Tracheal Smooth Muscle Research Articles

Muscarinic receptors blockade and nitric oxide production contribute in the relaxant effect of Berberis vulgaris extract on rat tracheal smooth muscle

Common barberry, or Berberis vulgaris (Berberidaceae), has been shown to possess multiple pharmacological activities. The present study evaluated the relaxant effect of a hydroalcoholic extract of B. vulgaris on rat tracheal smooth muscle (TSM) as well as possible molecular mechanisms. TSM samples were stimulated by 10μM methacholine or 60mM potassium chloride (KCl), and the effects of cumulative concentrations of the extract (0.1, 0.4, 1.6, 6.5mg/mL) and of theophylline (0.2, 0.4, 0.6 and 0.8mM) were examined. To assess the possible mechanism(s) of the plant relaxant effect, this effect was also examined on tissue incubated with atropine, chlorpheniramine, propranolol, diltiazem, glibenclamide, indomethacin, ω-nitro-L-arginine methyl ester (L-NAME) and papaverine. The results showed concentration-dependent relaxant effects of B. vulgaris on non-incubated TSM contracted by KCl and methacholine (P<0.05 to P<0.001). There was no significant difference in the relaxant effects of B. vulgaris between non-incubated tissue and tissue incubated with chlorpheniramine, propranolol, indomethacin, diltiazem, glibenclamide or papaverine. However, the relaxant effects of 1.6 and 6.5mg/mL of B. vulgaris on tissue incubated with L-NAME and of 6.5mg/mL of the extract on tissue incubated with atropine were significantly lower than on non-incubated tissue (P<0.05). The EC50 value of B. vulgaris on tissue incubated with chlorpheniramine was significantly higher than the non-incubated TSM (P<0.05). A relatively effective relaxant effect of B. vulgaris comparable to that of theophylline was shown. Muscarinic receptor blockade and nitric oxide production have been suggested as possible mechanisms for the relaxant effect.

Docosahexaenoic acid (DHA) selectively inhibits prostanoid TP receptor-mediated contractions of guinea pig tracheal smooth muscle

Docosahexaenoic acid (DHA) selectively inhibits prostanoid TP receptor-mediated contractions of guinea pig tracheal smooth muscle

Effect of NP-1815-PX (a P2X4 receptor antagonist) on the contraction of guinea pig tracheal smooth muscles

Effect of NP-1815-PX (a P2X4 receptor antagonist) on the contraction of guinea pig tracheal smooth muscles

Roles of Ca2+ sensitive K+ channel, phosphodiesterase inhibitor, and beta adrenergic activity in Tridax procumbens leaf extract relaxation of trachea smooth muscle in male Wistar rats

Roles of Ca2+ sensitive K+ channel, phosphodiesterase inhibitor, and beta adrenergic activity in Tridax procumbens leaf extract relaxation of trachea smooth muscle in male Wistar rats

Curcuma longa and curcumin affect respiratory and allergic disorders, experimental and clinical evidence: A comprehensive and updated review.

Curcuma longa and its constituents, mainly curcumin, showed various of pharmacological effects in previous studies. This review article provides updated and comprehensive experimental and clinical evidence regarding the effects of C. longa and curcumin on respiratory, allergic, and immunologic disorders. Using appropriate keywords, databases including PubMed, Science Direct, and Scopus were searched until the end of October 2021. C. longa extracts and its constituent, curcumin, showed the relaxant effect on tracheal smooth muscle, which indicates their bronchodilatory effect in obstructive pulmonary diseases. The preventive effects of extracts of C. longa and curcumin were shown in experimental animal models of different respiratory diseases through antioxidant, immunomodulatory, and anti-inflammatory mechanisms. C. longa and curcumin also showed preventive effects on some lung disorders in the clinical studies. It was shown that the effects of C. longa on pulmonary diseases were mainly due to its constituent, curcumin. Pharmacological effects of C. longa extracts and curcumin on respiratory, allergic, and immunologic disorders indicate the possible therapeutic effect of the plant and curcumin on these diseases.

Leukotriene B4 limits the effectiveness of fish oil in an animal model of asthma

This study aimed to evaluate the levels of eicosanoids derived from arachidonic acid (ARA) in the lungs of asthmatic rats supplemented with fish oil. The present data gives insight into the action of fish oil in asthma, related to its inability to modify the contractile capacity of tracheal smooth muscle reported previously in a model of asthma in rats. Male Wistar rats were supplemented daily with 1 g of fish oil/kg of body weight for 21 days. They were exposed to ovalbumin (OVA) after previous sensitization with OVA to induce asthma. Pulmonary levels of five eicosanoids were measured using immunoassay kits: PGE2, TXB2, LTB4, LXA4, and 8-iso PGF2α. In asthmatic rats, supplementation with fish oil resulted in lower concentrations of lung eicosanoids produced by cyclooxygenase-2 and 15-lipoxygenase: PGE2, TXB2, and LXA4, respectively. Fish oil supplementation also decreased the non-enzymatically produced eicosanoid 8-iso PGF2α. Fish oil supplementation did not affect LTB4, a metabolite of 5-lipoxygenase. The limited efficacy of fish oil supplementation in asthmatic rats is associated with a lack of action in reducing the levels of LTB4 in the lungs. Thus, fish oil differentially modulates the concentrations of eicosanoids derived from ARA via specific pathways in an animal model of asthma.

Cellular Mechanism Underlying the Facilitation of Contractile Response Induced by Tumor Necrosis Factor-α in Mouse Tracheal Smooth Muscle

The proinflammatory cytokine tumor necrosis factor-α (TNF-α) augments intracellular Ca2+ signaling and contractile responses of airway smooth muscles, leading to airway hyperresponsiveness. However, the underlying mechanism has not been fully elucidated. This study aimed to investigate the cellular mechanism of the potentiated contraction of mouse tracheal smooth muscle induced by TNF-α. The results showed that TNF-α triggered facilitation of mouse tracheal smooth muscle contraction in an epithelium-independent manner. The TNF-α-induced hypercontractility could be suppressed by the protein kinase C inhibitor GF109203X, the tyrosine kinase inhibitor genistein, the Src inhibitor PP2, or the L-type voltage-dependent Ca2+ channel blocker nifedipine. Following TNF-α incubation, the α1C L-type Ca2+ channel (CaV1.2) was up-regulated in cultured primary mouse tracheal smooth muscle cells. Pronounced phosphotyrosine levels were observed in mouse tracheas. In conclusion, this study shows that TNF-α enhanced airway smooth muscle contraction via protein kinase C-Src-CaV1.2 pathways, which provides novel insights into the pathologic role of proinflammatory cytokines in mediating airway hyperresponsiveness.

Effects of Allium cepa and Its Constituents on Respiratory and Allergic Disorders: A Comprehensive Review of Experimental and Clinical Evidence.

The health benefits of Allium cepa (A. cepa) have been proclaimed for centuries. Various pharmacological and therapeutic effects on respiratory, allergic, and immunologic disorders are shown by A. cepa and its constituents. Flavonoids such as quercetin and kaempferol, alk(en)yl cysteine sulfoxides including S-methyl cysteine sulfoxide and S-propyl cysteine sulfoxide, cycloalliin, thiosulfinates, and sulfides are the main compounds of the plant. A. cepa displays broad-spectrum pharmacological activities including antioxidant, anti-inflammatory, antihypertensive, and antidiabetic effects. Our objective in this review is to present the effects of A. cepa and its constituents on respiratory, allergic, and immunologic disorders. Different online databases were searched to find articles related to the effect of A. cepa extracts and its constituents on respiratory, allergic, and immunologic disorders until the end of December 2020 using keywords such as onion, A. cepa, constituents of A. cepa, therapeutic effects and pharmacological effects, and respiratory, allergic, and immunologic disorders. Extracts and constituents of A. cepa showed tracheal smooth muscle relaxant effects, indicating possible bronchodilator activities or relieving effects on obstructive respiratory diseases. In experimental animal models of different respiratory diseases, the preventive effect of various extracts and constituents of A. cepa was induced by their antioxidant, immunomodulatory, and anti-inflammatory effects. The preventive effects of the plant and its components on lung disorders induced by exposure to noxious agents as well as lung cancer, lung infection, and allergic and immunologic disorders were also indicated in the experimental and clinical studies. Therefore, this review may be considered a scientific basis for development of therapies using this plant, to improve respiratory, allergic, and immunologic disorders.

VIP/PACAP signaling as an alternative target during hyperoxic exposure in preterm newborns.

The use of oxygen therapy (high doses of oxygen - hyperoxia) in the treatment of premature infants results in their survival. However, it also results in a high incidence of chronic lung disease known as bronchopulmonary dysplasia, a disease in which airway hyper-responsiveness and pulmonary hypertension are well known as consequences. In our previous studies, we have shown that hyperoxia causes airway hyper-reactivity, characterized by an increased constrictive and impaired airway smooth muscle relaxation due to a reduced release of relaxant molecules such as nitric oxide, measured under in vivo and in vitro conditions (extra- and intrapulmonary) airways. In addition, the relaxation pathway of the vasoactive intestinal peptide (VIP) and/or pituitary adenylate cyclase activating peptide (PACAP) is another part of this system that plays an important role in the airway caliber. Peptide, which activates VIP cyclase and pituitary adenylate cyclase, has prolonged airway smooth muscle activity. It has long been known that VIP inhibits airway smooth muscle cell proliferation in a mouse model of asthma, but there is no data about its role in the regulation of airway and tracheal smooth muscle contractility during hyperoxic exposure of preterm newborns.

Bronchodilator Effect of Crataegus azarolus var aronia Unripped Fruit Extracts on Rat’s Tracheal Smooth Muscle

Objectives: The present study aimed to investigate the bronchodilator effect of different Crataegus azarolusvar aronia unripped fruit extracts on tracheal smooth muscle of rats and to study the roles of K channels andEDHFs in produced responses.Background: Crataegus is widely used in Kurdistan Region for the prevention of several diseases suchas respiratory, cardiovascular, hypertension …. etc. due to its content of several bioactive compounds likearomatic amines, phenolic acid, flavonoids, and proanthocyanidins.Method: The bronchodilator effects of various Crataegus fruit’s extracts on rat’s tracheal rings and the rolesof K+, Ca2+ channels and EDHFs in bronchodilation using specific blockers.Results: Most of Crataegus fruit’s extracts used showed a potent bronchodilator effect on trachea, in whichthe HME produced a highly significant dilation, followed by methanol and ethyl acetate extracts whichshowed a considerable relaxant effect. The results confirmed that the induced dilation was NO and PGI2dependent, along with activations of KATP and Kir and Kca while Kv plays a minor and limited role.Conclusion: The novel results indicate that HM, M, EA extracts prepared from Crataegus unripped fruitproduce a potent bronchodilator effect, which was NO and PGl2 dependent along with the activation of KATP,Kir and Kca2+ channels.

Relaxation Effect of Schisandra Chinensis Lignans on the Isolated Tracheal Smooth Muscle in Rats and Its Mechanism

Schisandra chinensis (S. chinensis) is one of the core drugs used for relieving cough and asthma in traditional Chinese medicine. However, there are few basic studies on the treatment of respiratory diseases with S. chinensis in modern pharmacology, and the material basis and mechanism of its antiasthmatic effect are still unclear. Lignans are the main active components of S. chinensis. The aim of this study was to observe the relaxation effect of S. chinensis lignans (SCL) on the tracheal smooth muscle of rats by in vitro tracheal perfusion experiments, and to explore the mechanism by preincubation with L-type calcium channel blocker verapamil, four potassium channel blockers glibenclamide, tetraethylamine, 4-aminopyridine and barium chloride (BaCl2), β-adrenoceptor blocker propranolol, nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME), and the cyclooxygenase inhibitor indomethacin, respectively. The results showed that SCL (0.25-1.75 mg/mL) reduced the contraction of isolated tracheal smooth muscle induced by acetylcholine, the preincubation with verapamil and glibenclamide could attenuate the relaxation effect, whereas propranolol, 4-aminopyridine, BaCl2, tetraethylamine, L-NAME, and indomethacin had no such effect. These results suggest that SCL has a significant relaxation effect on the isolated tracheal smooth muscle of rats, and the mechanism may be related to the inhibition of extracellular calcium influx and intracellular calcium release from the sarcoplasmic reticulum, as well as the activation of ATP-sensitive potassium channels. These findings may provide a pharmacological basis for the traditional use of S. chinensis to treat asthma.

Effect of TNF-α, IL-2, IL-5 and IL-6 on Rat Tracheal and Bronchial Smooth Muscle Contractions

Effect of TNF-α, IL-2, IL-5 and IL-6 on Rat Tracheal and Bronchial Smooth Muscle Contractions

Evaluation of the Antinociceptive, Antiallodynic, Antihyperalgesic and Anti-Inflammatory Effect of Polyalthic Acid.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are very commonly used, but their adverse effects warrant investigating new therapeutic alternatives. Polyalthic acid, a labdane-type diterpenoid, is known to produce gastroprotection, tracheal smooth muscle relaxation, and antitumoral, antiparasitic and antibacterial activity. This study aimed to evaluate the antinociceptive, antiallodynic, antihyperalgesic and anti-inflammatory effect of polyalthic acid on rats. Moreover, the effectiveness of treating hyperalgesia with a combination of polyalthic acid and naproxen was analyzed, as well as the type of drug–drug interaction involved. Nociception was examined by injecting 1% formalin into the right hind paw and thermal hyperalgesia and inflammation by injecting a 1% carrageenan solution into the left hind paw of rats. Allodynia was assessed on an L5/L6 spinal nerve ligation model. Polyalthic acid generated significant antinociceptive (56–320 mg/kg), antiallodynic (100–562 mg/kg), and antihyperalgesic and anti-inflammatory (10–178 mg/kg) effects. Antinociception mechanisms were explored by pretreating the rats with naltrexone, ODQ and methiothepin, finding the effect blocked by the former two compounds, which indicates the participation of opioid receptors and guanylate cyclase. An isobolographic analysis suggests synergism between polyalthic acid and naproxen in the combined treatment of hyperalgesia.

Elucidation of Mechanisms in Cu (II) Caused Hypercontraction of Rat Tracheal Rings.

Airway smooth muscle contraction is one of the primary factors involved in the initiation and progression of asthma which in turn is regulated by increased cytosolic Ca2+ concentration from intracellular stores and through transmembrane ion channels. Calcium-independent factors such as reactive oxygen species (ROS) generation, nitric oxide (NO) depletion and cyclooxygenase (COX) pathways also contribute to tracheal smooth muscle contraction. Studies on copper toxicity suggest significance of this essential micronutrient overdose in acute respiratory disorders, allergic asthma and ciliary motion in tracheal explants. However, the mechanism of copper caused hypercontraction upon direct exposure to tracheal smooth muscle is largely unknown. In this study we investigate the effect of copper exposure on isolated tracheal rings and relative contributions of various factors in acetylcholine-induced contractions. Results obtained suggest that rise in intracellular calcium concentration via voltage-operated Ca2+ channel (VOCC), store-operated Ca2+ channel (SOCC), stretch-activated channels (SAC) and TRP channel (transient receptor potential channel) activation is the major factor in copper-mediated hypercontraction. ROS generation or COX-dependent pathways do not appear to significantly contribute to Cu2+ caused hypercontraction.

Relaxant Effect of Urginea maritima on Tracheal Smooth Muscle Mediated by the Effect on Beta-2 Adrenergic, Muscarinic Receptors and Calcium and Potassium Channels.

Urginea maritima (U. maritima) showed anti-inflammatory, antioxidant, antibacterial, diuretic, vasodilatation, and wound-healing effects on fungal infections, cardiac disorders, digestive disorders, rheumatoid disease, and respiratory disorders such as bronchitis, bronchial nosocomial infections, and severe cough. To examine the bronchodilatory effect of U. maritima, the relaxant effect of its extract on rat tracheal smooth muscle (TSM) and its possible mechanism was examined in this study. Male Wistar rats' TSM were divided into eight groups (n = 8 in each group). Four of these groups were TSM tissues, contracted with KCl (60 mM) incubated with atropine, glibenclamide, and indomethacin and nonincubated TSM, while the other four groups were TSM tissues contracted with methacholine (10 μM) for 5 min, incubated with propranolol, chlorpheniramine, and diltiazem and nonincubated TSM. Cumulative concentrations of U. maritima extract (12.5, 25, 50, 100, 20, and 400 μg/ml) were then added to organ bath every 5 min. Theophylline (0.2, 0.4, 0.6, and 0.8 mM) as positive control and saline (1 ml) as negative control were also examined in nonincubated tissues. A concentration-dependent relaxant effect of U. maritima on nonincubated TSM contracted with KCl (60 mM) or methacholine (10 μM) (p < 0.01 and p < 0.001) was observed. The relaxant effects of U. maritima extract in the incubated tissues with glibenclamide, propranolol, diltiazem, atropine, and chlorpheniramine were significantly lower than those in the nonincubated tissues (p < 0.05 to p < 0.001). EC50 values of U. maritima extract in the incubated TSM with glibenclamide, propranolol, diltiazem, and atropine were significantly higher than those in the nonincubated tissues (p < 0.05 for diltiazem-incubated tissues and p < 0.001 for other cases). U. maritima extract displayed considerable relaxant effect on TSM comparable to the effect of theophylline. Beta-2 adrenoceptor stimulation and muscarinic receptor inhibition as well as potassium opening and calcium channels blocking effects are the possible mechanisms for the relaxant effects of the plant.

Regulation of smooth muscle contractility by the epithelium in rat tracheas: role of prostaglandin E2 induced by the neurotransmitter acetylcholine.

BackgroundPrevious studies have suggested the involvement of epithelium in modulating the contractility of neighboring smooth muscle cells. However, the mechanism underlying epithelium-derived relaxation in airways remains largely unclear. This study aimed to investigate the mechanism underlying epithelium-dependent smooth muscle relaxation mediated by neurotransmitters.MethodsThe contractile tension of Sprague-Dawley (SD) rat tracheal rings were measured using a mechanical recording system. Intracellular Ca2+ level was measured using a Ca2+ fluorescent probe Fluo-3 AM, and the fluorescence signal was recorded by a laser scanning confocal imaging system. The prostaglandin E2 (PGE2) content was measured using an enzyme-linked immunosorbent assay kit.ResultsWe observed that the neurotransmitter acetylcholine (ACh) restrained the electric field stimulation (EFS)-induced contraction in the intact but not epithelium-denuded rat tracheal rings. After inhibiting the muscarinic ACh receptor (mAChR) or cyclooxygenase (COX), a critical enzyme in prostaglandin synthesis, the relaxant effect of ACh was attenuated. Exogenous PGE2 showed a similar inhibitory effect on the EFS-evoked contraction of tracheal rings. Moreover, ACh triggered phospholipase C (PLC)-coupled Ca2+ release from intracellular Ca2+ stores and stimulated COX-dependent PGE2 production in primary cultured rat tracheal epithelial cells.ConclusionsCollectively, this study demonstrated that ACh induced rat tracheal smooth muscle relaxation by promoting PGE2 release from tracheal epithelium, which might provide valuable insights into the cross-talk among neurons, epithelial cells and neighboring smooth muscle cells in airways.

Insulin acutely increases agonist-induced airway smooth muscle contraction in humans and rats.

Obesity increases incidence and severity of asthma but the molecular mechanisms are not completely understood. Hyperinsulinemia potentiates vagally induced bronchoconstriction in obese rats. Since bronchoconstriction results from airway smooth muscle contraction, we tested whether insulin changed agonist-induced airway smooth muscle contraction. Obesity-prone and resistant rats were fed a low-fat diet for 5 wk and treated with insulin (Lantus, 3 units/rat sc) 16 h before vagally induced bronchoconstriction was measured. Ex vivo, contractile responses to methacholine were measured in isolated rat tracheal rings and human airway smooth muscle strips before and after incubation (0.5-2 h) with 100 nM insulin or 13.1 nM insulin like growth factor-1 (IGF-1). M2 and M3 muscarinic receptor mRNA expression was quantified by qRT-PCR and changes in intracellular calcium were measured in response to methacholine or serotonin in isolated rat tracheal smooth muscle cells treated with 1 µM insulin. Insulin, administered to animals 16 h prior, potentiated vagally induced bronchoconstriction in both obese-prone and resistant rats. Insulin, not IGF-1, significantly increased methacholine-induced contraction of rat and human isolated airway smooth muscle. In cultured rat tracheal smooth muscle cells, insulin significantly increased M2, not M3, mRNA expression and enhanced methacholine- and serotonin-induced increase in intracellular calcium. Insulin alone did not cause an immediate increase in intracellular calcium. Thus, insulin acutely potentiated agonist-induced increase in intracellular calcium and airway smooth muscle contraction. These findings may explain why obese individuals with hyperinsulinemia are prone to airway hyperreactivity and give insights into future targets for asthma treatment.

Effect of gold nanoparticles (AuNPs) on isolated rat tracheal segments

The AuNPs have been used in biomedicine as therapeutic tools for cancer. However, its role in the context of respiratory physiology has been little studied. This study aimed to determine the impact of AuNPs on respiratory smooth muscle tone, using a model of isolated tracheal rings from female and male rats precontracted with acetylcholine (ACh). AuNPs exerted a contractile effect only in the concentration of 100 ug/ml. This contractile effect was not modified by gender. The possible mediator +could be nitric oxide (NO), measured in a physiological solution containing the tracheal rings treated with different concentrations of AuNPs. The results obtained in this study show that the AuNPs are bio-inert in a concentration range of 0.1-10 μg/mL; however, 100 μg/mL could trigger airway hyperresponsiveness. Similar effects were obtained in isolated trachea rings treated with 100 μg/mL HAuCl4. An evaluation of HAuCl4 in physiological buffer at various HEPES concentrations (0-20 mM) showed the formation of AuNPs that could explain the contractile effect on the tracheal smooth muscle.

Relaxation effects of Eriobotrya japonica toward tracheal smooth muscle via action mechanism on histamine-1 receptor and phosphodiesterase-5 enzyme.

The Eriobotrya japonica leaves have the activity to relax the smooth muscle in the respiratory tract. However, the mechanism of action due to that activity has never been carried out. This study aims to determine the relaxation effects of E. japonica leaves extract in the isolated trachea of the guinea pigs through the inhibition of the histamine-1 (H-1) receptor and the phosphodiesterase-5 (PDE-5) enzyme. The determination of the relaxation effects was carried out by using histamine to contract smooth muscle within the tracheal tract, followed by adding cumulative concentrations of extract. Michaelis–Menten kinetics equation was used to determine the antagonist type of extract toward H-1 receptor. The understanding of mechanism of action of the extract toward PDE-5 enzyme was performed by incubating the smooth muscle using sildenafil. The percentage value of responses, originated from the relaxation effect of the extract toward the trachea was analyzed by using the t-independent test. The result showed that the extract was able to relax the smooth muscle, which was contracted by histamine, and there was a positive correlation between concentration and relaxation effect (P < 0.05; r = 0.973). The extract also antagonized the histamine as a noncompetitive antagonist. The incubation within the trachea with sildenafil demonstrated equal relaxation effect, produced by the extract. It can be concluded that E. japonica extract had relaxation effect within the isolated trachea as antagonist noncompetitive toward H-1 receptor and inhibitor of the PDE-5 enzyme.

Protective Effect of Nedocromil Against Insulin Induced Airway Hyper-Reactivity

Background: Use of inhalable insulin is limited because it causes airway hyper-reactivity. So present study was designed to ameliorate inhalational insulin induced airway hyper-responsiveness.Objectives: The objective of the study was to evaluate the acute effects of insulin on airway reactivity and protective effects of nedocromil against insulin induced airway hyper-reactivity on isolated tracheal tissues of guinea pigs in vitro.Material and Methods: This experimental study was carried out in Pharmacology department of Army Medical College Rawalpindi from January 2012 to July 2012. We observed acute effect of insulin (10-7- 10-3 M) and insulin pretreated with nedocromil (10-5 M) on isolated tracheal strip of guinea pig (n=6) in vitro by constructing cumulative concentration response curves. The tracheal smooth muscle contractions were recorded with Transducer on Four Channel Oscillograph.Results: Insulin significantly increased the tracheal smooth muscle contraction. The mean ± SEM of maximum amplitudes of contraction with insulin and insulin pretreated with nedocromil were 35 ± 1.13 mm and 27.8 ± 1.27 mm respectively. So nedocromil significantly antagonized insulin elicited contractile effect. Conclusion: Nedocromil significantly inhibited the insulin mediated airway hyper-reactivity in guinea pigs. So we suggest that pretreatment of inhaled insulin with nedocromil may have clinical implication in amelioration of its potential respiratory adverse effects.