Tachykinin Antagonists Research Articles

Cellular senescence-Related genes define the immune microenvironment and molecular characteristics in severe asthma patients

Recent studies have shown that cellular senescence is involved in the pathogenesis of severe asthma (SA). The objective of this study was to investigate the role of cellular senescence-related genes (CSGs) in the pathogenesis of SA. Here, 54 differentially expressed CSGs were identified in SA patients compared to healthy control individuals. Among the 54 differentially expressed CSGs, 3 CSGs (ETS2, ETS1 and AURKA) were screened using the LASSO regression analysis and logistic regression analysis to establish the CSG-based prediction model to predict severe asthma. Moreover, we found that the protein expression levels of ETS2, ETS1 and AURKA were increased in the severe asthma mouse model. Then, two distinct senescence subtypes of SA with distinct immune microenvironments and molecular biological characteristics were identified. Cluster 1 was characterized by increased infiltration of immature dendritic cells, regulatory T cells, and other cells. Cluster 2 was characterized by increased infiltration levels of eosinophils, neutrophils, and other cells. The molecular biological characteristics of Cluster 1 included aerobic respiration and oxidative phosphorylation, whereas the molecular biological characteristics of Cluster 2 included activation of the immune response and immune receptor activity. Then, we established an Random Forest model to predict the senescence subtypes of SA to guide treatment. Finally, potential drugs were searched for each senescence subgroup of SA patients via the Connectivity Map database. A peroxisome proliferator-activated receptor agonist may be a potential therapeutic drug for patients in Cluster 1, whereas a tachykinin antagonist may be a potential therapeutic drug for patients in Cluster 2. In summary, CSGs are likely involved in the pathogenesis of SA, which may lead to new therapeutic options for SA patients.

Tachykinin antagonists ameliorate surgically induced impairment of gastrointestinal motility in rats.

The protective effects of tachykinin receptor antagonists: SR140333 (NK1 receptor), SR48968 (NK2 receptor), and SB222200 (NK3 receptor) were tested in rats against a surgically induced postoperative inhibition of gut motility, a common complication of abdominal surgery. The small intestinal transit of Evans blue was measured 24-h post-surgery in untreated rats and animals subjected to skin incision, laparotomy, or laparotomy followed by gut evisceration and manipulation. Surgical procedures were conducted under diethyl ether anesthesia. In comparison to untreated and ether-anesthetized rats, animals undergoing skin incision, laparotomy, or laparotomy with gut evisceration and manipulation showed a significant decrease in the intestinal transit of Evans blue. The pretreatment with NK1 (3-100µg/kg), NK2 (3-30µg/kg), and NK3 (10-300µg/kg) blockers before surgery ameliorated the inhibitory effects of gut manipulation in a dose-dependent manner. Moreover, the submaximal and maximal doses of NK3 antagonists showed a trend toward reversing not only the inhibition caused by gut manipulation but also laparotomy. An additive effect of combining submaximal doses of NK1-3 blockers was observed in animals pretreated with NK1 +NK2 compared to single-agent NK1 and NK2 . Additionally, doublets: NK1 +NK3 or NK2 +NK3 and a triplet: NK1 +NK2 +NK3 proved to be more effective than NK2 antagonist alone. In contrast, NK1-3 blockers have not markedly affected the intestinal propulsion in untreated rats or animals subjected to skin incision or laparotomy. NK1-3 blockers ameliorated the suppressed small-bowel gut motility 24 post-surgery. Combined pretreatment with NK1-3 antagonists provided selective, additive benefits compared to single agents.

Distribution of Neurokinin 2 and 3 Receptor mRNA In the Normal Equine Gastrointestinal Tract and Effect of Inflammation on Neurokinin 1, 2, And 3 Receptor mRNA In the Equine Jejunum.

Abstract Objectives – To quantify neurokinin 2 and 3 receptor mRNA from nine regions throughout the equine intestinal tract, and to evaluate the effect of jejunal ischemia/reperfusion and intraluminal obstruction on neurokinin 1, 2, and 3 receptor mRNA. Methods – Specimens were harvested from 5 adult horses euthanized for reasons unrelated to gastrointestinal disease for the study of normal distribution of neurokinin receptor mRNA. Jejunal segments from 6 healthy adult horses subjected to intraluminal distension or ischemia/reperfusion injury were harvested to study the influence of inflammation on neurokinin 1, 2, and 3 receptor mRNA expression. RNA was isolated from normal tissues and also from tissues that underwent either a sham operation (control), 60 minutes of ischemia followed by 60 minutes of reperfusion (ISO), or 120 minutes of intraluminal distension (ILD) as part of an inflammatory model. RNA was reverse transcribed into cDNA. NK2 and NK3 primers were designed and mRNA was quantified using real-time PCR for all experimental groups. Results – Expression of NK2 receptor mRNA was highest for the duodenum and the body of the cecum. NK3 mRNA expression had high variability. In the inflammatory model, no statistical significant difference was noted between treatment groups for NK1 or NK3 receptor mRNA. NK2 receptor mRNA expression was significantly decreased for ILD when compared to control. Conclusions –The description of neurokinin receptor mRNA distribution throughout the equine intestinal tract is an important initial step towards determining potential clinical applications of tachykinin agonists and antagonists, as well as their role in gastrointestinal ischemia/reperfusion and intraluminal obstruction injury.

Original article Opioid agonist – tachykinin antagonist as a new analgesic with adjuvant anticancer properties

Opiate analgesics like morphine or fentanyl are the most widely used medicines for relieving severe acute or chronic pain, including cancer pain. Unfortunately, chronic pain treatment is associated with fast development of tolerance that creates the need to escalate the treatment doses. In addition, opiates may stimulate progression of cancer. Therefore, a new type of effective analgesic especially designed for chronic cancer pain treatment is needed. In this paper, a new opioid peptide analogue has been described as a new analgesic. The compound is characterized by very high agonist affinities to MOR and also high, but ten times lower affinity to DOR. Affinity to hNK1 as an antagonist is on the level of C-terminal hexapeptide fragment analogue of Substance P. The compound expressed reasonable antiproliferative properties toward various cancer cells. Interestingly, the peptide did not interfere with the proliferation of fibro-blasts. Therefore, the compound should be considered as a new analgesic for treatment of cancer-related pains with adjuvant anticancer properties which may support cancer treatments.

Effect of subchronic administration of tachykinin antagonists on response of guinea-pigs to mild and severe stress

The effects of subchronic subcutaneous treatment with tachykinin receptor antagonists over nine days on the repeated mild stress response induced by daily subcutaneous injections and on the severe acute stress induced by morphine withdrawal were investigated in guinea-pigs. The NK 1 receptor antagonist, L733,060, 0.25 mg/kg, significantly increased locomotor activity of guinea-pigs compared with animals subjected to repeated injection of the inactive enantiomer, but inhibited Fos-like immunoreactivity (Fos-LI) in the hypothalamus. In animals subjected to the acute severe stress of naltrexone-induced morphine withdrawal, treatment with the NK 1 antagonist, L733,060, produced reductions in Fos-LI in the spinal dorsal horn, whereas those treated with the NK 3 antagonist, SSR146,977, 0.3 mg/kg, had reduced Fos-LI in the dorsal horn, adrenal medulla, nucleus accumbens, ventral tegmental area and periaqueductal grey. Those animals treated with both NK 1 and NK 3 antagonists also had reduced Fos-LI in the amygdala and paraventricular nucleus of the thalamus. It was concluded that the NK 1 antagonist reduced the hypothalamic response to mild stress but the NK 3 antagonist was more effective in reducing the severe stress response to morphine withdrawal. Furthermore, combination of NK 1 and NK 3 antagonists was more effective than either antagonist in reducing the Fos-LI response to morphine withdrawal.

Locomotor activity and contracture of isolated ileum precipitated by naloxone following treatment of guinea-pigs with a single dose of morphine

Guinea-pigs treated with a single dose of morphine, 15 mg kg-1 s.c., exhibited an increase in locomotor activity 2 h later on injection of naloxone, 4 mg kg-1 i.p. At the same time, contracture of ileal preparations isolated from morphine-treated guinea-pigs occurred on addition of naloxone 1 microM. Contracture of the ileum was inhibited by the tachykinin antagonist, spantide, and was therefore presumably mediated by a substance P-like agent. This study has established a useful model for the parallel investigation of central and enteric nervous system mechanisms of opiate dependence.

Analysis of the mechanisms underlying the contractile response induced by the hydroalcoholic extract of Phyllanthus urinaria in the guinea-pig urinary bladder in-vitro.

The hydroalcoholic extract of Phyllanthus urinaria (Euphorbiaceae), substance P and substance P methyl ester all caused graded contractions in the guinea-pig urinary bladder. Responses to hydroalcoholic extract and substance P were markedly inhibited in calcium-free Krebs solution, this effect being reversed by reintroduction of calcium in the medium. The contraction in response to hydroalcoholic extract was unaffected by atropine, propranolol, prazosin, yohimbine, tetrodotoxin, w-conotoxin, nicardipine, HOE 140, guanethidine, staurosporine, phorbol ester or indomethacin, excluding the involvement of nervous mediated responses, or action via cholinergic, adrenergic, kinins, cyclo-oxygenase metabolites, protein kinase C or activation of L or N-type calcium channels. The selective NK1 tachykinin antagonist (FK 888), but not NK2 (SR 48968) antagonized substance P-induced contraction, but both drugs failed to effect Phyllanthus urinaria-induced contraction. Prolonged desensitization of guinea pig urinary bladder with capsaicin (10 microM) or preincubation of guinea-pig urinary bladder with capsazepine did not affect contraction caused by hydroalcoholic extract. Ruthenium red almost completely abolished capsaicin-induced contraction, but had no effect on hydroalcoholic extract-mediated contraction. Substance P and the hydroalcoholic extract caused marked potentiation of the twitch response in the preparations field stimulated. The facilitatory effect of substance P, but not that of hydroalcoholic extract, was prevented by the NK1 (FK 888), but not by NK2 (SR 48968) antagonist. We concluded that contraction induced by hydroalcoholic extract of Phyllanthus urinaria in the guinea pig urinary bladder involves direct action on smooth muscle and relies on the mobilization of extracellular calcium influx unrelated to activation of L- and N-type calcium channels or activation of protein kinase C mechanisms. In addition contraction caused by the hydroalcoholic extract of Phyllanthus urinaria in guinea-pig urinary bladder does not involve the activation of tachykinin or vanilloid receptors.

Development of new opioid agonist tachykinin antagonist chimeric compounds

Development of new opioid agonist tachykinin antagonist chimeric compounds

Opioid-substance P chimeric peptides

ABSTRACT Chimerization of tachykinin and opioid pharmacophores offers a new avenue for analgesic development. The complexities of such design are illustrated by the analgesic efficacy (via different mechanisms) of chimeras that combine pharmacophores with opioid activity and substance P activity, as well as those that combine opioid agonist and substance P antagonist moieties. Although the interaction between substance P and opioid neural systems is more complex than a simple one-way inhibition, the relative balance of activities between tachykinin and opioid pharmacophores will generally determine the net effect of the chimeric molecule as pro-nociceptive, antinociceptive, or neutral. Intriguingly, endomorphins—μ-opioid receptor agonists with high intrinsic activity—may owe some of this high activity to weak but significant antagonist proper ties at tachykinin NK2 receptors, implying that these native peptides are endogenous chimeric opioid agonist–tachykinin antagonist compounds.

Antisecretory and relaxatory effects of tachykinin antagonists in the guinea-pig intestinal tract.

Existing models used to study the mechanism of action and antagonism of tachykinergic effects on intestinal contraction and secretion suffer from technical problems and have not been fully characterized using specific tachykinin antagonists. Contraction of ileal segments by substance P, colonic circular muscle by beta-alanine-neurokinin A, and longitudinal muscle by senktide were used as models for neurokinin-induced contraction in the guinea-pig. Guinea-pig colonic epithelial tissue was stimulated by substance P and senktide to assess NK1- and NK3-mediated secretion. Using these models the potency of therapeutically useful compounds was determined. NK1 and NK2 activation directly contracted smooth muscle, while NK1-mediated secretion was nerve-mediated. NK3 stimulation of contraction and secretion was neurally mediated, involving cholinergic nerves and 5-HT release. NK1-mediated contraction and secretion were antagonized by SR140333 (pD'2 = 9.29 and pKb = 8.53); NK2-mediated contraction was antagonised by SR48968 (pD'2 = 8.35) and NK3-mediated contraction and secretion were antagonized by SB223412 (pKb = 8.97 and 8.79). The mixed antagonist MDL103392 blocked NK1- and NK2-mediated contraction with pKb values of 7.92 and 6.71 respectively and NK1-mediated secretion with a pKb value of 6.57. This data characterizes existing tachykinin antagonists, and should orientate the development of improved compounds as therapies for intestinal disease.

Electrical stimulation of the mucosa evokes slow EPSPs mediated by NK1 tachykinin receptors and by P2Y1 purinoceptors in different myenteric neurons

Slow excitatory postsynaptic potentials (EPSPs) in enteric neurons arise from diverse sources, but which neurotransmitters mediate specific types of slow EPSPs is unclear. We investigated transmitters and receptors mediating slow EPSPs in myenteric neurons evoked by electrical stimulation of the mucosa in guinea pig small intestine. Segments of ileum or jejunum were dissected to allow access to the myenteric plexus adjacent to intact mucosa, in vitro. AH and S neurons were impaled with conventional intracellular electrodes. Trains of stimuli delivered to the mucosa evoked slow EPSPs in AH neurons that were blocked or depressed by the neurokinin-1 (NK1) tachykinin antagonist SR140333 (100 nM) in 10 of 11 neurons; the NK3 tachykinin receptor antagonist SR142801 (100 nM) had no effect on slow EPSPs in seven of nine AH neurons. Single pulses to the mucosa evoked fast EPSPs and slow depolarizations in S neurons. The depolarizations were divided into intermediate (durations 300-900 ms) or slow (durations 1.3-9 s) EPSPs. The slow EPSPs were blocked by pyridoxal phosphate-6-axophenyl-2-4-disulfonic acid (30 microM, N = 3) or the specific P2Y(1) antagonist MRS 2179 (10 microM, N = 6) and were predominantly in anally projecting S neurons that were immunoreactive for nitric oxide synthase (NOS). In contrast, intermediate EPSPs were predominantly evoked in NOS-negative neurons; these were abolished by MRS 2179 (N = 8). Thus activation of pathways running from the mucosa excites three different types of slow EPSP in myenteric neurons, which are mediated by either a tachykinin (NK1, AH neurons) or a purine nucleotide (P2Y(1), S neurons).

Solid-phase synthesis of neurokinin A antagonists

During the preparation of the NK-2 selective tachykinin antagonist MEN 10208 (Thr-Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg-NH2) and its analogs by the solid-phase method employing the Boc strategy routinely used in our laboratory, we encountered difficulties in the coupling of hydrophobic amino acids D-Trp and Val. To study the coupling problems several syntheses of MEN 10208 and analogs were carried out with different activation strategies. These syntheses yielded considerable amounts of deletion sequences even though a negative Kaiser test was obtained after each coupling. Inaccessibility of the free amino group of the growing peptide due to steric hindrance of the hydrophobic residues during coupling, and for the ninhydrin complex during the Kaiser test, may account, at least in part, for the unsatisfactory synthetics results and for the false-negative ninhydrin tests. Repetition of each synthesis with the Fmoc strategy on a newly developed DOD resin for peptide amides using the DCC/HOBt chemistry gave superior results in terms of the yield and purity of the crude peptides. Therefore, the Fmoc strategy appears to offer advantages over the Boc method for the preparation of these peptides containing hydrophobic amino acids.

Inhibitory effect of the herbal antidepressant St. John’s wort (Hypericum perforatum) on rat gastric motility

St. John's wort (Hypericum perforatum) is a highly popular and effective herbal antidepressant that clinically interacts with a number of conventional drugs. Because alterations in gastric emptying can cause pharmacokinetic interactions, in the present study we evaluated the effect of a standardized extract prepared from the flowering tops of Hypericum perforatum (SJW extract) on rat gastric motility. Orally administered SJW extract delayed gastric emptying in vivo. In vitro studies showed that SJW extract was significantly more active in inhibiting acetylcholine (or prostaglandin E2)-induced contractions than electrical field stimulation (EFS)-induced contractions. The effect of SJW extract on EFS-induced contractions was unaffected by drugs that inhibit intrinsic inhibitory nerves or by tachykinin antagonists, but it was reduced by the 5-hydroxytryptamine antagonist methysergide. The inhibitory effect of SJW extract on acetylcholine-induced contractions was reduced by the sarcoplasmic reticulum Ca2+-ATPase inhibitor cyclopiazonic acid, but not by the L-type Ca2+ channel blocker nifedipine or by methysergide. Among the chemical constituents of SJW extract tested, hyperforin and, to a lesser extent, the flavonoids kaempferol and quercitrin, inhibited acetylcholine-induced contractions. It is concluded that SJW has a direct inhibitory effect on smooth muscle and could also possibly modulate gastric neurotransmission. If extended to humans, the inhibitory effect of SJW extract on gastric emptying in vivo could contribute, at least in part, to the clinical pharmacokinetic interactions between conventional medicines and this herbal antidepressant.

Tachykinin receptors in chronic inflammatory lower airway diseases

Preclinical models have highlighted the blockade of tachykinin NK1, NK2 and NK3 receptors as ideal targets for inflammatory lower airway diseases such as asthma and chronic obstructive pulmonary disease. In fact, NK1 antagonists reduce pulmonary neurogenic and non-neurogenic inflammation in several allergic and non-allergic models. Likewise, NK2 receptor antagonists have the potential to reduce airway motor responses by a local action on smooth muscle tone, by preventing airway hyperreactivity, and airway reflexes. NK3 antagonists join some properties of NK1 and NK2 receptor blockers as they are able to reduce both inflammatory and motor components in models of airway dysfunctions. Despite this evidence, early phase clinical testing of selective or mixed tachykinin antagonists have been largely disappointing. In fact, at doses selected for antagonising neurokinin A-induced bronchoconstriction, these compounds were inactive on bronchoconstriction induced by other kinds of challenge and did not reduce asthmatic symptoms or airway hyperreactivity following a brief course of treatment. The hope that these compounds could serve as disease controllers following a long-term treatment still remains, but the difficulties in the clinical testing of this hypothesis have discouraged most of the companies that have stopped development of tachykinin antagonists for these indications.

Effects of tachykinin antagonists on cholera toxin driven and distension driven intestinal secretion in rats in vivo

Effects of tachykinin antagonists on cholera toxin driven and distension driven intestinal secretion in rats in vivo

Effect of an NK1/NK2 Receptor Antagonist on Airway Responses and Inflammation to Allergen in Asthma

The tachykinins substance P and neurokinin A (NKA) are implicated in the pathophysiology of asthma. We tested the safety, tolerability, and pharmacologic and biological efficacy of a tachykinin NK(1)/NK(2) receptor antagonist, AVE5883, in patients with asthma in two double-blind, placebo-controlled crossover studies. The pharmacologic efficacy of a single inhaled dose (4.8 mg) of AVE5883 was tested against inhaled NKA in 20 patients with asthma. Subsequently, we studied the biological efficacy of the pharmacologically effective dose on inhaled allergen in a multiple-dose trial (4.8 mg three times per day, 9 d) in 12 patients with asthma with dual responses to inhaled house dust mite. On Day 8, an allergen challenge was conducted, and airway response was measured by FEV(1) until 9 hours postallergen. Exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and induced sputum were performed on Days 1, 7, and 9. AVE5883 had a bad taste, and transient bronchospasm occurred in some subjects. A single inhaled dose shifted the dose response to NKA by 1.2 doubling doses. Pretreatment with multiple doses of AVE5883 enhanced the allergen-induced early and late airway responses. There were no significant differences in the allergen-induced changes in exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and sputum cell differentials between placebo and AVE5883. Despite its demonstrated pharmacologic activity against inhaled NKA, multiple doses of AVE5883 increased the allergen-induced airway responses without affecting markers of airway hyperresponsiveness and airway inflammation. Our data question the prominent role of neurogenic inflammation in asthma and, consequently, the therapeutic potential of dual tachykinin antagonists.

Functional comparison of two evolutionary conserved insect neurokinin-like receptors

Tachykinins are multifunctional neuropeptides that have been identified in vertebrates as well as invertebrates. The C-terminal FXGXRa-motif constitutes the consensus active core region of invertebrate tachykinins. In Drosophila, two putative G protein-coupled tachykinin receptors have been cloned: DTKR and NKD. This study focuses on the functional characterization of DTKR, the Drosophila ortholog of the stable fly's tachykinin receptor (STKR). Tachykinins containing an alanine residue instead of the highly conserved glycine (FX AXRa) display partial agonism on STKR-mediated Ca 2+-responses, but not on cAMP-responses. STKR therefore seems to differentiate between a number of tachykinins. Gly- and Ala-containing tachykinins are both encoded in the Drosophila tachykinin precursor, thus raising the question of whether DTKR can also distinguish between these two tachykinin types. DTKR was activated by all Drosophila tachykinins and inhibited by tachykinin antagonists. Ala-containing analogs did not produce the remarkable activation behavior previously observed with STKR, suggesting different mechanisms of discerning ligands and/or activating effector pathways for STKR and DTKR.

Tachykinins: Role in Human Gastrointestinal Tract Physiology and Pathology

Tachykinins (TKs) and their receptors (NK1, NK2 and NK3), which are diffusely expressed in the human gastrointestinal tract, represent an endogenous modulator system regulating enteric secretomotor functions, inflammatory and immune responses, and visceral hypersensitivity, mainly during pathological gut diseases. Pathophysiological implications of TKs in the digestive tract include changes in TK innervation, in the expression of TKs and TK receptors, which result in inflammation- and immune-induced disturbances of gut functions, such as dysmotility (diarrhoea/constipation), secretory diarrhoea and visceral hyperalgesia. Increasing evidence correlates all these TKergic system abnormalities with gastrointestinal diseases of different etiology (i.e. inflammatory bowel diseases, irritable bowel syndrome). Accordingly, TK receptors have been identified as novel targets for the development of new therapeutic agents for clinical use. Available preclinical findings have shown that TK antagonists could counteract the most significant symptoms characterizing these gut diseases.

Ontogeny of excitatory and inhibitory control of gastrointestinal motility in the African clawed frog,Xenopus laevis

The transparent body wall of Xenopus laevis larvae during the first developmental stages allows in vivo studies of gastrointestinal tract activity. The purpose of this study was to chart the ontogeny of gut motility in Xenopus larvae and to identify the most important control systems during the first developmental stages. Coordinated descending contraction waves first occurred in the gut at Nieuwkoop and Faber stage 43 [0.8 +/- 0.1 contractions/min (cpm)] and increased to 4.9 +/- 0.1 cpm at stage 47. The cholinergic receptor agonist carbachol (5-10 microM) increased contraction frequency already at stage 43, as did neurokinin A (NKA, 0.3-1 microM). The muscarinic antagonist atropine (100 microM) first affected contraction frequency at stage 45, which coincides with the onset of feeding. The tachykinin antagonist MEN-10,376 (6 microM) blocked NKA-induced contractions but not spontaneous motility. Both sodium nitroprusside [nitric oxide (NO) donor, 1-10 microM] and vasoactive intestinal peptide (VIP, 0.1-1 microM) inhibited contractions from the earliest stage onward. Blocking NO synthesis using NG-nitro-L-arginine methyl ester (100 microM) had no effect per se, but antagonized VIP evoked inhibition at stage 47. We conclude that gastrointestinal motility is well developed in the Xenopus laevis larvae before the onset of feeding. Functional muscarinic and tachykinin receptors are present already at the onset of motility, whereas a cholinergic tone develops around the onset of feeding. No endogenous tachykinin tone was found. Functional VIP receptors mediate inhibition at the onset of motility. NO seems to mediate the VIP effect at later stages.

Airway mucus hypersecretion: Rationales for pharmacotherapy

Airway mucus hypersecretion is a key pathophysiological feature in many patients with asthma and chronic obstructive pulmonary disease (COPD). Consequently, it is important to develop drugs that inhibit mucus hypersecretion in these susceptible patients. Conventional therapy (anticholinergics, β2-adrenoceoptor agonists, corticosteroids, mucolytics and macrolide antibiotics) has variable efficacy in inhibiting airway mucus hypersecretion, and is less effective in COPD than in asthma. Novel pharmacotherapeutic targets are being investigated, including inhibitors of nerve activity, tachykinin antagonists, epoxygenase inducers, inhibitors of mucin exocytosis, inhibitors of mucin synthesis and goblet cell hyperplasia, inducers of goblet cell apoptosis, and purinoceptor antagonists and agonists to inhibit or hydrate secretions. However, real and theoretical differences differentiate the mucus hypersecretory phenotype in asthma from that in COPD. More information is required on these differences to identify spec...