Effects of neurokinin receptor antagonists in virus-infected airways

2000 ◽  
Vol 279 (1) ◽  
pp. L59-L65 ◽  
Author(s):  
David B. Jacoby ◽  
Bethany L. Yost ◽  
Thomas Elwood ◽  
Allison D. Fryer
Keyword(s):  
Electrical Stimulation ◽  
Receptor Antagonist ◽  
Acetylcholine Release ◽  
Parainfluenza Virus ◽  
Muscarinic Agonist ◽  
Receptor Function ◽  
Vagus Nerves ◽  
Neurokinin Receptor ◽  
Neurokinin 1 ◽  
Stimulation Of

We investigated the effects of a neurokinin-1 (NK1) receptor antagonist (SR-140333) and a NK2 receptor antagonist (SR-48968) on airway responsiveness and on the function of neuronal M2 muscarinic receptors, which normally inhibit vagal acetylcholine release, in guinea pigs infected with parainfluenza virus. Antagonists were given 1 h before infection and daily thereafter. Four days later, bronchoconstriction induced by either intravenous histamine (which is partly vagally mediated) or electrical stimulation of the vagus nerves was increased by viral infection compared with control. In addition, the ability of the muscarinic agonist pilocarpine to inhibit vagally induced bronchoconstriction was lost in virus-infected animals, demonstrating loss of neuronal M2 receptor function. Macrophage influx into the lungs was inhibited by pretreatment with both antagonists. However, only the NK1 receptor antagonist prevented M2 receptor dysfunction and inhibited hyperresponsiveness (measured as an increase in either vagally induced or histamine-induced bronchoconstriction). Thus virus-induced M2 receptor dysfunction and hyperresponsiveness are prevented by a NK1 receptor antagonist, but not by a NK2 receptor antagonist, whereas both antagonists had similar anti-inflammatory effects.

scholarly journals Dexamethasone prevents virus-induced hyperresponsiveness via multiple mechanisms

2003 ◽  
Vol 285 (2) ◽  
pp. L451-L455 ◽  
Author(s):  
Liliana Moreno ◽  
David B. Jacoby ◽  
Allison D. Fryer
Keyword(s):  
Virus Infection ◽  
Airway Hyperresponsiveness ◽  
Low Dose ◽  
Acetylcholine Release ◽  
Parainfluenza Virus ◽  
High Dose ◽  
Muscarinic Agonist ◽  
Receptor Function ◽  
Parasympathetic Nerves ◽  
High Dose Dexamethasone

In the lungs, neuronal M2 muscarinic receptors inhibit acetylcholine release from the parasympathetic nerves. Parainfluenza virus infection causes loss of M2 receptor function, which increases acetylcholine release and vagally mediated bronchoconstriction. Because glucocorticoids are known to inhibit airway hyperresponsiveness, we tested whether dexamethasone (6.5 or 65 μg/kg ip) prevents virus-induced hyperresponsiveness and M2 receptor dysfunction in guinea pigs. In controls, pilocarpine, a muscarinic agonist, inhibited vagally induced bronchoconstriction, demonstrating functional M2 receptors. However, in virus-infected animals, pilocarpine failed to inhibit vagally induced bronchoconstriction, demonstrating M2 receptor dysfunction. Frequency-dependent bronchoconstriction was greater in virus-infected animals than in controls, indicating airway hyperresponsiveness. Low-dose dexamethasone (6.5 μg/kg ip) treatment prevented virus-induced airway hyperresponsiveness, ameliorated M2 receptor dysfunction, and decreased viral content in the lungs without inhibiting virus induced inflammation. High-dose dexamethasone (65 μg/kg ip) prevented virus-induced hyperresponsiveness, completely reversed M2 receptor dysfunction, decreased viral titers, and decreased virus-induced inflammation. This high-dose dexamethasone also increased M2 receptor function in uninfected animals. In conclusion, dexamethasone prevented virus-induced hyperresponsiveness and M2 receptor dysfunction via multiple mechanisms.

Muscarinic Agonist–Induced Burst Firing in Immature Rat Olfactory Cortex Neurons In Vitro

1998 ◽  
Vol 79 (4) ◽  
pp. 2003-2012 ◽  
Author(s):  
M. Postlethwaite ◽  
A. Constanti ◽  
V. Libri
Keyword(s):  
Electrical Stimulation ◽  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Epileptiform Activity ◽  
Nmda Receptor Antagonist ◽  
Olfactory Cortex ◽  
Muscarinic Agonist ◽  
Immature Rat ◽  
Stimulation Of

Postlethwaite, M., A. Constanti, and V. Libri. Muscarinic agonist–induced burst firing in immature rat olfactory cortex neurons in vitro. J. Neurophysiol. 79: 2003–2012, 1998. Age-related changes in pre-/postsynaptic muscarinic (mAChR) and metabotropic-glutamate (mGluR) responsiveness were studied in slices of olfactory cortex from both immature [postnatal day 16–22 ( P16–P22)] and adult (≥P40) rats, using a conventional intracellular recording technique. In adult neurons, bath application of the mAChR agonist oxotremorine-M (OXO-M; 10 μM), or the selective mGluR agonist 1-aminocyclopentane-1S-3R-dicarboxylic acid (1S,3R-ACPD; 10 μM) evoked sustained membrane depolarizations, increases in input resistance, intense repetitive firing, and the appearance of a slow poststimulus afterdepolarizing potential (sADP). Excitatory postsynaptic potentials (EPSPs) evoked by local electrical stimulation of association fiber terminals were also depressed. In contrast, in neurons from immature slices, the 10 μM OXO-M–induced membrane depolarization was followed by the appearance of spontaneous rhythmic epileptiform activity, which was voltage independent and reversible on drug wash out. Epileptiform bursts were abolished or reduced by coapplication of tetrodotoxin (1 μM), atropine (1 μM), pirenzepine (100–200 nM), the N-methyl-d-aspartate (NMDA) receptor antagonist dl-amino-5-phosphonovaleric acid (dl-APV; 100 μM), the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 5–20 μM), the anesthetic-sedative barbiturate pentobarbitone (100 μM), or by raising the extracellular Mg2+ concentration, whereas a clear facilitatory effect was exhibited by the selective γ-aminobutyric acid-A (GABAA) receptor blocker (−)-bicuculline methiodide (10 μM). The epileptogenic effects induced by OXO-M were indistinguishable from those produced by 4-aminopyridine (4-AP; 100–200 μM), although these latter actions were unaffected by atropine. In slices from immature animals, electrical stimulation of layer III association fibers in the presence of 10 μM OXO-M was accompanied by a dramatic prolongation of evoked depolarizing postsynaptic potentials (PSPs), with the appearance of recurrent superimposed spike discharges. This effect was readily reversed on wash out of OXO-M. No comparable age-dependent differences were observed in the nature or time course of 1S,3R-ACPD–evoked pre- (or post)synaptic responses, even in immature cells where muscarinic epileptiform activity had previously been demonstrated. We suggest that the overall susceptibility toward muscarinic-induced epileptiform discharge in immature olfactory cortical neurons may depend on the functional integrity of presynaptic inhibitory mAChRs; additional contributing mechanisms were also considered.

Presynaptic modulation of acetylcholine release from cardiac parasympathetic neurons

1985 ◽  
Vol 248 (1) ◽  
pp. H33-H39 ◽  
Author(s):  
G. T. Wetzel ◽  
J. H. Brown
Keyword(s):  
Receptor Antagonist ◽  
Adrenergic Receptor ◽  
Acetylcholine Release ◽  
Electrical Field Stimulation ◽  
Inhibitory Effect ◽  
Muscarinic Agonist ◽  
Parasympathetic Nerve ◽  
Presynaptic Modulation ◽  
Rat Atria ◽  
Alpha Adrenergic Receptors

Acetylcholine can be released from parasympathetic nerve endings in rat atria by 57 mM K+ depolarization or by electrical field stimulation. We have studied the presynaptic modulation of [3H]acetylcholine release from superfused rat atria prelabeled with [3H]choline. Exogenous acetylcholine and the specific muscarinic agonist oxotremorine inhibit the stimulation-induced overflow of [3H]acetylcholine into the superfusion medium. The half-maximal inhibitory concentration (IC50) of oxotremorine is 0.3 microM. The cholinesterase inhibitor neostigmine also decreases K+-stimulated [3H]acetylcholine overflow, whereas the muscarinic antagonist atropine enhances the overflow of [3H]acetylcholine. These data suggest that acetylcholine release in atria is modulated through negative feedback by the endogenous transmitter. The sympathetic adrenergic neurotransmitter norepinephrine and the neurohormone epinephrine also inhibit the overflow of [3H]acetylcholine by approximately 60%. The IC50 values for the inhibitory effects of these catecholamines are 6.3 and 2.2 microM, respectively. The inhibitory effect of norepinephrine is blocked by the alpha-adrenergic receptor antagonist yohimbine but not by the beta-adrenergic receptor antagonist propranolol. We suggest that presynaptic muscarinic and alpha-adrenergic receptors participate in the physiological and pharmacological control of cardiac parasympathetic activity.

Excitatory amino acid receptors within NTS mediate arterial chemoreceptor reflexes in rats

1993 ◽  
Vol 265 (2) ◽  
pp. H770-H773 ◽  
Author(s):  
W. Zhang ◽  
S. W. Mifflin
Keyword(s):  
Electrical Stimulation ◽  
Amino Acid ◽  
Receptor Antagonist ◽  
Carotid Body ◽  
Excitatory Amino Acid ◽  
Pressor Responses ◽  
Carotid Body Chemoreceptors ◽  
Arterial Chemoreceptor ◽  
Stimulation Of ◽  
Arterial Baroreceptor

The nucleus tractus solitarius (NTS) is the primary site of termination of arterial baroreceptor and chemoreceptor afferent fibers. Excitatory amino acid (EAA) receptors within NTS have been shown to play an important role in the mediation of arterial baroreceptor reflexes; however, the importance of EAA receptors within NTS in the mediation of arterial chemoreceptor reflexes remains controversial. Therefore, in chloralose-urethan-anesthetized, mechanically ventilated, paralyzed rats, 4 nmol of the broad-spectrum EAA receptor antagonist kynurenic acid (Kyn) was injected into the NTS to observe the effects of EAA receptor blockade on the pressor responses evoked by either activation of ipsilateral carotid body chemoreceptors (by close arterial injection of CO2-saturated bicarbonate) or electrical stimulation of ipsilateral carotid sinus nerve (CSN). Under control conditions, activation of carotid body chemoreceptors and CSN stimulation evoked increases in arterial pressure of 27 +/- 2 (n = 24 sites) and 28 +/- 3% (n = 8), respectively. Kyn microinjection into NTS significantly reduced the pressor responses evoked by activation of carotid body chemoreceptors and electrical stimulation of the CSN for 20 and 25 min, respectively. Attenuation of pressor responses evoked by chemoreceptor activation were maximal at 20 min post-Kyn injection (13 +/- 2%), whereas CSN-evoked pressor responses were maximally attenuated at 15 min (6 +/- 4%). Microinjection into NTS of 4 nmol of xanthurenic acid, a structural analogue of Kyn with no EAA receptor antagonist properties, had no effect on chemoreceptor reflexes. We conclude that EAA receptors within NTS play an important role in the mediation of arterial chemoreceptor reflexes.

Ozone-induced airway hyperresponsiveness and loss of neuronal M2 muscarinic receptor function

1994 ◽  
Vol 76 (3) ◽  
pp. 1088-1097 ◽  
Author(s):  
A. H. Schultheis ◽  
D. J. Bassett ◽  
A. D. Fryer
Keyword(s):  
Muscarinic Receptor ◽  
Muscarinic Receptors ◽  
Ozone Exposure ◽  
Muscarinic Agonist ◽  
Receptor Function ◽  
Vagus Nerves ◽  
Parasympathetic Nerves ◽  
M2 Muscarinic Receptor ◽  
Release Of Acetylcholine ◽  
M2 Muscarinic Receptors

The effect of acute ozone exposure on the function of efferent parasympathetic nerves, M3 muscarinic receptors on airway smooth muscle, and inhibitory M2 muscarinic receptors on the parasympathetic nerves was studied. Immediately after exposure to 2.0 ppm ozone for 4 h, guinea pigs became hyperresponsive to electrical stimulation of the vagus nerves. The normal airway response to intravenous cholinergic agonists at this time demonstrates normal M3 receptor function. M2 muscarinic receptors on the nerves, which normally inhibit release of acetylcholine, were dysfunctional after ozone exposure, as demonstrated by the failure of the muscarinic agonist pilocarpine to inhibit, and the failure of the M2 antagonist gallamine to potentiate, vagally mediated bronchoconstriction. Thus, loss of inhibitory M2 muscarinic receptor function after ozone exposure potentiates release of acetylcholine from the vagus nerves, increasing vagally mediated bronchoconstriction. By 14 days, postozone responses to vagal nerve stimulation were not different from those of air-exposed animals and the function of the neuronal M2 muscarinic receptor was normal, confirming that ozone-induced hyperresponsiveness is reversible.

Effect of maropitant, a neurokinin 1 receptor antagonist, on anesthetic requirements during noxious visceral stimulation of the ovary in dogs

2011 ◽  
Vol 72 (12) ◽  
pp. 1576-1579 ◽  
Author(s):  
Pedro Boscan ◽  
Eric Monnet ◽  
Khursheed Mama ◽  
David C. Twedt ◽  
Jonathan Congdon ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Neurokinin 1 Receptor ◽  
Neurokinin 1 ◽  
Stimulation Of

Effects of WAY100635, a selective 5-HT1A-receptor antagonist on the micturition-reflex pathway in the rat

2001 ◽  
Vol 280 (5) ◽  
pp. R1407-R1413 ◽  
Author(s):  
Hidehiro Kakizaki ◽  
Mitsuharu Yoshiyama ◽  
Tomohiko Koyanagi ◽  
William C. De Groat
Keyword(s):  
Spinal Cord ◽  
Electrical Stimulation ◽  
Receptor Antagonist ◽  
Intrathecal Injection ◽  
Cervical Cord ◽  
Dependent Manner ◽  
Reflex Pathway ◽  
Micturition Reflex ◽  
Female Wistar Rats ◽  
Stimulation Of

5-Hydroxytryptamine (5-HT) receptors in the central nervous system have been implicated in the control of micturition. The present study was undertaken to evaluate the effects of a selective 5-HT1A-receptor antagonist { N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635)} on the micturition-reflex pathway in urethane-anesthetized female Wistar rats. Rhythmic isovolumetric bladder contractions evoked by bladder distension were abolished by 0.3- to 3-mg/kg iv or 30- to 100-μg intrathecal (it) administration of WAY100635 in a dose-dependent manner for periods of 3–15 min. Intrathecal injection of WAY100635 was effective only if injected at the L6-S1 spinal cord level, but not at the thoracic or cervical cord levels. WAY100635 (30–100 μg it) significantly reduced the amplitude of bladder contractions evoked by electrical stimulation of the pontine micturition center. However, the field potentials in the rostral pons evoked by electrical stimulation of pelvic nerve were not affected by intrathecal or intravenous injection of WAY100635. These results suggest that 5-HT1A receptors at the L6-S1 level of the spinal cord have an important role in the tonic control of the descending limb of the micturition-reflex pathway in the rat.

scholarly journals Innervation of enteric mast cells by primary spinal afferents in guinea pig and human small intestine

2014 ◽  
Vol 307 (7) ◽  
pp. G719-G731 ◽  
Author(s):  
Guo-Du Wang ◽  
Xi-Yu Wang ◽  
Sumei Liu ◽  
Meihua Qu ◽  
Yun Xia ◽  
...  
Keyword(s):  
Nervous System ◽  
Mast Cell ◽  
Small Intestine ◽  
Electrical Stimulation ◽  
Mast Cells ◽  
Guinea Pig ◽  
Mast Cell Protease ◽  
Human Small Intestine ◽  
Neurokinin 1 ◽  
Stimulation Of

Mast cells express the substance P (SP) neurokinin 1 receptor and the calcitonin gene-related peptide (CGRP) receptor in guinea pig and human small intestine. Enzyme-linked immunoassay showed that activation of intramural afferents by antidromic electrical stimulation or by capsaicin released SP and CGRP from human and guinea pig intestinal segments. Electrical stimulation of the afferents evoked slow excitatory postsynaptic potentials (EPSPs) in the enteric nervous system. The slow EPSPs were mediated by tachykinin neurokinin 1 and CGRP receptors. Capsaicin evoked slow EPSP-like responses that were suppressed by antagonists for protease-activated receptor 2. Afferent stimulation evoked slow EPSP-like excitation that was suppressed by mast cell-stabilizing drugs. Histamine and mast cell protease II were released by 1) exposure to SP or CGRP, 2) capsaicin, 3) compound 48/80, 4) elevation of mast cell Ca2+ by ionophore A23187, and 5) antidromic electrical stimulation of afferents. The mast cell stabilizers cromolyn and doxantrazole suppressed release of protease II and histamine when evoked by SP, CGRP, capsaicin, A23187, electrical stimulation of afferents, or compound 48/80. Neural blockade by tetrodotoxin prevented mast cell protease II release in response to antidromic electrical stimulation of mesenteric afferents. The results support a hypothesis that afferent innervation of enteric mast cells releases histamine and mast cell protease II, both of which are known to act in a diffuse paracrine manner to influence the behavior of enteric nervous system neurons and to elevate the sensitivity of spinal afferent terminals.

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