Mechanisms of the adenosine A2A receptor-induced sensitization of esophageal C fibers.

Clinical studies indicate that adenosine contributes to esophageal mechanical hypersensitivity in some patients with pain originating in the esophagus. We have previously reported that the esophageal vagal nodose C fibers express the adenosine A2A receptor. Here we addressed the hypothesis that stimulation of the adenosine A2A receptor induces mechanical sensitization of esophageal C fibers by a mechanism involving transient receptor potential A1 (TRPA1). Extracellular single fiber recordings of activity originating in C-fiber terminals were made in the ex vivo vagally innervated guinea pig esophagus. The adenosine A2A receptor-selective agonist CGS21680 induced robust, reversible sensitization of the response to esophageal distention (10-60 mmHg) in a concentration-dependent fashion (1-100 nM). At the half-maximally effective concentration (EC50: ≈3 nM), CGS21680 induced an approximately twofold increase in the mechanical response without causing an overt activation. This sensitization was abolished by the selective A2A antagonist SCH58261. The adenylyl cyclase activator forskolin mimicked while the nonselective protein kinase inhibitor H89 inhibited mechanical sensitization by CGS21680. CGS21680 did not enhance the response to the purinergic P2X receptor agonist α,ß-methylene-ATP, indicating that CGS21680 does not nonspecifically sensitize to all stimuli. Mechanical sensitization by CGS21680 was abolished by pretreatment with two structurally different TRPA1 antagonists AP18 and HC030031. Single cell RT-PCR and whole cell patch-clamp studies in isolated esophagus-specific nodose neurons revealed the expression of TRPA1 in A2A-positive C-fiber neurons and demonstrated that CGS21682 potentiated TRPA1 currents evoked by allylisothiocyanate. We conclude that stimulation of the adenosine A2A receptor induces mechanical sensitization of nodose C fibers by a mechanism sensitive to TRPA1 antagonists indicating the involvement of TRPA1.

Methods of Cough Assessment and Objectivization.

Cough is one of the most important airway defensive reflexes aimed at removing foreign particles or endogenously produced materials from the airways and provides protection against aspiration. Generally considered, cough is a vital physiological defensive mechanism for lung health. However, in case of cough dysregulation this reflex can become pathological and leads to an adverse influence on daily life. Therefore, it is necessary to effectively evaluate the severity of cough for its diagnosis and treatment. There are subjective and objective methods for assessing cough. These methods should help describe the heterogeneity of cough phenotypes and may establish better treatment by monitoring response to nonpharmacological or pharmacological therapies. It is important to keep in mind that the clinical assessment of cough should include both tools that measure the amount and severity of the cough. The importance of a combined subjective and objective evaluation for a comprehensive assessment of cough has been advocated in the guidelines of the European Respiratory Society on cough evaluation. This review article provides an overview of subjective and objective methods for assessing and monitoring cough in children and adults comparing to animal models. Key words Cough frequency; Cough intensity; Cough reflex sensitivity; Cough monitors; Cough assessment.

The effect of stimulation and unloading of baroreceptors on cough in experimental conditions.

Cough, the main airway defensive process, is modulated by multiple sensory inputs from the respiratory system and outside of it. This modulation is one of the mechanisms that contributes to the sensitization of cough pathways at the peripheral and/or central level via neuroplasticity and it manifests most often as augmented coughing. Cardiorespiratory coupling is an important mechanism responsible for a match between oxygenation and cardiac output and bidirectional relationships exist between respiration and cardiovascular function. While the impact of cough with the robust swings of the intrathoracic pressure on haemodynamic parameters and heart electrophysiology are well characterized, little is known about the modulation of cough by haemodynamic parameters - mainly the blood pressure. Some circumstantial findings from older animal studies and more recent sophisticated analysis confirm that baroreceptor stimulation and unloading alters coughing evoked in experiments. Clinical relevance of such findings is not presently known.

Adenosine-induced activation of esophageal nociceptors.

Clinical studies implicate adenosine acting on esophageal nociceptive pathways in the pathogenesis of noncardiac chest pain originating from the esophagus. However, the effect of adenosine on esophageal afferent nerve subtypes is incompletely understood. We addressed the hypothesis that adenosine selectively activates esophageal nociceptors. Whole cell perforated patch-clamp recordings and single-cell RT-PCR analysis were performed on the primary afferent neurons retrogradely labeled from the esophagus in the guinea pig. Extracellular recordings were made from the isolated innervated esophagus. In patch-clamp studies, adenosine evoked activation (inward current) in a majority of putative nociceptive (capsaicin-sensitive) vagal nodose, vagal jugular, and spinal dorsal root ganglia (DRG) neurons innervating the esophagus. Single-cell RT-PCR analysis indicated that the majority of the putative nociceptive (transient receptor potential V1-positive) neurons innervating the esophagus express the adenosine receptors. The neural crest-derived (spinal DRG and vagal jugular) esophageal nociceptors expressed predominantly the adenosine A(1) receptor while the placodes-derived vagal nodose nociceptors expressed the adenosine A(1) and/or A(2A) receptors. Consistent with the studies in the cell bodies, adenosine evoked activation (overt action potential discharge) in esophageal nociceptive nerve terminals. Furthermore, the neural crest-derived jugular nociceptors were activated by the selective A(1) receptor agonist CCPA, and the placodes-derived nodose nociceptors were activated by CCPA and/or the selective adenosine A(2A) receptor CGS-21680. In contrast to esophageal nociceptors, adenosine failed to stimulate the vagal esophageal low-threshold (tension) mechanosensors. We conclude that adenosine selectively activates esophageal nociceptors. Our data indicate that the esophageal neural crest-derived nociceptors can be activated via the adenosine A(1) receptor while the placodes-derived esophageal nociceptors can be activated via A(1) and/or A(2A) receptors. Direct activation of esophageal nociceptors via adenosine receptors may contribute to the symptoms in esophageal diseases.

The Prospect for Potent Sodium Voltage-Gated Channel Blockers to Relieve an Excessive Cough.

An excessive, irritable, productive or non-productive coughing associated with airway inflammation belongs to pathological cough. Increased activation of airway vagal nociceptors in pathological conditions results from dysregulation of the neural pathway that controls cough. A variety of mediators associated with airway inflammation overstimulate these vagal airway fibers including C-fibers leading to hypersensitivity and hyperreactivity. Because current antitussives have limited efficacy and unwanted side effects there is a continual demand for the development of a novel more effective antitussives for a new efficacious and safe cough treatment. Therefore, inhibiting the activity of these vagal C-fibers represents a rational approach to the development of effective antitussive drugs. This may be achieved by blocking inflammatory mediator receptors or by blocking the generator potential associated with the specific ion channels. Because voltage-gated sodium channels (NaVs) are absolutely required for action potentials initiation and conduction irrespective of the stimulus, NaVs become a promising neural target. There is evidence that NaV1.7, 1.8 and 1.9 subtypes are predominantly expressed in airway cough-triggering nerves. The advantage of blocking these NaVs is suppressing C-fiber irrespective to stimuli, but the disadvantage is that by suppressing the nerves is may also block beneficial sensations and neuronal reflex behavior. The concept is that new antitussive drugs would have the benefit of targeting peripheral airway nociceptors without inhibiting the protective cough reflex.

Voltage-gated sodium channels mediating conduction in vagal motor fibers innervating the esophageal striated muscle.

The vagal motor fibers innervating the esophageal striated muscle are essential for esophageal motility including swallowing and vomiting. However, it is unknown which subtypes of voltage-gated sodium channels (NaV1s) regulate action potential conduction in these efferent nerve fibers. The information on the NaV1s subtypes is necessary for understanding their potential side effects on upper gut, as novel inhibitors of NaV1s are developed for treatment of pain. We used isolated superfused (35 °C) vagally-innervated mouse esophagus striated muscle preparation (mucosa removed) to measure isometric contractions of circular striated muscle evoked by electrical stimulation of the vagus nerve. NaV1 inhibitors were applied to the de-sheathed segment of the vagus nerve. Tetrodotoxin (TTX) applied to the vagus nerve completely abolished electrically evoked contractions. The selective NaV1.7 inhibitor PF-05089771 alone partially inhibited contractions and caused a >3-fold rightward shift in the TTX concentration-inhibition curve. The NaV1.1, NaV1.2 and NaV1.3 group inhibitor ICA-121431 failed to inhibit contractions, or to alter TTX concentration-inhibition curves in the absence or in the presence of PF-05089771. RT-PCR indicated lack of NaV1.4 expression in nucleus ambiguus and dorsal motor nucleus of the vagus nerve, which contain motor and preganglionic neurons projecting to the esophagus. We conclude that the action potential conduction in the vagal motor fibers to the esophageal striated muscle in the mouse is mediated by TTX-sensitive voltage gated sodium channels including NaV1.7 and most probably NaV1.6. The role of NaV1.6 is supported by ruling out other TTX-sensitive NaV1s (NaV1.1-1.4) in the NaV1.7-independent conduction.

Various aspects of sex and gender bias in biomedical research.

The main role of research in medicine is to provide relevant knowledge which, after successful translation to clinical practice, improves the quality of healthcare. The sex bias which is still present in the majority of research disciplines prefers male subjects despite legislation changes in the US grant agencies and European research programme Horizon 2020. Male subjects (cells, animals) still dominate in preclinical research and it has detrimental consequences for women's health and the quality of science. Opposite bias exists for data obtained mainly in animal models utilizing female subjects (e.g. research in multiple sclerosis, osteoporosis) with skewed outcomes for men affected by these diseases. Either way, scientists are producing results which compromise half of the population. Assumptions that females as cohorts are more variable and another assumption that the oestrous cycle should be tracked in case the females are enrolled in preclinical studies were proven wrong. Variability of male versus female cohorts are comparable and do not only stem from hormonal levels. The widespread prevalence of sex differences in human diseases ultimately requires detailed experiments performed on both sexes, unless the studies are specifically addressing reproduction or sex-related behaviors.

The voltage-gated sodium channel NaV1.8 blocker A-803467 inhibits cough in the guinea pig.

Cough in respiratory diseases is attributed to the activation of airway C-fibers by inflammation. Inflammatory mediators can act on multiple receptors expressed in airway C-fibers, nonetheless, the action potential initiation in C-fibers depends on a limited number of voltage-gated sodium channel (NaV1) subtypes. We have recently demonstrated that NaV1.8 substantially contributes to the action potential initiation in the airway C-fiber subtype implicated in cough. We therefore hypothesized that the NaV1.8 blocker A-803467 inhibits cough. We evaluated the cough evoked by the inhalation of C-fiber activator capsaicin in awake guinea pigs. Compared to vehicle, intraperitoneal or inhaled A-803467 caused 30-50% inhibition of cough at the doses that did not alter respiratory rate. We conclude that the NaV1.8 blocker A-803467 inhibits cough in a manner consistent with its action on the C-fiber nerve terminals in the airways. Targeting voltage-gated sodium channels mediating action potential initiation in airway C-fibers may offer a means of cough inhibition that is independent of the stimulus.

Experimental allergic rhinitis-related cough and airway eosinophilia in sensitized guinea pigs.

Allergic rhinitis is one of the most common causes of chronic cough. The characteristic feature of allergic rhinitis is eosinophilic nasal inflammation. This study was determined to find the relation between airway eosinophils and chemically-induced cough in guinea pigs with antigen-induced rhinitis at the early and late allergic phases. Forty animals were sensitized with ovalbumin (OVA) and divided into four separated groups. Four weeks later, the sensitized animals were either once or repeatedly (6 times at 7-day intervals) intranasally challenged with OVA to develop experimental allergic rhinitis. The control group was given saline. Cough was elicited by inhalation of citric acid aerosols and evaluated at 30 min (early phase) or 24 h (late phase) after the 1st or 6th nasal challenge (NC) in the sensitized animals. The citric acid-induced cough was significantly increased in the sensitized animals in the early allergic phase after the first and repeated NC compared with the control values [14(9-19) vs. 16(10-17) vs. 8(6-10); P=0.049], whereas there was no significant increase in the cough response tested in the late allergic phase. A correlation between the cough intensity and the number of eosinophils from nasal mucosa only (P=0.008) was found.

Influence of chest gamma-irradiation on cough response in awake guinea pigs.

Radiotherapy of tumors in the chest and neck regions may have serious pulmonary side effects. It is well known that inflammation is an essential manifestation of radiation-induced injury. This can heal spontaneously, by specific treatment, or it may progress to more intensive inflammation up to irreversible pulmonary fibrosis. To prevent such complications, it would be useful to have a simple non-invasive and sensitive method for monitoring the course of airway and lung post-irradiation inflammation. This study is devoted to search for such a method. We supposed that cough response intensity (CRI) could be one of the methods, which we are looking for. Guinea pigs (Trik strain, n=32) were used in the study. Animals were divided into two subgroups. Animals of a non-untreated (NT) group (n=14; M=7, F=7) were submitted to sham chest irradiation. The animals of a treated (XRT) group (n=18; M=9, F=9) were exposed to a single dose of gamma rays. Cough was provoked by exposure of animals to citric acid aerosol (CA) in gradually increasing concentrations (0.05-1.6M). CRI testing was performed two days before sham/real chest irradiation, than on 1st, 3rd, 10th, 15th, 21st, and 28th days following the day of irradiation. CRI was quantified in each animal by counting the number of coughs induced by all used concentration of CA. We found a significant increase of CRI in the animals of XRT group on 10th and 21st day compared with the NT animals. An increase of CRI also was found inside the XRT group on the 10th day after irradiation compared with the pre-irradiation value of CRI.

Oral N-acetylcysteine reverses hyperoxia-related cough suppression in guinea pigs.

Hyperoxia-induced lung injury is well known in animal and human studies. We have previously shown that hyperoxic exposure of guinea pigs is associated with suppression of cough reflex. The goal of this study was to determine the effects of oral N-acetylcysteine (NAC) on hyperoxia-induced oxidative stress in lung tissue directed on cough reflex. The experimental group was pretreated with NAC daily for 7 days and subsequently exposed to 100% O2 for 60 h. Hyperoxic group inhaled 100% O2 only. The control group was exposed to normoxia. Cough was induced by inhalation of citric acid aerosol before and after exposure to oxygen. Cough was also induced by mechanical stimulation of airways in anesthetized animals just after the end of oxygen exposure. Our results showed a significant decrease (P=0.002) in citric acid-induced cough in hyperoxic animals and reversal of that effect in animals pretreated with NAC. In addition, there was a significant interaction between antioxidant therapy and hyperoxia (P=0.005). NAC also reversed the hyperoxia-induced inhibition of mechanically-induced cough. In conclusion, our results indicate that NAC attenuated hyperoxia-induced down-regulation of chemically and mechanically-induced cough.

Dietary intake of flavonoids and hyperoxia-induced oxidative stress related cough in guinea pigs.

There is many evidence that inhalation of high oxygen concentration has a toxic influence on pulmonary function and structures. Hyperoxia-induced oxidative stress is well characterized in rodents and has been used as a valuable model of human respiratory distress syndrome. We have previously shown that hyperoxic exposure of guinea pigs is associated with suppression of cough reflex. The goal of this study was to determine the effects of dietary intake of antioxidant flavonoids (Flavin7, Vita Crystal Slovakia Ltd., 2 ml/kg b.w.) on hyperoxia-induced oxidative stress in lung tissue directed on cough reflex. The experimental group (n = 8) was pretreated with Flavin7 as a single daily dose for 14 days and subsequently exposed to 100% 02 for 60 h. Hyperoxic group (n = 8) inhaled 100% Oz only. Control group (n = 8) was exposed to normoxia. Cough was induced by inhalation of citric acid aerosol at time before and after exposure to hyperoxia. Cough was also induced by mechanical stimulation of airways in anaesthetized animals just after the end of oxygen exposition. When to compare animal groups before and after hyperoxia, our results have shown a significant decrease 2 (1-6) vs 6 (4-6) p = 0.041 in citric acid-induced cough in hyperoxic animals and no significant changes 8 (5.5-8.5) vs 5 (4-6.5) p = 0.055 in animals with antioxidant therapy. Mechanically-induced cough after hyperoxia was not influenced by substitution with flavonoids. In conclusion, our results indicate that flavonoids attenuated hyperoxia-induced down-regulation especially of chemically-induced cough (Tab. 2, Fig. 2, Ref. 30). Full Text (Free, PDF) www.bmj.sk.

Early and late allergic phase related cough response in sensitized guinea pigs with experimental allergic rhinitis.

Cough is a common and important symptom of asthma and allergic rhinitis. Previous experimental evidence has shown enhanced cough sensitivity during early phase of experimental allergic rhinitis in guinea pigs. We hypothesized that airway inflammation during the late phase response after repeated nasal antigen challenge may affect the afferent sensory nerve endings in the larynx and tracheobronchial tree and may also modulate cough response. In the present study we evaluated the cough sensitivity during a period of early and late allergic response in sensitized guinea pigs after repeated nasal antigen challenges. Forty-five guinea pigs were sensitized with ovalbumin (OVA). Four weeks later 0.015 ml of 0.5 % OVA was intranasally instilled to develop a model of allergic rhinitis that was evaluated from the occurrence of typical clinical symptoms. Animals were repeatedly intranasally challenged either by OVA (experimental group) or by saline (controls) in 7-day intervals for nine weeks. Cough was elicited by inhalation of citric acid aerosols. Cough was evaluated at 1 or 3 h after the 6th nasal challenge and 17 or 24 h after the 9th nasal challenge. The cough reflex was significantly increased at 1 and 3 h after repeated nasal challenge in contrast to cough responses evoked at 17 and 24 h after repeated nasal challenge. In conclusion, enhanced cough sensitivity only corresponds to an early allergic response after repeated nasal challenges.

The effect of chemical stimulation of esophageal mucosa on citric acid induced cough and specific airway resistance in guinea pig.

BACKGROUND: Gastroesophageal reflux disease is one of the most common causes of chronic cough. The mechanism of the cough initiation in these patients remains unresolved. OBJECTIVES: This study was designed to investigate the effect of intraesophageal (IE) administration of capsaicin on cough and specific airway resistance (Saw) in guinea pigs. METHODS: Male TRIK strain guinea pigs were used. In the first experiment 12 controls received IE saline, 9 animals (group 1) received IE capsaicin (400 microM, 0.2 ml) and 12 guinea pigs (group 2) received IE capsaicin (400 microM, 0.2 ml) 24 hours after IE administration of hydrochloric acid (3 M, 0.2 ml). Cough induced by inhalation of citric acid (CA) and Saw was determined after IE administration of saline in controls and capsaicin in groups 1 a 2. In the second experiment, CA induced cough was determined in guinea pigs (n=13) in the beginning of the study (control response), after NaOH (1 M, 0.2 ml) was administered IE. One week later in conditions of corrosive esophagitis CA induced cough was determined after IE administration of capsaicin (cough during esophageal stimulation). RESULTS: There was no difference in CA induced cough between controls, group 1 and 2 (p=0.98). Saw was hot affected by IE capsaicin stimulation and CA inhalation in group 1 and group 2. There was no difference found between control cough response and those induced after IE capsaicin in animals with corrosive esophagitis (p=0.75). CONCLUSION: Esophageal stimulation with capsaicin did not trigger and/or modulate CA induced cough and Saw in guinea pigs models. (Fig. 5, Ref. 22.)

A comparison of monotherapy with lamotrigine or carbamazepine in patients with newly diagnosed partial epilepsy.

Monotherapy with lamotrigine or carbamazepine was evaluated in a multicentre open trial of patients aged 2 years and above with newly diagnosed partial epilepsy. A total of 417 patients were randomised to treatment with lamotrigine, while 201 patients received carbamazepine. Following a dose escalation period of 6 weeks, maintenance therapy (Weeks 7-24) was adjusted according to response. Efficacy was similar with both treatments (65% with lamotrigine, 73% with carbamazepine, P=0.085). Efficacy was assessed by the proportion of patients seizure free during the last 16 weeks of treatment; all subjects who remained in the study for at least 18 weeks after the week 4 visit were included in the analysis. More patients receiving lamotrigine completed the study (81%), compared with those receiving carbamazepine (77%). This difference was primarily due to discontinuation as a result of adverse events, reported by 34 (8%) of those treated with lamotrigine but 26 (13%) of those treated with carbamazepine. The proportion of patients who experienced adverse events in the lamotrigine group was lower (218 patients, 52%) compared with the carbamazepine group (120 patients, 60%). The proportion of patients with adverse events considered to be drug related was lower in the lamotrigine group (132 patients, 32%) compared with the carbamazepine group (83 patients, 41%). Somnolence was the only adverse event reported at an incidence of greater than 5% and where there was a difference of 5% or more between treatment groups (4% lamotrigine, 11% carbamazepine patients). The small subsets of elderly patients (aged 65 years or over) and paediatric patients (aged 2-12 years) also showed better tolerability to lamotrigine than to carbamazepine. In conclusion, monotherapy with lamotrigine is as effective as carbamazepine in patients with newly diagnosed partial epilepsy. Patients were able to tolerate lamotrigine better than carbamazepine, so more patients receiving lamotrigine were able to remain on therapy.

Modulation of experimentally-induced cough by stimulation of nasal mucosa in cats and guinea pigs.

Stimulation of afferent nerves in upper airways may contribute to the pathogenesis of chronic cough in chronic disorders of nose and/or sinuses. We tested the hypothesis that stimulation of the nasal afferent nerves enhances experimentally-induced cough. Intranasal administration of capsaicin (50 microM, 25 microl) did not evoke cough in anaesthetized cats, but enhanced cough induced by mechanical stimulation of the tracheobronchial mucosa (number of coughs, median [IQR]) (6.5 [5.5-8.5] versus 10 [7-14]; P = 0.028, n = 13). In contrast, intranasal histamine (16 mM, 25 microl) had no effect. Intranasal capsaicin (50 microM, 15 microl) did not evoke cough, but enhanced cough evoked by mechanical stimulation of the tracheobronchial mucosa (1 [1-3] versus 3 [2-4]; P = 0.0037, n = 15) in anaesthetized guinea pigs and cough induced by inhalation of citric acid (0.3M, 2 min) in awake guinea pigs (3 [2-5] versus 5 [3-7], P ? 0.0026, n = 23). We conclude that stimulation of nasal afferent nerves with capsaicin enhances experimentally-induced cough. Our results suggest that afferent inputs from the nose interact with the cough reflex pathways in a manner that enhances cough.

Effects of hyperoxia and allergic airway inflammation on cough reflex intensity in guinea pigs.

Toxic influence of high oxygen concentration on pulmonary function and structures has been known for many years. However, the influence of high oxygen concentration breathing on defensive respiratory reflexes is still not clear. In our previous experiments, we found an inhibitory effect of 100 % oxygen breathing on cough reflex intensity in healthy guinea pigs. The present study was designed to detect the effects of hyperoxia on cough reflex in guinea pigs with allergic airway inflammation. In the first phase of our experiment, the animals were sensitized with ovalbumin. Thirty-two sensitized animals were used in two separate experiments according to oxygen concentration breathing: 100 % or 50 % oxygen for 60 h continuously. In each experiment, one group of animals was exposed to hyperoxia, another to ambient air. The cough reflex was induced both by aerosol of citric acid before sensitization, then in sensitized animals at 24 h and 60 h of exposition to oxygen/air in awake animals, and by mechanical stimulation of airway mucosa in anesthetized animals just after the end of the experiment. In contrast to 50 % oxygen, 100 % oxygen breathing leads to significant decrease in chemically induced cough in guinea pigs with allergic inflammation. No significant changes were present in cough induced by mechanical stimulation of airways.

The influence of hyperoxia on cough reflex intensity in guinea pigs treated with bleomycin.

Inhalation of high concentration of oxygen produces a lung injury in men and experimental animals. In our previous experiment we have found suppression of cough reflex in healthy guinea pigs after an exposure to 100% O2 for 60 hours. This study was designed to find the effect of hyperoxia on cough reflex in guinea pigs with lungs damaged by bleomycin. We used 48 animals (300-400 g) in two separated experiments. 32 of them were intratracheally injected with 1.5 mg bleomycin (Bleocin, Nippon Kayaku Co., Ltd., Tokyo, Japan) for induction of lung damage according to the method described by Parizada et al (20). 16 animals were given saline, only (control). Animals of experimental group were divided into two subgroups according to the lapse of time from bleomycin application. 13 days after bleomycin application animals of the 1st subgroup (16) were exposed to 100% O2 (8) or to room air (8) for 48 h. Similarly, 20 days after bleomycin application guinea pigs of the 2nd subgroup (16) were exposed to 100% O2 (8) or air (8), respectively. Cough was provoked in conscious animals placed in bodyplethysmograph box by inhalation of citric acid aerosol (0.3 mol/L) before, then 13 or 20 days after bleomycin application, and finally at the end of 48-h exposition to 100% O2 (air). The number of coughs was counted from airflow trace recorded by pneumotachograph. Cough was also induced by mechanical stimulation of laryngopharyngeal (LPh) and tracheobronchial (TBr) region in anaesthetized animals (Urethane, 1.1 g/kg, i.p.) just after the end of oxygen exposition and was evaluated from the interpleural pressure record. The results have shown a tendency to inhibition of citric acid cough reflex in animals 13 days treated with bleomycin and exposed to 100% O2, and significant decrease in citric acid induced cough in animals 20 days treated with bleomycin and exposed to 100% O2. Significant changes were present in cough intensity induced by mechanical stimulation of TBr region of the guinea pigs airway treated with bleomycin and exposed to oxygen, too. (Tab. 1, Fig. 3, Ref: 29.)

[Functional and morphological changes in the respiratory organs of cats after long-term exposure to pure normobaric oxygen]. / Funkcné a morfologické zmeny dýchacích orgánov maciek dlhodobo exponovaných cistému normobarickému kyslíku.

BACKGROUND: Pulmonary oxygen toxicity is very well known and proved. The influence of hyperoxia on the respiratory reflexes is not known till now. MAIN PURPOSE: To ascertain if long-lasting breathing of pure normobaric oxygen (PNO) alter respiratory reflexes. METHODS: 34 adult cats of both sexes, weighing 2.5-4.0 kg, were used in two experiments. In the first experiment 16 animals with inserted chronic tracheal cannula (CTC) were used. In the second experiment 18 animals without CTC were employed. Part of animals in both experiments was exposed to PNO (day by day for 2 weeks, 10 h daily), remaining animals were exposed to room air under the same conditions. Side tracheal pressure was recorded in unanesthetized animals of the first experiment. The second experiment was performed in anaesthetised animals (Pentobarbital Spofa, 35 mg/kg, i.p.). Oesophageal pressure and blood pressure in femoral artery were recorded. Cough reflex, sneezing and aspiration reflexes were induced by mechanical stimulation of airway mucosa. Pulmonary chemoreflex was elicited by i.v. administration of 50 micrograms phenyl biguanid. Hering-Breuer inflation reflex was induced by lung inflation with pressure of 1 kPa. Reactivity of tracheal and pulmonary smooth muscle to histamine were measured in vitro. Differences in recorded parameters between animals exposed to PNO, and to room air, were tested by Mann-Whitney-Wilcoxon test and by Student's t-test. When p < 0.05, the differences were recognized as significant. RESULTS: Significant decreasing of the expiratory parameters of the cough induced from laryngopharyngeal mucosa, inhibition of sneezing, and inhibition of aspiration reflex, were found in animals exposed to PNO. Relaxing reaction of tracheal smooth muscle of control animals to histamine was reversed to contraction in animals exposed to PNO. Morphological changes of the respiratory tract induced by influence of oxygen were found CONCLUSION: Long-lasting breathing of PNO induced changes of respiratory reactions elicited mainly from upper airway.(Fig. 6, Tab. 3, Ref. 22)

Growth of the skull in babies with intracranial hypertension.

There are unknown all laws which determine the growth of the skull in the case of a hydrocephalic syndrom. Many factors depend certainly on the pathomechanism of the proper hydrocephalus. There is individual difference. Particularly is very uneasy to explain the definitive type of the skull after the treatment of the hydrocephalic syndrom.