A vagally mediated response to metabolic acidosis in anesthetized rabbits.

Pentobarbital sodium-anesthetized rabbits received 10-min infusions of acetic, lactic, or propionic acid delivered via a catheter to the right atrium at a rate of 1 mmol/min (n = 14). Arterial [H+] increased by 35.8 +/- 7.6 (SD) nmol/l, a decrease in pH of 0.27 +/- 0.04. By the end of the infusion period respiratory frequency (f), tidal volume (VT), and minute ventilation (V) had increased by 15.5 +/- 6.2 breaths/min, 7.3 +/- 2.7 ml, and 0.86 +/- 0.34 l/min, respectively. Arterial PCO2 (PaCO2) increased initially, but isocapnia was established during the latter half of the infusion (delta PaCO2 = 0.4 +/- 2.0 Torr). Bilateral cervical vagotomy eliminated the f response to acid infusions (n = 9, delta f = 0.6 +/- 2.4 breaths/min). The increase in VT (12.6 +/- 3.1 ml) was greater, but that in V (0.39 +/- 0.11 l/min) was less than in intact animals (P less than 0.05). PaCO2 remained elevated throughout the infusion (delta PaCO2 = 5.5 +/- 2.6 Torr), resulting in a greater rise in arterial [H+] (delta[H+]a = 53.6 +/- 6.6 nmol/l, delta pHa = -0.37 +/- 0.04). It is concluded that vagal afferents play a role in the f response to acute metabolic acidosis in rabbits.

Chemoreflexes in rabbits.

Criteria defining chemoreflexes (called responses) in rabbits have been established in relation to right atrial injection of 16 chemicals, and compared with previously-defined chemoreflexes of cats. A vagally mediated 'pulmonary' response elicited at latencies less than 1.6 sec consists only of an increased frequency of breathing due primarily to decrease of expiratory duration. A vagally mediated 'cardiac' response at latencies of 2-3 sec consists of bradycardia, hypotension and a respiratory component of decreased tidal volume. A 'non-vagal excitatory' response probably from the carotid bifurcation region consists predominantly of increased tidal volume, commencing at latencies greater than 2 sec. Stimuli eliciting 'pulmonary' responses were acetic, propionic, butyric, glycolic, lactic, glyoxilic and pyruvic acids, sodium dithionite and phenyl diguanide, and all also elicited the 'non-vagal excitatory' response. Phenyl diguanide additionally elicited the 'cardiac' response. No responses were elicited either by amino-substituted acids (glycine, beta- and L-alanine, 2-amino-butyric acid and GABA) or sodium salts of lactic and acetic acids, except occasionally beta-alanine and GABA elicited a 'non-vagal excitatory' response.

CO2/H+ receptors in the lungs of anaesthetized rabbits.

The CO2/H+ sensitivity of 'pulmonary' non-myelinated vagal afferent endings was investigated in anaesthetized rabbits using 'natural' stimuli of lactic (LA) and acetic (AA) acids, for comparison with previous results using sodium dithionite (NaD) and phenyl biguanide (PDG). Right atrial injections of these four chemicals demonstrated a respiratory reflex from 'pulmonary' endings, consisting primarily of a decrease in expiratory duration and consequent increase in respiratory frequency coincident with transient increase in PETCO2. Three of the chemicals (AA, LA and NaD) apparently activated the endings by increased [CO2] and/or [H+], since equimolar doses of sodium lactate and acetate were without effect. PDG additionally elicited respiratory and cardiovascular reflexes from 'cardiac' endings, suggesting that its activation of 'pulmonary' endings may differ from the other three stimuli. An unforeseen complication of these studies arose from using SPF (specific pathogen free) rabbits, but the consistency of different control values in SPF rabbits was established.

Role of vagal C-fiber afferents in respiratory response to hypercapnia.

The respiratory response to hypercapnia has been investigated in 10 anesthetized rabbits by use of a rebreathing technique. The responses were obtained in three situations: with one intact vagus nerve (control), during differential block of conduction, and after vagotomy. Differential block was achieved using anodal hyperpolarization by application of a direct current to the cervical vagus nerve. Great care was taken during the differential block to establish that all impulse conduction in myelinated fibers of the cervical vagus nerve was abolished but that the nonmyelinated fibers conducted normally. Additionally, in five more rabbits the nature of the differential block was confirmed from single-fiber recordings of activity in both myelinated and nonmyelinated fibers. The same increase in tidal volume in response to hypercapnia was present in all three experimental situations, indicating that it was not vagally mediated. The increase in frequency in response to hypercapnia in the control state was abolished by vagotomy but preserved when only the nonmyelinated fibers were functioning during the differential block. This increased frequency response, attributable to decreases in both inspiratory and expiratory durations, was usually enhanced during the differential block, despite the slower deeper pattern of breathing attributed to loss of activity in myelinated fibers. The implications of this reflex increase in frequency in response to hypercapnia, mediated by nonmyelinated vagal endings in the lung, are discussed.

Non-myelinated vagal lung receptors and their reflex effects on respiration in rabbits.

The response characteristics of non-myelinated vagal lung receptors have been studied in the anaesthetized rabbit. The results indicate that the behaviour of these endings strongly resembles those found in cats and dogs and that they can be classified into 'pulmonary' 'bronchial' and 'pulmonary-bronchial' groups depending on their accessibility from either circulation. Experiments involving pericardial block with local anaesthetic to exclude responses from cardiac receptors and the use of sodium dithionite as a novel stimulus to 'pulmonary' endings alone, have shown that the predominant effect of these endings in the anaesthetized rabbit is to increase respiratory frequency. Reflex responses from 'bronchial' endings similar provided sufficient amount of the activating chemical was given.

The non-adrenergic, vagal efferent system to the lung: does it exist, or is an artefact?

A third efferent pathway to the lungs - the non-adrenergic vagal inhibitory system - has previously been invoked to explain the residual neurally-mediated bronchodilatation, that is obtained after the administration of cholinergic and adrenergic blocking drugs. However, the experimental results cited as evidence for the existence of this third efferent pathway, can also be explained by an alternative mechanism, involving local axon reflexes in afferent fibres from lung receptors. If this latter explanation is correct, then the existence of the third efferent pathway is an artefact resulting from the experimental conditions. Caution should therefore be exercised before looking for ways of controlling this system, until it has been proven exactly which is the mechanism mediating it.

Do axon reflexes exist within the lung?

Circumstantial evidence is given in support of the hypothesis that vagal lung receptors are involved in local axon reflexes. All the components of such mechanisms are present, and teleologically it would make sense for them to exist. It is suggested that rapidly-adapting or irritant receptors produce local muscle relaxation as well as the centrally-mediated reflex bronchoconstriction in other parts of the lung. Conversely, it is suggested that slowly-adapting pulmonary stretch receptors produce the opposite effect - local bronchoconstriction and centrally-mediated reflex bronchodilatation. The third group of receptors - the non-myelinated endings or J receptors - probably behave like the rapidly-adapting receptors. The mechano, chemo, and nociceptive reasons for these local axon reflexes are presented, and the difficulties of testing their existence is discussed.

Role of pulmonary stretch receptors during breathing in rabbits, cats and dogs.

In order to mimic and then modify the input to the respiratory centre from pulmonary stretch receptors, the central ends of the cut cervical vagus nerves were electrically stimulated with a frequency determined by transpulmonary pressure through a voltage to frequency converter. At appropriate end-expiratory stimulation frequency and gain of the voltage to frequency converter, such stimulation restored the pre-vagotomised patterns of breathing in rabbits, cats and dogs. Mimicking the changes in activity from pulmonary stretch receptors that would be produced by such manoeuvres as hypercapnia, inflations and deflations, reproduced the responses in inspiratory duration that occurred with natural stimuli in the same animals with intact. There were some differences between the responses of expiratory durations to the natural and mimicked interventions; these may be related to the presence of increased expiratory muscle activity in the former. The results demonstrate that transpulmonary pressure-controlled stimulation of the afferent vagus nerves is a satisfactory method of mimicking and controlling the pulmonary stretch receptor feedback mechanism in studies on the control of breathing.

The direct effect on pulmonary stretch receptor discharge produced by changing lung carbon dioxide concentration in dogs on cardiopulmonary bypass and its action on breathing.

1. Single fibre pulmonary stretch receptor discharge was recorded in dogs on cardiopulmonary bypass. 2. Inhalation of CO2 depressed pulmonary stretch receptor discharge despite the absence of changes in arterial PCO2. This effect was particularly marked with airway CO2 levels below 5%. 3. Changing arterial PCO2, without changing airway CO2, had only small and insignificant effects on pulmonary stretch receptor discharge. 4. The effect of changes in airway CO2 on pulmonary stretch receptor discharge was rapid and correlated well in time with the reflex tachypnoea produced when CO2 was inhaled in conditions of cardiopulmonary bypass. 5. Stimulation of the central end of the cut vagus nerve was triggered from simultaneously recorded action potentials from a single pulmonary stretch receptor. 6. In these conditions, the reflex response to CO2 could be simulated provided that the pulmonary stretch receptor had an end-expiratory discharge. 7. It is suggested that the vagally mediated tachypnoeic response to changes in airway CO2 seen in conditions of cardiopulmonary bypass is due to the effect of CO2 on the end-expiratory discharge of pulmonary stretch receptors.

The effect of carbon dioxide in the airways and alveoli on ventilation; a vagal reflex studied in the dog.

1. The inhalation of CO(2) produces a tachypnoea only in the presence of intact vagus nerves; the present study was designed to examine the mechanism of this phenomenon in the dog.2. Closed-chest cardiopulmonary bypass was established in dogs weighing 16-24 kg, anaesthetized with chloralose. When the ;bypass' was established pulmonary blood flow ceased, P(A, CO2) was reduced and the respiratory rate slowed. 3-10% CO(2) in O(2) could then be inhaled without change in the level of P(a, CO2) set at the oxygenator.3. The addition of CO(2) in these concentrations to the inspired oxygen resulted in an increase in respiratory frequency, maximal at the first breath and sustained for the 1 min period of exposure. The increase in respiratory frequency was due to a shortening of expiratory duration. Inspiratory duration did not change. The response was absent after vagotomy.4. Inert gases in O(2), given as a control, had no effect on breathing.5. The effect of raising P(a, CO2) (by increasing the concentration of CO(2) in the gas equilibrating the blood in the oxygenator), was primarily to increase tidal volume.6. The ventilatory effect of inspiring CO(2)/O(2) mixtures was shown to be additive to the effect of raising P(a, CO2).7. These experiments show that an afferent vagal reflex originating from the lungs causes tachypnoea, when a dog, on ;bypass', inhales low concentrations of CO(2) in O(2).