Stimulation of rapidly adapting receptors in canine lungs by a single breath of cigarette smoke

Inhalation of smoke generated from high-nicotine cigarettes frequently evoked an immediate augmented inspiration in conscious dogs (J. Appl. Physiol. 54: 562-570, 1983); this reflex response was believed to result from a stimulation of rapidly adapting receptors in the lungs. To test this hypothesis, we recorded the vagal afferent activity arising from the rapidly adapting receptors in the lungs and delivered 120 ml of high- and low-nicotine cigarette smoke separately in a single ventilatory cycle in 20 anesthetized open-chest and artificially ventilated dogs. These receptors were stimulated on the first breath of delivery of smoke generated by high-nicotine cigarettes; activity increased from a base line of 0.9 +/- 0.2 to a peak of 9.9 +/- 1.2 (SE) impulses/breath (n = 58). After three to six breaths when the receptors' discharge returned toward base-line activity, a delayed increase of activity emerged (peak activity = 3.4 +/- 0.6 impulses/breath, n = 58) in 32 of the 58 receptors studied and lasted for three to seven breaths. By contrast, only a mild stimulatory effect of low-nicotine cigarette smoke was found, either immediately or after a delay, in 15 of the 54 receptors studied. We conclude that rapidly adapting receptors are stimulated by a single breath of cigarette smoke and that nicotine is the primary stimulant agent.     

Stimulation of vagal pulmonary C fibers by inhaled wood smoke in rats

Lai, C. J., and Y. R. Kou. Stimulation of vagalpulmonary C fibers by inhaled wood smoke in rats. J. Appl. Physiol. 84(1): 30-36, 1998.This studyinvestigated the stimulation of vagal pulmonary C fibers (PCs) by woodsmoke. We recorded impulses from PCs in 58 anesthetized, open-chest,and artificially ventilated rats and delivered 6 ml of wood smoke intothe lungs. Within 1 or 2 s after the smoke delivery, an intense andnonphasic burst of discharge [ = +7.4 ± 0.7 (SE)impulses/s, n = 68] was evoked in 60 of the 68 PCs studied and lasted for 4-8 s. This immediate stimulation was usually followed by a delayed and more sustained increase in C-fiber activity ( = +2.0 ± 0.4 impulses/s). The overall stimulation was not influenced by removal of smoke particulates (n = 15) or by pretreatment withvehicle (n = 8) for dimethylthiourea (DMTU; a hydroxyl radical scavenger) or indomethacin (Indo; a cyclooxygenase inhibitor). The immediate-phase stimulation was notaffected by pretreatment with Indo (n = 8) but was largely attenuated by pretreatment with DMTU(n = 12) or by a combined treatmentwith DMTU and Indo (DMTU+Indo; n = 8).Conversely, the delayed-phase stimulation was partially suppressedeither by DMTU or by Indo but was totally abolished by DMTU+Indo. Theseresults suggest that 1) thestimulation of PCs is linked to the gas phase of wood smoke and2) hydroxyl radical, but notcyclooxygenase products, is involved in the immediate-phasestimulation, whereas both metabolites are responsible for evoking thedelayed-phase stimulation.

     

Changes measured in arterial blood following a single breath of cigarette smoke in rabbits.

This paper describes a method for monitoring short term changes in arterial blood in rabbits in response to a single breath of cigarette smoke. The method was developed to investigate the observation that neutrophil transit times through the lung are extended during acute exposures to cigarette smoke (1). In this model, we sought to monitor the time course of appearance of diffusible gas from smoke to the blood stream, the appearance of lipid peroxidation products and the activation of neutrophils. New Zealand white rabbits were anesthetized and fitted with a tracheostomy tube and an aortic catheter. Smoke was collected in a syringe from a non-filtered cigarette and injected immediately via the tracheostomy tube. Blood samples were collected at 1 second intervals. Carboxyhemoglobin levels increased 108% over pre-smoke levels, peaking at 5-7 seconds after the start of smoke exposure. Serum conjugated dienes, as measured by change in absorbance of lipid extracts at 234 nm, increased 40%, peaking at 10-11 seconds. Thiobarbituric acid (TBA) reactive material exhibited a variable response, with a statistically insignificant maximum at 12 seconds. Serum myeloperoxidase activity was not affected by smoke inhalation. This method provides a model for studying the acute effects of smoke inhalation and provides some evidence for oxidant stress following a single breath of cigarette smoke.     

Effect of chronic cigarette smoke exposure on pulmonary vasomotion in beagle dogs

To study the effect of chronic cigarette smoke exposure on the resistive properties of the pulmonary vasculature, left lower lobes from 12 control beagles and 6 beagles who had smoked cigarettes (50 cigarettes/wk for 40 wk) were perfused in situ to measure the vascular pressure-flow relationship and the resistance of the three vascular segments with the arterial and venous occlusion technique. In control subjects the vascular resistance in the arterial, middle, and venous segments was 23, 36, and 41% of the total, respectively. The segmental distribution of vascular resistance was not significantly different in the cigarette smoke-exposed dogs, despite the fact that the absolute values were 30-40% less than that of the control group. The longitudinal distribution of resistance among the three vascular segments and their response to drugs were different in beagles than was previously found in mongrels. In all beagles the veins were considerably more reactive than arteries. Vasoconstriction with serotonin (5-HT) prostaglandin F2 alpha (PGF2 alpha), norepinephrine, histamine, and methacholine (M) infusion occurred predominantly in the veins. The effect of PGF2 alpha and 5-HT was totally different than that previously observed in mongrels in which the constriction was predominantly in the arteries. Chronic cigarette smoking reduced the basal pulmonary vascular resistance and attenuated the venoconstrictor response to 5-HT and M but potentiated the hypoxic pressor response of the microvessels.     

Two subgroups of lung vagal C-fibers with different vulnerabilities to blockades by perivagal capsaicin and vagal cooling in dogs

Perivagal capsaicin treatment and vagal cooling are two techniques that have been widely used to study the respiratory reflexes mediated by lung vagal C-fibers because they can block the neural conduction of unmyelinated fibers. We hypothesized that there are two subgroups of lung vagal C-fibers which have different vulnerabilities to blockades by these two techniques. To test this hypothesis, afferent activity arising from lung vagal C-fibers was recorded in 29 anesthetized, paralyzed, and artificially ventilated dogs. Afferent C-fiber activity was recorded before and after various concentrations of perivagal capsaicin treatment or before and during various temperatures of vagal cooling. Of the 89 lung vagal C-fibers studied, 73 fibers were classified as the group of "low resistance" to capsaicin, while the other 16 were classified as the group of "high resistance". The former group differed from the latter due to their afferent activity being blocked at relatively low concentrations of perivagal capsaicin and at relatively low temperatures of vagal cooling. Our results suggest that lung vagal C-fibers can be categorized into two subgroups, based upon their different blocking thresholds for perivagal capsaicin and vagal cooling. Our data may provide information for researchers to further differentiate the respiratory reflexes originating from these two subgroups of lung vagal C-fibers.     

Stimulation of vagal C-fibers alters timing and distribution of respiratory motor output in cats

Pulmonary vascular congestion or pulmonary embolism in humans produces shallow tachypnea, and indirect experimental evidence suggests that this characteristic breathing pattern may result from activation of vagal unmyelinated afferents from the lung. We have investigated, in decerebrate cats, reflex changes in breathing pattern and in the activation of the diaphragm, posterior cricoarytenoid, and thyroarytenoid muscles caused by activating C-fiber afferents in the vagus nerve. The right vagus nerve was sectioned distal to the origin of the recurrent laryngeal nerve, eliminating vagal afferent traffic although preserving motor innervation of the larynx on that side. The left cervical vagus was stimulated electrically, and efferent activation of the laryngeal muscles was avoided by cutting the left recurrent laryngeal nerve. Transmission to the brain of vagal afferent traffic resulting from this stimulation was controlled by graded cold block of the nerve cranial to the site of application of the stimulus. Activation of C-fibers, when A-fibers were blocked, significantly decreased respiratory period and amplitude of diaphragm inspiratory burst. In addition, this selective activation of vagal C-fibers augmented postinspiratory activity of the diaphragm and recruited phasic expiratory bursts in the thyroarytenoid. We conclude that, in unanesthetized decerebrate cats, afferent traffic of vagal C-fibers initiates a pontomedullary reflex that increases respiratory frequency, decreases tidal volume, and augments braking of expiratory airflow.     

Reflex cardiovascular responses caused by stimulation of pulmonary C-fibers with capsaicin in dogs

The purpose of these studies was to determine quantitatively the reflex cardiovascular responses to stimulation of the pulmonary C-fibers in dogs. We used a preparation in which the airway, pulmonary artery, and the pulmonary veins to the left lung were cannulated in situ. Ventilation and perfusion of the right lung maintained the animal in relatively normal homeostasis. Capsaicin, a decylenic acid amide of vanillylamine that selectively stimulates nerve endings of unmyelinated fibers (C-fibers), was injected into the left pulmonary artery in 5-ml boluses. Maximal reflex responses were obtained with concentrations as low as 0.8-1.6 X micrograms-1 X kg-1. Heart rate, hindlimb resistance, and left ventricular contractility were lowered transiently (the maximal responses showing declines of 40, 13, and 15.2%, respectively). As a result of these changes, combined with vasodilation in other resistance vessels, cardiac output fell 28% and blood pressure fell 35%. Interrupting the afferent neural pathway by severing the ipsilateral cervical vagus nerve eliminated these responses, confirming the distribution of their reflex origin. Although the role of these reflexes in homeostasis has not been decided, the results of this study suggest that the lungs of dogs, if appropriately stimulated, potentially can exert a major inhibitory influence on the neural regulation of cardiovascular function.     

Effect of PEEP on discharge of pulmonary C-fibers in dogs

Although positive end-expiratory pressure (PEEP) is believed to depress cardiac output and arterial pressure by compressing the vena cava and the heart, it is unclear whether PEEP also depresses these variables by a reflex arising from an inflation-induced stimulation of pulmonary C-fibers. We therefore recorded the impulse activity of 17 pulmonary C-fibers in barbiturate-anesthetized dogs with closed chests, while we placed the expiratory outlet of a ventilator under 5-30 cmH2O. Increasing PEEP in a ramp-like manner stimulated 12 of the 17 pulmonary C-fibers, with activity increasing from 0.0 +/- 0.1 to 0.9 +/- 0.2 imp/s when end-expiratory pressure equaled 15 cmH2O. When PEEP was increased in a stepwise manner to 15-20 cmH2O and maintained at this pressure for 15 min, pulmonary C-fibers increased their firing rates, but the effect was small averaging 0.2-0.3 imp/s after the 1st min of this maneuver. We conclude that pulmonary C-fibers are unlikely to be responsible for causing much of the decreases in cardiac output and arterial pressure evoked by sustained periods of PEEP in both patients and laboratory animals. These C-fibers, however, are likely to be responsible for causing the reflex decreases in these variables evoked by sudden application of PEEP.     

Nicotine-induced respiratory effects of cigarette smoke in dogs

We report that nicotine is responsible for both a blood-borne stimulation of the respiratory center and a direct effect on intrathoracic airway tone in dogs. We introduced cigarette smoke into the lungs of donor dogs and injected arterial blood obtained from them into the circulation of recipient dogs to show that a blood-borne material increased breathing and airway smooth muscle tone. Smoke from cigarettes containing 2.64 mg of nicotine was effective; that from cigarettes containing 0.42 mg of nicotine was not. Nicotine, in doses comparable to the amounts absorbed from smoke, also increased breathing and tracheal smooth muscle tension when injected into the vertebral circulation of recipient dogs. Finally, blockade of nicotine receptors in the central nervous system and in the airway parasympathetic ganglia inhibited the effects of inhaled cigarette smoke and intravenous nicotine on the respiratory center and on bronchomotor tone. We conclude that nicotine absorbed from cigarette smoke is the main cause of cigarette smoke-induced bronchoconstriction. It caused central respiratory stimulation, resulting in increased breathing and airway smooth muscle tension, and had a direct effect on airway parasympathetic ganglia as well.     

Mechanisms of stimulation of vagal pulmonary C fibers by pulmonary air embolism in dogs

Chen, H. F., B. P. Lee, and Y. R. Kou. Mechanisms ofstimulation of vagal pulmonary C fibers by pulmonary air embolism indogs. J. Appl. Physiol. 82(3):765-771, 1997.We investigated the involvement of thecyclooxygenase metabolites and hydroxyl radical (^· OH) in thestimulation of vagal pulmonary C fibers (PCs) by pulmonary air embolism(PAE). Impulses were recorded from PCs in 51 anesthetized, open-chest,and artificially ventilated dogs. Fifty of 59 PCs were stimulated byinfusion of air into the right atrium (0.2 ml ^· kg^{1 ·} min¹for 10 min). As a group (n = 59), PCactivity increased from a baseline of 0.4 ± 0.1 to a peak of 1.7 ± 0.2 impulses/s during the period from 1 min before to 2 min afterthe termination of PAE induction. In PCs initially stimulated by PAEinduction, PAE was repeated after the intervening treatment (iv) withsaline (n = 9), ibuprofen (acyclooxygenase inhibitor; n = 11), ordimethylthiourea (a ^· OH scavenger;n = 12). The responses of PCs to PAEwere not altered by saline vehicle but were abolished by ibuprofen and significantly attenuated by dimethylthiourea. Although hyperinflation of the lungs reversed the PAE-induced bronchomotor responses, it didnot reverse the stimulation of PCs (n = 8). These results suggest that 1)cyclooxygenase products are necessary for the stimulation of PCs byPAE, whereas changes in lung mechanics are not, and2) the functional importance ofcyclooxygenase products may be mediated in part through the formationof ^· OH.

     

Acute effects of cigarette smoke on breathing in rats: vagal and nonvagal mechanisms

The acute ventilatory response to inhalation of cigarette smoke was studied in anesthetized Sprague-Dawley rats. Cigarette smoke (6 ml, 50%) generated by a machine was inhaled spontaneously via a tracheal cannula. Within the first two breaths of smoke inhalation, a slowing of respiration resulting from a prolonged expiratory duration (173 +/- 6% of the base line; n = 32) was elicited in 88% of the rats studied. This initial inhibitory effect on breathing was not affected either by an increase (410%) in the nicotine content of the cigarette smoke or by pretreatment with hexamethonium (33 mg/kg iv). However, bilateral vagotomy completely eliminated the initial ventilatory inhibition. Cooling both vagi to 5.1 degrees C blocked the reflex apneic response to lung inflation, but it did not abolish the inhibitory effect of smoke. After the initial response, a rapid shallow breathing pattern developed and reached its peak 5-12 breaths after inhalation of high-nicotine cigarette smoke; this delayed response could not be prevented by vagotomy and was undetectable after inhalation of low-nicotine smoke. We conclude that the initial inhibitory effect of smoke on breathing is mediated by vagal bronchopulmonary C-fiber afferents, which are stimulated by smoke constituents other than nicotine, whereas the delayed tachypneic response to smoke is caused by the absorbed nicotine.     

Stimulation of rapidly adapting pulmonary stretch receptors by pulmonary lymphatic obstruction in dogs

The effects of pulmonary lymphatic obstruction and pulmonary venous congestion on the activities of slowly adapting receptors (SAR) and rapidly adapting receptors (RAR) of the airways were examined in anaesthetized, artificially ventilated dogs. In 11 out of 12 RAR (12 dogs) examined, pulmonary lymphatic obstruction for a period of 20 min produced a sustained significant increase in activity without a significant change in peak airway pressure and dynamic compliance. The activity remained significantly elevated even after the pulmonary lymphatic obstruction was released. This stimulus was without effect on the SAR (n = 5 dogs). Pulmonary venous congestion alone increased the RAR activity (n = 7 dogs) significantly without producing significant changes in airway mechanics. Lymphatic obstruction, when superimposed upon congestion, did not produce a further significant increase in activity. In four dogs the effect of pulmonary venous congestion (left atrial pressure increased from 7.6 +/- 1.7 to 16.3 +/- 2.7 mmHg) (1 mmHg = 133.3 Pa) on pulmonary lymphatic flow was examined. The procedure caused a significant increase in lymph flow. These results suggest that in the dog, the RAR activity is influenced by changes in the pulmonary extravascular space.     

Acute effects of cigarette smoke inhalation on peripheral airways in dogs

We studied the acute effects of the inhalation of cigarette smoke on the central and peripheral airways of 35 open-chested and tracheotomized dogs by the direct measurement of central (Rc) and peripheral (Rp) airway resistances. Rc was calculated by dividing the pressure difference between a tracheal catheter and a retrograde catheter by mouth flow, and Rp was obtained by dividing the pressure difference between the retrograde catheter and a pleural capsule by mouth flow. The pleural capsule was attached to the pleural surface for alveolar pressure measurement. Rc and Rp were measured by the 2-Hz forced oscillation method. With lung inhalation of the smoke of two-thirds of one cigarette in vagi intact dogs, Rp increased to 239% of the control value and Rc increased to 112%. After bilateral vagotomy, Rp increased to 143% and Rc increased to 104%. Propranolol did not influence the results. Hexamethonium and atropine both blocked these responses when vagi were intact. When the upper trachea, larynx, and nasopharynx, which were completely blocked by vagotomy, were exposed to the smoke of two-thirds of a cigarette, Rp increased to 155% and Rc increased to 144%. We thus conclude that cigarette smoke causes a major increase in Rp, mainly via the vagal reflex and partially via the stimulation of parasympathetic ganglia (probably nicotine), and a minor increase in Rc via vagal reflex.