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The sensory innervation of the lung is well known to be innervated by nerve fibers of both vagal and sympathetic origin. Although the vagal afferent innervation of the lung has been well characterized, less is known about physiological effects mediated by spinal sympathetic afferent fibers. We hypothesized that activation of sympathetic spinal afferent nerve fibers of the lung would result in an excitatory pressor reflex, similar to that previously characterized in the heart. In this study, we evaluated changes in renal sympathetic nerve activity ( RSNA) and hemodynamics in response to activation of TRPV1‐sensitive pulmonary spinal sensory fibers by agonist application to the visceral pleura of the lung and by administration into the primary bronchus in anesthetized, bilaterally vagotomized, adult Sprague‐Dawley rats. Application of bradykinin ( BK) to the visceral pleura of the lung produced an increase in mean arterial pressure ( MAP), heart rate ( HR), and RSNA. This response was significantly greater when BK was applied to the ventral surface of the left lung compared to the dorsal surface. Conversely, topical application of capsaicin (Cap) onto the visceral pleura of the lung, produced a biphasic reflex change in MAP, coupled with increases in HR and RSNA which was very similar to the hemodynamic response to epicardial application of Cap.
This reflex was also evoked in animals with intact pulmonary vagal innervation and when BK was applied to the distal airways of the lung via the left primary bronchus. In order to further confirm the origin of this reflex, epidural application of a selective afferent neurotoxin (resiniferatoxin, RTX) was used to chronically ablate thoracic TRPV1‐expressing afferent soma at the level of T1–T4 dorsal root ganglia pleura. This treatment abolished all sympatho‐excitatory responses to both cardiac and pulmonary application of BK and Cap in vagotomized rats 9–10 weeks post‐ RTX. These data suggest the presence of an excitatory pulmonary chemosensitive sympathetic afferent reflex. This finding may have important clinical implications in pulmonary conditions inducing sensory nerve activation such as pulmonary inflammation and inhalation of chemical stimuli.
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Introduction In a wide range of physiological and pathophysiological conditions, the heart and lungs work in synergy in order to maintain adequate oxygenation of tissues (Coleridge and Coleridge; Mazzone and Undem ). The majority of research to date has focused on the role of pulmonary vagal neurons on sensing and regulating respiratory and upper airway function (Bergren and Peterson ). The vagus is a mixed nerve containing afferents that consist of fast conducting myelinated A fibers, slow conducting unmyelinated C fibers, and parasympathetic cholinergic efferent fibers. Stimulation of vagal sensory fibers has been shown to regulate rate and depth of breathing, basal tidal volume via the Herring–Breuer reflex (Carr and Undem ) (Paintal ) (Widdicombe and Lee ), cough (Canning and Chou; Taylor‐Clark ), and innervation of neuroepithelial bodies (Chang et al. The bradycardia observed in response to lung inflation (Shepherd ) and to inhalation of noxious stimuli (Hazari et al.; Hooper et al.
) is thought to be mediated by afferents of vagal origin. Although the traditional view has been that vagal‐derived afferents are the predominant sensory fibers within the lung, a number of studies have alluded to the presence of pulmonary spinal afferents using immunostaining (Nonomura et al. ) and retrograde labeling (Springall et al.; Kummer et al. However, the exact role and function of spinal afferent neurons in the lung is still unknown.
Previous studies have indicated pressor, depressor, and biphasic blood pressure responses to cardiopulmonary spinal afferent activation (Weaver; Kostreva et al.; Wang et al.; Soukhova‐O'Hare et al.; Hooper et al. The differences in whether an excitatory or inhibitory blood pressure response was observed in these studies are likely due to the preparations and experimental protocols used.
Therefore, to date, the effect of specific pulmonary spinal afferent activation on cardiovascular regulation remains inconclusive. In this study, we hypothesized that similar to the sympathetic afferent cardiac pressor and exercise pressor reflexes of spinal origin in the rat, an excitatory pulmonary spinal pressor reflex exists when lung visceral pleura spinal afferent endings are stimulated with physiological and pharmacological TRPV1 agonists. We aimed to study the location of chemosensitive sympathetic spinal afferents within the dorsal and ventral lung surfaces, as well as internally within the lung via bronchial administration of agonist in vagotomized rats.
The effects of activation of the spinal pulmonary chemosensitive reflex on cardiovascular function and RSNA in both vagotomized and nonvagotomized rats were measured. The spinal origin of these afferents was studied by activating lung surface nerve terminals with and without denervation of TRPV1 afferent neurons in the thoracic dorsal root ganglia (DRG).
Animal models Experiments were performed on male Sprague‐Dawley (SD) rats weighting 300–400 g (Charles River, USA). These experiments were approved by the Institutional Animal Care and Use Committee of the University of Nebraska Medical Center and carried out under the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and complies with the animal ethics guidelines or the Journal of Physiology as outline in the editorial by Grundy. Animals were housed in an on‐site facility and were allowed to acclimate for at least 1 week following arrival to their new environment. Water and laboratory rat chow were provided ad libitum, and animals were housed in 12 h light/dark cycles.
For chronic surgical procedures, isoflurane (2%) was administered for induction and maintenance of anesthetic, analgesia of bupenex (0.05 mg/kg) was given on the day of surgery, and carprofen (5 mg/kg) for 3 days postsurgery as postprocedure pain management. An overdose of pentobarbital (150 mg/kg) was used for rat euthanasia as approved by the supervising veterinarian and the Panel on Euthanasia of the American Veterinary Medical Association. Euthanasia was confirmed by cervical dislocation and removal of vital organs. General surgical preparation for acute experiments For the acute terminal experiments, rats were anesthetized with urethane (800 mg/kg ip) and α‐chloralose (40 mg/kg ip). Anesthetic plane was monitored by establishing rats were unresponsives to pedal withdrawal and corneal reflexes. The trachea was cannulated, and rats were ventilated artificially with room air supplemented with oxygen (40% O 2). A Millar catheter (SPR 524; size, 3.5‐Fr; Millar Instruments, Houston, TX) was advanced through the right common carotid artery and progressed into the aorta and left in place to record arterial pressure (AP).
Mean arterial pressure (MAP) and heart rate (HR) were derived from the arterial pressure pulse using Chart 7.1 software and an analog to digital converter (PowerLab model 16S; AD Instruments, Colorado Springs, CO). The right jugular vein was cannulated for intravenous injections and administration of saline at a rate of 3 mL/h. Body temperature was maintained between 37 and 38°C by a heating pad.
In most of the experiments, the cervical vagal nerves were cut bilaterally to prevent any reflex responses observed from vagal afferent activation, so as to observe only responses related to pulmonary spinal afferent activation. In some experiments, the vagal nerves were left intact in order to determine whether the pulmonary pressor reflex was still present with intact pulmonary vagal innervation. Recording renal sympathetic nerve activity In acute surgical preparations described above, RSNA was recorded as previously described (Gao et al.; Wang et al.; Becker et al. In brief, the left kidney, renal artery, and nerves were exposed through a left retroperitoneal flank incision. Sympathetic nerves running on or beside the renal artery were identified. The renal sympathetic nerves were placed on a pair of platinum–iridium recording electrodes and cut distally to avoid recording afferent activity. Nerve activity was amplified (×10,000) and filtered (bandwidth: 100 to 3000 Hz) using a Grass P55C preamplifier.
The nerve signal was displayed on a computer where it was rectified, integrated, sampled (1 KHz), and converted to a digital signal by the PowerLab data acquisition system. At the end of the experiment, the rat was euthanized with an overdose of pentobarbital sodium. Muktha muktha serial actors list. Respective noise levels were subtracted from the nerve recording data before percent changes from baseline were calculated. Integrated RSNA (iRSNA) was normalized as 100% of mean baseline during the control period (Becker et al. Activation of cardiac or pulmonary spinal afferents Epicardial application of capsaicin (Cap) and bradykinin (BK) has been demonstrated to effectively stimulate cardiac spinal afferents via the TRPV1 receptor (Zahner et al. ) and the bradykinin receptor 2 (BKR2), respectively (Soukhova‐O'Hare et al.; Mazzone and Undem ).
Therefore, a similar approach was employed to activate cardiac or pulmonary spinal afferents in this study. The chest was opened through the fourth intercostal space.
A square of filter paper (3 × 3 mm) saturated with Cap (10 μg/mL), or BK (1 or 10 μg/mL), was applied randomly to the ventral or dorsal surface of the left lung, distant from the hilum. In order to prevent the agonist from activating cardiac spinal afferents being absorbed into the main pulmonary vessels, special attention was paid to avoid placing the filter paper too close to the hilum. Hemodynamics and RSNA were continuously recorded. After the responses peaked, the lung was rinsed three times with 10 mL of warm normal saline. Thirty minutes were allowed to elapse between subsequent stimulations, to allow MAP, HR, and RSNA to return and stabilize at control levels. After the ventral and dorsal lung applications, we also applied BK and Cap onto the surface of left ventricular free wall of the heart in the same vagotomized rats to investigate whether both agents evoked similar hemodynamic and neural responses from the heart. Intrabronchial application of BK was performed by administering 100 μL of saline to test any affect of vehicle administration, followed by a bolus injection of 100 μL of BK 10 μg/mL, into the left primary bronchus by a specially adapted ventilation tube that was positioned at the opening of the primary bronchus, with catheter progressed 2 mm into the left primary bronchus, this allowed for the animal to be continuously ventilated while the drug was being applied.
One hour was allowed between applications of saline and BK. Intrabronchial experiments were performed in a separate group of animals because it was not possible to “wash” the drug out, and it could not be confirmed that the drug would no longer be active within the lung, potentially compounding repeated drug applications in the animal. Upper thoracic spinal sympathetic afferent denervation In some rats, the upper thoracic spinal sympathetic afferents were chronically ablated prior to study.
Briefly, rats were anesthetized using 2–3% isoflurane:oxygen mixture. Rats were placed in the prone position, and a small midline incision was made in the region of the T13–L1 thoracic vertebrae.
Following dissection of the superficial muscles, two small holes (approximately 2 × 2 mm) were made in the left and right sides of T13 vertebrae. A polyethylene catheter (PE‐10) was inserted into the subarachnoid space via one hole and gently advanced about 4 cm approximating the T1 level. The upper thoracic sympathetic afferent ganglia were ablated by injecting resiniferatoxin (RTX; Sigma‐Aldrich), an ultrapotent agonist of the TRPV1 receptor into the subarachnoid space via the catheter. RTX has been shown to ablate the TRPV1‐positive spinal afferent nerve endings on the heart (Wang et al., ). RTX (1 mg; Sigma‐Aldrich) was dissolved in a 1:1:8 mixture of ethanol, Tween‐80 (Sigma‐Aldrich), and isotonic saline.
The first injection of RTX (6 μg/mL, 10 μL) was made at a very slow speed (1 min) to minimize the diffusion of the drug. The catheter was then pulled back to T2, T3, and T4, respectively, to perform serial injections (10 μL/each) at each segment.
The catheter was withdrawn, and the same injections were repeated on the other side. Silicone gel was used to seal the hole in the T13 vertebra. The skin overlying the muscle was closed with a 3‐0 polypropylene simple interrupted suture, and betadine was applied to the wound. For postprocedure pain management, buprenorphine (0.05 mg/kg) was subcutaneously injected immediately after surgery and twice daily for 2 days. Terminal experiments were carried out 9‐10 weeks post‐TRPV1 neuronal ablation.
Immunofluorescence labeling of TRPV1 receptors in thoracic dorsal root ganglia and spinal cord To confirm that epidural T1–T4 application of RTX successfully ablated the TRPV1‐expressing DRG neurons, immunofluorescence labeling experiments were conducted on the T1–T4 DRGs and spinal cord. At the end of the study, rats ( n = 3/each group) were anesthetized with pentobarbital sodium (40 mg/kg, i.p.), and perfused through the aorta, first with 100 mL heparinized saline followed by 500 mL 4% paraformaldehyde (in 0.1 mol/L sodium phosphate buffer, PBS, pH = 7.4). The thoracic DRGs and spinal cord were immediately removed and immersed in the 4% paraformaldehyde solution overnight at 4°C. The tissues were then transferred to 30% sucrose in PBS and kept in the solution until they sank to the bottom. DRGs were sectioned at 14 μm, and the spinal cord at 30 μm on a Leica cryostat (−20°C) and thawed onto gelatin‐coated slides.
The double immunostaining of TRPV1 receptors with isolectin IB4 (a C‐fiber neuronal marker) in DRGs (Wang et al. ) and triple immunostaining of TRPV1 receptors with the isolectin IB4 and substance P (SP, an peptidergic C‐fiber neuron marker), in ganglionic or spinal cord sections, was performed by pre‐incubation of 10% goat serum for 60 min, prior to incubation with rabbit anti‐TRPV1 antibody (1:200 dilution, NB100‐1617, Novus Biologicals, Littleton, CO, USA) and/or mouse anti‐SP antibody (1:200 dilution, sc‐58591, Santa Cruz, Inc, Dallas, TX USA) overnight at 4°C. Sections were then washed with PBS and incubated with fluorescence‐conjugated secondary antibody (Alexa 488‐conjugated goat anti‐rabbit IgG and pacific blue‐conjugated goat anti‐mouse IgG, 1:200, Invitrogen, CA, USA) and Alexa Fluor R 568 conjugated isolectin‐B4 (1:200, Invitrogen, CA, USA) for 60 min at room temperature. Slides were observed on a Leica fluorescent microscope, and images captured using a digital camera system.
No staining was seen when a negative control was performed with PBS instead of the primary antibody (data not shown). Statistical analysis Statistical analysis was designed to test the hypotheses that the application of agonists to the surface of the lung would cause a change in hemodynamic parameters (MAP, HR), and RSNA compared to application of saline to the lung surface, or postspinal sympathetic ablation with RTX. Treatments were randomized between experiments so that agonists were not applied in the same order in each group. RTX, vagal intact, and bronchial application of agonists were each performed in a separate set of animals. Number of samples “ n” equals the number of animals in each group. Statistics were analyzed using GraphPad Prism.
Differences between treatments were determined by a one‐way ANOVA followed by the Dunnett's post hoc test to correct for multiple comparisons. All values are expressed as mean ± SE of the mean (SEM). Vehicle Ventral Cap 10 Dorsal Cap 10 ( n = 6) Depressor ( n = 7) Pressor ( n = 10) Depressor ( n = 5) Pressor ( n = 5) Baseline ∆ Change Baseline ∆ Change Baseline ∆ Change Baseline ∆ Change Baseline ∆ Change MAP (mmHg) 93.6 ± 3.9 0.8 ± 0.5 92.7 ± 5.0 −15.0 ± 2.2 85.8 ± 6.5 13.9 ± 1.9 88.4 ± 6.0 −20.0 ± 3.4 84.8 ± 6.5 7.6 ± 1.9 HR (bpm) 385.7 ± 12.7 1.7 ± 0.9 379 ± 12.3 0.7 ± 1.6 394 ± 14.1 15.4 ± 3.2 388.2 ± 12.9 −1.2 ± 1.0 381.5 ± 10.1 10.8 ± 1.5 RSNA (%.baseline) 100% 1.5 ± 1.1 100% 41.0 ± 4.4 100% 78.1 ± 12.4 100% 41.1 ± 23.8 100% 74.0 ± 18.8. Pulmonary application of bradykinin in vagotomized rats Topical application of BK onto the ventral surface of the lung produced a robust, dose‐dependent increase in MAP, HR, and RSNA in anesthetized, vagotomized rats (Fig. The latency from application of agonist to onset of sympatho‐excitation was very short (. (A) representative recording showing the response to topical application of bradykinin ( BK) (10 μg/mL) on to the ventral surface of the lung in an anesthetized and vagotomized rat. Arterial blood pressure ( AP), mean arterial blood pressure ( MAP), heart rate ( HR), renal sympathetic nerve activity ( RSNA), integrated RSNA ( iRSNA) as a% of baseline.
(B) Group mean data of the change in MAP from baseline. (C) Group mean data of the change in HR from baseline.
(D) Group mean data of the change in RSNA from baseline, (Veh, n = 6; BK (10 μg/mL): ventral, n = 11; dorsal, n = 7). Data presented as mean ± SEM.
Pulmonary application of capsaicin in vagotomized rats To selectively stimulate pulmonary spinal TRPV1‐containing afferents, we applied Cap (10 μg/mL), a potent agonist of the TRPV1 receptor, onto the visceral pleura of the lung in anesthetized, bilaterally vagotomized rats. Topical application of Cap produced a biphasic change in blood pressure in most animals, which was different from the response to topical pulmonary application of BK (Fig. The depressor response preceded the pressor response (observed in 7 of 10 animals, Fig. A and B).
Furthermore, the depressor response was significantly greater with application of Cap to the dorsal lung surface compared to the ventral lung surface, whereas the pressor response was significantly greater with ventral application of Cap compared to dorsal. However, in 3 of 10 animals, we only observed a pure pressor response to topical application of Cap to either side of the lung, indicating the variability in blood pressure regulation that exists when pulmonary TRPV1‐positive afferents are stimulated in these rats.
In spite of the variability in AP responses, HR and RSNA always increased during Cap application (Fig. And Table ), similar to that seen during pulmonary BK application.
The latency of the increase in HR and RSNA for Cap was similar to that seen for BK application. (A) representative recording showing that topical application of capsaicin (Cap) (10 μg/mL) on to the ventral surface of the lung, produces a predominant depressor response.
(B) Representative raw data trace showing topical application of Cap (10 μg/mL) on to the dorsal surface of the lung exhibiting a biphasic blood pressure response combined with pure tachycardia and sympatho‐excitation, (A and B) in an anesthetized double‐vagotomized rat. (C–F) Group mean change from baseline, (ventral, depressor n = 7, pressor n = 10. Dorsal, depressor n = 5, pressor n = 5.) Data presented as mean ± SEM.
Representative recordings (A and B) and summary data (C–D) showing the effect of epicardial application of BK (A) and Cap (B) (10 μg/mL) on hemodynamic parameters in anesthetized and vagotomized rats. Similar to lung application, epicardial application of BK evoked a pressor response, tachycardia, and sympatho‐excitation, whereas epicardial application of Cap caused similar biphasic AP response in most vagotomized rats (five of eight rats). In three of eight animals, we only observed a pure pressor response to epicardial application of Cap. ( n = 8 in BK and Cap pressor groups, n = 5 in the Cap depressor group.) Data presented as mean ± SEM. Pulmonary application of bradykinin and capsaicin in rats with intact vagi To establish whether this pulmonary pressor reflex still exists in the presence of pulmonary vagal innervation, experiments were repeated in anesthetized rats with intact vagal nerves. Topical application of BK (10 μg/mL) and Cap (10 μg/mL) produced an increase in MAP, HR, and RSNA compared to vehicle controls when applied to the ventral visceral pleura of the lung (Fig. Cap also produced a depressor response in six of eight animals studied (MAP: Cap 10 μg/mL depressor −8.7 ± 1.2 mmHg), as previously shown in Figure A depressor response was only observed in MAP.
This demonstrates that a very similar response is observed in animals with intact thoracic vagal innervation as in those animals with bilateral vagotomy. (A) representative recording showing topical application of bradykinin ( BK) 10 μg/mL on to the ventral surface of the lung in an anesthetized rat with intact vagus nerve. (B) Representative recording showing topical application of Cap (10 μg/mL) on to the ventral surface of the lung in an anesthetized rat with intact vagus nerve. (C–E) Group mean data, change from baseline. (C) MAP (Veh n = 4.
BK (10 μg/mL) n = 9. Cap (10 μg/mL) pressor n = 8, depressor n = 6.) (D) HR (Veh n = 4. BK (10 μg/mL) n = 9. Cap (10 μg/mL) pressor n = 8.) E, RSNA (Veh n = 4. BK (10 μg/mL) n = 9.
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Cap (10 μg/mL) pressor n = 8.) Data presented as mean ± SEM. Intrabronchial application of bradykinin in vagotomized rats To test the physiological implications of intrabronchial application of BK (acting as and inhaled activator of spinal afferents), BK 10 μg/mL or saline vehicle was administered directly into the lung at the level of the primary bronchi through a tracheal cannula in vagotomized, anaesthetized rats. BK produced a significant cardiac pressor response and increase in sympathetic nerve activity compared to vehicle control (Fig.
This suggests that the phenomenon observed with pulmonary surface application of BK is reproducible when BK is applied onto the airways. Ablation of sympathetic spinal ganglia with RTX abolished neural and hemodynamic changes to cardiac and pulmonary topical application of bradykinin and capsaicin In order to confirm the spinal afferent origin of pulmonary BK‐induced sympatho‐excitation, we performed pulmonary spinal afferent denervation by T1–T4 epidural application with the selective afferent neurotoxin RTX. Epidural application of RTX reduced the number of both TRPV1‐positive and IB4‐positive DRG neurons at the thoracic levels (Fig. A and B). As a consequence of reduced TRPV1‐positive DRG neurons by RTX application, the TRPV1‐positive terminal density in the dorsal horn of thoracic spinal cord was also diminished in RTX‐treated rats. Considering that the TRPV1 receptor is expressed in both peptidergic (substance P‐positive) and nonpeptidergic (IB4‐positive) DRG soma and nerve terminals, ablation of TRPV1‐positive DRG neurons also caused a reduction in both substance P‐positive and IB4‐positive terminal density in the dorsal horn (Fig. A).
In functional experiments, we confirmed that epidural application of RTX abolished the pressor and sympatho‐excitatory responses to pulmonary topical application of BK (Fig. C–G and Table ), and abolished both the pressor and the depressor changes in response to Cap (Fig. D–G and Table ) in both the lung and the heart. This indicates that the hemodynamic responses to topical pulmonary and cardiac BK and Cap are due to activation of a spinal afferent pathway. The efficacy of epidural T1–T4 application of RTX in ablating the cardiac/pulmonary sympathetic afferent reflex in rats.
(A) Representative images showing that the TRPV1‐positive terminal density at the dorsal horn of T2 spinal cord was largely diminished in RTX‐treated rats, which was associated with both reduced substance P‐positive (Peptidergic C‐fiber marker) and IB4‐positive (nonpeptidergic C‐fiber marker) terminal density at the dorsal horn. (B) Representative images showing that epidural application of RTX largely reduced the number of both TRPV1‐positive and IB4‐positive (a C‐fiber marker) neurons in T2 dorsal root ganglion. (C and D) Representative raw data trace showing topical application of BK (10 μg/mL) and Cap (10 μg/mL) onto the ventral surface of the lung (C, n = 9) or heart (D, n = 5) in anesthetized, vagotomized rats after pretreatment with T1–T4 epidural RTX to ablate sympathetic spinal afferents.
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(E–G) Group mean data showing that topical application of BK and Cap onto lung and heart caused very little hemodynamic or neural response in rats with epidural T1–T4 application of RTX. Data presented as mean ± SEM.
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