[Problems of regulation of breathing]. / Problémy kolem regulace dýchání.

Knowledge about the regulation of breathing has pronounced clinical consequences. In the review the concepts of control and regulation of breathing are defined. Regulation based on the chemical feed back is well documented. Apart from that, attention is paid to unproven, hypothetical regulations. Among them, the regulation of the breathing pattern and that of functional residual lung capacity are of especial interest. Not less important is the cortical or volitional regulation of breathing, which is so far almost unexplored. An important problem represents abnormalities of the regulation of breathing. The disturbance can either follow a damage of the system of regulation, or it can be the result of conflict of priorities among the individual regulatory systems. Also this area is built on hypotheses which need experimental and clinical verification. Hand in hand with it goes the problem of regulation of breathing in disease. In conclusion, problems for elucidation are summarized.

Effects of lung volume reduction surgery in hamsters with elastase-induced emphysema.

Lung volume reduction surgery (LVRS) has been shown to improve respiratory mechanics in selected patients with severe emphysema. This is thought to be due to an improvement in lung elastic recoil. This study was aimed at gaining further understanding about the effects of LVRS on respiratory mechanics and airway function. Control hamsters instilled with saline (Ctrl; n=8) were compared with emphysematous animals that underwent either a sham operation (Sham; n=7) or an LVRS (LVRS; n=7). As expected, there was a significant increase in the static lung volumes in the Sham as compared to the Ctrl group and a significant decrease of these volumes in LVRS as compared to the Sham group. Surprisingly, emphysema was associated with a significant increase and LVRS with a significant decrease in vital capacity. Despite a tendency toward an increase in lung compliance as compared to Sham, indices of maximal expiratory flows tended to decrease with LVRS. As opposed to humans, there was no change in the distribution of airway diameters in Sham compared to Ctrl. These findings appear to be largely explained by the high compliance of the hamster chest wall. This allows for better matching between the emphysematous lung and the chest-wall sizes than in humans.

Hyperinflation: control of functional residual lung capacity.

Hyperinflation is the consequence of a dysbalance of static forces (determining the relaxation volume) and/or of the dynamic components. The relaxation volume is determined by an equilibrium between the elastic recoil of the lungs and of the chest walls. The dynamic components include the pattern of breathing, upper airway resistance and postinspiratory activity of inspiratory muscles. The respiratory and laryngeal muscles are under control and thus both static and dynamic hyperinflation can be secured. Our knowledge of the mechanism of increased FRC is based on clinical observations and on experiments. The most frequent stimuli leading to a dynamic increase of functional residual lung capacity (FRC) include hypoxia and vagus afferentation. Regulation of FRC is still and undetermined concept. The controlled increase of FRC, hyperinflation, participates in a number of lung diseases.

Lung volume reduction surgery does not improve diaphragmatic contractile properties or atrophy in hamsters with elastase-induced emphysema.

It is claimed that lung volume reduction surgery (LVRS) improves inspiratory muscle function. As diaphragm structure and function are not directly appraisable in patients, we studied the effects of LVRS on the diaphragm in vitro contractile properties and morphology in hamsters with elastase-induced emphysema. Four months after intratracheal instillation of elastase (40 U/100 g), hamsters underwent either bilateral LVRS (LVRS, n = 11) or a sham operation (SHAM, n = 8). Four animals died during the perioperative period in LVRS (n = 7). Hamsters instilled with saline served as control (CTL, n = 8). Animals were studied at the age of 9 mo. LVRS was associated with a significant 25% decrease in functional residual capacity compared to SHAM (p < 0.05). Compared with CTL, LVRS and SHAM showed a significant 18% and 14% reduction in diaphragm mass, respectively (p = 0.02). LVRS had a significantly decreased twitch tension compared to CTL and SHAM (p < 0.01). Both LVRS and SHAM showed increased resistance to muscle fatigue compared with CTL. The histochemical analysis revealed a significant shift from type IIx/b toward type IIa fibers in LVRS and SHAM compared with CTL. In conclusion, emphysema is associated with functional adaptations but LVRS does not appear to beneficially alter the diaphragm contractile and morphological characteristics in hamsters with elastase-induced emphysema.

[Pulmonary vagal afferents in man]. / Aferentní plicní vagus u cloveka.

Vagal afferentation from the lungs is mediated via various types of nerve fibers and is a prerequisite of numerous pulmonary reflexes. A review of studies on the morphology and functional examination of pulmonary vagal receptors is presented. Apart from the most frequently studied pulmonary stretch receptors also the role of irritant receptors and C-fibers is described. It is difficult to verify in man findings from animal experiments. Therefore, the studies testing the existence of pulmonary vagal reflexes in man are emphasised in the review. The importance of vagus nerves in cough, breathlessness, tachypnoea, in the control of the work of breathing and in the pattern of breathing is mentioned.

Inotropic effects of aminophylline on canine diaphragm are enhanced by hyperinflation.

During acute hyperinflation, patients with chronic obstructive pulmonary disease are likely to have foreshortened inspiratory muscles. Because the effects of aminophylline on contractile properties of the foreshortened diaphragm have never been studied in vivo, we compared these effects with those obtained at functional residual capacity (FRC). In 12 anesthetized dogs, bilateral phrenic nerve stimulation (1, 10, 20, and 100 Hz) was performed at FRC and near total lung capacity (TLC) before and 1 h after each injection of aminophylline, given in cumulative doses of 20, 40, and 80 mg/kg (serum levels of 18.7 +/- 6.3, 29.9 +/- 5.9, and 60.4 +/- 11.9 mg/l, respectively). Passive diaphragm shortening from FRC to TLC, measured in eight animals, averaged 30 +/- 12% of the resting length and increased to 35 +/- 12 and 34 +/- 13% after 40 and 80 mg/kg, respectively. After aminophylline, the increase in transdiaphragmatic pressure at FRC did not reach statistical significance, whereas near TLC transdiaphragmatic pressure significantly increased with 80 mg/kg at all stimulus frequencies (e.g., at 20 Hz from 4.4 +/- 2.9 to 6.7 +/- 2.9 cmH2O) and with 40 mg/kg at 10 and 20 Hz. Diaphragm length changes during stimulation were unchanged after aminophylline both at FRC and near TLC. We conclude that aminophylline has a pronounced inotropic effect on foreshortened canine diaphragm, even at concentrations close to the therapeutic range in humans.

Respiratory and cardiovascular effects of inhaled and intravenous bradykinin, PGE2, and PGF2 alpha in dogs.

Prostaglandins (PGs) and bradykinin act as potent respiratory irritants in both normal and asthmatic subjects, but their sites of action are unknown. We compared the cardiorespiratory effects of bradykinin, PGE2, and PGF2 alpha nebulized into the isolated "in situ" larynx, inhaled into the tracheobronchial tree, and injected intravenously in anesthetized spontaneously breathing dogs. Laryngeal administration only resulted in a brief burst of rapid shallow breaths produced by bradykinin (1,000 micrograms/ml) in one of five dogs. Tracheobronchial administration of bradykinin (1,000 micrograms/ml) increased breathing rate and tidal volume (VT) in four of seven dogs without changing cardiovascular parameters, whereas PGE2 (500 micrograms/ml) caused similar effects in two of six dogs. Lower concentrations of both agents were essentially without effect. PGF2 alpha (50-500 micrograms/ml) inhaled into the lower airway increased breathing rate, reduced VT, and caused a concentration-dependent bronchoconstriction that was significantly reduced by atropine. Inhaled PGF2 alpha only slightly increased arterial blood pressure (5.8 +/- 2.8%) and heart rate (12.0 +/- 6.4%). Intravenous PGF2 alpha (5 micrograms/kg) increased upper and lower airway resistances, which were accompanied by a decrease in breathing rate and VT, hypertension, and bradycardia. Bradykinin (1 micrograms/kg) and PGE2 (1 and 3 micrograms/kg) produced apnea followed by rapid shallow breathing, bradycardia, and hypotension. These results indicate that the tracheobronchial tree is considerably more responsive to aerosolized bradykinin, PGE2, and PGF2 alpha than the laryngeal region. Moreover, the stronger effects produced by intravascular administration suggest a greater accessibility of rapidly adapting stretch receptors and C-fiber endings from the vascular bed than from the airway lumen.

Respiration after phrenicotomy and hydrocortisone treatment in anaesthetized rats.

The study was designed to determine the extent to which respiratory muscle wasting, resulting from corticosteroid-induced atrophy, may affect respiration in normal rats and in rats with denervated diaphragm. Twenty four male Wistar rats were divided into four groups: 1) controls with sham operation (SX) and vehicle injections: 2) SX with eight hydrocortisone (HC) injections (60 mg.kg-1.day-1 i.m.); 3) phrenicotomized (PX), injected with vehicle; 4) PX and HC-treated. HC treatment was started on the thirteenth day after surgery. Under urethane anaesthesia, tidal volume, respiratory rate, arterial carbon dioxide tension (PaCO2) and occlusion pressure were measured at rest and after 5 min of stimulated-breathing induced by added dead space 22nd day after surgery. All HC-treated animals decreased body weight by 32% compared to untreated rats. The diaphragm weight was reduced in PX rats by 29%, and after HC by 44%, while in PX rats with HC treatment diaphragm weight decreased by only 21%. PX rats (HC-untreated) had the lowest minute ventilation and occlusion pressure. There was no difference in ventilation between control and both HC-treated groups at rest. However, ventilation in PX and HC-treated rats did not increase upon stimulation, and the occlusion pressure increased significantly only in the HC-untreated animals. We conclude that in the rat, HC treatment did not affect resting ventilation, but it impaired ventilation performance, during increased demand, in animals handicapped by diaphragm denervation.

Hypoventilation after acute phrenicotomy of the urethane anaesthetized rats.

The aim of this study was to explore the mechanism resulting in hypoventilation in rats with denervated diaphragm. Bilateral cervical phrenicotomy (PX) was performed in 15 male rats anaesthetized with urethane (1.3 g/kg i.p.); other 8 rats were sham operated (SX). Ventilation, PaCO2 and the integrated EMG of the external intercostal muscles (iEMG) were measured before and after the surgery, at regular intervals, up to 4 hours postoperatively. During the 4 hours after PX there was a progressive decrease in minute ventilation and an increase in PaCO2 compared with the control values and with that in the SX rats. The increase in PaCO2 was accompanied by an increase in the peak amplitude of the iEMG to 155 +/- 18% of control values after PX and to 228 +/- 33% 4 hours later. Despite the augmented EMG activity tidal volume gradually decreased. The iEMG of the intercostal muscles, however, did not reach a maximum because the shortlasting stimulation of breathing by acute hypercapnia and hypoxia as the result of added dead space (0.5 ml) increased the iEMG still further. These results indicate that both the central and peripheral mechanisms contribute to hypoventilation in anaesthetized rats with denervated diaphragm.

Fixed breathing frequency decreases end-tidal PCO2 in humans.

We tested the effect of a fixed breathing frequency on the partial pressure of CO2 in the end-tidal air (PETCO2) in resting healthy subjects. In the first experiment, three different rates of breathing were dictated: the same frequency of breathing as the subject's control one (1f), a double frequency (2f), and half of the control frequency (0.5f). 10 min dictate of 1f and 2f induced a decrease of PETCO2. The dictate of 0.5f had no significant effect on PETCO2. In the second experiment, 1f was dictated for 30 min, inducing a decrease of PETCO2 throughout the duration of the dictate. These results demonstrate that fixing the breathing frequency by the dictate affects the chemostatic control of ventilation.

Aminophylline enhances ventilation in phrenicotomized rats.

The aim was to test the effects of aminophylline (AP) on breathing of phrenicotomized rats. Fifty seven male rats of the Wistar strain were anaesthetized with 1.3 g.kg-1 urethane i.p. They were phrenicotomized, divided into 6 groups and given 5, 10, 20, 40 and 80 mg.kg-1 AP i.v. or a corresponding volume of saline. Ventilation, tracheal occlusion pressure and arterial blood gases were measured. In all animals phrenicotomy resulted in hypoventilation with corresponding hypoxaemia (from control 11.9 +/- 1.0 to 10.4 +/- 0.8 kPa) and hypercapnia (from control 4.6 +/- 0.5 to 5.5 +/- 0.6 kPa). In the control group (with saline) 4 h later the PaO2 was 8.6 +/- 1.1 kPa and PaCO2 7.2 +/- 0.6 kPa. After AP 1 h after phrenicotomy the minute ventilation increased in a dose-dependent manner by 1-66%. 4 h after phrenicotomy the minute ventilation of rats with 20 and 40 mg.kg-1 of AP was significantly higher than that of the control group. AP prevented hypoventilation when injected into phrenicotomized rats. The results give no unequivocal basis from which to decide the proportion of central and peripheral effects of AP.

Breathing of phrenicotomized rats.

Bilateral paralysis of the diaphragm can result in normo or hypoventilation, according to the species studied. Our aim was to ascertain the results of bilateral phrenicotomy in the rat and, if hypoventilation should be present, to try to identify its pathophysiology. We used 33 male rats under urethane anaesthesia (1.3 g/kg i.p.). They were divided into three groups: control animals, rats with bilateral phrenicotomy and a group with two doses of pentobarbital (25 mg/kg i.p. each) on top of the urethane anaesthesia. We observed pronounced hypoventilation both in the rats after phrenicotomy and those with pentobarbital. At comparable levels of hypoventilation (PaCO2 = 5.61 +/- 0.28 kPa immediately after phrenicotomy and 5.91 +/- 0.25 kPa after the first dose of pentobarbital; and 7.21 +/- 0.47 kPa 4 hours after phrenicotomy and 7.38 +/- 0.39 kPa after the second dose of pentobarbital) the only difference was a longer relative duration of inspiration in phrenicotomized rats; (0.39 +/- 0.04 and 0.34 +/- 0.04 after phrenicotomy; 0.32 +/- 0.04 and 0.24 +/- 0.05 in rats after pentobarbital). Immediately after phrenicotomy and 2 and 4 hours later, and also after both doses of pentobarbital breathing was stimulated by hypoxia and hypercapnia due to the additional external dead space (0.5 ml) for 5 min. There was no pronounced differences in the ventilatory response to the dead space between the two groups; the response changed from an isocapnic (in control rats and before phrenicotomy or pentobarbital) to an isoventilatory one (four hours after phrenicotomy and after the second dose of pentobarbital). The rats after the second dose of pentobarbital did not, however, survive the added dead space.(ABSTRACT TRUNCATED AT 250 WORDS)

Reflex responses to capsaicin: intravenous, aerosol, and intratracheal administration.

Intravenous capsaicin elicits the "pulmonary chemoreflex" (apnea, bradycardia, and hypotension) presumably through the stimulation of "pulmonary C-fibers." The present study was designed to ascertain whether tracheobronchial C-fibers play a role in the above reflex response. We compared the effects of capsaicin injected intravenously, administered as an aerosol, and administered topically into the intrathoracic trachea in anesthetized dogs (n = 17) and rats (n = 17). We measured esophageal, subglottic, and arterial pressures together with abdominal muscle electromyogram. Changes in expiratory duration [(TE), measured as the ratio TEtest to TEcontrol, mean +/- SD] due to capsaicin were similar with all three routes of administration in both dogs (intravenous, 7.9 +/- 4.6; aerosol, 5.5 +/- 3.1; topically into intrathoracic trachea, 7.1 +/- 4.8) and rats (intravenous, 22.6 +/- 10.3; aerosol, 11.1 +/- 8.2; topically into intrathoracic trachea, 21.6 +/- 4.6). An increase in laryngeal resistance was a constant finding in the rat, but it was less frequent in the dog. Cardiovascular responses consisting of bradycardia and hypotension occurred with all three routes of administration but had longer delays than the respiratory responses. Capsaicin instillation into the extrathoracic trachea in dogs (n = 7) also induced qualitatively similar cardiorespiratory responses. We conclude that 1) capsaicin-sensitive receptors are accessible from both the pulmonary circulation and the airway lumen and 2) afferents, even in the extrapulmonary portion of the tracheobronchial tree, can play a role in the reflex responses to intraluminal capsaicin.

The pattern of breathing and the ventilatory response to breathing through a tube and to physical exercise in sport divers.

Well-trained divers can be expected to differ from healthy controls in their ventilatory response to breathing through a tube and to physical exercise. Therefore, we measured their minute ventilation (VE) at rest and during breathing through a tube combined with two levels of physical exercise (1 or 2 W.kg body weight-1). For breathing through a tube an additional dead space of 600 ml was used. All divers were trained in the breath-hold technique and in the use of the breathing apparatus. Their mean period of training as divers was 9 +/- 6 years. The approximate age of the subjects was 25 years. The pattern of breathing and the oxygen uptake were measured by spirometer, the end-tidal concentration of CO2 was measured and all experiments were carried out above sea level. The ventilation of the divers at rest was comparable to that of the controls. During physical exercise it was smaller whether during breathing through a tube or not. The inadequate increase of VE during exercise in divers was associated with hypercapnia only at a higher physical work intensity (of 2 W.kg-1). This finding is interpreted as a lower chemoregulatory response to the combined stimuli of hypercapnia, hypoxia and physical exercise. In some situations significant bradypnoea and higher tidal volumes were found in the divers.

Methods of assessment of respiratory muscle fatigue (RMF).

Methods to assess fatigue of respiratory muscles, technical conditions and possibilities of practical application are discussed.

Elastic properties of the rat respiratory system related to age.

The experiments were performed on male rats of the Wistar strain under urethane anaesthesia (1.3 g/kg i.p.). Changes of oesophageal and tracheal pressures were registered in a group of 30 spontaneously breathing, supine rats, of 295 +/- 13 g average body weight during lung inflations with 1-5 ml of air. In another group of 25 rats of 70 +/- 6 g average body weight (young rats) we made the measurements during inflation with volumes 0.5-2 ml. The measurements were also performed in a group of 10 paralyzed, ventilated rats with 347 +/- 24 g average body weight and inflations 1-5 ml. Compliance of the lungs (CL), chest wall (CW) and of the respiratory system (Crs) was calculated from the linear part of the pressure-volume curve during inflation. The results indicate: 1. Cw is significantly (p less than 0.001) higher in young (134.7 ml.kPa-1.kg-1) than in adult rats (44.1 ml.kPa-1.kg-1). CL (related to body weight) is not significantly different in young and adult rats. 2. Cw is significantly (p less than 0.001) higher than CL. 3. No difference was observed in CLs Cw and Crs between paralyzed and spontaneously breathing animals.