Pulmonary Receptors Research Articles

Characteristics of vagal afferent activity in rats: Three types of pulmonary receptors responding to collapse, inflation, and deflation of the lung

To elucidate the characteristics of vagal afferent fibers arising from rat lungs, single-unit activity from pulmonary stretch receptors and two other types of pulmonary receptors was recorded. In the latter, one type of receptor, termed deflation-sensitive receptors in this study, was stimulated only in the expiratory phase of normal respiration. Moreover, this type of receptor exhibited persistent discharges resulting in a train or burst of impulses with collapse and forced deflation, respectively. The decrease of discharge frequency during collapse was slow and the average adaptation index was 20%, indicating a slowly adapting characteristic. Upon forced deflation, the discharge frequency increased with increasing negative pressure to −158 mm H2O intratracheal pressure. The other type of receptor, termed irritant-like receptors, responded to both deflation and inflation. In addition, they displayed rapidly adapting and irregular discharges during maintained inflation. These results indicate that rat vagus nerves deliver afferent information from at least three types of pulmonary receptors: pulmonary stretch and lung irritant-like receptors and the receptors specifically sensitive to expiration or lung deflation. Furthermore, the possibility is postulated that vagal deflation-sensitive receptors are related to the peripheral mechanism in normal respiration and Hering-Breuer deflation reflex in rats.

Respiratory arrhythmias and airway CO2, lung receptors, and central inspiratory activity.

The purpose of this study was to determine whether hypocapnia affects heart rate secondary to an effect on pulmonary receptors. Dogs were anesthetized and placed on cardiopulmonary bypass. Interrelationships among airway CO2, central inspiratory activity, and lung receptor effects on respiratory-related heart rate changes (respiratory arrhythmias) were studied after vagal efferent activity was increased secondary to baroreceptor stimulation. Hypocapnia, isolated to the lungs, produced an increase in the magnitude of the respiratory arrhythmias observed. Two mechanisms may produce these results. Hypocapnia affects pulmonary receptors, which 1) reflexly alter heart rate and 2) modulate breathing frequency, thus altering the dynamics of the respiratory arrhythmias that were produced. The results also suggested that the reflex increase in heart rate in response to lung inflation and the Hering-Breuer expiratory-facilitatory reflex are either produced by different pulmonary receptors or by the same pulmonary receptors but may be mediated by different central mechanisms.

The Role of Pulmonary Vascular Amine Receptors in Regulating Pulmonary Vascular Tonea

The Role of Pulmonary Vascular Amine Receptors in Regulating Pulmonary Vascular Tone^a

New applications of radionuclide studies in thoracic imaging.

Future radionuclide studies in the lung will encompass not only improved evaluation of regional ventilation and perfusion in pulmonary embolism and lung cancer, but should also provide new information about alveolar-capillary permeability, cell kinetics in the lung, and pulmonary metabolism and receptors. With this increase in the scope of pulmonary nuclear medicine must come further refinement of current imaging techniques and development of new radiopharmaceuticals. Pulmonary emission tomography (via single photons or positrons), which reduces or eliminates functional superimposition in the lung, seems to be the most promising technique for performing such studies. In the area of new radiopharmaceuticals, radiolabeled monoclonal antibodies appear promising for studies of lung cancer. These developments suggest that the next few years will be exciting ones for those interested in pulmonary radionuclide studies.

Ventilation studied with circulatory occlusion during two intensities of exercise.

Our purpose was to study the possible role of a pulmonary chemoreceptor in the control of ventilation during exercise. Respiratory gas exchange was measured breath-by-breath at two intensities of exercise with circulatory occlusion of the legs. Eight male subjects exercised on a cycle ergometer at 49 and 98 W for 12 min; circulation to the legs was occluded by thigh cuffs (26.7 kPa) for two min after six min of unoccluded exercise. PETCO2 and VO2 decreased and PETO2 increased significantly during occlusion at both workloads. Occlusion elicited marked hyperventilation, as evidenced by sharp increases in VE, VE/VCO2, and VE/VO2. A sudden sharp increase in PETCO2 was seen 12.3 +/- 0.5 and 6.5 +/- 1.2s after cuff release in all subjects during exercise at 49 and 98 W, respectively. At 49 W a post-occlusion inflection in VE was seen in 7 subjects 21.1 +/- 5.8s after the PETCO2 inflection. Three subjects showed an inflection in VE at 98 W 23.3 +/- 7.5 s after the PETCO2 inflection. There were significant increases in PETCO2, VO2, VCO2 and VE after cuff release. VE mirrored VCO2 better than VO2, post occlusion. On the basis of a significant lag time between inflections in PETCO2 and VE following cuff release, it is concluded that the influences of a pulmonary CO2 receptor were not seen.

Changes in the Pulmonary Glucocorticoid Receptor Content in the Course of Interstitial Disease

The level of cytosolic glucocorticoid receptors (GR) was measured in 12 open-chest lung biopsies of interstitial pulmonary diseases. The results showed an increase in the GR content in the diseased lungs correlated to the degree of septal cellularity in nine cases. Two pulmonary sarcoidosis and one end-stage idiopathic pulmonary fibrosis patients presented higher levels of GR than those predicted by the septal cellularity. It was concluded that the GR content of the lungs increases in the course of interstitial diseases, reflecting the number of cells that express cytosolic GR in pulmonary parenchyma.

Vagal expiratory afferent discharges during spontaneous breathing

Expiratory discharges in cervical afferent vagal fibres during spontaneous respiration were observed in anesthetized animals (17 rabbits, 4 cats and 2 monkeys). The percentages of such units among the total observed fibres was 11% in rabbits, 5% in monkeys, 2% in cats. All the experiments were done after section of the recurrent laryngeal nerve and the abdominal branches of the vagus nerve. Changing the intraesophageal pressure from +15 mm Hg to −25 mm Hg by injection or suction of air into or out of the esophagus, of which the abdominal end had been ligated, did not affect the expiratory discharges significantly suggesting that the receptors were not in the esophagus. Injection of air into the lungs to elevate the intratracheal pressure to 5 mm, 10 mm or 15 mm Hg could not excite such receptors. Collapse of the lungs caused by artificial pneumothorax produced continuous discharges in such fibres. Inflation of collapsed lungs by an artificial respiration pump stopped the sustained discharges immediately. The average conduction velocity of the afferent fibres was 25.5 m/s. It seems that this is a type of slowly adapting, low threshold pulmonary receptor with medium sized afferent fibres. The adequate stimulus of such receptors is deflation of the lungs. The possible advantage of participation of such receptors, in addition to the pulmonary stretch (inflation) receptors, in regulation of normal respiration is discussed in the light of the concept of ‘paired receptors’.

Effects of early hypoxia on breathing pattern in rabbit pups before and after vagotomy

We examined the influence of vagal pulmonary receptors exerted on the breathing pattern and inspiratory activities of phrenic nerve and intercostal electromyograms (EMG) during hypoxia in rabbit pups. Animals in their second week of life were anaesthetized with ketamine (50 mg/kg) and acepromazine (3 mg/kg) and tracheostomized. While they breathed spontaneously, we recorded tidal volume (VT), integrated phrenic activity (PHR), integrated external intercostal EMG (INT), and blood pressure (BP). To prevent secondary ventilatory depression, animals were exposed to 12% O2 (balanced with N2) for no longer than 5 min before and after vagotomy. All measurements were taken from 1 min following the onset of hypoxic exposure until the end of the run. During hypoxia, VT, PHR, and INT increased in intact rabbit pups. There was an almost immediate decrease in BP that was maintained during the total period of hypoxia exposure. Hypoxia resulted in inconsistent changes in inspiratory (TI) and expiratory (TE) time in intact animals. Following vagotomy, PHR, INT, VT, BP, and TE responses were the same as in intact animals. However, TI significantly decreased in all animals. In response to hypoxia with and without vagal feedback, INT increased less than PHR in most cases. Qualitatively similar effects of hypoxia were observed in an adult rabbit. The results reveal that the increase in VT and the shortening of TI in response to hypoxia do not depend on vagal feedback in rabbits during the early postnatal period. In fact TI shortening was significant only without vagal feedback.

Pulmonary responsiveness to methacholine and disodium hexachloroplatinate (Na 2PtCl 6) aerosols in cynomolgus monkeys ( Macaca fascicularis)

Hyperreactivity of the airways is a common finding in human asthma, and responsiveness to inhaled methacholine aerosols is routinely used for assessing airway irritability. Workers in precious metal refineries demonstrate pulmonary signs suggestive of asthma, presumably related to exposure to soluble platinum salts. In these workers, evidence of physiologic dysfunction precedes immunologic evidence (skin test) of disease, suggesting an initial pharmacologic mechanism. With a primate animal model for the screening of occupational asthmogens, 24 Cynomolgus monkeys were evaluated for their comparative pulmonary responsiveness to inhaled aerosols of methacholine and sodium hexachloroplatinate (Na 2PtCl 6). Average pulmonary flow resistance ( R L), dynamic compliance ( C L dyn), maximum expiratory flow volume (MEFV), and respiratory frequency changes were evaluated after bronchoprovocation challenge. Both agents produced dose-dependent increases in R L, dose-dependent decreases in C L dyn and MEFV, and no effect on respiratory rates. Analyses of the correlation between concentration effects of the two agents showed no association between cholinergic airway irritability status and Na 2PtCl 6-induced bronchoconstriction. Na 2PtCl 6 bronchoprovocation produced significantly greater flow impairment at lower lung volumes when compared to methacholine concentrations with equipotent effects on R L and C L dyn. These compounds have differential effects on peripheral airway function. The lack of respiratory rate change seen on bronchoprovocation with these compounds, in comparison to the rapid shallow breathing in anesthetized monkeys following irritant or histamine challenge, indicates that neither aerosol stimulated pulmonary irritant receptors.

The Effects of Morphine and Morphine-Related Compounds on the Rate of Afferent Discharges from the Pulmonary Receptors in Bullfrog

We examined the effects of morphine and morphine-related compounds on the rate of afferent discharges from the pulmonary receptors in bullfrog. Morphine (1 × 10−5-1 × 10−3 M) decreased the rate of spontaneous afferent discharges in a concentration-dependent manner, but hardly affected the rate of afferent discharges synchronized with lung inflation. Dihydrocodeine, naloxone and dextrorphan had the same effects as morphine. Levallophan (1 × 10−4 M), pentazocine (1 × 10−4 M) and pethidine (1 × 10−3 M) clearly decreased both rates of the spontaneous afferent discharges and the afferent discharges synchronized with iung inflation. In the presence of naloxone or levallorphan at the concentration of 1 × 10−5 M, morphine (1 × 10−5 and 1 × 10−4 M) caused an additive decrease in the rate of afferent discharges. Dextromethorphan and apomorphine at the concentration of 1 × 10−4 M caused an increase in the rate of spontaneous afferent discharges followed by decrease in both rates of the spontaneous afferent discharges and the afferent discharges synchronized with lung inflation. When dextromethorphan or apomorphine was washed out and the rates of afferent discharges were almost restored to the levels before application of each drug, reapplication of these drugs caused no increase in the rate of spontaneous afferent discharges, but the drugs inhibited the generation of afferent discharges. AN of these drugs did not affect the flow rate of perfusion solution from the pulmonary vein.

Ventilatory and cardiovascular responses of the unanaesthetized chicken, Gallus domesticus, to the respiratory stimulants etamiphylline and almitrine

1. 1. The ventilatory and cardiovascular effects of i.v. administration of the respiratory stimulants etamiphylline and almitrine were investigated in conscious or decerebrate adult female domestic fowl. 2. 2. Infusion of etamiphylline (100 mg· kg −1) or injection of almitrine (2mg· kg −1) evoked a potent long-lasting stimulation of ventilation in both conscious and decerebrate fowl. 3. 3. The pattern of the respiratory response was characteristically different to that observed in mammals in that the increased minute volume of ventilation was attained by large increases in respiratory frequency accompanied by a reduction in tidal volume. 4. 4. The pattern of respiration following drug-induced stimulation was, in some birds, typical of thermal panting although neither etamiphylline nor almitrine caused significant increases in body temperature. 5. 5. Differences in the pattern of responses of the rate and depth of breathing may be attributed in part to the differences in pulmonary receptor systems involved in the control of breathing in birds and mammals.

Rapidly-adapting receptor activity and intratracheal pressure in guinea pigs I. Action of leukotriene C 4

Leukotriene C 4 (LTC 4) is a major component of slow-reacting substance of anaphylaxis (SRS-A) and is a potent bronchoconstrictor. In humans LTC 4 results in bouts of coughing which suggests stimulation of pulmonary receptors involved in a reflex mechanism. Furthermore, atropine reduces the effect of both LTC 4 and SRS-A. To test the hypothesis that LTC 4 stimulates the rapidly-adapting or “irritant” receptor (RAR) of the airways, we administered LTC 4 by both intravenous injection (10–1000 ng) and by aerosol delivery ( 1 ug/ml) to the lungs of guinea pigs while recording arterial blood pressure, intratracheal pressure, and nerve activity from RARs. LTC 4 (i.v.) concurrently increased both nerve activity and intratracheal pressure even at low doses in a dosedependent manner. Therefore, a direct action of LTC 4 (i.v.) upon the RAR is difficult to conclude. The separation of peak tracheal pressure and peak nerve activity was apparent with aerosol delivery of LTC 4. The pattern of RAR activity during LTC 4 aerosol challenge was unrelated to respiratory phase. FPL 55712 blocks the effects of SRS-A. We challenged the lung with 500 ng LTC4 intravenously before and after FPL 55712 injection (2.5 mg/kg). FPL 55712 blocked the increases of both tracheal pressure and RAR activity.

Respiratory volume-timing relationship during sustained elevation of functional residual capacity

In 7 spontaneously breathing dial-urethane anesthetized cats a negative pressure was produced arounf the thorax and abdomen to increase the functional residual capacity (FRC) by about 1 tidal volume for up to 60 min. A tracheal cannula was connected to a resistive manifold for selective loading of inspiration or expiration. Two resistive loads and tracheal occlusion were presented six times each at control FRC (FRCc), after 60 min at elevated FRC (FRCe) and 30 min after return to FRCc. Inspiratory and expiratory durations (Ti and Te) were measured from diaphragmatic EMG. We observed that Ti at FRCe (0.88 ± 0.11 sec) was not significantly shorter than Ti at FRCc (1.06 ± 0.14 sec). Tracheal occlusion at FRCe caused a shorter Ti (1.37 ± 0.15 sec) than at FRCc (1.79 ± 0.21 sec) (P < 0.05). The slope (m) of the Vi-Ti relationship generated by the resistive loads at FRCe was steeper (m = −65 ± 7 ml·sec−1) and shifted upward from the Vi-Ti curve at FRCc (−50 ± 6 ml·sec−1) (P < 0.05). The Ve-Te relationship at FRCe was not significantly changed from control. Thirty minutes following return to FRCc, Ti was still slightly shorter (0.96 ± 0.11 sec) than the initial Ti at FRCc.We conclude: (1) The slope of the Vi-Ti relationship is determined to a great extent by the total lung volume. However, under the conditions of sustained elevation of FRC, this relationship is influenced by the partial adaptation of slowly adapting pulmonary receptors SARs. (2) The increased SAR activity at end expiration during FRCe may not influence the control of Te.

Alveolar macrophages in idiopathic pulmonary fibrosis have glucocorticoid receptors, but glucocorticoid therapy does not suppress alveolar macrophage release of fibronectin and alveolar macrophage derived growth factor.

Although glucocorticoids are the most widely used therapeutic modality in the treatment of idiopathic pulmonary fibrosis (IPF), the administration of these agents infrequently arrests the progressive fibrosis of this disorder. In this context, the present study was designed to determine if the lack of effect of glucocorticoid therapy in IPF could be explained, in part, by a lack of effect of glucocorticoids on alveolar macrophage release of fibronectin and alveolar macrophage derived growth factor (AMDGF), mediators thought to play a role in the accumulation of fibroblasts associated with the fibrosis of this disease. Patients with IPF were studied in 2 groups, those receiving glucocorticoid therapy and those not receiving therapy. The release of fibronectin by alveolar macrophages of IPF patients was elevated compared to release of fibronectin from alveolar macrophages obtained from normal volunteers (p less than 0.01). However, the release of fibronectin was no different in treated and untreated patients with IPF (p greater than 0.2). Like fibronectin, the release of AMDGF by alveolar macrophages of IPF patients was elevated compared to release of AMDGF from alveolar macrophages obtained from normal volunteers (p less than 0.01), but there was no difference in treated and untreated IPF patients (p greater than 0.2). Sequential evaluation of IPF patients before and after glucocorticoid therapy demonstrated no impact of glucocorticoid therapy on alveolar macrophage release of fibronectin and AMDGF. The inability of glucocorticoids to suppress fibronectin and AMDGF release was not due to a lack of glucocorticoid receptors in IPF patients because alveolar macrophages from patients and from normal volunteers bound glucocorticoids similarly.(ABSTRACT TRUNCATED AT 250 WORDS)

R-enantiomer of timolol: a potential selective ocular antihypertensive agent.

Various studies were conducted to evaluate the effects of timolol, an S-enantiomer, relative to its R-enantiomer upon intraocular pressure and related ocular systems in the rabbit. The R-enantiomer was about one-third as potent as timolol in displacing 3H-dihydroalprenolol binding to iris-ciliary body tissue, reducing aqueous humor formation, and lowering intraocular pressure of alpha-chymotrypsin hypertensive eyes. In contrast, the R-enantiomer was 50 to 90 times less potent than timolol in antagonizing the effects of isoproterenol on pulmonary and atrial beta-adrenergic receptors. The data indicate that the R-enantiomer may lower intraocular pressure in man at concentrations less likely than timolol to block extraocular beta-adrenergic receptors. Finally, to account for the differential effect of the R-enantiomer upon ocular as opposed to extraocular beta-adrenergic receptors, it is tentatively suggested that this agent may also act upon a population of ocular beta-adrenergic receptors showing relatively poor stereoselectively.

Mechanism of hyperpnea induced by changes in pulmonary blood flow.

Increases in pulmonary blood flow can elicit hyperpnea. To examine the mechanisms responsible, we surgically isolated the systemic and pulmonary circulations in six dogs and independently controlled PCO2, PO2, and blood flow in each circuit. Anesthesia was induced with ketamine and maintained with halothane. Systemic venous return was drained from the right atrium and passed through a membrane oxygenator and heat exchanger; blood was returned to the ascending aorta (Qs). An identical bypass was established for the pulmonary circulation, draining blood from the left atrium and returning it to the pulmonary artery (Qp). The lungs were initially ventilated with room air. Qs and systemic arterial CO2 gas tension were maintained at approximately 0.080 1 X min-1 X kg-1 and 40 Torr, respectively. Pulmonary arterial CO2 gas tension was set near 55 Torr, and Qp varied. Ventilatory drive was assessed by minute integration (MI) of the activity recorded from the central end of the left C5 root of the phrenic nerve. MI increased as much as 160% above control as Qp was increased over the range of 0.025 (control) to 0.175 1 X min-1 X kg-1. When pulmonary CO2 gradients were eliminated by a rebreathing technique, MI was independent of Qp. These results suggest that CO2-sensitive pulmonary receptors respond to the change in pulmonary PCO2 gradients which occur when Qp is elevated (breathing room air) augmenting ventilation.

THE EFFECT OF THEOPHYLLINE ON THE HYPOXIC VENTILATORY RESPONSE IN THE NEWBORN PIGLET: ROLE OF THE VAGUS

We have previously demonstrated that theophylline, an adenosine antagonist, reduces hypoxic ventilatory depression in the newborn piglet. In order to investigate the possibility that the stimulatory effects of theophylline we observed were due to effects on vagal pulmonary receptors, we compared the effect of theophylline on the hypoxic ventilatory response in intact and vagotomized newborn piglets. Five newborn piglets less than 3 days of age were exposed to 10 % oxygen under three experimental conditions: 1) intact; 2) after vagotomy; and 3) vagotomy + theophylline. Each animal was anesthetized with ketamine and xylazine, intubated, and the femoral artery catheterized. The vagi were identified but left intact prior to the onset of the experiments. Recordings of expiratory flow and integrated volume, EKG, and arterial blood pressure were obtained during six minutes of hypoxia first before and then beginning 30 minutes after vagotomy. Theophylline (15 mg/kg) was then administered over 10 minutes and after 30 minutes the experiment was repeated. The effect of hypoxia on minute ventilation in each of the three conditions is shown in the graph. Vagotomy alone had no effect on the hypoxic ventilatory response. The addition of theophylline, however, resulted in a greater increase above baseline after 6 minutes of hypoxia (38.7 +/−17.3 %) compared to vagotomy alone (19.8 +/− 15.0 %)(p<0.02). The difference in ventilation was due to changes in frequency rather than tidal volume. We conclude that vagal afferents do not influence the newborn hypoxic ventilatory response and that the effects of methyl xanthines on hypoxic ventilatory depression are not mediated by the vagus.

Glucocorticoids increase pulmonary Epidermal Growth Factor receptors in female and male fetal rabbit

Experimental evidence in animals and humans suggest that glucocorticoids enhance fetal pulmonary maturation. Mechanisms of glucocorticoid effects remain unclear; but apparently include up regulation of fetal pulmonary insulin and β-adrenergic receptors. A role of Epidermal Growth Factor (EGF) in fetal lung maturation through plasma membrane bound receptors has been recently proposed. Betamethasone, 0.085 mg/kg, was administered on 25th and 26th day of gestation to the rabbit doe. Fetal pulmonary EGF receptor characteristics in male or female fetuses were studied on the 27th day of pregnancy. The percent specific binding of 125-I-EGF to lung plasma membranes (LPM) and the number of receptor sites per mg of LPM protein or DNA content were significnatly higher in the glucocorticoid treated female as well as male fetuses when compared to the control pups, with no difference in the Kd. Presence of high affinity receptors for EGF and their up regulation by glucocorticoids support the hypothesis that EGF plays an important role in fetal lung maturation and that some of the beneficial effects of glucocorticoids in decreasing the incidence of HMD may be mediated through its interaction with EGF.

Effect of chemoreceptor and pulmonary receptor stimulation on dilator nares EMG activity in the dog.

To define the relationship between central control of upper airway muscles and respiratory muscle function, the electromyographic responses of the dilator nares muscles to stimulation of chemoreceptors and pulmonary receptors were studied in six anesthetized dogs. Only at maximal levels of hypoxia was the inspiratory activity of the dilator nares significantly increased. Hypercapnic stimulation increased the inspiratory activity with each incremental increase in CO2. Pulmonary stretch receptor stimulation produced by lung inflation inhibited dilator nares activity. Pulmonary irritant receptor stimulation by intravenously administered histamine increased dilator nares activity, as did pulmonary J receptor stimulation by the intravenous administration of capsaicin.

Pulmonary resistance and compliance changes evoked by pulmonary opiate receptor stimulation

The administration of [D-Ala 2, Met 5]enkephalinamide (DAME, 10–250 gmg/kg) or morphine sulfate (MS, 2 mg/kg) into the right atrium (RA) of spontaneously breathing decerebrate rats caused an increase in lung resistance (R L) and a decrease in dynamic compliance (C dyn). The maximal percentage increase in R L for DAME (250 μg/kg) and MS (2 mg/kg) was 120 ± 21 and 160 ± 40%, respectively, occurring during the first 30 s following an initial period of apnea, and subsiding within 1.5–2.0 min. The fall in C dyn (DAME = −31 ± 8%; MS = −35 ± 4%) followed a more prolonged time course returning to control within 4–5 min. These responses were completely abolished by pretreatment with naloxone HCl (100 μg/kg i.v.), as well as bilateral cervical vagotomy. Pretreatment with antihistaminic, antiserotinergic, and antimuscarinic agents had no effect on the opioid induced changes in R L and C dyn. Further studies carried out in ventilated animals showed blockade of the mechanical responses following the administration of neuromuscular blockers, C 7 spinal cord transection, and ventral midline opening and retraction of the chest. Electromyograms obtained from intercostal muscles showed excitation of expiratory motor units and inhibition of inspiratory motor units following the administration of opioids. Similar results were obtained with phenyldiguanide (PDG), a known stimulant of pulmonary J-receptors. However, PDG effects were not blocked by naloxone. It was concluded that changes in R L resulted from a decrease in thoracic volume and resultant decrease in the radial traction of the airways. Changes in C dyn were caused by spasm of expiratory muscles of the chest wall.