Histamine-induced Bronchoconstriction Research Articles

The Bronchoprotective Effects of Dual Pharmacology, Muscarinic Receptor Antagonist and β2 Adrenergic Receptor Agonist Navafenterol in Human Small Airways.

Bronchodilators and anti-inflammatory agents are the mainstream treatments in chronic obstructive and pulmonary disease (COPD) and asthma. The combination of β2 adrenergic receptor (β2AR) agonists and muscarinic antagonists shows superior bronchoprotective effects compared to these agents individually. Navafenterol (AZD8871) is a single-molecule, dual pharmacology agent combining muscarinic antagonist and β2AR agonist functions, currently in development as a COPD therapeutic. In precision-cut human lung slices (hPCLS), we investigated the bronchoprotective effect of navafenterol against two non-muscarinic contractile agonists, histamine and thromboxane A2 (TxA2) analog (U46619). Navafenterol pre-treatment significantly attenuated histamine-induced bronchoconstriction and β2AR antagonist propranolol reversed this inhibitory effect. TxA2 analog-induced bronchoconstriction was attenuated by navafenterol pre-treatment, albeit to a lesser magnitude than that of histamine-induced bronchoconstriction. Propranolol completely reversed the inhibitory effect of navafenterol on TxA2 analog-induced bronchoconstriction. In the presence of histamine or TxA2 analog, navafenterol exhibits bronchoprotective effect in human airways and it is primarily mediated by β2AR agonism of navafenterol.

Pharmacological screening of Acalypha indica L.: Possible role in the treatment of asthma

Ethnopharmacological relevanceAcalypha indica Linn (Euphorbiaceae), a popular traditional medicine, is an erect herb found throughout various parts of India. In Ayurveda, Acalypha indica was commonly used in asthma and allergy. However, no attempts were made in past to validate the antiasthmatic potential of Acalypha indica.Aim of the study: The present study was aimed to assess the anti-asthmatic potential of ethanolic extracts of Acalypha indica leaves (EAIL) using various experimental animal models. Materials and methodsEAIL was analyzed using different screening methods such as acetylcholine and histamine-induced contraction of goat tracheal chain, clonidine-induced catalepsy in mice, milk-induced leucocytosis and eosinophilia in mice, clonidine-induced mast cell degranulation in rats, passive paw anaphylaxis in rats, histamine-induced bronchoconstriction in guinea pigs, and ovalbumin (OVA)-induced histopathological alterations in mice. ResultsData received in the present study showed that EAIL drastically antagonized acetylcholine and histamine-induced contraction of goat tracheal chain, suggesting its anticholinergic and antihistaminic activity respectively. The duration of immobility, produced by clonidine, was found to be decreased in mice which showed its H1 receptor blocking activity. In milk-induced leucocytosis and eosinophilia in mice, EAIL significantly reduced the number of leucocytes and eosinophils suggesting its adaptogenic and anti-allergic potential. Inhibition of clonidine-induced mast cell degranulation in rats displayed its mast cell stabilizing potential. Reduction of paw edema in passive paw anaphylaxis exhibited antianaphylactic activity of EAIL. Guinea pigs were protected from histamine-induced bronchoconstriction by EAIL which revealed its bronchodilator potential. Furthermore, the histopathological architecture of lung tissue was near to normal. ConclusionOur results contribute towards validation of the traditional use of Acalypha indica in the treatment of asthma due to the presence of a wide range of phytoconstituents. Hence our investigation revealed that EAIL possessed strong antiasthmatic property by virtue of various mechanisms.

EVALUATION OF ANTI-ASTHMATIC ACTIVITY OF CAPPARIS DECIDUA

Objective: The present study was conducted to determine the anti-asthmatic activity of Capparis decidua.Methods: The acute oral toxicity study was conducted as per OECD guidelines, and the extract was proved to be safe up to the dose of 2000 mg/kg.The anti-asthmatic activity of C. decidua was evaluated using various experimental models such as histamine-induced bronchoconstriction in guineapigs and milk-induced leukocytosis in mice, histamine-induced bronchospasm in guinea pigs, studies on pre convulsive time and milk-inducedleukocytosis in mice, studies on blood.Results: Antihistaminic drugs Chlorpheniramine maleate and ethanolic extract of C. decidua significantly protected the guinea pigs against histamineinducedbronchospasm. The ethanolic section of C. decidua has dramatically prolonged the latent period of convulsions compared to control. Ethanolicextract of C. decidua suppresses the milk-induced leukocytosis by stabilizing the oxidative stress in the surrounding tissue.Conclusion: The results obtained in the above study suggest the ethanolic extract of C. decidua possesses significant anti-asthmatic activity.

In vivo bronchodilator evaluation of the ethanolic extract of the stems of Jatropha macrantha Müll.Arg.

Context: Asthma is characterized by hyperresponsiveness and bronchoconstriction, induced by histamine and other noxes, with a prevalence in Peru of 20.7-28.2%, which is why, in traditional medicine, Jatropha macrantha Müll.Arg is used. Aims: To evaluate the in vivo bronchodilator activity of the ethanolic extract of the stems of J. macrantha. Methods: The powdered material of the stem of J. macrantha was extracted with ethanol 96° by maceration; then, the phytochemical screening was carried out. The doses of 200, 400 and 800 mg/kg of the extracts were subjected to in vivo evaluation in guinea pigs (Cavia porcellus) with 1% histamine-induced bronchoconstriction, determining the latency period and the intensity of the effect. Results: Phytochemical sieving showed alkaloids, catechins, flavonoids, tannins and terpenes. The activity was observed at the three doses of the J. macrantha extract, being higher at a single dose of 400 mg/kg, with a latency period of 33.0 ± 1.02 s, asphyxia 84.5 ± 1.08 s and anaphylaxis 105.6 ± 0.59 s. The analysis of variance and Dunnett’s test resulted with p<0.05 as statistically significant. Conclusions: The results showed bronchodilator activity of the ethanolic extract of J. macrantha at an average dose of 400 mg/kg, orally, in Cavia porcellus.

Dexmedetomidine targets miR-146a and participates in the progress of chronic obstructive pulmonary disease in vivo and in vitro.

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease and the third leading cause of death in the world. Dexmedetomidine has been reported to effectively inhibit histamine-induced bronchoconstriction. However, the molecular mechanism of dexmedetomidine in COPD has not been found. To explore the role and mechanism of dexmedetomidine in COPD, and to provide theoretical basis for clinical treatment of COPD. The expression of miR-146a was regulated by mimics or inhibitor and the relative expression of apoptotic proteins p53, Bax and Bcl-2 in human bronchial epithelial 16HBE cells was determined by real-time PCR and Western blot. Dexmedetomidine was treated for 16HBE cells and alveolar epithelial type II cells (AEC2), the cell apoptosis was detected by TUNEL and Hoechst33342 staining. A COPD rat model was established by smoking to test the effects of dexmedetomidine on the progression of COPD. The levels of IL-6, IL-1β and TNF-α in serum were measured by ELISA and the protein concentration of bronchoalveolar lavage fluid (BALF) was also detected in dexmedetomidine treated COPD rat model. miR-146a promoted 16HBE cell apoptosis and reduced cell proliferation. Additionally, dexmedetomidine was showed to reduce the 16HBEL cell apoptosis through reducing the expression of miR-146a. Moreover, dexmedetomidine regulated cell apoptosis and cell apoptosis through miR-146a in AEC2 cells. More importantly, dexmedetomidine attenuated the morphology and pathology of COPD rat model. Dexmedetomidine reduced 16HBE cells and AEC2 cell apoptosis and attenuated COPD by down-regulating miR-146a.

Cryptolepine, the major alkaloid of Cryptolepis sanguinolenta (Lindl.) Schlechter (Apocynaceae), attenuates early and late-phase symptoms of asthma

Aqueous root extract of Cryptolepis sanguinolenta has been used traditionally to treat many upper respiratory tract disorders. Besides its well-known broad spectrum antimicrobial activity, we had reasoned that cryptolepine can directly attenuate the symptoms of asthma. Therefore, this study evaluates cryptolepine, the main compound of the aqueous extract of Cryptolepis sanguinolenta, on early and late-phase symptoms of asthma attack. In the early phase study, isolated cryptolepine was evaluated on its ability to reverse histamine-induced bronchoconstriction and reduce histamine release from mast cells and bronchial mucus secretion. In the late phase study, cryptolepine was evaluated on its ability to affect airway inflammation and hypersensitivity as well as its ability to attenuate airway remodeling induced by ovalbumin. In the early asthma phase study, Cryptolepine (10–100 mg/kg) significantly and dose dependently inhibited Histamine-induced bronchoconstriction in guinea pigs. The protection lasted beyond 24 h. It also decreased the volume and optical density of bronchial secretions in mice. Cryptolepine (10–100 µg /mL) stabilized mesentery mast cells in vitro against Compound 48/80 -induced degranulation. In the late phase study, cryptolepine (10–100 mg/kg) prevented ovalbumin-induced airway obstruction and basal membrane smooth muscle hypertrophy. It significantly reduced systemic leukocytosis and inflammatory cell infiltration into airways in antigen-sensitized animals. Using the skin prick test, cryptolepine reduced the hypersensitivity to allergen challenge in antigen-sensitized animals. Cryptolepine's effects in the late phase was similar to dexamethasone (1 mg/kg) used as standard drug. Cryptolepine attenuates both early and late phase symptoms of asthma. It reduces bronchospasms, bronchial secretions, airway remodeling and hypersensitivity. This gives scientific credence to the traditional usage of cryptolepis extracts in upper respiratory tract disorders.

ANTIHISTAMINIC ACTIVITY MODELS

Histamine is referred to as common allergic reactions and symptoms. Most of them are compared to histamine intolerance. Some common responses involved with this intolerance may vary but include headaches or migraines, nasal congestion or sinus problems, fatigue, hives, digestive problems, irregular menstrual cycle, nausea, and vomiting. Histamine is derived from a natural amino acid, S-histidine, through the histidine decarboxylase/ aromatic decarboxylase catalysis. Histamine is the compound that the mast cell generates for the immune response. Histamine promotes gastrointestinal secretion and induces capillary dilation, bronchial smooth muscle constriction, and reduced blood pressure. Antihistamines are medicinal products to treat allergic rhinitis and allergies. This includes the in vitro animal model and in-vivo tissue preparation antihistaminic activity. Animal models are significant instruments for understanding the pathological process of human illnesses in experimental medical science. Medicines associated with antihistamine include antiallergy, antivertigo, antimigraine, sedatives, antiemetic, etc. Elderly people are much more likely than youthful people to develop sleepiness from the use of antihistamines. The most common drugs used are cetirizine, levocetirizine, chlorpheniramine, diphenhydramine, loratadine, cimetidine, and fexofenadine. Animal models include histamine-induced bronchoconstriction, passive paw anaphylaxis, milk-induced leukocytosis and eosinophilia, clonidine, and haloperidol-induced catalepsy. While tissue models include isolated goat, and guinea-pig trachea chain preparation, as well as an isolated guinea pig, rat, mice ileum tissue preparation, and the dose-response curve of histamine, were plotted. The focus of the study had been on herbal plants and medicinal products, as they can effectively boost a variety of circumstances without significant adverse side effects. We can assess antihistaminic activity by using plant extracts or any synthetic drug.

Effect of Protease-Activated Receptor-2-Activating Peptide on Guinea Pig Airway Resistance and Isolated Tracheal Strips.

Purpose:Protease-activated receptors (PARs) are a family of G-protein-coupled receptors distributed in a number of tissues. PAR-2 is expressed on airway epithelium and smooth muscles and overexpressed under pathological conditions, such as asthma and chronic obstructive pulmonary disease. However, the role of PAR-2 in airways has not yet been defined. In this study, we investigated the role of PAR-2-activating peptide (SLIGRL) on histamine-induced bronchoconstriction and the mechanisms underlying the bronchoprotective effect both in vivo and in vitro.Materials and Methods:The effect of SLIGRL was tested in vivo using histamine-induced bronchoconstriction in the guinea pig and in vitro using isolated tracheal spiral strips.Results:In vivo pretreatment with SLIGRL significantly reduced the histamine-induced increased bronchoconstriction. Neither propranolol nor vagotomy abolished the inhibitory effect of SLIGRL. Furthermore, indomethacin or glibenclamide did not antagonize the inhibitory response to SLIGRL. In isolated tracheal spiral strips in vitro, SLIGRL did not affect the contractile response to acetylcholine or potassium chloride; however, histamine-induced contraction was inhibited in a dose-dependent manner.Conclusion:Our data demonstrate the protective effect of SLIGRL in airways; however, this effect appears to be mediated independently of prostanoids, nitric oxide, circulating adrenaline, ATP-sensitive K + channels, and vagal stimulation.

Design, Synthesis, Biological Evaluation, and In Silico ADMET Studies of 1,8-Naphthyridine Derivatives as an H1-receptor Inhibitor

In the present study, 1,8-naphthyridine-3-carboxylic acid derivatives (5a1, 5a2, 5b1, and 5b2) were designed, synthesized, and screened for their in vitro H1-antihistaminic activity. H1R inhibitory activity of the synthesized derivatives was calculated by the modified Van Arman technique, histamine-induced bronchoconstriction in guinea pigs. A good bronchorelaxant effect of compounds was observed in histamine-contracted guinea pig tracheal chain through H1-receptor antagonism. In addition, the hypothetically resulted compounds are checked for their reliability on other in silico drug designing online web services like SwissADME predictor. In silico ADMET analysis results show that all the derivatives had negligible toxicity, good absorption, and solubility profile. These compounds may serve as possible lead for establishing safe and effective antihistaminic agent(s).

Anti-inflammatory and bronchodilatory constituents of leaf extracts of Anacardium occidentale L. in animal models

ObjectiveAnacardium occidentale L. leaf is useful in the treatment of inflammation and asthma, but the bioactive constituents responsible for these activities have not been characterized. Therefore, this study was aimed at identifying the bioactive constituent(s) of A. occidentale ethanolic leaf extract (AOEL) and its solvent-soluble portions, and evaluating their effects on histamine-induced paw edema and bronchoconstriction. MethodsThe bronchodilatory effect was determined by measuring the percentage protection provided by plant extracts in the histamine-induced bronchoconstriction model in guinea pigs. The anti-inflammatory effect of the extracts on histamine-induced paw edema in rats was determined by measuring the increase in paw diameter, after which the percent edema inhibition was calculated. The extracts were analyzed using gas chromatography-mass spectrometry to identify the bioactive constituents. Column chromatography and Fourier transform infrared spectroscopy were used respectively to isolate and characterize the constituents. The bronchodilatory and anti-inflammatory activities of the isolated bioactive constituent were evaluated. ResultsHistamine induced bronchoconstriction in the guinea pigs and edema in the rat paw. AOEL, hexane-soluble portion of AOEL, ethyl acetate-soluble portion of AOEL, and chloroform-soluble portion of AOEL significantly increased bronchodilatory and anti-inflammatory activities (P < 0.05). Oleamide (9-octadecenamide) was identified as the most abundant compound in the extracts and was isolated. Oleamide significantly increased bronchodilatory and anti-inflammatory activities by 32.97% and 98.41%, respectively (P < 0.05). ConclusionThese results indicate that oleamide is one of the bioactive constituents responsible for the bronchodilatory and anti-inflammatory activity of A. occidentale leaf, and can therefore be employed in the management of bronchoconstriction and inflammation.

PKC-dependent regulation of Kv7.5 channels by the bronchoconstrictor histamine in human airway smooth muscle cells.

Kv7 potassium channels have recently been found to be expressed and functionally important for relaxation of airway smooth muscle. Previous research suggests that native Kv7 currents are inhibited following treatment of freshly isolated airway smooth muscle cells with bronchoconstrictor agonists, and in intact airways inhibition of Kv7 channels is sufficient to induce bronchiolar constriction. However, the mechanism by which Kv7 currents are inhibited by bronchoconstrictor agonists has yet to be elucidated. In the present study, native Kv7 currents in cultured human trachealis smooth muscle cells (HTSMCs) were observed to be inhibited upon treatment with histamine; inhibition of Kv7 currents was associated with membrane depolarization and an increase in cytosolic Ca2+ ([Ca2+]cyt). The latter response was inhibited by verapamil, a blocker of L-type voltage-sensitive Ca2+ channels (VSCCs). Protein kinase C (PKC) has been implicated as a mediator of bronchoconstrictor actions, although the targets of PKC are not clearly established. We found that histamine treatment significantly and dose-dependently suppressed currents through overexpressed wild-type human Kv7.5 (hKv7.5) channels in cultured HTSMCs, and this effect was inhibited by the PKC inhibitor Ro-31-8220 (3 µM). The PKC-dependent suppression of hKv7.5 currents corresponded with a PKC-dependent increase in hKv7.5 channel phosphorylation. Knocking down or inhibiting PKCα, or mutating hKv7.5 serine 441 to alanine, abolished the inhibitory effects of histamine on hKv7.5 currents. These findings provide the first evidence linking PKC activation to suppression of Kv7 currents, membrane depolarization, and Ca2+ influx via L-type VSCCs as a mechanism for histamine-induced bronchoconstriction.

Effects of nebulised magnesium sulphate on inflammation and function of the guinea-pig airway

Magnesium sulphate is a potential treatment for acute severe asthma. However, the mechanisms and dose-response relationships are poorly understood. The first objective of this study was to examine whether inhaled magnesium sulphate exerts bronchodilator activity measured as bronchoprotection against histamine-induced bronchoconstriction in conscious guinea-pigs alone and combined with salbutamol. Secondly, we examined whether inhaled magnesium sulphate inhibits airways inflammation and function in models of neutrophilic and eosinophilic lung inflammation induced, respectively, by inhaled lipopolysaccharide or the inhaled antigen, ovalbumin (OVA). Airway function was measured in conscious guinea-pigs as specific airway conductance (sGaw) by whole-body plethysmography. Anti-inflammatory activity was measured against lung inflammatory cell influx induced by OVA inhalation in OVA-sensitised animals or by lipopolysaccharide (LPS) exposure of non-sensitised animals. Airway function (sGaw) was measured over 24h after OVA exposure. Airway hyperresponsiveness to inhaled histamine and inflammatory cells in bronchoalveolar lavage fluid were recorded 24h after OVA or LPS challenge. Histamine-induced bronchoconstriction was inhibited by inhaled magnesium sulphate or salbutamol alone and in combination, they produced synergistic bronchoprotection. LPS-induced neutrophil influx was inhibited by 6 days pretreatment with magnesium sulphate. Early and late asthmatic responses in OVA sensitised and challenged animals were attenuated by magnesium sulphate. Lung inflammatory cells were increased by OVA, macrophages being significantly reduced by magnesium sulphate. Nebulised magnesium sulphate protects against histamine-induced bronchoconstriction in conscious guinea-pigs and exerts anti-inflammatory activity against pulmonary inflammation induced by allergen (OVA) or LPS. These properties of magnesium sulphate explain its beneficial actions in acute asthma.

Pulmonary liposomal formulations encapsulated procaterol hydrochloride by a remote loading method achieve sustained release and extended pharmacological effects

Drug inhalation provides localized drug therapy for respiratory diseases. However, the therapeutic efficacy of inhaled drugs is limited by rapid clearance from the lungs. Small hydrophilic compounds have short half-lives to systemic absorption. We developed a liposomal formulation as a sustained-release strategy for pulmonary delivery of procaterol hydrochloride (PRO), a short-acting pulmonary β2-agonist for asthma treatment. After PRO-loaded liposomes were prepared using a pH gradient (remote loading) method, 100-nm liposomes improved residence times of PRO in the lungs. PRO encapsulation efficiency and release profiles were examined by screening several liposomal formulations of lipid, cholesterol, and inner phase. Although PRO loading was not achieved using the conventional hydration method, PRO encapsulation efficiency was >60% using the pH gradient method. PRO release from liposomes was sustained for several hours depending on liposomal composition. The liposomal formulation effects on the PRO behavior in rat lungs were evaluated following pulmonary administration in vivo. Sustained PRO release was achieved using simplified egg phosphatidylcholine (EPC)/cholesterol (8/1) liposome in vitro, and greater PRO remnants were observed in rat lungs following pulmonary administration. Extended pharmacological PRO effects were observed for 120min in a histamine-induced bronchoconstriction guinea pig model. We indicated the simplified EPC/cholesterol liposome potential as a controlled-release PRO carrier for pulmonary administration.

Synthesis of 1-Substituted-4-(Pyridin-4-yl) [1,2,4] Triazolo [4,3-a] Quinazolin-5(4H)-ones as a New Class of H1- Antihistaminic Agents

Purpose : To synthesize a new series of 1-substituted-4-(pyridin-4-yl) [1,2,4] triazolo [4,3-a]quinazolin- 5(4H)-ones and evaluate them for H1-antihistaminic activity with negligible side effects in guinea pigs. Methods : The synthesized compounds were characterized by Infrared spectroscopy (IR), proton nuclear magnetic resonance ( 1 H-NMR) and mass spectrometry (MS) data. The purity of the compounds was determined by elemental analysis. The antihistaminic activity of the compounds was evaluated in guinea pigs by histamine-induced bronchoconstriction method. Results : Among the series, 1-methyl-4-(pyridin-4-yl) [1,2,4] triazolo [4,3-a] quinazolin-5(4H)-one (S5) was the most potent with 72.85 % protection and its potency was comparable to that of the reference, chlorpheniramine maleate (70.09 %). Interestingly, the sedative property of compound S5 was negligible (5.09 %) when compared to chlorpheniramine maleate (29.58 %). Conclusion : Compound S5 can serve as a lead molecule for further development into a new class of H1-antihistaminic agents. Keywords : Quinazolin-5-ones, Antihistaminic activity, Histamine, Bronchoconstriction

EVALUATION OF HELIANTHUS ANNUUS L. LEAVES EXTRACT FOR THE ANTIDIARRHEAL AND ANTIHISTAMINIC ACTIVITY

The objective of this study was to evaluate the anti diarrh eal and anti histaminic activity of ethanolic extract of the leaves of Helianthus annuus L. at the dos e of 250 mg/kg and 500 mg/kg body weight using cas tor oil induced diarrhoea and gastro intestinal transit model for anti diarrheal activity and histamine induced bronchocon striction on guinea pigs and microshock model o n rabbits for antihistaminic activity . At various doses (250 and 500mg/kg body weight), the extract showed a remarkable antioxidant activity when compared to ascorbic acid. Results also confirmed that Helianthus annuus L. decrease s the severity of diarrhoea and possess the anti - histaminic potential to treat the allergic disorders .

Discovery of AZD3199, An Inhaled Ultralong Acting β2 Receptor Agonist with Rapid Onset of Action.

A series of dibasic des-hydroxy β2 receptor agonists has been prepared and evaluated for potential as inhaled ultralong acting bronchodilators. Determination of activities at the human β-adrenoreceptors demonstrated a series of highly potent and selective β2 receptor agonists that were progressed to further study in a guinea pig histamine-induced bronchoconstriction model. Following further assessment by onset studies in guinea pig tracheal rings and human bronchial rings contracted with methacholine (guinea pigs) or carbachol (humans), duration of action studies in guinea pigs after intratracheal (i.t.) administration and further selectivity and safety profiling AZD3199 was shown to have an excellent over all profile and was progressed into clinical evaluation as a new ultralong acting inhaled β2 receptor agonist with rapid onset of action.

Bronchoprotection by Olodaterol Is Synergistically Enhanced by Tiotropium in a Guinea Pig Model of Allergic Asthma

The novel once-daily β₂-agonist bronchodilator drug olodaterol has recently been shown to be effective in patients with allergic asthma for >24 hours. An increased cholinergic tone common to these patients may decrease the effectiveness of β₂-agonists. This could provide a rationale for combination therapy with olodaterol and the long-acting anticholinergic tiotropium to aim for a once-daily treatment regimen. In guinea pigs, we evaluated the protective effects of olodaterol, alone and in combination with tiotropium, on airway responsiveness to histamine, which is partially mediated by a cholinergic reflex mechanism. In addition, using a guinea pig model of acute allergic asthma, we examined the cooperative effects of these bronchodilators on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyper-responsiveness (AHR) to histamine, and airway inflammation. It was demonstrated that the protective effect of olodaterol against histamine-induced bronchoconstriction was synergistically enhanced and prolonged in the presence of tiotropium. In addition, tiotropium synergistically augmented both the reversal of and the protection against the allergen-induced AHR after the EAR by olodaterol. Olodaterol and tiotropium were highly effective in inhibiting the magnitude of the allergen-induced EAR and LAR, and both reactions were fully inhibited by the combination of these drugs. It is remarkable that these effects were not associated with an effect on inflammatory cell infiltration in the airways. In conclusion, the results indicate that combination therapy with olodaterol and tiotropium may be highly effective in the treatment of allergen-induced asthmatic reactions and AHR.

In reply: is dexmedetomidine or remifentanil alone an optimal sedation scheme for awake intubation?

We thank Dr. Xue and coworkers for their thoughtful comments on our study. They have raised basically three questions. Firstly, they mention that there is still no optimal drug for awake intubation to meet all criteria and point out the usage of a single agent to provide sedation in our article as the main limitation of the study design. We quite agree that there is, as yet, no ideal drug. In fact, one of the purposes for our study was to find more desirable drugs to improve patients’ satisfaction during and after awake intubation. As a highly selective alpha-2 agonist, dexmedetomidine exerts sedative, analgesic and anxiolytic characteristics without respiratory depression during awake intubation. It has been reported as a sole sedative for awake fiberoptic intubation, particularly in managing critical airways [1, 2]. Remifentanil is an attractive alternative because of its analgesic, sedative and anti-tussive characteristics. The TCI mode for remifentanil makes it applicable in clinical practice [3]. We think the comparison of the two drugs’ efficacy in awake fiberoptic intubation is quite meaningful. Moreover, we used single drugs in our study considering the potential confounding influences of other agents. Secondly, they query the relatively high occurrence of coughing in our study. Dexmedetomidine is reported to blunt histamine-induced bronchoconstriction [4]. Pretreatment with a small dose of dexmedetomidine decreases sufentanil-induced coughs in anesthetic induction regardless of its sedative effect [5]. On the other hand, remifentanil’s effect on cough suppression seems to be dose dependent [6]. We administered the dosage to avoid respiratory depression in our pilot study. Although we reported the relatively high incidence of coughs in the dexmedetomidine group in our manuscript [7], most patients exhibit a slight cough of less than 2 s in reality. Thirdly, Dr. Xue suggests that dexmedetomidine has no amnestic effect. However, a previous study indeed indicated that a small dose of dexmedetomidine results in about a 50 % impairment of memory [8]. Despite remifentanil having a weaker amnestic effect, it is important to note that patients in the remifentanil group did not suffer from recall of events and this is reflected in patients’ satisfaction score.

Low Voltage Vagal Nerve Stimulation Reduces Bronchoconstriction in Guinea Pigs Through Catecholamine Release

Electrical stimulation of the vagus nerve at relatively high voltages (e.g., >10 V) can induce bronchoconstriction. However, low voltage (≤2 V) vagus nerve stimulation (VNS) can attenuate histamine-invoked bronchoconstriction. Here, we identify the mechanism for this inhibition. In urethanea-nesthetized guinea pigs, bipolar electrodes were attached to both vagus nerves and changes in pulmonary inflation pressure were recorded in response to i.v. histamine and during VNS. The attenuation of the histamine response by low-voltage VNS was then examined in the presence of pharmacologic inhibitors or nerve ligation. Low-voltage VNS attenuated histamine-induced bronchoconstriction (4.4 ± 0.3 vs. 3.2 ± 0.2 cm H(2) O, p < 0.01) and remained effective following administration of a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester, and after sympathetic nerve depletion with guanethidine, but not after the β-adrenoceptor antagonist propranolol. Nerve ligation caudal to the electrodes did not block the inhibition but cephalic nerve ligation did. Low-voltage VNS increased circulating epinephrine and norepinephrine without but not with cephalic nerve ligation. These results indicate that low-voltage VNS attenuates histamine-induced bronchoconstriction via activation of afferent nerves, resulting in a systemic increase in catecholamines likely arising from the adrenal medulla.

Phosphodiesterase inhibitors. Part 5: Hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration

(−)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti-inflammatory agent. N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition. Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition. Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics. In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress histamine-induced bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration.