Neurophysiological basis for neurogenic-mediated articular cartilage anabolism alteration

This study was designed to investigate the pathways involved in neurogenic-mediated articular cartilage damage triggered by a nonsystemic distant subcutaneous or intra-articular inflammation. The cartilage damage was assessed 24 h after subcutaneous or intra-articular complete Freund's adjuvant (CFA) injection measuring patellar proteoglycan (PG) synthesis (ex vivo [Na2 35SO4] incorporation) in 96 Wistar rats. Unilateral subcutaneous or intra-articular injection of CFA induced significant decrease (25–29%) in PG synthesis in both patellae. Chronic administration of capsaicin (50 mg · kg−1 · day−1 during 4 days), which blunted the normal response of C fiber stimulation, prevented the bilateral significant decrease in cartilage synthesis. Similarly, intrathecal injection of MK-801 (10 nmol/day during 5 days), which blocked the glutamatergic synaptic transmission at the dorsal horn of signal originating in primary afferent C fibers, eliminated the CFA-induced PG synthesis decrease in both patellae. Chemical sympathectomy, induced by guanethidine (12.5 mg · kg−1 · day−1 during 6 wk), also prevented PG synthesis alteration. Finally, compression of the spinal cord at the T3-T5 level had a similar protective effect on the reduction of [Na2 35SO4] incorporation. It is concluded that the signal that triggers articular cartilage synthesis damage induced by a distant local inflammation 1) is transmitted through the afferent C fibers, 2) makes glutamatergic synaptic connections with the preganglionic neurons of the sympathetic system, and 3) involves spinal and supraspinal pathways.

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Diaphragmatic responses to graded stimulation of pulmonary C-fibers with capsaicin

Journal of Applied Physiology ◽

10.1152/jappl.1985.59.5.1487 ◽

1985 ◽

Vol 59 (5) ◽

pp. 1487-1494 ◽

Cited By ~ 2

Author(s):

J. R. Coast ◽

S. S. Cassidy

Keyword(s):

Dose Response ◽

Strain Gauge ◽

Contraction Rate ◽

C Fibers ◽

C Fiber ◽

Shallow Breathing ◽

Fiber Stimulation ◽

Rapid Shallow Breathing ◽

Stimulation Of

It has been suggested that pulmonary C-fiber stimulation is responsible for the rapid shallow breathing that accompanies pulmonary edema. However, pulmonary C-fiber stimulation also causes apnea. To determine whether it was possible for both responses to occur from one stimulus, we infused varying concentrations of capsaicin (a compound that selectively stimulates C-fiber receptors in the dog) into an in situ vascularly isolated dog lung and measured rates and strengths of diaphragmatic contractions with a strain gauge sutured to the diaphragm and electromyogram electrodes implanted in the diaphragm. There was a dose response to capsaicin in that increased doses were related directly with the duration of cessation of diaphragmatic contractions (2–100 s) and inversely with the latency from the start of stimulation to the beginning of the cessation of diaphragmatic contractions (100–5 s). There was no evidence, however, of rapid shallow breathing in this set of experiments. Either a gradual return to normal rate from prolonged contraction intervals or no change in contraction rate was seen, depending on capsaicin concentration. We conclude that the primary diaphragmatic response to pulmonary C-fiber stimulation is a cessation of diaphragmatic contractions rather than rapid shallow contractions.

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TRPM8 function and expression in vagal sensory neurons and afferent nerves innervating guinea pig esophagus

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00336.2014 ◽

2015 ◽

Vol 308 (6) ◽

pp. G489-G496 ◽

Cited By ~ 13

Author(s):

Xiaoyun Yu ◽

Youtian Hu ◽

Fei Ru ◽

Marian Kollarik ◽

Bradley J. Undem ◽

...

Keyword(s):

Transient Receptor Potential ◽

Calcium Influx ◽

Ex Vivo ◽

Receptor Potential ◽

Sensory Transduction ◽

Dependent Manner ◽

Preferential Expression ◽

C Fibers ◽

C Fiber ◽

Transient Receptor

Sensory transduction in esophageal afferents requires specific ion channels and receptors. TRPM8 is a new member of the transient receptor potential (TRP) channel family and participates in cold- and menthol-induced sensory transduction, but its role in visceral sensory transduction is still less clear. This study aims to determine TRPM8 function and expression in esophageal vagal afferent subtypes. TRPM8 agonist WS-12-induced responses were first determined in nodose and jugular neurons by calcium imaging and then investigated by whole cell patch-clamp recordings in Dil-labeled esophageal nodose and jugular neurons. Extracellular single-unit recordings were performed in nodose and jugular C fiber neurons using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. TRPM8 mRNA expression was determined by single neuron RT-PCR in Dil-labeled esophageal nodose and jugular neurons. The TRPM8 agonist WS-12 elicited calcium influx in a subpopulation of jugular but not nodose neurons. WS-12 activated outwardly rectifying currents in esophageal Dil-labeled jugular but not nodose neurons in a dose-dependent manner, which could be inhibited by the TRPM8 inhibitor AMTB. WS-12 selectively evoked action potential discharges in esophageal jugular but not nodose C fibers. Consistently, TRPM8 transcripts were highly expressed in esophageal Dil-labeled TRPV1-positive jugular neurons. In summary, the present study demonstrated a preferential expression and function of TRPM8 in esophageal vagal jugular but not nodose neurons and C fiber subtypes. This provides a distinctive role of TRPM8 in esophageal sensory transduction and may lead to a better understanding of the mechanisms of esophageal sensation and nociception.

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Mechanisms of the adenosine A2Areceptor-induced sensitization of esophageal C fibers

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00350.2014 ◽

2016 ◽

Vol 310 (3) ◽

pp. G215-G223 ◽

Cited By ~ 11

Author(s):

M. Brozmanova ◽

L. Mazurova ◽

F. Ru ◽

M. Tatar ◽

Y. Hu ◽

...

Keyword(s):

Transient Receptor Potential ◽

Mechanical Response ◽

Kinase Inhibitor ◽

Ex Vivo ◽

Receptor Potential ◽

P2x Receptor ◽

C Fibers ◽

C Fiber ◽

Transient Receptor ◽

Stimulation Of

Clinical studies indicate that adenosine contributes to esophageal mechanical hypersensitivity in some patients with pain originating in the esophagus. We have previously reported that the esophageal vagal nodose C fibers express the adenosine A2Areceptor. Here we addressed the hypothesis that stimulation of the adenosine A2Areceptor induces mechanical sensitization of esophageal C fibers by a mechanism involving transient receptor potential A1 (TRPA1). Extracellular single fiber recordings of activity originating in C-fiber terminals were made in the ex vivo vagally innervated guinea pig esophagus. The adenosine A2Areceptor-selective agonist CGS21680 induced robust, reversible sensitization of the response to esophageal distention (10–60 mmHg) in a concentration-dependent fashion (1–100 nM). At the half-maximally effective concentration (EC50: ≈3 nM), CGS21680 induced an approximately twofold increase in the mechanical response without causing an overt activation. This sensitization was abolished by the selective A2Aantagonist SCH58261. The adenylyl cyclase activator forskolin mimicked while the nonselective protein kinase inhibitor H89 inhibited mechanical sensitization by CGS21680. CGS21680 did not enhance the response to the purinergic P2X receptor agonist α,β-methylene-ATP, indicating that CGS21680 does not nonspecifically sensitize to all stimuli. Mechanical sensitization by CGS21680 was abolished by pretreatment with two structurally different TRPA1 antagonists AP18 and HC030031 . Single cell RT-PCR and whole cell patch-clamp studies in isolated esophagus-specific nodose neurons revealed the expression of TRPA1 in A2A-positive C-fiber neurons and demonstrated that CGS21682 potentiated TRPA1 currents evoked by allylisothiocyanate. We conclude that stimulation of the adenosine A2Areceptor induces mechanical sensitization of nodose C fibers by a mechanism sensitive to TRPA1 antagonists indicating the involvement of TRPA1.

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Anesthetic blockade of the dorsolateral funiculus enhances evoked activity of spinal cord dorsal horn neurons

Journal of Neurophysiology ◽

10.1152/jn.1991.66.1.140 ◽

1991 ◽

Vol 66 (1) ◽

pp. 140-152 ◽

Cited By ~ 10

Author(s):

L. M. Pubols ◽

D. A. Simone ◽

N. A. Bernau ◽

J. D. Atkinson

Keyword(s):

Spontaneous Activity ◽

Dorsal Horn ◽

Tibial Nerve ◽

Spinal Cord Dorsal Horn ◽

Dorsal Horn Neurons ◽

C Fibers ◽

C Fiber ◽

Dorsolateral Funiculus ◽

Electrical Stimuli ◽

Fiber Stimulation

1. A previous study of cat lumbar dorsal horn neurons found reduced responsiveness to A-fiber stimulation 1.5-12 h after thoracic dorsolateral funiculus (DLF) lesions. The present study was undertaken to determine whether this was due to the loss of descending activity or to factors specifically associated with injury by examining the response properties of dorsal horn cells before and during lidocaine blockade of the ipsilateral DLF. Electric shocks applied to the dorsal columns were used to search for dorsal horn cells. Noxious and nonnoxious cutaneous mechanical stimuli and graded electrical stimuli applied to the tibial nerve were used to activate peripheral afferent fibers. Cells were classed as low threshold (LT), high threshold (HT), or multireceptive (MR), according to their responses to natural stimuli. Baseline data were collected from a total of 58 cells. Twelve of these were further studied after lidocaine injection of the DLF. All cells examined with lidocaine were in dorsal horn laminae III-V. 2. All cells responded to activation of tibial nerve A fibers. However, the median threshold for the HT and MR cells (200 microA) was significantly higher than that of the LT cells (75 microA). Some cells in each class were also activated by C fibers (10, 70, and 64% of the LT, HT, and MR cells, respectively). 3. For the cells that were further characterized by lidocaine blockade of the DLF, all LT cells (n = 3) responded only to A-fiber stimulation, and all HT (n = 3) and MR cells (n = 6) responded to both A- and C-fiber stimulation. 4. For LT cells, responses evoked by mechanical and electrical stimuli were unaltered by lidocaine blockade. 5. HT and MR cells showed enhanced responses to electrical stimulation of C fibers during DLF blockade. There was no consistent effect of the blockade on A-fiber-evoked responses. 6. Two of three HT and four of six MR cells studied with lidocaine had spontaneous activity, which exhibited a small but significant increase during DLF blockade. 7. Receptive fields for noxious stimulation expanded in two of six MR cells during DLF blockade. Two of three HT cells developed responses to tactile stimuli during the blockade. 8. In two additional cells (1 HT and 1 MR), spontaneous activity and responses to C-fiber input increased after the DLF was cut.(ABSTRACT TRUNCATED AT 400 WORDS)

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Deoxycholic Acid Activates and Sensitizes Vagal Nociceptive Afferent C-fibers in Guinea Pig Esophagus

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00187.2021 ◽

2021 ◽

Author(s):

Xiaoyun Yu ◽

Youtian Hu ◽

Mingwei Yu ◽

Bradley J Undem ◽

Shaoyong Yu

Keyword(s):

Bile Acid ◽

Deoxycholic Acid ◽

Ex Vivo ◽

Acid Reflux ◽

Proton Pump Inhibitor Therapy ◽

Patch Clamp Recording ◽

C Fibers ◽

Subsequent Response ◽

C Fiber ◽

Inward Currents

Bile acid reflux in the esophagus plays a role in the pathogenesis of certain esophageal disorders where it can induce esophageal pain and heartburn. The present study aimed to determine whether bile acid, deoxycholic acid (DCA), directly activates and sensitizes esophageal vagal nociceptive afferent C-fiber subtypes. DCA-elicited effects on vagal nodose and jugular neurons were studied by calcium imaging. Its effects on esophageal-labeled nodose and jugular neurons were then determined by patch-clamp recording. At nodose and jugular C-fiber nerve endings in the esophagus, DCA-evoked action potentials (APs) were compared by extra-cellular single-unit recordings in ex vivo esophageal-vagal preparations. DCA application induced calcium influxes in nodose and jugular neurons and elicited inward currents in esophageal-labeled nodose and jugular neurons. In the presence of DCA, the current densities elicited by capsaicin were enhanced in those labeled neurons. Consistently, DCA perfusion at nerve terminals in the esophagus evoked APs in about 50% of esophageal nodose and jugular C-fibers. In DCA-sensitive C-fibers, DCA perfusion also sensitized the fibers such that the subsequent response to capsaicin was amplified. Collectively, these results provide new evidence that DCA directly activates and sensitizes nociceptive nodose and jugular C-fibers in the esophagus. Such activation and sensitization effects may contribute to bile acid-induced esophageal nociceptive symptoms that are refractory to proton-pump inhibitor therapy.

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Pattern of Cardiorespiratory Afferent Convergence to Solitary Tract Neurons Driven by Pulmonary Vagal C-Fiber Stimulation in the Mouse

Journal of Neurophysiology ◽

10.1152/jn.1998.79.5.2365 ◽

1998 ◽

Vol 79 (5) ◽

pp. 2365-2373 ◽

Cited By ~ 79

Author(s):

Julian F. R. Paton

Keyword(s):

Respiratory Activity ◽

Atrial Pressure ◽

Right Atrial ◽

Solitary Tract ◽

C Fibers ◽

C Fiber ◽

Central Respiratory Activity ◽

Fiber Stimulation ◽

Cardiac Receptors ◽

Stimulation Of

Paton, Julian F. R. Pattern of cardiorespiratory afferent convergence to solitary tract neurons driven by pulmonary vagal C-fiber stimulation in the mouse. J. Neurophysiol. 79: 2365–2373, 1998. The central integration of signals from pulmonary vagal C-fibers (or type-J receptors) with those arising from cardiac, peripheral chemoreceptor, and baroreceptor afferents to neurons within the nucleus of the solitary tract (NTS) was studied in an arterially perfused working heart–brain stem preparation of adult mouse. Pulmonary vagal C-fibers were excited by right atrial injection of phenylbiguanide (PBG) while cardiac receptors were stimulated by left ventricular injection of veratridine (1–3 μg/kg) or mechanically by distension of the left ventricle (20–50 μl perfusate) using an indwelling cannula. Carotid body chemoreceptors were activated by aortic injection of Na cyanide, whereas baroreceptors were stimulated by increasing arterial perfusion pressure. Stimulation of pulmonary C-fibers and cardiac, chemo-, and baroreceptors all produced a reflex bradycardia (23–133 bpm). Central respiratory activity, as recorded from the phrenic nerve, was depressed by stimulating pulmonary C-fibers and cardiac and baroreceptors but enhanced in amplitude and frequency during chemoreceptor stimulation. Twenty-seven NTS neurons were excited and three were inhibited after pulmonary C-fiber stimulation displaying decrementing discharges with a peak firing frequency of up to 42 Hz (15 ± 2.2 Hz, mean ± SE) that lasted for 8.8 ± 0.9 s. These responses occurred <1 s from the end of the PBG injection that was within the pulmonary circulation time. None of these cells responded to increases in right atrial pressure. All cells excited by PBG were also driven synaptically after electrical stimulation of the ipsilateral cervical vagus nerve at a latency of 32.9 ± 3.2 ms (range 20–62 ms). None of these neurons had ongoing activity related to central respiratory activity. Convergence from cardiorespiratory afferents to 21 neurons driven by pulmonary C-fibers was tested. Twenty-five percent of cells were selectively excited by chemical stimulation of cardiac receptors alone, 19% were driven by peripheral chemoreceptors, and 38% responded to both cardiac and chemoreceptor activation. In contrast, only 13% of the cells activated by PBG injection responded to stimulation of baroreceptors and only 6% to cardiac mechanoreceptor stimulation. None of these neurons were activated by increasing right atrial pressure. The data indicate a high proportion of afferent convergence from pulmonary C-fibers, cardiac receptors, and peripheral chemoreceptors in the NTS. However, these neurons appear not to integrate inputs from cardiovascular mechanoreceptors. The significance of the data is discussed in relation to pathological disease states such as pulmonary congestion and cardiac failure.

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Mast cell-mediated long-lasting increases in excitability of vagal C fibers in guinea pig esophagus

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00277.2007 ◽

2007 ◽

Vol 293 (4) ◽

pp. G850-G856 ◽

Cited By ~ 35

Author(s):

Shaoyong Yu ◽

Marian Kollarik ◽

Ann Ouyang ◽

Allen C. Myers ◽

Bradley J. Undem

Keyword(s):

Mast Cells ◽

Guinea Pig ◽

Action Potential ◽

Receptor Antagonist ◽

Ex Vivo ◽

Receptor Activation ◽

Intraluminal Pressure ◽

H1 Receptor ◽

C Fibers ◽

C Fiber

Several esophageal pathologies are associated with an increased number of mast cells in the esophageal wall. We addressed the hypothesis that activation of esophageal mast cells leads to an increase in the excitability of local sensory C fibers. Guinea pigs were actively sensitized to ovalbumin. The mast cells in the esophagus were selectively activated ex vivo by superfusion with ovalbumin. Action potential discharge in guinea pig vagal nodose esophageal C-fiber nerve endings was monitored in the isolated (ex vivo) vagally innervated esophagus by extracellular recordings. Ovalbumin activated esophageal mast cells, leading to the rapid release of ∼20% of the tissue histamine stores. This was associated with a consistent and significant increase in excitability of the nodose C fibers as reflected in a two- to threefold increase in action potential discharge frequency evoked by mechanical (increases in intraluminal pressure) stimulation. The increase in excitability persisted unchanged for at least 90 min (longest time period tested) after ovalbumin was washed from the tissue. This effect could be prevented by the histamine H1 receptor antagonist pyrilamine, but once the increase in excitability occurred, it persisted in the nominal absence of histamine and could not be reversed even with large concentrations of the histamine receptor antagonist. In conclusion, activation of esophageal mast cells leads to a pronounced and long-lived increase in nociceptive C-fiber excitability such that any sensation or reflex evoked via the vagal nociceptors will likely be enhanced. The effect is initiated by histamine acting via H1 receptor activation and maintained in the absence of the initiating stimulus.

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Baclofen attenuates cardiorespiratory effects of vagal C fiber stimulation in rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y95-206 ◽

1995 ◽

Vol 73 (10) ◽

pp. 1485-1494 ◽

Cited By ~ 9

Author(s):

Erin Seifert ◽

Teresa Trippenbach

Keyword(s):

Nucleus Tractus Solitarius ◽

Control Of Breathing ◽

Aminobutyric Acid ◽

C Fibers ◽

Arterial Blood ◽

Cardiorespiratory Response ◽

C Fiber ◽

The Right ◽

Fiber Stimulation ◽

Cgp 35348

We tested the hypothesis that γ-aminobutyric acid (GABA) acting on GABAB receptors modulates vagal C fiber mediated reflexes. The effects of a GABAB receptor agonist, (−)-baclofen, injected bilaterally into the nucleus tractus solitarius (NTS), on the cardiorespiratory response to C fiber stimulation with phenyldiguanide (PDG) introduced into the right atrium were evaluated in urethane-anesthetized Wistar rats. We recorded integrated diaphragmatic EMG (Di) and mean arterial blood pressure (ABP). Before injections of baclofen into the NTS, PDG caused bradycardia, hypotension, and apnea, followed by a decrease in Di amplitude and variable changes in respiratory timing. Only injections of baclofen at 0.6 mm caudal to the obex reduced or prevented the PDG-evoked apnea. In contrast, independent of site of injection baclofen diminished bradycardia and the decrease in Di in postapnea breaths. The ABP response to PDG was never affected by baclofen. A GABAB receptor antagonist, CGP 35348, fully restored the responses to PDG, but CGP 35348 alone did not affect the responses to PDG. Our results suggest that GABAB receptors are present on neurons in the medullary pathway of vagal C fibers. In the caudal NTS, GABAB receptors modulate the PDG-evoked apnea, and within the larger area of the NTS these receptors modulate bradycardia and postapnea patterns of breathing. The absence of effects of CGP 35348 alone implies that GABAB receptors on the vagal C fiber pathway are not tonically active in rats.Key words: control of breathing, phenyldiguanide, CGP 35348, GABAB receptors, pulmonary chemoreflex.

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Regional Genetic Responses of Porcine Talar Articular Cartilage to Impact Injury

Foot & Ankle Orthopaedics ◽

10.1177/2473011419s00121 ◽

2019 ◽

Vol 4 (4) ◽

pp. 2473011419S0012

Author(s):

Evan (Hank) Bryant ◽

Kailey Mansour ◽

C.Y. Charles Huang ◽

Jonathan R. Kaplan ◽

Amiethab A. Aiyer

Keyword(s):

Articular Cartilage ◽

Ex Vivo ◽

Cartilage Damage ◽

Rna Extraction ◽

Posterior Region ◽

Anterior Region ◽

Inferior Aspect ◽

Catabolic Genes ◽

Post Traumatic ◽

Impact Injury

Category: Ankle Arthritis Introduction/Purpose: The ankle is at greatest risk for post-traumatic osteoarthritis (PTOA) in comparison to the hip or knee. Adaptive changes to the cartilaginous topography may be a marker for where cartilage damage poses the greatest risk of development of osteoarthritis. The objective of this study was to elucidate the mechanism of PTOA by analyzing the changes in regional genetic expression of inflammatory markers after impact injury in an ex-vivo porcine model. Methods: Talus bones were recovered from 5 porcine ankles. A drop tower was used to induce injury by dropping a 1000 g weight from a height of 15 cm on the talus. Following the injury the bone was cultured for 24 hours. Four 6-mm cartilage plugs were harvested from the inferior aspect of each talus bone and a small slice of each plug was used for cell imaging. The remaining cartilage plugs were flash frozen with liquid nitrogen and stored at -80°C for ribonucleic acid (RNA) extraction and analysis of gene expression. Expression of inflammatory and catabolic genes (IL1-ß, TNF-a, ADAMTS-5, ADAMTS-4, MMP-3 and MMP-13) was compared among the samples obtained from the non-impacted and impacted sites of the anterior and posterior regions. Student t-test was performed to examine the differences between the control (non-impact) and impacted samples from each region and between the control samples from the anterior and posterior regions. Results: The current porcine impact model demonstrated significant up-regulation of several inflammatory cytokines and metalloproteinases by impact force. Among the genes tested, TNF-a, ADAMTS-4, and MMP-3 showed increased expression at impact sites (p<0.05) compared to non-impact sites in the posterior region (Figure 1) whereas no differences were found in the anterior region. Interestingly, the non-impacted samples in the anterior region exhibited significantly higher expression of TNF-a, ADAMTS-4, MMP-3 and ADAMTS-5 than those of the posterior region (p<0.05). Conclusion: The results of the current ex-vivo porcine impact study demonstrate significant up-regulation of inflammatory and catabolic genes 24 hours after porcine talus bone impaction. These findings highlight the relevance of regional differences in post- traumatic ankle inflammation; the posterior region of porcine talar articular cartilage demonstrated increased sensitivity in response to injury. The anterior region illustrated greater resistance to injury, showing less gene up-regulation compared to the posterior region of the same ankle. These findings suggest that location of cartilage injury may play a crucial role in the development of inflammatory response, chondrocyte apoptosis, and subsequent osteoarthritis of the ankle.

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Pulmonary C-fiber stimulation by capsaicin evokes reflex cholinergic bronchial vasodilation in sheep

Journal of Applied Physiology ◽

10.1152/jappl.1992.72.2.770 ◽

1992 ◽

Vol 72 (2) ◽

pp. 770-778 ◽

Cited By ~ 17

Author(s):

H. M. Coleridge ◽

J. C. Coleridge ◽

J. F. Green ◽

G. H. Parsons

Keyword(s):

Bronchial Artery ◽

Systemic Arterial Pressure ◽

Right Atrial ◽

Adrenergic Blockade ◽

C Fibers ◽

Arterial Blood ◽

C Fiber ◽

The Common ◽

Vagal Cooling ◽

Fiber Stimulation

We investigated changes in bronchial blood flow (Qbr) associated with capsaicin-induced stimulation of pulmonary C-fibers in seven anesthetized and two unanesthetized sheep. A Doppler flow probe chronically implanted around the common bronchial artery provided a signal (delta F, kHz) linearly related to bronchial arterial blood velocity (Vbr, cm/s), which was proportional to Qbr. An index of bronchial vascular conductance (Cbr, in arbitrary units) was calculated as the ratio of Vbr to systemic arterial pressure (Pa). Right atrial injection of capsaicin evoked a prompt pulmonary chemoreflex (apnea, bradycardia, and hypotension), with immediate increases in Vbr (average +34%) and Cbr (+63%) that reached a maximum approximately 7 s after the injection. A second increase in Vbr, but not in Cbr, occurred approximately 12 s later, coinciding with an increase in Pa. Vagal cooling (0 degrees C) prevented the pulmonary chemoreflex; it also abolished the immediate increases in Vbr and Cbr in four of six sheep and substantially reduced them in two sheep; it did not affect the late increases in Vbr and Pa. Results after atropine indicated that the immediate increases in Vbr and Cbr were mainly cholinergic. In two sheep a small residual vasodilation survived combined cholinergic and adrenergic blockade and may have been due to peripheral release of neurokinins.

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