ABSTRACT
Non-adrenergic non-cholinergic (NANC) nerves release bronchoactive tachykinins such as substance P (SP) and neurokinin A (NKA) that can induce features of asthma. The airway response to NKA in humans closely resembles that of methacholine (M). Hence, we investigated the relationship between airway responsiveness to NKA and M in subjects with asthma. To this end, we analyzed baseline data of 27 subjects with mild persistent asthma (20F/7M) 19-46 y; FEV1 81-136% pred.; PC20FEV1 (M)<80 micromol/mL) participating in a proof-of-concept study. All subjects were non-smokers and asthma was controlled by on demand short-acting beta2-agonists only. Dose-response curves to M (0.15-80 micromol/mL) and NKA (3.4 (10(-3))-0.88 micromol/mL) were performed on two separate days, and airway response was measured by FEV1 until a > or = 20% fall from baseline (PC20FEV1). Twenty-two subjects reached a PC20FEV1 on both occasions. The PC20FEV1 values of both agonists correlated significantly (Spearman's r=-0.721; p=0.0002), and the relationship was given by 10log(PC20FEV1(NKA))= -1.36 + (0.60 x 10log(PC20FEV1(M)). We have demonstrated a significant relationship between airway responsiveness to NKA and methacholine in asthma. This suggests that both agonists may share common final pathways in causing bronchoconstriction in patients with mild persistent asthma. Based on our data and previous studies in asthma, it can be hypothesized that this direct NKA-induced bronchoconstrictor response may be mediated by predominant stimulation of the tachykinin NK-2 receptors on airway smooth muscle cells.
Subject(s)
Asthma/chemically induced , Bronchoconstrictor Agents/adverse effects , Methacholine Chloride/adverse effects , Neurokinin A/adverse effects , Adult , Bronchial Provocation Tests , Female , Humans , Male , Middle Aged , Respiratory Function TestsABSTRACT
Inhalation of neurokinin A (NKA) causes bronchoconstriction in patients with asthma. In vitro both tachykinin NK1 and NK2 receptors can mediate airway contraction. In this study the authors examined the effects of a single dose of the dual tachykinin NK1/NK2 receptor antagonist, DNK333, on NKA-induced bronchoconstriction in asthma. A total of 19 male adults with mild asthma completed a randomised, double-blind, placebo-controlled crossover trial. Increasing concentrations of NKA (3.3x10(-9) to 1.0x10(-6) mol x mLP(-1)) were inhaled at 1 and 10 h intervals after a single oral dosing with either DNK333 (100 mg) or a placebo. It was observed that DNK333 did not affect baseline lung function but did protect against NKA-induced bronchoconstriction in those patients. The mean log10 provocative concentration causing a 20% fall in forced expiratory volume in one second for NKA was -5.6 log10 mol x mL(-1) at 1 h after DNK333 treatment and -6.8 log10 mol x mL(-1) after placebo. This was equivalent to a difference of 4.08 doubling doses, which decreased to a difference of 0.90 doubling doses 10 h after treatment. The results shown in this report indicate that DNK333 blocks neurokinin A-induced bronchoconstriction in patients with asthma.
Subject(s)
Asthma/physiopathology , Aza Compounds/pharmacology , Benzamides/pharmacology , Bronchoconstriction/drug effects , Neurokinin A/adverse effects , Receptors, Tachykinin/antagonists & inhibitors , Administration, Inhalation , Adolescent , Adult , Aza Compounds/administration & dosage , Aza Compounds/pharmacokinetics , Benzamides/administration & dosage , Benzamides/pharmacokinetics , Cross-Over Studies , Double-Blind Method , Humans , Middle Aged , Neurokinin A/administration & dosageABSTRACT
1. MEN 11420 (nepadutant) is a potent, selective and competitive antagonist of tachykinin NK2 receptors. 2. The objective of the present study was to assess the capability of the drug to antagonize the stimulatory effects of neurokinin A (NKA) on gastrointestinal motility, as well as to change the fasting migrating motor complex (MMC). 3. Thirty-four male volunteers were randomized to treatment with either placebo or MEN 11420 in a double-blinded manner. Effects of MEN 11420 (8 mg intravenously) were evaluated as changes in phases I, II and III of MMC, as well as contraction frequency, amplitude and motility index during baseline conditions and during stimulation of motility using NKA (25 pmol kg(-1) min(-1) intravenously). 4. NKA preceded by placebo increased the fraction of time occupied by phase II, increased contraction frequency, amplitude and motility index. 5. MEN 11420 effectively antagonized the motility-stimulating effects of NKA. MEN 11420 reduced the phase II-stimulating effect of NKA. In addition, the stimulatory effect of NKA on contraction frequency and amplitude, as well as motility index were inhibited by MEN 11420. MEN 11420 did not affect the characteristics of MMC during saline infusion. 6. Plasma levels of MEN 11420 peaked during the first hour after infusion and decreased to less than half during the first 2 h. 7. In conclusion, intravenous MEN 11420 effectively inhibited NKA-stimulated, but not basal gastrointestinal motility, and was well tolerated by all subjects.
Subject(s)
Gastrointestinal Motility/drug effects , Intestine, Small/drug effects , Neurokinin A/pharmacology , Peptides, Cyclic/pharmacology , Receptors, Neurokinin-2/antagonists & inhibitors , Abdominal Pain/chemically induced , Adolescent , Adult , Double-Blind Method , Flushing/chemically induced , Headache/chemically induced , Humans , Infusions, Intravenous , Intestine, Small/physiology , Male , Middle Aged , Muscle Contraction/drug effects , Myoelectric Complex, Migrating/drug effects , Nausea/chemically induced , Neurokinin A/adverse effects , Neurokinin A/blood , Peptides, Cyclic/adverse effects , Peptides, Cyclic/blood , Receptors, Neurokinin-2/physiology , Sodium Chloride/pharmacology , Time Factors , Vomiting/chemically inducedABSTRACT
The purposes of the present study were i) to determine whether neuropeptides induce the nasal obstruction in guinea pigs, and ii) to examine the possible involvement of neuropeptides in allergic nasal obstruction. The decrease in nasal cavity volume was determined by acoustic rhinometry as an index of nasal obstruction. In non-sensitized guinea pigs, substance P (SP), neurokinin A (NKA) and calcitonin gene-related peptide (CGRP) caused the nasal obstruction 10 to 30 min after their intranasal application. LY303870 (1 mg/kg), a tachykinin NK1-receptor antagonist; SR48968 (1 mg/kg), a tackykinin NK2-receptor antagonist; and CGRP(8-37) (50 nmol/kg), a CGRP1-receptor antagonist, administered intravenously before the intranasal application of the neuropeptides, inhibited the responses induced by SP, NKA and CGRP, respectively. In the guinea pigs sensitized with dinitrophenyl-coupled Ascaris suum allergenic extract, the intranasal antigen challenge caused nasal obstruction. The response was biphasic and consisted of the early phase response (EPR) and the late phase response (LPR), which developed 30 min and 6 h, respectively, after the antigen challenge. Intravenous administration of LY303870 (1 mg/kg) before the antigen challenge inhibited the EPR, while those of SR48968 (1 mg/kg) and CGRP(8-37) (50 nmol/kg) inhibited the LPR. The present results suggest that neuropeptides are involved in the allergic nasal obstruction.