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We investigated the effects of halothane, enflurane, and isoflurane on the activity of 43 tracheo-bronchial slowly adapting stretch receptors (SARs) and 16 rapidly adapting irritant receptors (RARs) in 5 anesthetized, vagotomized, paralyzed, and artificially ventilated dogs. The 43 SARs were classified into 2 subtypes: (i) 17 low-threshold SARs with an expiratory discharge at FRC that were active throughout the respiratory cycle and (ii) high-threshold SARs active only in respiration. Ventilating the lungs with 5% of each anesthetic caused a significant increase in the inspiratory discharge of low-threshold SARs, whereas the expiratory discharge was inhibited or altogether silenced. While the activity of the majority of high-threshold SARs increased during the administration of the three volatile anesthetics, it decreased in those with a particulary high recruitment threshold. There was however, a consistent increase in the pressure threshold at which all SARs were recruited. Ventilating the lungs with 5% of each anesthetic cuased a significant decrease in activity of RARs. Our results indicate that all three halogenated anesthetics inhibit RAR at concentrations rangig from 1% to 5%.

The effects of halothane, enflurane, and isoflurane on laryngeal receptors were investigated in 6 anesthetized dogs breathing spontaneously through a tracheostomy. Single unit action potentials were recorded from the peripheral cut end of the superior laryngeal nerve (SLN) while different concentrations of volatile anesthetics (1.25, 2.5, 5.0%) were administered in the expiratory direction at a constant air-flow (6 l/min) for 1 min through the functionally isolated upper airway. A total of 21 respiratory-modulated mechanoreceptors, 18 "irritant" receptors, and 7 cold receptors were studied. The overall results obtained from the 16 respiratory-modulated mechanoreceptors challenged with the 3 anesthetic gases disclosed a prevalent inhibitory effect and halothane proved to be the most effective of the 3 gases. The activity during both the inspiratory and expiratory phase was significantly reduced only by halothane (inspiratory phase, P0.01; expiratory phase, P0.05), while neither isoflurane nor enflurane caused significant changes in receptor activity. Of the 18 irritant receptors, 14 receptors increased their activity in a dose-related manner in response to one or more of the anesthetics although the effect of halothane was more pronounced than those of enflurane and isoflurane. All of the 7 cold receptors consistently increased their activity in a dose-related manner in response to halothane whereas 3 of 7 receptors were insensitive to enflurane and 4 of 7 receptors were insensitive to isoflurane. Our results indicate that, while all three commonly used anesthetics can have an effect on different types of laryngeal receptors, the effects of halothane are more pronounced than those of the other two gases in terms of changes in receptor activity.

It has been previously found that volatile anesthetics significantly affect the activity of laryngeal receptors. In this study we have investigated the respiratory effects of these volatile anesthetics delivered into the upper airway of newborn and adult dogs. Experiments were performed on 17 5-14-day-old, 3 26-28-day-old and 3 adult dogs, anesthetized and breathing spontaneously through a tracheostomy. In the youngest age group, halothane decreased ventilation (VE) to 37.6 +/- 6.8% of control (mean +/- SE; P0.01) due to a decrease in both frequency and tidal volume. Peak inspiratory and expiratory flows, and esophageal pressure (Pes) were depressed also (60.8 +/- 6.5%, 51.6 +/- 7.1% and 66.5 +/- 8.1% of control, respectively; P0.01). Superior laryngeal nerve (SLN) section abolished the changes in VE, but residual significant decreases in peak flows and Pes were still present and disappeared only after topical anesthetization of the nasal cavities. Isoflurane had similar but weaker effects on VE (74.2 +/- 2.8% of control; P0.01), accompanied by a decrease in peak inspiratory and expiratory flows and Pes. SLN section abolished these changes. In the 26-28 day age group there was only a decrease in peak inspiratory airflow with the halothane challenge; isoflurane did not have any effect. In the adult dogs halothane caused only a marginal decrease in inspiratory time. The depressive effects of halothane and isoflurane should be considered when they are used for induction of anesthesia in newborns.

Although constant airflow through the upper airway has been shown to induce ventilatory depression in anesthetized newborn animals, the role of laryngeal temperature in this response has not been studied. Experiments were performed in fourteen 1-5 day-old anesthetized puppies breathing through a tracheostomy. Tidal volume and laryngeal temperature were recorded while a constant stream of air (15-25 ml/sec) at room temperature was passed in the expiratory direction for 20 sec through the isolated upper airway. Warm (35-37 degrees C), humidified air at the same flow served as control. When laryngeal temperature was decreased by 7.5 +/- 0.9 degrees C, a marked change in breathing pattern was observed (VT = 54 +/- 5, TI = 187 +/- 33, TE = 636 +/- 179, VT/TI = 45 +/- 10% of control; n = 9). Warm air at the same flow induced no significant changes. Superior laryngeal nerve section abolished the effects of cooling on breathing pattern. In 5 puppies we compared the effect of 'fast' and 'slow' laryngeal cooling. Fast trials altered breathing pattern earlier than slow trials. We conclude that the depressant effect of airflow through the upper airway is entirely due to a decrease in laryngeal temperature and is mediated by superior laryngeal nerve afferents.

The purpose of this study was to relate the carbon dioxide (CO2) response of laryngeal receptors to their behavior during the breathing cycle (i.e, their response to transmural pressure changes, laryngeal movement or decreases in temperature)_or during exposure to irritant stimuli (water or cigarette smoke). In 9 anesthetized mongrel dogs breathing spontaneously through a tracheostomy, unit activity from the superior laryngeal nerve was recorded while warmed and humidified gas mixtures (air or 10% CO2 in O2) were passed, for 1 min, through the functionally isolated upper airway in the expiratory direction. None of the 10 cold receptors studied were affected by CO2. Eleven of 20 laryngeal non-modulated mechanoreceptors were stimulated (from 0.3 to 1.6 imp/sec) by exposure to CO2. These CO2-responsive receptors were also stimulated by known irritant stimuli (cigarette smoke, water), although not all receptors which responded to these irritants were stimulated by CO2. Twelve of 33 respiratory-modulated receptors were affected by CO2; 4 were stimulated and 8 inhibited. Receptors inhibited by CO2 were also inhibited by negative pressure while receptors stimulated by CO2 were also stimulated by negative pressure. These results show that CO2-responsive laryngeal receptors are not specialized endings. Although it is not clear to what extent each separate group of laryngeal receptors is involved, each may contribute to the reflex bradypnea which has been observed during exposure of the upper airway to elevated levels of CO2. However, the importance of CO2-responsive laryngeal receptors in physiological conditions remains unclear.

To investigate whether osmoreceptor mechanisms or the renin-angiotensin system might be involved in respiratory regulation of H+ homeostasis, plasma osmolality was acutely lowered by approximately 10 mOsm in 7 awake mongrel dogs by a gastric water load (20 ml.kg-1 distilled, deionized water). Plasma renin activity (PRA) was measured as an indicator of angiotensin II levels. During these studies PaCO2 and [H+]a reflected the spontaneous level of ventilation (VE); higher levels of VE were correlated with lower PaCO2 and [H+]a, indicating a nonchemical drive to breathe. Stimulation of ventilation to lower PaCO2 following the water load was positively correlated with increase in PRA and decrease in plasma osmolality, but not with change in osmolality alone. An increased VE, a decreased ventilatory response curve (VRC) threshold for PaCO2, and a lower PaCO2 occurred with increase in PRA. Conversely, a lower or acutely decreased PRA, due to administration of arginine vasopressin, was correlated with a lower VE, an increase in the VRC threshold for PaCO2, and a higher PaCO2. Ventilatory control of PaCO2 during acute lowering of osmolality may be related to a central inter-action between osmolality and the renin-angiotensin system.

The effects of aerosolizing distilled water and isosmolal dextrose in the isolated larynx on the activity of pressure-responsive receptors and laryngeal muscles were studied in anesthetized dogs. Following water aerosolization, the mean discharge of pressure-responsive laryngeal mechanoreceptors during upper airway breathing and occlusion was 151% and 138% respectively of that present after saline aerosolization. During delivery of water aerosol, the peak activity of the posterior cricoarytenoid muscle increased to 229 +/- 56% of control; no effects were present on the thyroarytenoid muscle activity. Saline or isosmolal dextrose aerosols did not have any effect on the activity of either muscle. The reflex increase in posterior cricoarytenoid muscle activity due to laryngeal negative pressure was enhanced (163%) when the negative pressure challenge was repeated following distilled water aerosol. These results suggest that alteration in laryngeal surface liquid composition modifies the response of pressure-responsive laryngeal receptors and thereby the reflex activation of airway patency maintaining muscles.

Although bronchoconstriction in response to C-fibre stimulation has been reported to be weak or absent in the newborn, pulmonary resistance and compliance have not been measured. We tested the hypothesis that capsaicin reflexly activates pulmonary efferent outflow to airway smooth muscle in the newborn. We measured breath-by-breath responses of inspiratory lung resistance (RLi) and dynamic compliance (CLdyn) in 13 newborn dogs and 4 newborn pigs during right heart injections of saline, capsaicin (25-50 micrograms/kg) and acetylcholine (ACh). Repeat capsaicin injections at 5 min intervals were made to test for desensitization in the newborn dog. All newborn dogs and 2 of 4 newborn pigs displayed a brisk bronchoconstriction; in the dog, RLi increased maximally by 97% +/- 13 (SE) and CLdyn decreased maximally by 32% +/- 2. In both species, initial capsaicin injections (CAP1) caused a long latency (time to peak heart rate 26.8 +/- 2 and 20 sec +/- 2.5) increase in heart rate (40% +/- 11 and 20.1% +/- 8.2 for the newborn dog and pig respectively). In the dog, but not the pig, capsaicin responses after the ACh trial (CAP2 and CAP3) caused a short latency bradycardia while the long latency tachycardia continued to be expressed in both species. The maximal changes in RLi and CLdyn, and the bradycardia, were reduced (i.e. desensitized) by 36%, 53% and 63% respectively if capsaicin injection was repeated within 5 min. Muscarinic blockade with atropine abolished the bronchoconstrictor and bradycardia responses to capsaicin but had no effect on the tachycardia. We conclude that the newborn possesses the neural circuitry to mount a bronchoconstrictor response to C-fibre stimulation. We speculate that the response is designed to reduce dead space and stabilize highly compliant airways of the newborn during the rapid shallow breathing that is typically associated with C-fibre stimulation.

Upper airway cooling depresses ventilation in the newborn dog. Since airway cooling stimulates laryngeal cold receptors and inhibits laryngeal mechanoreceptors, the type of afferent ending responsible for this reflex cannot be easily identified. l-menthol, a specific stimulant of cold receptors in the absence of any cooling, has been used to ascertain the discrete role of upper airway cold receptors in this ventilatory depression. Experiments were carried out in 8 anesthetized 7-14-day-old dogs breathing through a tracheostomy with the upper airway functionally isolated. Constant flows of warm air (37 degrees C), with and without addition of l-menthol, and cold air (25 degrees C) were delivered through the upper airway in the expiratory direction. As compared to warm air trials, cold air and warm air + l-menthol trials greatly reduced ventilation (57.5 +/- 10.7% and 52.8 +/- 11.7% of control, respectively; P less than 0.01) mostly due to a prolongation of Te (291.2 +/- 106.4% and 339.2 +/- 90.0%, respectively, P less than 0.01). Section of the superior laryngeal nerve abolished the response to cold air. However, a residual depressive effect of l-menthol was still present in 3 of 5 animals and was abolished by nasal anesthesia, suggesting the involvement of nasal cold receptors. The results suggest that in the newborn dog stimulation of laryngeal cold receptors, without any concurrent inhibition of laryngeal mechanoreceptors, is a sufficient stimulus to cause respiratory depression.

We have investigated the various sensory modalities represented in the laryngeal nerves of the guinea pig. In addition, we have examined the defensive responses to mechanical stimuli and capsaicin instillation into the laryngeal lumen of the same species. Recording from both the whole superior laryngeal nerve and from single units of the same nerve revealed the presence of afferent activity related (1) to the contraction of laryngeal muscles and/or the 'tracheal tug', (2) to transmural pressure changes, either positive or negative and (3) to mechanical and chemical irritants. The irritant type receptors of this species, when challenged with water solutions, show two distinct patterns of activation: some behave as osmoreceptors, some respond to the lack of chloride ions. Challenges with capsaicin solutions activated one ending with the characteristics of a C-fiber receptor that failed to respond to a subsequent trial. This behavior is consistent with the reflex apnea, dependent on an intact laryngeal innervation, induced by capsaicin instillation that was not elicitable on repeating the challenge. Cough to mechanical probing of the supraglottic area depended on an intact SLN, whereas cough elicited from the subglottic area depended on an intact RLN. Cough to mechanical stimulation could not be desensitized by capsaicin. These findings suggest the presence of two independent afferent pathways for defensive responses.

The primary purpose of this study was to ascertain whether laryngeal receptors activated by water are specialized endings or whether they also respond to other stimuli, such as pressure, temperature and laryngeal motion as they occur during the breathing cycle. In 35 anesthetized mongrel dogs, breathing spontaneously through a lower cervical tracheostomy, water and other test solutions at approximately 37°C were injected into the functionally isolated larynx with a small catheter. Of the 130 receptors studied, none of the cold receptors (N = 13) responded to water, whereas approximately 60% of all laryngeal mechanoreceptors (72 of 117) responded with either a short delay, short duration or a long delay, long duration response. In general the former pattern of response was exhibited by nonrespiratory-modulated receptors, whereas the latter was typical of respiratory- modulated receptors. The specific nature of the stimulus (hypotonicity or lack of chloride ion) of the water response was further studied in 53 receptors with isoosmotic solutions of dextrose and sodium gluconate. The long delay, long duration response was dependent on a decreased osmolality, while the short delay, short duration response was dependent on the lack of chloride ion of the test solutions. All water-responsive receptors tested (N = 17) were blocked within 50 sec by topically applied 2% lidocaine and thus presumed to be superficial. However, 10 receptors which did not respond to water were also blocked within 50 sec, suggesting that not all superficial receptors are stimulated by water. Based on these observations, we propose that changes in osmolality or ionic composition of the laryngeal surface liquid could play an important role in modifying reflexes involved in the maintenance of upper airway patency.