway contraction. Systemic as well as inhaled amitriptyline ameliorated the resistance of IPL after acetylcholine provocation. With the flexiVent setup, we demonstrated that the acetylcholine-induced rise in central and tissue resistance was much more marked in untreated animals than in amitriptyline-treated ones. Additionally, we provide clear evidence that amitriptyline dilatates pre-contracted airways as effectively as a combination of typical bronchodilators such as IBMX and salbutamol. Conclusion Amitriptyline is a drug of high potential, which inhibits acute bronchoconstriction and induces bronchodilatation in pre-contracted airways. It could be one of the first therapeutic agents in asthmatic disease to have powerful effects on the TH2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled.

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Section: Discussionmentioning

confidence: 99%

Amitriptyline inhibits bronchoconstriction and directly promotes dilatation of the airways

Hempel,

Klein,

Michely

et al. 2023

Respir Res

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“…Amitriptyline inhibited the contractile responses of rat tracheal ring to SPC (10 μM): the concentration of amitriptyline (mean ± standard deviation) required to exert 50% inhibition (IC 50 ) was 98.2 ± 21.8 μM, respectively [172].…”

Section: Therapeutic Effects Of Spc and Spc Antagonistsmentioning

confidence: 99%

Role of Sphingosylphosphorylcholine in Tumor and Tumor Microenvironment

Park

Lee

2019

Cancers

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Sphingosylphosphorylcholine (SPC) is a unique type of lysosphingolipid found in some diseases, and has been studied in cardiovascular, neurological, and inflammatory phenomena. In particular, SPC’s studies on cancer have been conducted mainly in terms of effects on cancer cells, and relatively little consideration has been given to aspects of tumor microenvironment. This review summarizes the effects of SPC on cancer and tumor microenvironment, and presents the results and prospects of modulators that regulate the various actions of SPC.

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“…To evaluate the mechanism of FLX, muscle strips were incubated with each antagonist for 20 min and contraction was induced by EFS. They were then administrated with FLX and the inhibitory effect of FLX on EFS-induced muscle contraction was compared in the absence and presence of antagonists; L-NAME (10 µmol/l) [48], atropine (1 µmol/l) [49], guanethidine (10 µmol/l) [50], bicuculline (10 µmol/l), phacolfen (10 µmol/l), methysergide (100 µmol/l), ketanserin (1 µmol/l), ondansetron (1 µmol/l), GR 113808 (10 µmol/l) [49], nifedipine (1 µmol/l), calcium ionophore A23187 (1 µmol/l) [51], U73122 (1 µmol/l), chelerythrine (10 µmol/l), ML-9 (10 µmol/l), Y27632 (1 µmol/l) [52], TEA (10 mmol/l), 4-AP (100 µmol/l) and glybenclamide (10 µmol/l) [33]. Muscle strips were equilibrated for 30 min after washing with Kreb's solution for 3 times between each part within each sets of experiment.…”

Section: Methodsmentioning

confidence: 99%

Signal Transduction Underlying the Inhibitory Mechanism of Fluoxetine on Electrical Field Stimulation Response in Rat Ileal Smooth Muscle

Khin

Zaw²,

Sohn³

2017

Pharmacology

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Fluoxetine (FLX), a well-known antidepressant drug under the class of selective serotonin reuptake inhibitor, exerts its action by inhibiting the reuptake of serotonin selectively. In some studies, it has been demonstrated that FLX relaxes the intestinal smooth muscle. In this study, we aimed at studying the signal transduction pathway underlying the muscle relaxation effect of FLX on electrically stimulated rat ileal muscle contraction. To investigate the possible mechanism involved, various antagonists were used. It was found that inhibition with L-N^G-nitroarginine methyl ester, ondansetron, GR113808 and bicuculline enhanced the relaxation effect of FLX. However, the effect of FLX was nullified under the presence of atropine, calcium channel modulator (calcium ionophore A23187), and potassium channel blockers (tetraethylammonium chloride, 4-aminopyridine and glybenclamide). Specific pathway-inhibiting antagonists, Y27632 (Rho-kinase inhibitor) and U73122 (phospholipase-C inhibitor) reversed the antagonistic effect of FLX, while ML-9 (myosin light chain kinase inhibitor) and chelerythrine (protein kinase C inhibitor) augmented the FLX-induced inhibition effect. Taken together, we concluded that FLX exerts the inhibitory effect on electric field stimulation response in rat ileal smooth muscle by the inhibition of muscarinic receptors, decrease of intracellular calcium level by inhibiting phospholipase C and opens the potassium channels.

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Effects of amitriptyline, a tricyclic antidepressant, on smooth muscle reactivity in isolated rat trachea

Cited by 4 publications

References 26 publications

Amitriptyline inhibits bronchoconstriction and directly promotes dilatation of the airways

Amitriptyline inhibits bronchoconstriction and directly promotes dilatation of the airways

Role of Sphingosylphosphorylcholine in Tumor and Tumor Microenvironment

Signal Transduction Underlying the Inhibitory Mechanism of Fluoxetine on Electrical Field Stimulation Response in Rat Ileal Smooth Muscle

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