Sympathetic and parasympathetic nervous control of airway resistance in dog lungs

We studied autonomic nervous control of central (Rc), peripheral (Rp), and extremely peripheral (Rep) airway resistances using a combination of a retrograde catheter method and a pleural capsule method. Airflow through the pleural capsule enabled us to measure Rep, which mainly reflected the resistance of local bronchioles less than 0.6 mm in diameter. Rp of the airways less than about 2 mm in diameter was not negligibly small at any lung volume (VL). With vagi intact, Rc increased at high as well as low VL, whereas Rp and Rep increased sharply as VL decreased. Vagal stimulation increased Rp more markedly than Rc, and Rep least of all. Propranolol augmented total airway resistance (Rtot) two to four times as much as vagal stimulation, mainly because of increased Rp. Stimulation of stellate ganglia inhibited up to half the increase of Rtot elicited by vagal stimulation; most of the inhibition occurred in Rp, but little in Rc and Rep. Our data suggest that both sympathetic and parasympathetic control is more extensive for Rp than for Rc or Rep.     

Effects of hemodynamic edema formation on peripheral vs. central airway mechanics

The mechanisms governing increased central (Rc) and peripheral airway resistance (Rp) during hemodynamic edema formation were studied in anesthetized dogs. Rc and Rp were measured by forced oscillation at 1 Hz by use of a retrograde catheter to partition resistance and a pleural capsule to detect alveolar pressure. After elevation of left atrial pressure to 30 cmH2O by inflation of the left atrial balloon, Rc gradually increased an average of 60% above control in approximately 100 min. Vagotomy had a small influence on the change. On the other hand, Rp with vagus nerves intact increased triphasically: first, it increased transiently by 160% above the control value within 15-20 min before returning to near base line. It then increased gradually for approximately 40 min and finally rose sharply up to five times the control value after approximately 100 min. With vagi cut, the initial phase disappeared, but the second gradual and final rapid phases were not affected. Several sequential mechanisms of increased Rp can be proposed: 1) transient bronchoconstriction mediated by vagal reflex; 2) gradual formation of peribronchial edema; and 3) a sharp increase in airway fluid and formation of bronchial froth. In addition, narrowing of the airways by vascular engorgement may have contributed to the increase of Rp throughout all stages.     

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.     

Role of bronchopulmonary C-fiber afferents in the apneic response to cigarette smoke

The role of vagal bronchopulmonary C-fiber afferents in eliciting the immediate changes in breathing pattern after acute inhalation of cigarette smoke was assessed with a selective blockade of myelinated vagal afferents (innervating both stretch and irritant receptors) utilizing the method of differential cooling. In 15 of 17 chloralose-anesthetized dogs tested, spontaneous inhalation of cigarette smoke (19.7% avg conc, 500-700 ml vol) reproducibly caused the following immediate responses: apnea, bradycardia, and hypotension. These responses occurred within 1 to 2 breaths of smoke inhalation and were followed by a delayed hyperpnea. The apneic duration reached 326 +/- 33% (SE) (n = 15) of the mean base-line expiratory duration. Differential cold block of both vagi (coolant temperature 8.4 +/- 0.3 degrees C) abolished the reflex apnea induced by a positive-pressure (7-10 cmH2O) lung inflation but did not affect the apneic response to smoke inhalation (345 +/- 35%). The smoke-induced apnea was completely abolished by lowering the coolant temperature to -1.3 +/- 0.2 degrees C (n = 10) or by bilateral vagotomy (n = 5) and returned to the control level after both vagi were rewarmed. Based on these results, we suggest that the immediate apneic response to inhaled cigarette smoke is elicited by a stimulation of vagal C-fiber afferents in the lungs and airways.     

Dose-response curves of central and peripheral airways to nicotine injections in dogs

The dose-response curves of the central and peripheral airways to intravenously injected nicotine were studied in 55 anesthetized dogs. With intact vagi, nicotine caused a dose-dependent increase in central airway resistance (Rc) similar to the increase in peripheral airway resistance (Rp) at concentrations ranging from 4 to 64 micrograms/kg. However, the responses of both Rc and Rp fell progressively when sequential doses of nicotine greater than 256 micrograms/kg were administered. With intact vagi and the administration of propranolol, there was a greater increase in Rp than in Rc at a nicotine dose of 64 micrograms/kg (P less than 0.05). With vagotomy, the responsiveness of both central and peripheral airways to nicotine decreased with doses of nicotine less than 64 micrograms/kg, but with doses of nicotine greater than 256 micrograms/kg the suppressive effect of nicotine on both Rc and Rp was less than that seen with intact vagi. Under conditions in which the vagi were cut and atropine administered, the responsiveness of nicotine was even further depressed. Combinations either of atropine and chlorpheniramine or atropine and phenoxybenzamine also completely blocked reactions to nicotine. Additionally reactions to nicotine were completely blocked by hexamethonium. These results suggest that nicotine increases both Rc and Rp mainly through a vagal reflex and stimulation of the parasympathetic ganglia.     

Vagal control of central and peripheral pulmonary resistance in developing piglets

To study the postnatal maturation of vagal control of airway muscle tone, we determined the effects of vagotomy and supramaximal vagal stimulation on the resistance of the respiratory system in eight newborn and seven 6-wk-old piglets. Because the lung periphery has distinctive responses to cholinergic agonists and a lower density of vagal fibers and cholinergic receptors than the central airways, we partitioned the respiratory resistance of the piglets between central airways (Rc) and peripheral airways and lung tissue (Rp) with bronchial catheters inserted in a retrograde manner. The piglets were anesthetized with alpha-chloralose and ventilated with positive airway pressure. Vagotomy did not change Rc or Rp in either the newborn or the 6-wk-old piglets. Vagal stimulation, on the other hand, increased both Rc (median increase 53% in the newborn and 72% in the 6-wk-old piglets) and Rp (54 and 42%, respectively). At all states of vagal tone, Rp increased as the lungs were inflated, suggesting a large contribution of tissue viscoelasticity to this resistance. Our results demonstrate that vagal bronchomotor tone is absent during mechanical ventilation with positive pressure in the developing piglet. However, vagal innervation of both central airways and tissue contractile elements is functionally competent at the time of birth in this species.     

Partitioning of pulmonary resistance in calves

Nine right apical lobes of healthy Friesian calves and 10 right apical lobes of double-muscled calves of Belgian White and Blue (BWB) breed were suspended in an airtight box, inflated at a constant transpulmonary pressure (Ptp), and subjected to quasi-sinusoidal pressure changes (amplitude: 0.5 kPa) at a frequency of 30 cycles/min. Lobar resistance (RL) was partitioned at six different lung volumes into three components: central airway resistance (Rc), small airway resistance (Rp), and tissue resistance (Rt). Pressure in small airways (2-3 mm ID) was measured with a retrograde catheter. Alveolar pressure was sampled in capsules glued onto the punctured pleural surface. RL was minimal at values of Ptp comprised between 0.5 and 0.7 kPa and increased at higher and lower values of Ptp. At a Ptp of 0.5 kPa, Rc, Rp, and Rt represented 30, 15, and 55% of RL, respectively, in Friesian calves and 25, 25, and 50% in BWB calves. Rp increased markedly at low lung volumes. Rt was responsible for the increase of RL at high Ptp. Rc tended to decrease at high Ptp. The significantly higher values of Rp in BWB calves (P less than 0.05) might explain the sensitivity of this breed to severe bronchopneumonia.     

Acute effects of acrolein on breathing: role of vagal bronchopulmonary afferents.

Spontaneous inhalation of acrolein vapor (350 ppm, 1 ml/100 g body wt) elicited an immediate and transient inhibitory effect on breathing in anesthetized rats, characterized by a prolongation of expiratory duration and accompanied by a bradycardia; ventilation was reduced by 47 +/- 6%, which returned to baseline after three to seven breaths. When both vagi were cooled to 6.6 +/- 0.1 degrees C, the reflex apneic response to lung inflation was completely abolished but the bradypneic response to acrolein was not affected. After perineural capsaicin treatment of both cervical vagi to selectively block the capsaicin-sensitive C-fiber afferents, acrolein no longer evoked an inhibitory effect on breathing; conversely, an augmented inspiration was consistently elicited with the first breath of acrolein inhalation, which was subsequently abolished by cooling both vagi to 6.5 degrees C. The inhibitory effect of inhaling acrolein at a lower concentration (200 ppm) was not detectable, whereas that of a higher concentration (600 ppm) was more intense and prolonged. All these responses were completely eliminated by bilateral vagotomy. These results suggest that inhaled acrolein activated both vagal C-fiber endings and rapidly adapting irritant receptors in the airways, but the acrolein-induced inhibitory effect on breathing was elicited primarily by the C-fiber afferent stimulation.     

Relationship of central and peripheral airway resistance to lung volume in dogs

We could not reconcile reported relationships between lung resistance measurements and lung volume with bronchographic and anatomic studies showing that airway diameters change monotonically with lung volume and that small airways change diameter proportionately at least as much as large ones. Accordingly we measured central and peripheral airways resistances with a new technique. The relevant pressures were measured with a tracheal cannula, a wedged retrograde catheter, and two parenchymal needles in seven open-chested dogs while pleural pressure was oscillated at 1 Hz. In contrast to previous studies, the volume dependency of peripheral resistance was at least as great as that of central resistance with vagi intact, the volume dependencies of central and peripheral resistances were not abolished by vagotomy, and neither resistance increased systematically at high volumes. Volume dependency of central resistance resembled predictions for isotropic expansion of airways with vagi cut but increased with bronchomotor tone. These results fit generally with bronchographic data. Previous studies may have been affected by volume dependency due to "tissue resistance" and catheter phase lags.     

Cigarette smoke-induced bronchoconstriction in dogs: vagal and extravagal mechanisms

We reassessed the severity of cigarette smoke-induced bronchoconstriction and the mechanisms involved in anesthetized dogs. To evaluate the severity of smoke-induced bronchoconstriction, we measured airway pressure and airflow resistance (Rrs, forced oscillation method). We studied the mechanisms in other dogs by measuring airway pressure, central airway smooth muscle tone in tracheal segments in situ, and respiratory center drive by monitoring phrenic motor nerve output, including the role of vagal and extravagal nerves vs. the role of blood-borne materials during inhalation of cigarette smoke. Rrs increased more than fourfold with smoke from one cigarette delivered in two tidal volumes. About half the airway response was due to local effects of smoke in the lungs. The remainder was due to stimulation of the respiratory center, which activated vagal motor efferents to the airway smooth muscle. Of this central stimulation, about half was due to blood-borne materials and the rest to vagal pulmonary afferents from the lungs. We conclude that inhalation of cigarette smoke in dogs causes severe bronchoconstriction which is mediated mainly by extravagal mechanisms.     

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.     

Stimulation of vagal pulmonary C-fibers by a single breath of cigarette smoke in dogs

Inhalation of cigarette smoke into the lower airway via a tracheostomy evokes immediate apnea, bradycardia, and systemic hypotension in dogs. These responses can still be evoked when conduction in myelinated vagal fibers is blocked preferentially by cooling but are abolished by vagotomy, suggesting that they are mediated by afferent vagal C-fibers. To examine this possibility, we recorded impulses in pulmonary C-fibers in anesthetized, open-chest dogs and delivered 120 ml cigarette smoke to the lungs in a single ventilatory cycle. Pulmonary C-fibers were stimulated within 1 or 2 s of the delivery of smoke generated by high-nicotine cigarettes, activity increasing from 0.3 +/- 0.1 to a peak of 12.6 +/- 1.3 (SE) impulses/s, (n = 60); the evoked discharge usually lasted 3-5 s. Smoke generated by low-nicotine cigarettes evoked a milder stimulation in 33% of pulmonary C-fibers but did not significantly affect the overall firing frequency (peak activity = 2.2 +/- 1.1 impulses/s, n = 36). Hexamethonium (0.7-1.2 mg/kg iv) prevented C-fiber stimulation by high-nicotine cigarette smoke (n = 12) but not stimulation by right atrial injection of capsaicin. We conclude that pulmonary C-fibers are stimulated by a single breath of cigarette smoke and that nicotine is the constituent responsible.     

Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure.

To partition the central and peripheral airway resistance in awake humans, a catheter-tipped micromanometer sensing lateral pressure of the airway was wedged into the right lower lobe of a 3-mm-ID bronchus in 5 normal subjects, 7 patients with chronic bronchitis, 8 patients with emphysema, and 20 patients with bronchial asthma. We simultaneously measured mouth flow, transpulmonary pressure, and intra-airway lateral pressure during quiet tidal breathing. Total pulmonary resistance (RL) was calculated from transpulmonary pressure and mouth flow and central airway resistance (Rc) from intra-airway lateral pressure and mouth flow. Peripheral airway resistance (Rp) was obtained by the subtraction of Rc from RL. The technique permitted identification of the site of airway resistance changes. In normal subjects, RL was 3.2 +/- 0.2 (SE) cmH2O.l-1.s and the ratio of Rp to RL was 0.24 during inspiration. Patients with bronchial asthma without airflow obstruction showed values of Rc and Rp similar to those of normal subjects. Although Rc showed a tendency to increase, only Rp significantly increased in those patients with bronchial asthma with airflow obstruction and patients with chronic bronchitis and emphysema. The ratio of Rp to RL significantly increased in three groups of patients with airflow obstruction (P less than 0.01). These observations suggest that peripheral airways are the predominant site of airflow obstruction, irrespective of the different pathogenesis of chronic airflow obstruction.     

Vagal influence on compensatory ovarian growth is important only briefly after hemicastration

Hemicastration induces growth of the remnant ovary in the rat. As evidenced by the effects of total abdominal vagotomy, vagal innervation markedly influences this compensatory ovarian growth. In the present experiments, vagotomy inhibited compensatory ovarian growth when performed immediately after hemicastration, but not when delayed until 4.5 hr after hemicastration. Brief exposure of subdiaphragmal portion of the vagi nerves to 2% lidocaine shortly before hemicastration also inhibited compensatory growth. Fifteen minutes after hemicastration, markedly elevated tissue concentrations of cyclic adenosine monophosphate (cAMP) were recorded in the remnant ovaries. This accumulation of cAMP was inhibited by vagotomy that preceded hemicastration, as well as by lidocaine pretreatment of the vagi nerves, and partly by vagotomy that followed 10 min after hemicastration. At 5 hr after hemicastration, tissue cAMP concentrations in the remnant ovaries were not elevated and were not affected by vagotomy. The present results suggest that vagal influence on the compensatory ovarian growth is important only during a short period of time after hemicastration (apparently shorter than 4.5 hr), and that it, at least briefly after hemicastration, includes neural input to the ovary.     

Acute effect of cigarette smoke on laryngeal receptors

Upper airway exposure to cigarette smoke elicits reflex changes in breathing pattern. To examine whether laryngeal afferents are affected by cigarette smoke, neural activity was recorded from the peripheral cut end of superior laryngeal nerve in anesthetized dogs. A box-balloon system, connected to the breathing circuit, allowed smoke to be inhaled spontaneously through the isolated upper airway while preserving its normal respiratory flow and pressure. Our results showed the following. Inhalation of cigarette smoke (25-50% concentration, 300-400 ml) caused a marked increase in activity of laryngeal irritant receptors which were either silent or randomly discharging during control breathing [their activity increased from a control value of 1.67 +/- 0.50 (mean +/- SE; n = 21) to a peak of 5.03 +/- 0.85 impulses/s in 11-15 s]. The activity of laryngeal cold receptors was reduced to 77.3 and 63.8% of control (n = 9) during the two breaths of smoke inhalation, respectively. After returning toward the base-line activity, a more pronounced inhibition (26.3% of control) occurred at three to nine breaths after the smoke inhalation. A small but significant decrease (88.5% of control) in the inspiratory discharge of laryngeal mechanoreceptors was observed during the first test breath. These effects were independent of the CO2 content of the smoke. Furthermore, there was no difference between the responses of these laryngeal afferents to high- and low-nicotine cigarette smoke.     

Vagal afferents essential for abdominal muscle activity during lung inflation in cats.

Maintained inflation of the lung evokes abdominal muscle activity in anesthetized cats only if the vagus nerves are intact, indicating the importance of vagal receptors. The location of these receptors was determined in 14 anesthetized cats by comparing prevagotomy inflation responses of the abdominal muscles and diaphragm to the responses obtained after section of the thoracic vagi at one of three different levels. The abdominal muscle and diaphragm responses to maintained lung inflation persisted following vagotomy below the roots of the lung or denervation of the heart and great vessels. Denervation at the root of the lung, however, abolished the abdominal muscle response and the Hering-Breuer inflation reflex of the diaphragm. It is concluded that pulmonary receptors are essential for the abdominal expiratory activity, but vagal receptors in the abdomen, esophagus, trachea, heart and great vessels are not.     

Cigarette smoke acutely increases collateral resistance in excised dog lobes

The acute effects of cigarette smoke or drug inhalation on collateral conductance (Gcoll) were studied in freshly excised dog lobes held at fixed volumes. A double-lumen catheter was wedged into a segmental bronchus, and air, smoke, or aerosol flowed into the blocked segment at a constant pressure of 2 cmH2O. A capsule glued over a small area of perforated pleura of the segment was used to measure alveolar pressure; the capsule could also be used to measure small airway flow (Vcap) through the segment. Gcoll was almost linearly dependent on lung volume, rising about fivefold between 20 and 100% inflation (30 cmH2O). During smoke inhalation Gcoll began decreasing almost immediately, roughly halving with the first cigarette and falling to about 20% after two cigarettes. Similar proportions were obtained at other lung volumes. Pulmonary conductance (oscillator) in the remainder of the lobe decreased only modestly to 78% of control after two cigarettes. In lobes exposed to 4.5% CO2 after air Gcoll rose 25-50%, but Vcap increased only 5-10%. However, acetylcholine chloride aerosol reduced both flows by similar ratios. Isoproterenol did not prevent or reverse smoke-induced collateral constriction but did reverse the effects of acetylcholine on both pathways. These results suggest that in excised lungs aerosols acted on larger segmental airways in series with collateral channels and with peripheral airways, whereas CO2 and particularly cigarette smoke provoked more marked effects on the most distal smooth muscle.     

Effects of pulmonary congestion on airway reactivity to histamine aerosol in dogs

We examined the effect of acute pulmonary vascular congestion on bronchial reactivity in dogs in a standard challenge protocol. Airway responsiveness to histamine whose concentration was varied in a stepwise incremental fashion was assessed from changes in pulmonary resistance (RL) and dynamic compliance (Cdyn) in 10 anesthetized dogs. Brief acute pulmonary congestion was created by inflating a balloon placed in the left atrium to raise left atrial pressure to 20-30 cmH2O for 1 min. Pulmonary congestion did not change RL in the control condition. However, after histamine inhalation, RL was further increased by pulmonary congestion, making the two effects synergistic. This phenomenon could not be observed with vagi cut. Pulmonary congestion decreased Cdyn in all dogs regardless of histamine concentration, with or without vagotomy. We conclude that pulmonary vascular congestion makes the bronchi hyperreactive through vagal reflexes. The reduction in Cdyn caused by pulmonary congestion appears to stem mainly from the narrowing of peripheral airways by adjacent vascular engorgement.     

Effects of aerosol histamine and carbachol on central and peripheral airflow resistance in sheep

Sixteen anesthetized artificially ventilated open-chest sheep were prepared with retrograde catheters to allow for measurement of dynamic compliance of the lungs (Cdyn), total airflow resistance of the lungs (RL), and central (Rc) and peripheral (Rp) airflow resistance. Twelve sheep received aerosol histamine and 12 sheep received aerosol carbachol. Eight sheep received and responded to both aerosol histamine and aerosol carbachol. Three sheep received both aerosol histamine and aerosol carbachol but failed to respond to both agents. Under base-line conditions, for the 16 sheep, 69% of total RL was located in the peripheral component, Rp, and 31% in the central component, Rc. Aerosol histamine caused only peripheral small airway changes while aerosol carbachol predominantly effected the central large airways. When aerosol histamine responsiveness, defined using Cdyn or Rp, was compared to aerosol carbachol responsiveness using Rc, a correlation was demonstrable (r = 0.84, n = 8, P less than 0.05). It is possible in sheep to cause relatively pure peripheral small airway and relatively pure central large airway changes by using different bronchoconstrictor agents. Aerosol histamine and aerosol carbachol responsiveness correlated with each other in these artificially ventilated anesthetized sheep.     

迷走神经在心率变异性中的作用

采用功率谱和近似熵 (approximateentropy ,ApEn)的方法 ,分析清醒家兔在双侧迷走神经保留 ,右、左侧迷走神经切断以及双侧迷走神经同时切断时心搏间期 (RRI)的变化。结果显示 :双侧迷走神经保留时功率谱中高频功率 (HF)、低频功率 (LF)及ApEn值均高于双侧及单侧迷走神经切断时 (P <0 0 5 ) ,LF/HF比值最小 ;切断单侧迷走神经 ,ApEn变小 ,LF/HF比值在右侧迷走神经切断时增大 ,而切断左侧迷走时LF/HF比值无明显变化 ;双侧迷走神经切断后LF/HF比值最大 ,ApEn最低。结果表明 :心率变异主要由迷走神经调节 ,右侧迷走神经起主要作用 ;传统心率变异性测量方法与非线性方法所得结果一致