scholarly journals Epinephrine enhances the sensitivity of rat vagal chemosensitive neurons: role of β3-adrenoceptor

2007 ◽  
Vol 102 (4) ◽  
pp. 1545-1555 ◽  
Author(s):  
Qihai Gu ◽  
You-Shuei Lin ◽  
Lu-Yuan Lee
Keyword(s):  
Right Atrial ◽  
Intracellular Camp ◽  
Lung Inflation ◽  
Adrenoceptor Antagonist ◽  
C Fibers ◽  
Baseline Activity ◽  
Adrenoceptor Agonist ◽  
Intracellular Ca ◽  
Sensitizing Effect ◽  
Ganglion Neurons

This study was carried out to determine whether epinephrine alters the sensitivity of rat vagal sensory neurons. In anesthetized rats, inhalation of epinephrine aerosol (1 and 5 mg/ml, 3 min) induced an elevated baseline activity of pulmonary C fibers and enhanced their responses to lung inflation (20 cmH2O, 10 s) and right atrial injection of capsaicin (0.5 μg/kg). In isolated rat nodose and jugular ganglion neurons, perfusion of epinephrine (3 μM, 5 min) alone did not produce any detectable change of the intracellular Ca2+ concentration. However, immediately after the pretreatment with epinephrine, the Ca2+ transients evoked by chemical stimulants (capsaicin, KCl, and ATP) were markedly potentiated; for example, capsaicin (50 nM, 15 s)-evoked Ca2+ transient was increased by 106% after epinephrine ( P < 0.05; n = 11). The effect of epinephrine was mimicked by either BRL 37344 (5 μM, 5 min) or ICI 215,001 (5 μM, 5 min), two selective β3-adrenoceptor agonists, and blocked by SR 59230A (5 μM, 10 min), a selective β3-adrenoceptor antagonist, whereas pretreatment with phenylephrine (α1-adenoceptor agonist), guanabenz (α2-adrenoceptor agonist), dobutamine (β1-adrenoceptor agonist), or salbutamol (β2-adrenoceptor agonist) had no significant effect on capsaicin-evoked Ca2+ transient. Furthermore, pretreatment with SQ 22536 (100–300 μM, 15 min), an adenylate cyclase inhibitor, and H89 (3 μM, 15 min), a PKA inhibitor, completely abolished the potentiating effect of epinephrine. Our results suggest that epinephrine enhances the excitability of rat vagal chemosensitive neurons. This sensitizing effect of epinephrine is likely mediated through the activation of β3-adrenoceptor and intracellular cAMP-PKA signaling cascade.

scholarly journals Hydrogen sulfide induces hypersensitivity of rat capsaicin-sensitive lung vagal neurons: role of TRPA1 receptors

2013 ◽  
Vol 305 (7) ◽  
pp. R769-R779 ◽  
Author(s):  
Chun-Chun Hsu ◽  
Ruei-Lung Lin ◽  
Lu-Yuan Lee ◽  
You Shuei Lin
Keyword(s):  
Hydrogen Sulfide ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Right Atrial ◽  
Sodium Hydrosulfide ◽  
Lung Inflation ◽  
Baseline Activity ◽  
Intracellular Ca ◽  
Transient Receptor ◽  
Sensitizing Effect

The sensitization of capsaicin-sensitive lung vagal (CSLV) afferents by inflammatory mediators is important in the development of airway hypersensitivity. Hydrogen sulfide (H2S) is an endogenous mediator inducing hyperalgesia through transient receptor potential ankyrin 1 (TRPA1) receptors located on nociceptors. We conducted this study to determine whether H2S elevates the sensitivity of rat CSLV afferents. In anesthetized, artificially ventilated rats, the inhalation of aerosolized sodium hydrosulfide (NaHS, a H2S donor) caused no significant changes in the baseline activity of CSLV afferents. However, the afferent responses to right atrial injection of capsaicin or phenylbiguanide and to lung inflation were all markedly potentiated after NaHS inhalation. By contrast, the inhalation of its vehicle or NaOH (with a similar pH to NaHS) failed to enhance the afferent responses. Additionally, the potentiating effect on the afferent responses was found in rats inhaling l-cysteine (a substrate of H2S synthase) that slowly releases H2S. The potentiating effect of NaHS on the sensitivity of CSLV afferents was completely blocked by pretreatment of HC-030031 (a TRPA1 receptor antagonist) but was unaffected by its vehicle. In isolated rat CSLV neurons, the perfusion of NaHS alone did not influence the intracellular Ca2+ concentration but markedly potentiated the Ca2+ transients evoked by capsaicin. The NaHS-caused effect was totally abolished by HC-030031 pretreatment. These results suggest that H2S induces a nonspecific sensitizing effect on CSLV fibers to both chemical and mechanical stimulation in rat lungs, which appears mediated through an action on the TRPA1 receptors expressed on the nerve endings of CSLV afferents.

Ozone enhances excitabilities of pulmonary C fibers to chemical and mechanical stimuli in anesthetized rats

1998 ◽  
Vol 85 (4) ◽  
pp. 1509-1515 ◽  
Author(s):  
Ching-Yin Ho ◽  
Lu-Yuan Lee
Keyword(s):  
Low Dose ◽  
Acute Exposure ◽  
Right Atrial ◽  
Mechanical Stimuli ◽  
Lung Inflation ◽  
C Fibers ◽  
Arterial Blood ◽  
Baseline Activity ◽  
Tracheal Pressure ◽  
C Fiber

Acute exposure to ozone (O3) enhances pulmonary chemoreflex response to capsaicin, and an increased sensitivity of bronchopulmonary C-fiber afferent endings may be involved. The present study was aimed at determining the effect of O3 on the responses of pulmonary C fibers to chemical and mechanical stimuli. A total of 31 C fibers were studied in anesthetized, open-chest, and vagotomized rats. During control, right atrial injection of a low dose of capsaicin abruptly evoked a short and mild burst of discharge [0.77 ± 0.28 impulses (imp)/s, 2-s average]. After acute exposure to O3 (3 parts/million for 30 min), there was no significant change in arterial blood pressure, tracheal pressure, or baseline activity of C fibers. However, the stimulatory effect of the same dose of capsaicin on these fibers was markedly enhanced (6.05 ± 0.88 impulses/s; P < 0.01) and prolonged immediately after O3 exposure, and returned toward control in 54 ± 6 min. Similarly, the pulmonary C-fiber response to injection of a low dose of lactic acid was also elevated after O3 exposure. Furthermore, O3 exposure significantly potentiated the C-fiber response to constant-pressure (tracheal pressure = 30 cmH2O) lung inflation (control: 0.19 ± 0.07 imp/s; after O3: 1.12 ± 0.26 imp/s; P < 0.01). In summary, these results show that the excitabilities of pulmonary C-fiber afferents to lung inflation and injections of chemical stimulants are markedly potentiated after acute exposure to O3, suggesting a possible involvement of these afferents in the O3-induced changes in breathing pattern and chest discomfort in humans.

Selected Contribution: Hypersensitivity of pulmonary C fibers induced by adenosine in anesthetized rats

2003 ◽  
Vol 95 (3) ◽  
pp. 1315-1324 ◽  
Author(s):  
Qihai Gu ◽  
Ting Ruan ◽  
Ju-Lun Hong ◽  
Nausherwan Burki ◽  
Lu-Yuan Lee
Keyword(s):  
Receptor Antagonist ◽  
Potential Role ◽  
Right Atrial ◽  
Adenosine Infusion ◽  
Lung Inflation ◽  
C Fibers ◽  
Baseline Activity ◽  
Tracheal Pressure ◽  
C Fiber

Compelling clinical evidence implicates the potential role of adenosine in development of airway hyperresponsiveness and suggests involvement of pulmonary sensory receptors. This study was carried out to determine the effect of a low dose of adenosine infusion on sensitivity of pulmonary C-fiber afferents in anesthetized open-chest rats. Infusion of adenosine (40 μg · kg-1 · min-1 iv for 90 s) mildly elevated baseline activity of pulmonary C fibers. However, during adenosine infusion, pulmonary C-fiber responses to chemical stimulants and lung inflation (30 cmH2O tracheal pressure) were markedly potentiated; e.g., the response to right atrial injection of capsaicin (0.25 or 0.5 μg/kg) was increased by more than fivefold (change in fiber activity = 2.64 ± 0.67 and 16.27 ± 3.11 impulses/s at control and during adenosine infusion, n = 13, P < 0.05), and this enhanced response returned to control in ∼10 min. The potentiating effect of adenosine infusion was completely blocked by pretreatment with 8-cyclopentyl-1,3-dipropylxanthine (100 μg/kg), a selective antagonist of the adenosine A1 receptor, but was not affected by 3,7-dimethyl-1-propargylxanthine (1 mg/kg), an A2-receptor antagonist, or 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (2 mg/kg), an A3-receptor antagonist. This potentiating effect was also mimicked by N6-cyclopentyladenosine (0.25 μg·kg-1·min-1 for 90 s), a selective agonist of the adenosine A1 receptor. In conclusion, our results showed that infusion of adenosine significantly elevated the sensitivity of pulmonary C-fiber afferents in rat lungs and that this potentiating effect is likely mediated through activation of the adenosine A1 receptor.

scholarly journals Hypersensitivity of vagal pulmonary C-fibers induced by increasing airway temperature in ovalbumin-sensitized rats

2015 ◽  
Vol 309 (10) ◽  
pp. R1285-R1291
Author(s):  
Yu-Jung Lin ◽  
Ruei-Lung Lin ◽  
Mehdi Khosravi ◽  
Lu-Yuan Lee
Keyword(s):  
Steady State ◽  
Direct Evidence ◽  
Right Atrial ◽  
Brown Norway ◽  
C Fibers ◽  
Baseline Activity ◽  
C Fiber ◽  
Chemical Stimuli ◽  
Sensitizing Effect ◽  
Norway Rats

Our recent study has shown that hyperventilation of humidified warm air (HWA) triggered cough and reflex bronchoconstriction in patients with mild asthma. We suggested that a sensitizing effect on bronchopulmonary C-fibers by increasing airway temperature was involved, but direct evidence was lacking. This study was carried out to test the hypothesis that HWA enhances the pulmonary C-fiber sensitivity in Brown-Norway rats sensitized with ovalbumin (Ova). In anesthetized rats, isocapnic hyperventilation of HWA for 3 min rapidly elevated airway temperature to a steady state of 41.7°C. Immediately after the HWA challenge, the baseline fiber activity (FA) of pulmonary C-fibers was markedly elevated in sensitized rats, but not in control rats. Furthermore, the response of pulmonary C-fibers to right atrial injection of capsaicin in sensitized rats was significantly higher than control rats before the HWA challenge, and the response to capsaicin was further amplified after HWA in sensitized rats (ΔFA = 4.51 ± 1.02 imp/s before, and 9.26 ± 1.74 imp/s after the HWA challenge). A similar pattern of the HWA-induced potentiation of the FA response to phenylbiguanide, another chemical stimulant of C-fibers, was also found in sensitized rats. These results clearly demonstrated that increasing airway temperature significantly elevated both the baseline activity and responses to chemical stimuli of pulmonary C-fibers in Ova-sensitized rats. In conclusion, this study supports the hypothesis that the increased excitability of these afferents may have contributed to the cough and reflex bronchoconstriction evoked by hyperventilation of HWA in patients with asthma.

scholarly journals Sensitizing effects of chronic exposure and acute inhalation of ovalbumin aerosol on pulmonary C fibers in rats

2008 ◽  
Vol 105 (1) ◽  
pp. 128-138 ◽  
Author(s):  
Guangfan Zhang ◽  
Ruei-Lung Lin ◽  
Michelle E. Wiggers ◽  
Lu-Yuan Lee
Keyword(s):  
Right Atrial ◽  
Brown Norway ◽  
Lung Inflation ◽  
Inflammatory Reactions ◽  
C Fibers ◽  
C Fiber ◽  
Inhalation Challenge ◽  
Sensitizing Effect ◽  
And Control ◽  
Norway Rats

The effect of ovalbumin (Ova) sensitization on pulmonary C-fiber sensitivity was investigated. Brown-Norway rats were sensitized by intraperitoneal injection of Ova followed by aerosolized Ova three times per week for 3 wk. Control rats received the vehicle. At the end of the third week, single-unit fiber activities (FA) of pulmonary C fibers were recorded in anesthetized, artificially ventilated rats. Our results showed the following: 1) Ova sensitization induced airway inflammation (infiltration of eosinophils and neutrophils) and airway hyperresponsiveness in rats; 2) baseline FA in sensitized rats was significantly higher than that in control ones; 3) similarly, the pulmonary C-fiber response to right atrial injection of capsaicin was markedly higher in sensitized rats, which were significantly amplified after the acute Ova inhalation challenge; and 4) similar patterns, but smaller magnitudes of the differences in C-fiber responses to adenosine and lung inflation, were also found between sensitized and control rats. In conclusion, Ova sensitization elevated the baseline FA and excitability of pulmonary C fibers, and the hypersensitivity was further potentiated after the acute Ova inhalation challenge in sensitized rats. Chronic allergic inflammatory reactions in the airway probably contributed to the sensitizing effect on these lung afferents.

Testosterone-augmented contractile responses to α1- and β1-adrenoceptor stimulation are associated with increased activities of RyR, SERCA, and NCX in the heart

2009 ◽  
Vol 296 (4) ◽  
pp. C766-C782 ◽  
Author(s):  
Sharon Tsang ◽  
Stanley S. C. Wong ◽  
Song Wu ◽  
Gennadi M. Kravtsov ◽  
Tak-Ming Wong
Keyword(s):  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Contractile Responses ◽  
Adrenoceptor Antagonist ◽  
Cardiac Contractile ◽  
Plasmic Reticulum ◽  
Adrenoceptor Agonist ◽  
Intracellular Ca ◽  
Developed Pressure ◽  
Stimulation Of

We hypothesized that testosterone at physiological levels enhances cardiac contractile responses to stimulation of both α1- and β1-adrenoceptors by increasing Ca2+ release from the sarcoplasmic reticulum (SR) and speedier removal of Ca2+ from cytosol via Ca2+-regulatory proteins. We first determined the left ventricular developed pressure, velocity of contraction and relaxation, and heart rate in perfused hearts isolated from control rats, orchiectomized rats, and orchiectomized rats without and with testosterone replacement (200 μg/100 g body wt) in the presence of norepinephrine (10−7 M), the α1-adrenoceptor agonist phenylephrine (10−6 M), or the nonselective β-adrenoceptor agonist isoprenaline (10−7 M) in the presence of 5 × 10−7 M ICI-118,551, a β2-adrenoceptor antagonist. Next, we determined the amplitudes of intracellular Ca2+ concentration transients induced by electrical stimulation or caffeine, which represent, respectively, Ca2+ release via the ryanodine receptor (RyR) or releasable Ca2+ in the SR, in ventricular myocytes isolated from the three groups of rats. We also measured 45Ca2+ release via the RyR. We then determined the time to 50% decay of both transients, which represents, respectively, Ca2+ reuptake by sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and removal via the sarcolemmal Na+/Ca2+ exchanger (NCX). We correlated Ca2+ removal from the cytosol with activities of SERCA and its regulator phospholamban as well as NCX. The results showed that testosterone at physiological levels enhanced positive inotropic and lusitropic responses to stimulation of α1- and β1-adrenoceptors via the androgen receptor. The increased contractility and speedier relaxation were associated with increased Ca2+ release via the RyR and faster Ca2+ removal out of the cytosol via SERCA and NCX.

Alveolar hypercapnia augments pulmonary C-fiber responses to chemical stimulants: role of hydrogen ion

2002 ◽  
Vol 93 (1) ◽  
pp. 181-188 ◽  
Author(s):  
Qihai Gu ◽  
Lu-Yuan Lee
Keyword(s):  
Hydrogen Ion ◽  
Right Atrial ◽  
Mechanical Stimuli ◽  
Hydrogen Ions ◽  
Lung Inflation ◽  
C Fibers ◽  
Arterial Blood ◽  
Blood Ph ◽  
C Fiber

To determine whether the excitabilities of pulmonary C fibers to chemical and mechanical stimuli are altered by CO2-induced acidosis, single-unit pulmonary C-fiber activity was recorded in anesthetized, open-chest rats. Transient alveolar hypercapnia (HPC) was induced by administering CO2-enriched gas mixture (15% CO2, balance air) via the respirator inlet for 30 s, which rapidly lowered the arterial blood pH from a baseline of 7.40 ± 0.01 to 7.17 ± 0.02. Alveolar HPC markedly increased the responses of these C-fiber afferents to several chemical stimulants. For example, the C-fiber response to right atrial injection of the same dose of capsaicin (0.25–1.0 μg/kg) was significantly increased from 3.07 ± 0.70 impulses/s at control to 8.48 ± 1.52 impulses/s during HPC ( n = 27; P < 0.05), and this enhanced response returned to control within ∼10 min after termination of HPC. Similarly, alveolar HPC also induced significant increases in the C-fiber responses to right atrial injections of phenylbiguanide (4–8 μg/kg) and adenosine (0.2 mg/kg). In contrast, HPC did not change the response of pulmonary C fibers to lung inflation. Furthermore, the peak response of these C fibers to capsaicin during HPC was greatly attenuated when the HPC-induced acidosis was buffered by infusion of bicarbonate (1.36–1.82 mmol · kg−1 · min−1 for 35 s). In conclusion, alveolar HPC augments the responses of these afferents to various chemical stimulants, and this potentiating effect of CO2 is mediated through the action of hydrogen ions on the C-fiber sensory terminals.

Calcium transient evoked by nicotine in isolated rat vagal pulmonary sensory neurons

2007 ◽  
Vol 292 (1) ◽  
pp. L54-L61 ◽  
Author(s):  
Jennings Xu ◽  
Wenbin Yang ◽  
Guangfan Zhang ◽  
Qihai Gu ◽  
Lu-Yuan Lee
Keyword(s):  
Sensory Neurons ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Calcium Transient ◽  
Sensory Nerves ◽  
Right Atrial ◽  
Neuronal Nicotinic Acetylcholine Receptors ◽  
C Fibers ◽  
Intracellular Ca ◽  
Intense Burst

It has been shown that inhaled cigarette smoke activates vagal pulmonary C fibers and rapidly adapting receptors (RARs) in the airways and that nicotine contained in the smoke is primarily responsible. This study was carried out to determine whether nicotine alone can activate pulmonary sensory neurons isolated from rat vagal ganglia; the response of these neurons was determined by fura-2-based ratiometric Ca2+ imaging. The results showed: 1) Nicotine (10−4 M, 20 s) evoked a transient increase in intracellular Ca2+ concentration ([Ca2+]i) in 175 of the 522 neurons tested (Δ[Ca2+]i = 142.2 ± 12.3 nM); the response was reproducible, with a small reduction in peak amplitude in the same neurons when the challenge was repeated 20 min later. 2) A majority (59.7%) of these nicotine-sensitive neurons were also activated by capsaicin (10−7 M). 3) 1,1-Dimethyl-4-phenylpiperazinium iodide (DMPP; 10−4 M, 20 s), a selective agonist of the neuronal nicotinic acetylcholine receptors (NnAChRs), evoked a pattern of response similar to that of nicotine. 4) The responses to nicotine and DMPP were either totally abrogated or markedly attenuated by hexamethonium (10−4 M). 5) In anesthetized rats, right atrial bolus injection of nicotine (75–200 μg/kg) evoked an immediate (latency <1–2 s) and intense burst of discharge in 47.8% of the pulmonary C-fiber endings and 28.6% of the RARs tested. In conclusion, nicotine exerts a direct stimulatory effect on vagal pulmonary sensory nerves, and the effect is probably mediated through an activation of the NnAChRs expressed on the membrane of these neurons.

Sensitization of isolated rat vagal pulmonary sensory neurons by eosinophil-derived cationic proteins

2008 ◽  
Vol 294 (3) ◽  
pp. L544-L552 ◽  
Author(s):  
Qihai Gu ◽  
Michelle E. Wiggers ◽  
Gerald J. Gleich ◽  
Lu-Yuan Lee
Keyword(s):  
Sensory Neurons ◽  
Direct Action ◽  
Input Resistance ◽  
Sensory Nerves ◽  
Lung Inflation ◽  
Cationic Proteins ◽  
C Fibers ◽  
Current Clamp Mode ◽  
Sensitizing Effect ◽  
Isolated Rat

It has been shown that airway exposure to eosinophil-derived cationic proteins stimulated vagal pulmonary C fibers and markedly potentiated their responses to lung inflation in anesthetized rats (Lee LY, Gu Q, Gleich GJ, J Appl Physiol 91: 1318–1326, 2001). However, whether the effects resulted from a direct action of these proteins on the sensory nerves was not known. The present study was therefore carried out to determine the effects of these proteins on isolated rat vagal pulmonary sensory neurons. Our results obtained from perforated whole cell patch-clamp recordings showed that pretreatment with eosinophil major basic protein (MBP; 2 μM, 60 s) significantly increased the capsaicin-evoked inward current in these neurons; this effect peaked ∼10 min after MBP and lasted for >60 min; in current-clamp mode, MBP substantially increased the number of action potentials evoked by both capsaicin and electrical stimulation. Pretreatment with MBP did not significantly alter the input resistance of these sensory neurons. In addition, the sensitizing effect of MBP was completely abolished when its cationic charge was neutralized by mixing with a polyanion, such as low-molecular-weight heparin or poly-l-glutamic or poly-l-aspartic acid, before its delivery to the neurons. Moreover, a similar sensitizing effect was also generated by other eosinophil granule-derived proteins (e.g., eosinophil peroxidase). These results demonstrate a direct, charge-dependent, and long-lasting sensitizing effect of cationic proteins on pulmonary sensory neurons, which may contribute to the airway hyperresponsiveness associated with airway infiltration of eosinophils under pathophysiological conditions.

scholarly journals P2X2 receptors differentiate placodal vs. neural crest C-fiber phenotypes innervating guinea pig lungs and esophagus

2008 ◽  
Vol 295 (5) ◽  
pp. L858-L865 ◽  
Author(s):  
Kevin Kwong ◽  
Marian Kollarik ◽  
Christina Nassenstein ◽  
Fei Ru ◽  
Bradley J. Undem
Keyword(s):  
Guinea Pig ◽  
Neural Crest ◽  
Single Cell ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Receptor Activation ◽  
Rt Pcr ◽  
C Fibers ◽  
Embryonic Origin ◽  
Ganglion Neurons

The lungs and esophagus are innervated by sensory neurons with somata in the nodose, jugular, and dorsal root ganglion. These sensory ganglia are derived from embryonic placode (nodose) and neural crest tissues (jugular and dorsal root ganglia; DRG). We addressed the hypothesis that the neuron's embryonic origin (e.g., placode vs. neural crest) plays a greater role in determining particular aspects of its phenotype than the environment in which it innervates (e.g., lungs vs. esophagus). This hypothesis was tested using a combination of extracellular and patch-clamp electrophysiology and single-cell RT-PCR from guinea pig neurons. Nodose, but not jugular C-fibers innervating the lungs and esophagus, responded to α,β-methylene ATP with action potential discharge that was sensitive to the P2X3 (P2X2/3) selective receptor antagonist A-317491. The somata of lung- and esophagus-specific sensory fibers were identified using retrograde tracing with a fluorescent dye. Esophageal- and lung-traced neurons from placodal tissue (nodose neurons) responded similarly to α,β-methylene ATP (30 μM) with a large sustained inward current, whereas in neurons derived from neural crest tissue (jugular and DRG neurons), the same dose of α,β-methylene ATP resulted in only a transient rapidly inactivating current or no detectable current. It has been shown previously that only activation of P2X2/3 heteromeric receptors produce sustained currents, whereas homomeric P2X3 receptor activation produces a rapidly inactivating current. Consistent with this, single-cell RT-PCR analysis revealed that the nodose ganglion neurons innervating the lungs and esophagus expressed mRNA for P2X2 and P2X3 subunits, whereas the vast majority of jugular and dorsal root ganglia innervating these tissues expressed only P2X3 mRNA with little to no P2X2 mRNA expression. We conclude that the responsiveness of C-fibers innervating the lungs and esophagus to ATP and other purinergic agonists is determined more by their embryonic origin than by the environment of the tissue they ultimately innervate.

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