Vagal afferent and reflex responses to changes in surface osmolarity in lower airways of dogs.

In anesthetized dogs we examined the sensitivity of afferent vagal endings in the lungs to changes in airway fluid osmolarity. Injection of 0.25-0.5 ml/kg water or hyperosmotic sodium chloride solutions (1,200-2,400 mmol/l) into a lobar bronchus caused bradycardia, arterial hypotension, apnea followed by rapid shallow breathing, and contraction of tracheal smooth muscle. All effects were abolished by vagotomy. We examined the sensory mechanisms initiating these effects by recording afferent vagal impulses arising from the lung lobe into which the liquids were injected. Water stimulated pulmonary and bronchial C-fibers and rapidly adapting receptors; isosmotic saline and glucose solutions were ineffective. Hyperosmotic saline (1,200-9,600 mmol/l, 0.25-1 ml/kg) stimulated these afferents in a concentration-dependent manner. Stimulation began 1-10 s after the injection and sometimes continued for several minutes. Responses of slowly adapting stretch receptors varied. Our results suggest that non-isosmotic fluid in the lower airways initiates defense reflexes by stimulating pulmonary and bronchial C-fibers and rapidly adapting receptors. Conceivably, stimulation of these afferents as a result of evaporative water loss from airway surface liquid could contribute to exercise-induced asthma.     

Bronchial vasodilator pathways in the vagus nerve of dogs

Bronchialvasodilation in dogs is mediated largely by vagal pathways. To examinethe relative contribution of cholinergic and noncholinergicparasympathetic pathways and of sensory axon reflexes to vagalbronchial vasodilation, we electrically stimulated the peripheral vagusnerve in 10 chloralose-anesthetized dogs and measured bronchial arteryflow. Moderate-intensity electrical stimulation (which did not activateC-fiber axons) caused a rapid voltage- and frequency-dependentvasodilation. After atropine, vasodilation was slower in onset andreduced at all voltages and frequencies: bronchial vascular conductanceincreased by 9.0 ± 1.5 (SE)ml · min¹ · 100 mmHg¹ during stimulationbefore atropine and 5.5 ± 1.4 ml · min¹ · 100 mmHg¹ after(P < 0.02). High-intensitystimulation (sufficient to recruit C fibers) was not studied beforeatropine because of the resulting cardiac arrest. After atropine,high-intensity stimulation increased conductance by 12.0 ± 2.5 ml · min¹ · 100 mmHg¹. Subsequent blockadeof ganglionic transmission, with arterial blood pressure maintained bya pressure reservoir, abolished the response to moderate-intensitystimulation and reduced the increase to high-intensity stimulation by82 ± 5% (P < 0.01). In 13 other dogs, we measured vasoactive intestinalpeptide-like immunoreactivity in venous blood draining from thebronchial veins. High-intensity vagal stimulationincreased vasoactive intestinal peptide concentration from 5.7 ± 1.8 to 18.4 ± 4.1 fmol/ml (P = 0.001). The results suggest that in dogs cholinergic and noncholinergicparasympathetic pathways play the major role in vagal bronchial vasodilation.

     

Cigarette smoke in lungs evokes reflex increase in tracheal submucosal gland secretion in dogs.

Stimulation of pulmonary C-fibers (PCs) by capsaicin and of rapidly adapting receptors (RARs) by reduced lung compliance reflexly increases airway submucosal gland secretion in dogs. Because both PCs and RARs are stimulated by cigarette smoke (nicotine being the primary stimulus), we performed experiments in anesthetized open-chest artificially ventilated dogs (with aortic nerves cut) to determine whether cigarette smoke reflexly stimulates airway secretion. We measured submucosal gland secretion by counting the hillocks in a 1.2-cm2 field of tracheal epithelium coated with tantalum dust. Secretion was stimulated by delivery of 40-320 ml smoke from high-nicotine cigarettes to the lower trachea, secretion rate increasing from 7.4 +/- 1.3 to 48.1 +/- 5.1 hillocks.cm-2.min-1. Results of cutting the pulmonary vagal branches or carotid sinus nerves or both indicated that the secretory response was initiated by stimulation of lower respiratory vagal afferents and augmented several seconds later by stimulation of carotid chemoreceptors. Results of cooling the cervical vagus nerves to 7 and 0 degrees C indicated that most of the vagally mediated increase in secretion was due to stimulation of afferent lung C-fibers.     

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.     

Rapidly adapting receptor activity in dogs is inversely related to lung compliance

We examined the response of pulmonary rapidly adapting receptors (RAR's) to changes in dynamic lung compliance (Cdyn) in the physiological range. RAR impulse activity was recorded from the cervical vagus nerves in anesthetized open-chest dogs whose lungs were ventilated at constant rate and tidal volume (VT), with a positive end-expiratory pressure (PEEP) of 3-4 cmH2O. After hyperinflation to produce maximal Cdyn, RAR's were silent or fired sparsely and irregularly. Reducing Cdyn in steps by briefly removing PEEP increased firing proportionately, and RAR's began to discharge vigorously in inflation. Activity was restored to control by hyperinflating the lungs. Activity also increased when we increased inflation rate, and hence the rate of change of airway pressure (dP/dt), by reducing inflation time, keeping VT and cycle length constant. RAR's were stimulated more when dP/dt was increased by reducing compliance than when dP/dt was increased by increasing inflation rate. We conclude that RAR's are sensitive to changes in Cdyn and speculate that excitatory input from RAR's may help to maintain VT as the lungs become stiffer.     

Stimulation of afferent vagal endings in the intrapulmonary airways by prostaglandin endoperoxide analogues

Two cyclic ether (CE) analogues of the prostaglandin endoperoxide PGH₂, CE I and CE II, have been found to exert powerful stimulant effects on lung ‘irritant’ receptors and bronchial C-fiber endings after intravascular or aerosol administration in open-chest dogs under Dial-pentobarbital anesthesia. ‘Irritant’ receptors responded to a dose as small as 0.1 μg/kg CE II, injected into the right atrium. CE II was twice as effective as CE I and 10–20 times more potent than PGF_2α. As an aerosol, it exceeded histamine in potency by more than 800 times. ‘Irritant’ receptor stimulation was always associated with decrease in lung compliance and increase in lung resistance. Isoproterenol which reduced the latter effects also diminished the response of ‘irritant’ receptors. Left atrial injection of GE_S had only weak and delayed effects. CE-induced ‘irritant’ receptor firing declined or ceased during ventilatory arrest in expiration and following hyperinflation of the lungs. In contrast to ‘irritant’ receptors, C-fibers responded more effectively and more rapidly, and in the absence of mechanical changes, when the drugs were injected into the left atrium as compared to right atrial injection. These findings suggest that CE-induced ‘irritant’ receptor stimulation is secondary to changes in lung mechanics, whereas C-fiber stimulation is a direct effect upon the nerve ending.