Pulmonary Receptors Research Articles

Coronary chemoreflex evoked by intrapericardial nicotine has a somatic component.

Stimulation of vagally innervated cardiac or pulmonary receptors reflexly evokes depressor responses called the coronary chemoreflex and pulmonary depressor reflex, respectively. The efferent arm of the pulmonary depressor reflex contains a somatic component wherein monosynaptic and polysynaptic muscle reflexes are attenuated. The purpose of the present investigation was to determine whether the efferent arm of the coronary chemoreflex also attenuates the monosynaptic knee-jerk reflex. Cardiac receptors were stimulated by injection of nicotine and bradykinin into the pericardial sac of 15 chloralose-anesthetized (50 mg/kg) cats. The knee-jerk reflex was elicited by tapping the patellar tendon intermittently. Intrapericardial nicotine attenuated the knee-jerk reflex by -26.2 +/- 6.5%. The attenuation was mediated by the vagus nerves, because vagotomy abolished the nicotine-induced attenuation. Stimulation of cardiac receptors evoked the attenuation, because blockade using intrapericardial procaine abolished the nicotine-induced attenuation. On the other hand, intrapericardial bradykinin augmented the knee-jerk reflex by 17.5 +/- 3.3%. The effect was not mediated by the vagus nerves; vagotomy did not abolish the bradykinin-induced augmentation. Changes in the knee-jerk reflex were not correlated with changes in blood pressure or heart rate evoked by intrapericardial nicotine or bradykinin. These findings demonstrate that reflex somatomotor responses accompany the reflex autonomic responses elicited by cardiac receptors. The somatic component of the vagally mediated coronary chemoreflex could contribute to the fainting reaction associated with exertional syncope of aortic stenosis and vasovagal syncope.

The mechanism of respiratory rhythm generation during constant flow assisted mechanical ventilation in the decerebrated dog.

In awake human subjects input from the forebrain has significant effects on the respiratory pattern during assisted (AMV) and controlled (CMV) mechanical ventilation. The hypothesis in this animal study was that if the influence from the forebrain is eliminated, the respiration during AMV and that during CMV is controlled by the same mechanism. Fifteen decerebrated and tracheostomized dogs were subjected to CMV with a variety of combinations of tidal volume and frequency. The respiratory rhythm during CMV was simulated by a mathematical model composed of the central respiratory activity and inputs from pulmonary receptors. During AMV, the respiratory cycle duration was prolonged, and this was found to be the summated effect of prolonged Ttg (ventilator trigger period) and shortened Tinf (lung inflation period). When these changes in Ttg and Tinf were included, the model for CMV predicted respiratory changes during AMV. We concluded that the basic mechanism controlling AMV and CMV may be the same.

Extra-Adrenal Nonneuronal Epinephrine and Phenylethanolamine-N-Methyltransferase

Publisher Summary Phenylethanolamine- N -methyltransferase (PNMT) is an enzyme that specifically methylates P-hydroxylated phenylethanolamines. Epinephrine (Epi) is synthesized in the adrenal from norepinephrine (NE) by this PNMT. NE can also be N-methylated by a less specific N -methyltransferse (NMT) that N-methylates many amines. NMT is distinguished from PNMT by the ability of NMT to convert dopamine into [ 3 H]epinine and by the selective effect of PNMT inhibitors to block N-methylation by PNMT but not by NMT. This chapter summarizes several studies suggesting that Epi has a profound effect on pulmonary function. It stimulates α and β receptors in the lung and has a particularly high affinity for β 2 receptors. Stimulation of pulmonary adrenergic receptors by Epi causes bronchodilation. The Epiforming capacity of lung homogenates has been inhibited by the PNMT inhibitor SKF 29661 about half as well as in adrenal but better than in cardiac ventricle. It appears that 50% of lung Epi-forming activity is from PNMT and 50% from NMT. Studies on Epi-forming activity in human tissues have shown that PNMT and NMT activity is detectable in most tissues. PNMT activity predominates in heart and lung, whereas NMT is more prevalent in kidney, liver, bronchus, and trachea. Overall, tissue Epi levels correlated with PNMT activity but not with NMT. Moreover, human PNMT appears to be responsive to thyroid hormones. Red blood cells (RBC)-PNMT activity has been below normal levels in hypothyroid patients and returned to normal levels when the patients became euthyroid after chronic thyroxin treatment. On the other hand, hyperthyroid subjects have elevated RBC-PNMT activity. NMT activity has not been altered by either hypothyroidism or hyperthyroidism.

Role of vagal lung C-fibres in the cardiorespiratory effects of capsaicin in monkeys

Apnoea, bradycardia and hypotension were elicited by right atrial injections of capsaicin in anaesthetized monkeys. At the threshold dose (2.5 ± 0.3 μg/kg), tachypnoea was elicited (latency 1.6 ± 0.2 s) which got replaced by apnoea with higher doses of capsaicin. These responses persisted (1) after cooling the cervical vagi to 6–8°C, and (2) after instilling xylocaine into the pericardial sac. Tachypnoea and apnoea were elicited after bilateral cervical vagotomy also, but only with higher doses and after a longer latency (5.0 ± 0.3 s). Right atrial injection of capsaicin and insufflation of halothane stimulated vagal pulmonary C-fibre receptors with a latency of 1.7 ± 0.7 s and 0.2 ± 0.1 s, respectively. Tachypnoea/apnoea, bradycardia and hypotension were elicited by left atrial injection of capsaicin also (threshold dose: 5.0 ± 1.2 μg/kg). The respiratory responses persisted (1) after instilling xylocaine into the pericardial sac, and (2) after bilateral cervical vagotomy suggesting that they were due to stimulation of non-cardiac receptors with sympathetic afferents. It is concluded that the initial respiratory responses elicited by right atrial injection of capsaicin were due to stimulation of pulmonary C-fibre receptors with vagal afferents.

Adaptation of pulmonary receptors in the spontaneously breathing anaesthetized rat.

It has been suggested that species with high breathing frequencies have pulmonary stretch receptors which adapt more rapidly than species with low breathing frequencies. This has proved not to be so. Our hypothesis is that this theory is in fact correct if modified so that overall rate of adaptation of afferent vagal activity, i.e. the sum of stretch and rapidly adapting receptors, is considered. A rapidly breathing species, such as the rat, would thus have a greater proportion of rapidly adapting receptors, than a more slowly breathing species. To test this hypothesis, we measured the proportion of rapidly adapting pulmonary mechanoreceptors in spontaneously breathing rats for comparison with existing results from more slowly breathing species. We found there to be one rapidly adapting receptor for every three slowly adapting receptors present. This measurement has not previously been made in spontaneously breathing rats. The ratio of rapidly to slowly adapting pulmonary receptors in the species sequence cat-rabbit-rat is the same as the ratio of their breathing frequencies (3:4:10). We propose that the difference in proportion of slowly to rapidly adapting pulmonary receptors in different species may be related to their eupnoeic breathing frequency.

Ventilatory relief of the sensation of the urge to breathe in humans: are pulmonary receptors important?

1. The sensation of an urge to breathe (air hunger) associated with a fixed level of hypercapnia is reduced when ventilation increases. The aim of the present study was to investigate whether pulmonary receptors are important in this mechanism. 2. Five heart-lung transplant (HLT) subjects and five control subjects were studied during periods of mechanical and spontaneous ventilation. End-tidal Pco2 (PET,CO2) was increased by altering the level of inspired CO2. Throughout, subjects rated sensations of air hunger. Air hunger was also monitored during and immediately following maximal periods of breath-holding. 3. When the level of mechanical ventilation was fixed, both groups experienced a high degree of air hunger when PET,CO2 was increased by about 10 mmHg. At similar levels of hypercapnia, both groups derived relief from approximately twofold increases in tidal volume, although relief was slightly less effective in HLT subjects. This was reversible, with decreases in the level of mechanical ventilation rapidly giving rise to increased ratings of air hunger. 4. With breath-holding, all subjects obtained some respiratory relief within 2 s of the break point; there was no significant difference between the groups. 5. The results suggest that sensations of an urge to breathe induced by hypercapnia can be modulated by changes in tidal volume in the presumed absence of afferent information from the lung.

(S,S)- and (S,R)-1′-[ 18F]fluorocarazolol, ligands for the visualization of pulmonary β-adrenergic receptors with PET

The β-adrenoceptor antagonist carazolol has been labelled with fluorine-18 in the isopropyl group via a reductive alkylation by [ 18F]-fluoroacetone of the corresponding (S)-desisopropyl compound according to a known procedure. The introduction of fluorine in the isopropyl group creates a new stereogenic centre resulting in the formation of (S,S)- and (S,R)-1′-[ 18F]fluorocarazolol, which were separated by HPLC. Tissue distribution studies were performed in male Wistar rats. Both the (S,S)- and (S,R)-diastereomers (S.A. 500–2000 Ci/mmol; 18.5–74 TBq/mmol) showed high uptake in lung and heart, which could be blocked by pretreatment of the animals with (±)-propranolol. No significant differences were observed between the biodistribution of the two diastereomers. Metabolite analysis showed a rapid appearance of polar metabolites in plasma, while at 60 min postinjection 92% and 82% of the total radioactivity in lung and heart was unmetabolized 1′-[ 18F]fluorocarazolol. In a PET-study with male Wistar rats, the lungs were clearly visualized and the pulmonary uptake was decreased after pretreatment of the animals with (±)-propranolol. The heart could not be visualized. Similar results were obtained in PET-studies with lambs.

Autoradiographic mapping of pulmonary NK1 and NK2 tachykinin receptors and changes after repeated antigen challenge in guinea pigs.

An autoradiographic technique was used to study the distribution of changes in pulmonary NK1 and NK2 receptors in guinea pig lung after repeated antigen challenge. Specific labeling of [3H]CP96345 (NK1 receptors) and [3H]SR48968 (NK2 receptors) was localized over the tracheal and bronchial smooth muscle; the density of binding increased towards smaller airways with a higher density for [3H]CP96345 binding. Bronchial epithelium and pulmonary blood vessels were also labeled densely with [3H]CP96345. No remarkable difference in the pattern of distribution of pulmonary NK1 and NK2 tachykinin receptors was observed between control, vehicle-challenged, and repeatedly antigen-challenged (weekly for three times) guinea pigs. A significant reduction in specific labeling of [3H]CP96345 (p < 0.01) and [3H]SR48968 (p < 0.05) over pulmonary structures was observed in antigen-challenged compared to control or vehicle-challenged animals. This study provides evidence that NK1 and NK2 tachykinin receptors are both localized to smooth muscle of all sizes in guinea pig airways and provides further evidence for a discrete distribution of NK1 and NK2 tachykinin receptors, consistent with their relative functional activities. In an established model of airway inflammation a decrease in the expression of NK1 and NK2 tachykinin receptors was evident on several different cell types within the lung, and this could influence airway and vascular reactivity.

CO2-sensitive olfactory and pulmonary receptor modulation of episodic breathing in bullfrogs.

Breathing was monitored during normocarbia, hypercarbia (6% CO2 in air), and the period immediately after the return to normocarbic conditions in intact, olfactory-denervated, and vagotomized bullfrogs. In intact frogs, ventilation increased during hypercarbia, but the breathing pattern remained episodic. Immediately upon return to air, there was a further paradoxical increase in breathing frequency, and breathing became continuous in most frogs. Results obtained from animals after olfactory receptor denervation indicate that tonic stimulation of olfactory receptors by airway CO2 inhibited breathing during hypercarbia. Measurements of the kinetics of changes in airway and arterial blood CO2 levels support the suggestion that the sudden release of this inhibition on the return to normocarbic conditions was responsible for the posthypercarbic hyperpnea. Vagotomy increased ventilation during normocarbia. Hypercarbia now caused a change in breathing pattern but had no net effect on total ventilation, suggesting that pulmonary vagal feedback inhibited ventilation during normocarbia but stimulated ventilation during hypercarbia. Although olfactory and pulmonary receptor feed-back shape the breathing pattern, they were not responsible for initiating or terminating the episodes of breathing.

Pulmonary Artery Endothelial Cell Function in Swine Pseudomonas Sepsis

A substantial increase in pulmonary vascular resistance is associated with sepsis and its sequelae (sepsis syndrome and septic shock). It is postulated that increased resistance may result from sepsis-induced endothelial cell injury or altered vasoreactivity secondary to pulmonary hypertension. We, therefore, tested the hypothesis that sepsis causes endothelial cell injury and that increased pulmonary pressure alters vascular reactivity. Young swine (15–25 kg) were anesthetized and ventilated. Septic animals received a 1-hr infusion of livePseudomonas aeruginosa(n= 11), and the control cohort received 0.9% NaCl (n= 7). All animals were studied for 300 min following the infusion. Postmortem branches of peripheral pulmonary arteries were prepared and tested in a vessel myograph. Ring segments were set to 90% of the circumference the vessels would have at pressures of 20, 30, 40, or 50 mmHg (L90), corresponding to varying pulmonary pressures observed in sepsis. A high dose of potassium was used to obtain maximum possible contraction. Prostaglandin was used to precontract the vessels before testing endothelial cell responses to acetylcholine or bradykinin. Sodium nitroprusside was added at the end of each experiment to obtain maximum possible smooth muscle relaxation. No differences in contraction or relaxation were observed when vessels were set to different pressures (i.e., 20 vs 50 mmHg). Maximum possible contraction to KCl was significantly decreased after 300 min of sepsis compared to control. No differences between groups were found in contractility to prostaglandin. Bradykinin-induced EDRF/NO production, mediated by BK2receptors, was not altered inPseudomonassepsis (97–98% of total relaxation control and 91–95% septic cohort). Response to acetylcholine was significantly decreased after sepsis (89–95% of total relaxation control and 51–61% of septic cohort relaxation). Decreased response to acetylcholine could not be attributed to decreased smooth muscle sensitivity to nitric oxide because the response to bradykinin plus sodium nitroprusside was not altered following sepsis. Vessel reactivity was not altered by increasing pressure settings reflective of changing pulmonary pressurein vivo.These results strongly suggest a sepsis-induced alteration in pulmonary artery endothelial cell receptor sensitivity to acetylcholine, independent of changing pulmonary arterial pressures. This is the first time this decrease has been shown in pseudomonas sepsis.

Pulmonary targeting of liposomal triamcinolone acetonide phosphate.

To explore the use of triamcinolone acetonide phosphate liposomes as a pulmonary targeted drug delivery system. Triamcinolone acetonide phosphate liposomes composed of 1,2-distearoyl phosphatidylcholine and 1,2-distearoyl phosphatidyl glycerol and triamcinolone acetonide 21-phosphate dipotassium salt were prepared by dispersion and extruded through polycarbonate membranes. Encapsulation efficiency and in vitro stability at 37 degrees C were assessed after size exclusion chromatography. TAP liposomes (TAP-lip) or TAP in solution (TAP-sol) were delivered to rats either by intratracheal instillation (IT) or intravenous (IV) administration. Pulmonary targeting was assessed by simultaneous monitoring of glucocorticoid receptor occupancy over time in lung (local organ) and liver (systemic organ) using an ex vivo receptor binding assay as a pharmacodynamic measure of glucocorticoid action. In vitro studies in different fluids over 24 hours, showed that more than 75% of the TAP remained encapsulated in liposomes. Cumulative pulmonary effects after IT administration of TAP-lip were 1.6 times higher than liver receptor occupancy. In contrast, there was no difference in the pulmonary and hepatic receptor occupancy time profiles when TAP was administered intratracheally as a solution. No preferential lung targeting was observed when TAP-lip was administered IV. As indicated by the mean effect times, lung receptor occupancy was sustained only when TAP-lip was administered IT. Intratracheal administration of TAP-lip provided sustained receptor occupancy, and increased pulmonary targeting which was superior to IT administration of TAP-sol or IV administration of TAP-lip. The use of liposomes may represent a valuable approach to optimize sustained delivery of glucocorticoids to the lungs via topical administration.

Regeneration of Respiratory Pathways within Spinal Peripheral Nerve Grafts

Central respiratory neurons exhibit normal activity after axonal regeneration within blind-ended peripheral nerve grafts (PNGs) inserted near the corresponding cell bodies in the medullary respiratory centers. Part of these medullary respiratory neurons project toward the spinal cord and contribute to descending respiratory pathways that control respiratory motoneurons. The present work investigates to what extent cervical respiratory pathways could be directed out of the central nervous system within PNGs inserted distant to the medullary respiratory nuclei. In adult rats (n=13), autologous segments of the peroneal nerve were implanted into the ventrolateral part of the C2 spinal cord at the level of the descending respiratory pathways. Two to four months after grafting, electrophysiological recording of teased graft filaments (n=562) revealed the presence of regenerated nerve fibers with unitary impulse traffic (n=164) in all tested PNGs (n=6). Respiratory discharges (n=52) corresponded to efferent and afferent activity. Efferent respiratory discharges (n=32) originated from central respiratory neurons which remained functional and preserved afferent connections. Retrograde horseradish peroxidase labeling applied to the distal cut end of PNGs (n=7) revealed stained (42/1997) neurons in areas where respiratory cells have been described. Afferent respiratory discharges (n=20) were synchronized with lung inflation but their origin (stretch pulmonary receptors and/or respiratory muscle receptors) was not determined. On the basis of additional data from light and electron microscopy of PNGs, comparison was made between anatomical, retrograde labeling, and electrophysiological data. The main conclusion is that spinal PNGs appear to be able to promote axonal regeneration of functional respiratory efferent and afferent pathways.

Bronchospasm During Pneumoperitoneum

Bronchospasm During Pneumoperitoneum

Effects of pulmonary denervation on renal sympathetic and heart rate responses to hypoxia.

We hypothesized that the renal sympathetic nerve activity (RSNA) response to hypoxia is attenuated because of stimulation of pulmonary receptors by the increase in ventilation. RSNA was measured during 20 min of severe hypoxia (8% O2) in conscious New Zealand White rabbits with intact lung innervation and in rabbits with surgical denervation of the lungs (LDX). LDX decreased resting breathing frequency but had no effect on resting mean arterial pressure (MAP), heart rate (HR), or RSNA. In intact rabbits, 4 min of hypoxia resulted in elevated RSNA (from 14 +/- 2 to 29 +/- 3% of smoke-elicited maximum), bradycardia (delta-65 +/- 12 beats/min), and no change in MAP (delta 2 +/- 2 mmHg). Bradycardia diminished with time, but elevated RSNA was maintained throughout the 20-min exposure. LDX enhanced the initial bradycardia (delta-113 +/- 11 beats/min, P < 0.01) but had no effect on the RSNA response (35 +/- 2% of maximum) to hypoxia. LDX did not alter steady-state responses of HR or RSNA, but MAP declined over time (-11 +/- 2 mmHg). These results suggest that in conscious rabbits pulmonary receptors have a minor influence on control of sympathetic activity to viscera during severe hypoxemia.

Phenyl biguanide does not inhibit locomotion in conscious rabbits

Stimulation of cardiopulmonary vagal C fibers with phenyl biguanide (PBG) reflexly inhibits locomotion in addition to causing depression of blood pressure (BP), heart rate (HR), and respiration in cats and rats. We investigated whether PBG caused somatomotor inhibition during exercise in the rabbit, a species in which it is known that the hemodynamic and respiratory responses to PBG are mediated by cardiac rather than by pulmonary receptors. In eight New Zealand White rabbits, BP, HR, and hindlimb electromyographic (EMG) responses to 60 and 120 micrograms/kg PBG and saline vehicle were evaluated during two separate 3-min exercise bouts at 10 m/min at 0% grade. During exercise, 60 micrograms/kg PBG decreased BP (-27 +/- 4 mmHg) and HR (-95 +/- 16 beats/min) but did not inhibit locomotion as suggested by the EMG response (+112 +/- 8% of preinfusion EMG). Hemodynamic and EMG responses to 120 micrograms/kg PBG were similar to 60 micrograms/kg PBG. Saline infusion during exercise had no effect on HR, BP, or locomotion (+114 +/- 8% of preinfusion EMG). Locomotion is not inhibited by PBG in rabbits, which suggests that PBG-induced reflex somatomotor inhibition observed in other species is primarily mediated by pulmonary rather than by cardiac receptors.

Exercise- and Cold-Induced Asthma

Exercise- and cold-induced asthma are commonly recognized respiratory disorders. The asthmatic response includes several factors contributing to airway narrowing, and thus increased airway resistance. These include airway smooth muscle contraction, mucus accumulation, and bronchial vascular congestion as well as epithelial damage and vascular leakage. The etiology for these disorders is nonantigenic. The primary stimulus is probably a combination of airway cooling and drying (leading to hypertonicity of airway lining fluid). Symptoms generally do not occur during the stimulus period (e.g., exercise) itself. This protection may in part be due to increased catecholamine levels during exercise. The early phase response, which occurs 5 to 15 min poststimulus, may be mediated through a combination of (a) direct influences, (b) vagal reflexes triggered by airway sensory receptors, or (c) responses to mediator release. Spontaneous recovery occurs within 30 min to 2 hrs. There is usually a refractory period of about 1 to 2 hrs during which responses to further stimuli are attenuated. This may be due to depletion of histamine and other mediators. As well, prostaglandin release (mediated via LTD4 which is released during exercise) inhibits further airway narrowing. A late phase response has been reported 4 to 10 hrs poststimulus in some patients. These reactions are accompanied by a second release of histamine and other mediators that cause inflammatory responses and epithelial damage. However, the exercise dependence of this response is debated.

Protective effects of a glucocorticoid on downregulation of pulmonary beta 2-adrenergic receptors in vivo.

We investigated the in vivo effects of a glucocorticoid on beta-agonist-induced downregulation of beta 1- and beta 2-adrenergic receptors (determined by [125I]iodocyanopindolol binding), mRNA expression (assessed by Northern blotting), and gene transcription (using nuclear run-on assays) in rat lung. Dexamethasone (Dex) (0.2 mg/kg/d, days 1-8) increased beta 1- and beta 2-receptor numbers by 70 and 69% above control, respectively, but did not change their mRNA expression. Isoproterenol (Iso) (0.96 mg/kg/d, days 2-8) decreased beta 1- and beta 2-receptor numbers by 48 and 51%, respectively, and also reduced mRNA expression by 69 and 57%, respectively. The combination of Dex and Iso resulted in no net change in beta 2-receptor number and its mRNA expression, although there was a significant reduction in beta 1-receptor number and mRNA expression. The mapping of beta 1- and beta 2-receptors by receptor autoradiography confirmed these findings over alveoli, epithelium, endothelium, and airway and vascular smooth muscle. We also measured the activation of the transcription factor, cyclic AMP response element binding protein (CREB) using an electrophoretic mobility shift assay. CREB-like DNA-binding activity was decreased after Iso treatment but this decrease was prevented after treatment with Dex. Nuclear run-on assays revealed that the transcription rate of the beta 1-receptor gene did not alter after Dex treatment, but was reduced after Iso treatment. The transcription rate of the beta 2-receptor gene was increased after Dex treatment by approximately twofold, but there was no change after Iso treatment. We conclude that glucocorticoids can prevent homologous downregulation of beta 2-receptor number and mRNA expression at the transcriptional level without affecting beta 1-receptors and that the transcription factor CREB may be involved in this phenomenon. Such an effect may have clinical implications for preventing the development of tolerance to beta 2-agonists in asthmatic patients treated with beta-agonist bronchodilators.

Role of G proteins in the vasodilator response to endothelin isopeptides in vivo

The purpose of the present study was to determine the influence of pertussis toxin (PTX) on the pulmonary and systemic vasodilator responses to endothelin (ET) isopeptides in the intact cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone was actively increased by an intralobar arterial infusion of U-46619, intralobar arterial bolus injections of ET-1, ET-2, and ET-3 decreased lobar arterial pressure and systemic vascular resistance in a dose-related manner. The vasodilator responses to ET-1 and ET-2 in the cat lung were abolished by PTX pretreatment, whereas PTX pretreatment did not alter the pulmonary vasodilator response to ET-3 and cromakalim, a specific ATP-sensitive potassium (KATP) channel activator, and the systemic vasodilator responses to all ET isopeptides studied. Glipizide, an inhibitor of KATP channels, inhibited the pulmonary vasodilator responses to ET-1, ET-2, and ET-3, whereas the systemic vasodilator responses to these isopeptides were not changed. The present data are the first to provide a functional correlate in vivo suggesting the existence of different signal transduction mechanisms for two pulmonary vascular ET receptor subtypes, ETA-like that is PTX sensitive and has greater sensitivity to ET-1 and ET-2 (than to ET-3) and ETc-like that is PTX insensitive and has sensitivity to ET-3 (than to ET-1 and ET-2). However, both ET-receptor subtypes promote vasodilation in the adult pulmonary vascular bed by activating KATP channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hypoxia on reflex responses of tracheal submucosal glands.

The effects of moderate sustained normocapnic hypoxia on tracheal submucosal gland reflex responses were studied. Experiments were performed in anesthetized, paralyzed, and mechanically ventilated dogs. The changes in the number of secreting glands and volume of secreted fluid in the subsequent period of time were recorded after 15-30 min of controlled ventilation with room air [arterial PO2 (PaO2) 86 +/- 3 Torr], hypoxic gas mixture (PaO2 49 +/- 4 Torr), or 100% O2 (PaO2 339 +/- 39 Torr), under isocapnic and isohydric conditions. The hillocks method was used to quantify the changes in submucosal gland secretion. The changes in secretion 30 s after stimulation of pulmonary C-fiber receptors by right atrial injection of capsaicin (10 micrograms/kg; n = 10) were markedly lower during moderate hypoxia than in normoxia or hyperoxia. Differences in the number of liquid droplets and the volume of secreted fluid were statistically significant (P < 0.05 and P < 0.001, respectively). Stimulation of airway rapidly adapting receptors by lung deflation increased airway secretion; the number of "hillocks" and the volume of secreted fluid were lower in hypoxic than in hyperoxic state. Differences between response curves for the number of glands activated and secreted volume were statistically significant (P < 0.05 and P < 0.001). The number of glands activated by substance P given locally by arterial infusion was not affected by the state of oxygenation, but the calculated volume of secreted fluid was lower during the hypoxic state than under hyperoxic condition (P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Pretreatment with an antibody to interleukin-5 prevents loss of pulmonary M2 muscarinic receptor function in antigen-challenged guinea pigs.

Inhalational challenge with antigen decreases the function of inhibitory M2 muscarinic autoreceptors on parasympathetic nerves in the lung, increasing the release of acetylcholine from the vagus nerves and potentiating vagally induced bronchoconstriction. It is possible that eosinophils cause M2 receptor dysfunction, perhaps by releasing positively charged proteins that are M2 receptor antagonists. Because of the probable role of interleukin-5 in initiating and maintaining the eosinophil infiltration, we tested the function of neuronal M2 receptors in antigen-challenged guinea pigs after pretreatment with a monoclonal antibody to interleukin-5 (TRFK-5). Ovalbumin was given intraperitoneally to sensitize the animals. Three weeks later, the animals were injected intraperitoneally with either TRFK-5 (240 micrograms/kg i.p.) or saline. Beginning three days later, they were challenged with an ovalbumin aerosol for 5 min on each of four consecutive days. M2 receptor function was tested 24 h after the last antigen challenge. Electrical stimulation of both vagi caused bronchoconstriction and bradycardia. In control animals, pilocarpine attenuated, and gallamine potentiated, vagally induced bronchoconstriction by stimulating and blocking neuronal M2 muscarinic receptors, respectively. In challenged animals that did not receive TRFK-5, these effects were markedly reduced, confirming M2 receptor dysfunction. In TRFK-5-treated guinea pigs, the effects of both pilocarpine and gallamine were the same as those in control animals, demonstrating normal M2 receptor function. Pretreatment with TRFK-5 selectively inhibited the migration of eosinophils into the lungs as measured by lung lavage. Thus the function of M2 muscarinic receptors in antigen-challenged guinea pigs can be protected by inhibiting eosinophil influx into the lungs.