1 Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis, Davis, California 95616; and 2 Division of Clinical Immunology, Department of Medicine, The Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland 21224
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ABSTRACT |
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In vitro antigen challenge has multiple
effects on the excitability of guinea pig bronchial parasympathetic
ganglion neurons, including depolarization, causing phasic neurons to
fire with a repetitive action potential pattern and potentiating
synaptic transmission. In the present study, guinea pigs were passively sensitized to the antigen ovalbumin. After sensitization, the bronchi were prepared for in vitro electrophysiological
intracellular recording of parasympathetic ganglia neurons to
investigate the contribution of cyclooxygenase activation and
prostanoids on parasympathetic nerve activity. Cyclooxygenase
inhibition with either indomethacin or piroxicam before in vitro
antigen challenge blocked the change in accommodation. These
cyclooxygenase inhibitors also blocked the release of prostaglandin
D2 (PGD2) from bronchial tissue during antigen
challenge. We also determined that PGE2 and
PGD2 decreased the duration of the action potential after
hyperpolarization, whereas PGF2 potentiated synaptic
transmission. Thus prostaglandins released during antigen challenge
have multiple effects on the excitability of guinea pig bronchial
parasympathetic ganglia neurons, which may consequently affect the
output from these neurons and thereby alter parasympathetic tone in the
lower airways.
asthma; bronchoconstriction; synaptic transmission; ganglia; guinea pig
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INTRODUCTION |
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PREVIOUS STUDIES using the guinea pig bronchus isolated from ovalbumin-sensitized animals demonstrated that mast cells surrounding airway parasympathetic ganglia degranulate on allergen challenge. Concomitant with this response are several changes in the electrophysiological properties of principal neurons within the airway parasympathetic ganglia (14). The electrophysiological changes caused by allergen exposure are consistent with an overall increase in the efficacy of synaptic transmission (19). These changes would likely lead to substantial decrease in the amount of preganglionic input airway parasympathetic ganglia neurons can filter, first demonstrated by Mitchell and colleagues (8), and thus a generalized increase in parasympathetic tone in the airway. The electrophysiological effects of antigen exposure include membrane depolarization, changes in input resistance, a substantial decrease in action potential accommodation (the neurons generate more action potentials during prolonged excitatory membrane stimulation) (14), and an increase in synaptic transmission (19).
It is likely that the effect of antigen challenge on parasympathetic ganglion neurons is secondary to the actions of autacoids released from mast cells (12, 14) and perhaps other inflammatory cells (1) in the airway wall. Exposing the isolated guinea pig airway to the sensitizing antigen leads to the release of classic mast cell mediators such as histamine, cysteinyl leukotrienes, and prostaglandin D2 (PGD2) (20). In addition, these mediators can act on other cell types in the airways, resulting in a cascade of autacoid release that includes all of the prostanoids (20). Among these mediators, histamine was found to mimic the effect of antigen challenge on membrane depolarization (14), confirmed by inhibition of the antigen-induced responses following H1 receptor antagonism (12); histamine had no effect on active membrane properties. Cysteinyl leukotriene exposure had little effect on the electrophysiological properties of bronchial ganglion neurons (14). In the present study, we address the hypothesis that cyclooxygenase (COX) activation and consequent prostanoid formation contributes significantly to antigen-induced increases in excitability of bronchial parasympathetic neurons.
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METHODS |
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The methods for animal sensitization and euthanasia were approved by the Johns Hopkins Animal Care and Use Committee, The Johns Hopkins University (Baltimore, MD).
Passive and active sensitization. Male albino guinea pigs (Dunkin-Hartley), weighing 150-200 g, were actively or passively sensitized for specific antigen challenge according to a protocol previously described (18). Briefly, actively sensitized animals received intraperitoneal injections of ovalbumin (OVA; 10 mg/kg) on days 1, 3, and 5 and were killed by carbon dioxide asphyxiation and exsanguination 21-41 days after the last injection, and serum was collected from these animals. Each passively sensitized animal (150-200 g) received an intraperitoneal injection (1 ml/kg) of serum rich in antibodies directed against OVA (from actively sensitized animals) 1-2 days before the animal was killed. "Serum control" refers to guinea pigs treated with serum from age-matched, nonallergic guinea pigs. Otherwise, "control" refers to preantigen challenge or vehicle response in tissue from sensitized animals.
Tissue preparation. Passively sensitized guinea pigs were killed by a sharp blow to the head and exsanguinated. The thorax was opened, and the lungs, bronchi, and trachea were removed and placed in Krebs bicarbonate buffer (composition in mM: 118 NaCl, 5.4 KCl, 1.0 MgSO4, 1.9 CaCl2, 1.0 NaH2PO4, 25 NaHCO3, and 11.1 dextrose) maintained at room temperature (20-23°C) and equilibrated with 95% O2-5% CO2, pH 7.4.
The methods for tissue preparation and ganglia location have been recently described (10). Briefly, the right bronchus was isolated from the trachea and lung parenchyma, cut along the ventral surface, and opened as a sheet. The bronchus was transferred and pinned with minuten pins, as a sheet, to the Sylgard-covered floor of a recording chamber (0.1-ml vol). With the use of transmitted light, ganglia were located on the serosal surface of the right primary bronchus without the aid of staining. The tissue was continuously superfused with Krebs bicarbonate buffer (36-37°C, 5-8 ml/min) and equilibrated for at least 60 min before experimentation. To verify whether the animal had been sensitized, tracheal rings were connected to a force transducer and similarly equilibrated in an organ bath; the bronchi were used only if the tracheal rings contracted in the presence of OVA (10 µg/ml) to a level >50% of maximal contraction.Electrophysiological methods.
Intracellular micropipettes were fabricated from thick-walled
borosilicate capillary stock (0.5-mm inside diameter, 1.0-mm outside
diameter; World Precision Instruments, Sarasota, FL) by a
Brown-Flaming microelectrode puller (P-87; Sutter Instruments, San
Rafael, CA). Electrodes were filled with an electrolyte solution of 3 M
KCl (pH 7.4). The micropipettes were connected by an Ag-AgCl wire in an
electrode holder (Axon Instruments, Foster City, CA) to an electrometer
(Axoclamp 2A; Axon Instruments), and an Ag-AgCl pellet in the bath was
connected to the headstage ground. The electrode direct current
resistance in Krebs solution was 60 M. Impalement of the neurons was
aided by a brief 40-50-ms overcompensation (i.e., buzz) of the
capacitance neutralization circuit of the amplifier. The delivery of
constant-current pulses through the microelectrode was controlled by a
computer (Apple Macintosh; Apple Computer, Cupertino, CA) equipped with
an analog-to-digital translation interface. Recorded intracellular
membrane voltage properties were displayed online with a chart recorder
and an oscilloscope-simulation/data storage program (AxoData; Axon
Instruments) and later analyzed with the AxoGraph program (Axon Instruments).
Antigen responses. The effect of bath-applied OVA (10 µg/ml) on active and synaptic membrane properties of bronchial parasympathetic ganglion neurons from serum control and sensitized animals was studied. The concentration of OVA chosen has previously been shown to cause optimal mast cell degranulation in guinea pig bronchi (18) and to be the lowest concentration that consistently depolarizes bronchial parasympathetic ganglion neurons in actively and passively sensitized guinea pigs (12, 14). OVA was perfused directly over the parasympathetic ganglion preparation for 2-4 min, a period of time previously reported to produce peak responses after drug application (11); if histamine receptor antagonists were not used, the neurons depolarized, and then current clamped to the pre-OVA resting membrane potential before measurement of action and synaptic potentials. The effect of antigen application on active membrane properties, such as action potential AHP amplitude and duration, were monitored. During antigen or prostaglandin application, the amplitudes of 50 consecutive fEPSPs were recorded and averaged. In time control studies, fEPSP amplitudes did not vary significantly over the periods used at these frequencies. For fEPSP experiments, the histamine H1 receptor antagonist pyrilamine (1 µM), histamine H2 and H3 receptor antagonists burimamide (30 µM) and atropine (0.1 µM) were added to the Krebs buffer at least 1 h before experimentation. A single neuron from each animal was used for antigen challenge. The effects of OVA on sensitized tissue was studied in the presence of COX inhibitors piroxicam (0.05 µM) or indomethacin (3.0 µM).
Prostaglandin release measurements. The right and left bronchi were isolated from passively sensitized guinea pigs and placed in Krebs buffer solution. The buffer solution was maintained at 37°C and gassed with 95% O2 and 5% CO2. The left and right bronchi were divided into four equal rings and placed in tubes containing Krebs buffer solution (2.5 ml); thus each tube contained one section from each bronchus. The buffer bathing the tissue was replaced with fresh solution at 15-min intervals for 90 min. After this period of equilibration, the tissue was incubated in 2.5 ml of either Krebs buffer or Krebs buffer containing piroxicam (0.05 µM) or indomethacin (3.0 µM) for an additional 30 min, after which a 100-µl sample was taken to determine the quantities of prostaglandins released spontaneously before OVA challenge. The tissues were then treated with OVA (10 µg/ml) in the presence or absence of COX inhibitors for 15 min, at the end of which a 100-µl sample was collected for analysis.
Prostaglandin release was assayed using combined gas chromatography-electron capture mass spectrophotometry (GC/MS) as previously described (3). Briefly, a 100-µl aliquot of sample was added to 300 µl of acetone in a silanized vial. A mixture of a known quantity (0.1 ng) of 3,3,4,4,-tetradeuterated PGE2, PGD2, PGF2Materials.
QX-314 was purchased from Alomone Labs (Jerusalem, Israel). Reagents
used to prepare the Krebs solution were purchased from J. T. Baker
Chemicals (Phillipsburg, NJ). All remaining reagents were purchased
from Sigma (St. Louis, MO). At the dilutions used (1:10,000) in these
studies, dimethyl sulfoxide (piroxicam), ethanol (prostaglandins,
indomethacin), or distilled water (atropine, pyrilamine, burimamide,
OVA) had no effect on the active or passive properties of
parasympathetic ganglion neurons. Final dilutions of all drugs were
made in Krebs buffer solution.
Data analysis. All data are expressed as the arithmetic means ± SE. Control values for resting membrane potential, membrane Ri, cumulative AHP duration, and amplitude were noted before each drug application. These values were compared with peak changes evoked by antigen challenge or drug application using one-way ANOVA, followed by Student's t-test. Peak changes evoked by antigen with and without COX inhibitors were compared using unpaired analysis. Statistical tests were performed using Statview statistics program (Abacus Concepts, Lafayette, CA). Statistical significance was accepted at the 0.05 level of probability (P).
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RESULTS |
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Exposing bronchi isolated from passively sensitized guinea pigs to
OVA resulted in the production and release of each of all prostaglandins measured with the exception of PGF2
(Table 1). OVA caused a 10- to 20-fold
increase in the production of PGD2 and thromboxanes and an
approximate threefold increase in PGE2 and PGI2
(measured as the metabolite, 6-keto-PGF2). As expected, indomethacin significantly inhibited the antigen-induced increase in
prostaglandin release from the bronchus (Table 1).
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OVA inhibited action potential accommodation in bronchial
ganglion neurons, and this antigen-induced effect was blocked by indomethacin. In phasic neurons, a prolonged, suprathreshold
depolarizing pulse (500 ms, 1.0 nA) elicited 3 ± 0.2 (n = 12) action potentials, followed by accommodation
to the stimulus (Fig. 1A).
After antigen challenge (OVA, 10 µg/ml, 5 min), the same
neurons elicited a greater than sixfold increase in the number of
action potentials to the same stimulus (Fig. 1B;
n = 12, P = 0.01), an effect that does
not reverse during washout of OVA (lasting 40.3 ± 10.4 min; n = 12). In the presence of indomethacin (3 µM),
antigen challenge (OVA, 10 µg/ml) had no effect on accommodation
eliciting 5 ± 2 action potentials [P = 0.4 compared with control (pre-OVA) response, n = 8; Fig.
1C]. In phasic neurons from control animals (injected with
regular serum), OVA (10 µg/ml) had no effect on accommodation properties (P = 0.8; n = 6). For the
afterhyperpolarization duration following single or multiple action
potentials, we recorded either no change in some neurons
(n = 4) or a decrease of 21 or 37% (after 4 action
potentials at 25 Hz) in the remaining cells after antigen challenge
(P = 0.1, n = 6).
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We determined whether another COX inhibitor, piroxicam, structurally unrelated to indomethacin, would also inhibit antigen-induced inhibition of accommodation. Piroxicam (0.05 µM) effectively inhibited OVA-induced production of prostaglandins in bronchial tissue (Table 1). Piroxicam mimicked the effects of indomethacin on antigen-induced changes in action potential accommodation. In the presence of piroxicam (0.05 µM), antigen challenge (OVA, 10 µg/ml) had no effect on action potential accommodation in phasic neurons (Fig. 1D; n = 8), eliciting 4 ± 1 action potentials. These results are summarized in Fig. 1E.
To determine whether prostaglandins released during antigen challenge
affected synaptic transmission, the effects of antigen (10 µg/ml of
OVA) on the amplitude of the fEPSP was determined with and without COX
inhibitors. In control neurons, vagus nerve stimulation elicited fEPSPs
that were subthreshold for action potential formation with an amplitude
of 13 ± 3 mV (n = 6, Fig. 2A). After antigen challenge
(10 µg/ml of OVA), the fEPSP were significantly increased to 19 ± 2 mV (n = 6; P = 0.02). In two experiments when QX-314 was not used to block regenerative
spikes (see METHODS), this increase in fEPSP amplitude was
sufficient to drive the cell to threshold for action potential
generation (n = 2; e.g., Fig. 2B). After
antigen challenge (10 µg/ml OVA) in the presence of indomethacin (3 µM), fEPSPs were not increased, averaging 14 ± 3 mV
(n = 6). Likewise, OVA challenge in the presence of
piroxicam (0.05 µM) did not increase fEPSP amplitude (12 ± 4 mV, P = 0.4, n = 5, Fig.
2C). The effects of antigen on excitatory potentials, with
and without COX inhibitors, are summarized in Fig. 2E. In
ganglia neurons from serum control animals (injected with regular
serum), OVA (10 µg/ml) had no effect on fEPSP amplitudes (P > 0.05; n = 4).
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The effects of exogenous prostaglandins on active and synaptic membrane
properties were also determined. Among the prostaglandins found to be
increased by OVA exposure (Table 1), only PGD2 (0.1 µM)
mimicked the effect of antigen challenge on action potential accommodation (Fig. 3A; Table
2). Exposing the tissue
to PGE2, PGI2,
PGF2, or thromboxane A2 (0.1 µM)
as well as the thromboxane mimetic U-46619 (0.1 µM, n = 4; data not shown) had no effect on action potential accommodation.
In addition, PGD2 (0.1 µM) decreased the duration of the
cumulative action AHP by 28 ± 1% (Table 2). A more profound
decrease in AHP duration was observed after bath application of
PGE2 (0.1 µM; n = 6, Fig. 3B;
Table 2).
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None of the prostanoids found to be significantly elevated on OVA
exposure (PGD2, PGE2, thromboxane
A2, or prostacyclin) mimicked the effect of OVA in causing
an increase in fEPSP amplitude. Paradoxically, PGF2
mimicked the effect of OVA in this regard, causing a 28 ± 17%
increase in fEPSP amplitude (P < 0.05, n = 6; Fig. 4), occasionally to action potential threshold (2 of 6 neurons).
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DISCUSSION |
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The data provide direct evidence that the immediate hypersensitivity response in guinea pig airway tissue is associated with an increase in synaptic efficacy, as directly assessed by quantifying the amplitude of fEPSPs, in bronchial parasympathetic ganglia. In addition, the results support our previous finding that antigen challenge causes a substantial decrease in the accommodative properties of bronchial ganglion neurons. It has previously been shown that the frequency of action potentials arising from preganglionic neurons is far greater than the frequency of action potentials leaving the ganglia along postganglionic fibers (8, 11). In other words, the bronchial parasympathetic ganglia appear to be sites at which parasympathetic activity is filtered. This occurs because many of the preganglionic action potentials entering the bronchial parasympathetic ganglia evoke fEPSPs that are below threshold for action potential discharge in the ganglion neurons. The increase in synaptic efficacy (increase in fEPSP amplitude) and decrease in accommodation would likely lead to a decrease in the filtering capacity of the ganglia and consequently an overall increase in parasympathetic activity at effector tissue in the airway (smooth muscle, glands, etc.).
We previously reported that histamine was responsible for antigen-induced membrane depolarization and increases in Ri in guinea pig bronchial ganglia but had no effect on action potential properties (12). Results from the present study support the hypothesis that prostaglandins are the primary autacoids responsible for antigen-induced decreases in accommodation and increases in fEPSP amplitude in bronchial ganglia. Pretreatment of the bronchi with the COX inhibitor indomethacin prevented both the antigen-induced increase in synaptic efficacy and decrease in accommodation. That this effect was due to COX inhibition and not due to some other nonselective action of the drug is supported by the finding that piroxicam, another cyclooxygenase inhibitor, also prevented the antigen-induced neuronal effects. It is difficult to pharmacologically dissect out whether COX-1 or COX-2 (or both) enzymes are responsible for synthesizing the prostanoids involved with the decreased accommodation and increase in fEPSPs. In many cell types in the body, including mast cells (6, 16), COX-1 is constitutively produced and is activated during the immediate hypersensitivity reaction, whereas COX-2 is inducible and is active in the delayed phase as well as in chronically inflamed tissue (16). Nevertheless, it can be stated that indomethacin is a nonselective COX inhibitor, whereas at the concentration used in the present study, piroxicam is somewhat selective for inhibiting the COX-1 enzyme (e.g., Ref. 17).
We previously reported that accommodation in phasic neurons could be reduced either by activation of the potassium current with characteristics similar to A-current or by inhibiting calcium-activated potassium current(s) (9). That PGD2 decreased the AHP duration after repetitive action potentials (an indicator of calcium-activated potassium current) suggests this current may be associated with the decrease in accommodation. However, that PGE2 inhibited the afterhyperpolarization after repetitive action potentials, but did not affect accommodation, indicates that inhibition of the calcium-activated potassium current responsible for AHP is not associated with the antigen-induced decrease in accommodation. Similarly, in guinea pig gallbladder ganglia, PGE2 attenuates the AHP in parasympathetic neurons and also has no effect on accommodation (5). On the basis of our previous study (9), it is possible that effect of PGD2 (and antigen) on accommodation involves activation of the A-current; the results presented in the present study may provide evidence for a unique role for PGD2 in regulation of the A-current and action potential accommodation.
The results shed some light on the nature of the particular COX product responsible for the antigen-induced decrease in accommodation. Antigen exposure leads to significant increases in the production and release of PGD2, PGE2, thromboxane, and prostacyclin. Among these eicosanoids, however, only PGD2 was capable of mimicking the effect of antigen on decreasing action potential accommodation. These data, along with the data obtained with the COX inhibitors, provide strong support for the hypothesis that antigen-induced changes in accommodation are secondary to the formation of PGD2. The cellular source of the PGD2 cannot be discerned from the data, but mast cells are likely candidates. These data may also provide a possible mechanism for prostaglandin-induced increases in acetylcholine release from prejunctional nerve fibers in the lower airways (7). However, other studies have suggested inhibitory effects of prostaglandins on airway cholinergic parasympathetic activity (2, 4, 5).
The nature of the prostaglandin responsible for the
antigen-induced increase in fEPSP amplitude is less obvious. When
studied at a concentration of 0.1 µM (so that some receptor
selectivity could be appreciated), only PGF2 affected
fEPSP amplitude. However, unlike our previously reported study on
antigen-induced prostaglandin release from guinea pig tracheal tissue
(20), PGF2
was not significantly elevated
in bronchial superfusate on antigen exposure. This paradox may be
explained by the possibility that antigen did indeed increase
PGF2
production within or near the ganglia, and this
level was greater than the PGF2
levels in the
superfusate. It is possible that the method of extraction and assay may
have differed from those previously used (20). Alternatively, from our exogenously applied prostaglandin experiments, perhaps concentrations >0.1 µM are needed for other prostaglandins to mimic the effect of antigen challenge on fEPSPs. It should be noted,
however, that a concentration of 0.1 µM PGD2 or
PGE2 was sufficient to affect other electrophysiological
membrane properties of the ganglion neurons (Table 1).
In conclusion, the COX enzyme(s), activated during specific antigen
challenge, initiate(s) the release of large quantities of
prostaglandins in guinea pig bronchial tissue. Some of these prostaglandins differentially affect membrane properties of intrinsic ganglia neurons. Antigen-induced PGD2 production appears to
effectively inhibit action potential accommodation in ganglion neurons,
such that many more action potentials can be evoked during prolonged stimulation. PGF2 is effective at directly increasing
synaptic efficacy in the bronchial ganglia, as noted by a substantial
increase in fEPSP amplitude. Such changes in excitability, considered
along with the effects of endogenously released histamine
(12), may contribute to increases in parasympathetic tone
in the lower airways associated with allergen exposure.
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ACKNOWLEDGEMENTS |
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This work was supported by the National Heart, Lung, and Blood Institute (A. C. Myers, B. J. Undem).
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. C. Myers, Division of Clinical Immunology, Dept. of Medicine, The Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle 1A62, Baltimore, MD 21224 (E-mail: amyers{at}jhmi.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published January 10, 2003;10.1152/ajplung.00332.2002
Received 3 October 2002; accepted in final form 9 December 2002.
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