ACE-inhibitors and defence reflexes of the airways.

The group of angiotensin-converting enzyme (ACE) inhibitors is one of the drugs of choice for the treatment of hypertension and congestive heart disease. However, it has been reported that in some of patients ACE-inhibitors induce hyperreactivity of the airways with occurrence of a persistent dry cough, dyspnoe and wheezing. We supposed that the mechanism of these hyperreactivity is connected to accumulation of bradykinin, tachykinins and other inflammatory mediators in the airways. Increased local concentration of inflammatory neuropeptides stimulates bronchial C fibres and rapidly adapting receptors and provoke the cough reflex. Inflammatory processes in the airways could be followed by contraction of airway smooth muscle. In this study, our aim was to measure the changes of the number and intensity of mechanical induced cough in cats, which were treated for days with enalapril (5 mg/kg b.w.). After 15 days of treatment the reactivity of the lung and tracheal smooth muscles to the bronchoconstrictor mediator histamine was estimated. As to our finding 15 days of administration of enalapril results in significant increase of cough parameters measured with a more significant sensitivity of the laryngopharyngeal part. In the experimental animals we observed increased reactivity of bronchial smooth muscle to histamine after 15 days of enalapril treatment. The reactivity of the lung smooth muscle to the histamine was not significantly changed. These results confirmed the increased cough sensitivity and increased bronchial reactivity after enalapril treatment. These experimental animal model may be useful for the investigation of the pharmacological minimization of respiratory adverse effect of ACE-inhibitors.     

Influence of sulphur dioxide breathing on defensive reflexes of the airways

The influence of sulphur dioxide (SO2) on cough and expiratory reflexes was studied in 22 anaesthetized (pentobarbital, 30 mg/kg i.v.) rabbits. The cough reflex (CR) was elicited by tracheobronchial mucous membrane stimulation, using a soft venous catheter. In order to induce the expiratory reflex (ER) irritation of the larynx was performed by a silon fibre loop. The strength of both reflexes was assessed from the interpleural pressure fluctuation before SO2 breathing, immediately after, and 30-120 minutes after SO2 breathing had been stopped. The animals breathed SO2 in 200-300 ppm concentration through a tracheal cannula. The influence of SO2 on the direct dependence of lung inflation pressure magnitude (LIPM) on strength of the expiratory reflex (ERS) was tested. It was found that elicitability and strength of the cough reflex decreased immediately after SO2 breathing had been stopped, and did not reach the preexposure level at the end of the experiment, i.e. 2 hours after discontinuation of SO2 breathing. The direct dependence of LIPM on ERS in unaffected rabbits [10] was abolished immediately after SO2 breathing had been stopped but was present again 30-60 minutes later, and did not differ significantly from the control values. The results give evidence of the strong depressive influence of SO2 on the defensive reflexes of the airways in rabbits.     

Effect of hypoxia on the excitability of two cranial reflexes in unanaesthetized fetal sheep

In fetal sheep acute hypoxia causes a decreased incidence of breathing movements and motor activity, and the excitability of polysynaptic reflexes in the hindlimbs is depressed. To determine whether this inhibitory effect extends to other areas in the fetal CNS, we have studied the effect of hypoxia on two reflexes with cranial pathways. The digastric (jaw opening) reflex was elicited by stimulation of the dental nerve through a pair of stainless steel electrodes implanted into the mandible (4 fetuses). The thyroarytenoid muscle of the larynx was reflexly activated by stimulation of the superior laryngeal nerve by a cuff electrode (4 fetuses). Low level stimulation at 1.5-2 X threshold was repeated at approximately 2 min intervals for 3-4 h; the stimulation did not alter the pattern of electrocortical activity, breathing movements, or cause arousal. The amplitude of the digastric reflex was greatest during low voltage electrocortical activity; conversely, the amplitude of the thyroarytenoid reflex was greatest during high voltage electrocortical activity. Isocapnic hypoxia lasting 30-60 min (16 trials), in which the PaO2 was reduced to 12-14 mmHg, did not reduce the amplitude of either reflex. The reduction of thyroarytenoid reflex amplitude which normally occurred during low voltage electrocortical activity was not present during hypoxia. These experiments show that the inhibitory effects of hypoxia on spinal reflexes, breathing movements and motor activity do not include these cranial pathways.     

Effects of hypoxia on respiratory defence reflexes. Effects of thirty hours' oxygen deficiency on cough, the expiration reflex and sneezing in awake cats

The authors studied, in 11 awake adult cats, the parameters of the expiration reflex (ER), tracheobronchial (TB) and laryngopharyngeal (LPh) cough, the respiratory rate (f), tidal volume (VT), the end tidal fractional CO2 concentration (FETCO2), the pH, the blood gases and the heart rate during 30 hours' isobaric hypoxic hypoxia (FO2 = 0.11). During the whole 30 hours the cats developed hypocapnic hypoxemia, f remained unchanged and VT was markedly elevated. In the acute phase (15 min) of hypoxic hypoxia of the same intensity, changes in respiratory parameters were the same and the intensity of respiratory reflexes increased significantly (Tatár et al. 1984). During prolonged hypoxic hypoxia there were no statistically significant changes in the intensity of the ER and of TB and LPh cough. The authors assume that some adaptation of the central mechanisms regulating the defence reflexes of the airways took place; this hypothesis is warranted, because an increase in the susceptibility of the cough centre during constant conditions of the stimulation of cough receptors would not be biologically expedient. The different changes in the intensity of respiratory defense reflexes in the acute and the prolonged phase of hypoxic hypoxia in the presence of identical changes in respiratory parameters are further indirect evidence pointing to the existence of functional differences between the respiratory centre and the cough centre.     

Bulbar respiratory activity during defensive airways reflexes in cats

Experiments in anaesthetized nonparalyzed cats indicated that mechanical stimulation of the airways and a longitudinal split of the brainstem cause marked alterations of the regulatory function of the bulbar respiratory neurones. The resulting changes in breathing and in defensive airways reflexes depend on intactness of the relevant structures of both halves of the "respiratory centre" and their interconnections.     

The bactericidal/permeability-increasing protein (BPI) in the innate defence of the lower airways

The human BPI (bactericidal/permeability-increasing protein), stored in primary azurophilic granula of neutrophil granulocytes and produced by mucosal epithelia, has been known for decades to bind LPS (lipopolysaccharide) with very high affinity and to efficiently kill Gram-negative bacteria. Thus BPI potentially represents a central component of the innate immune system to directly combat microbes and modulate subsequent adaptive immune responses. Especially in the lungs, which are frequently exposed to a variety of inhaled pathogens, antimicrobial innate defence molecules such as BPI, are of exceptional relevance. In the present review, we highlight possible functions of BPI during acute pneumonia and CF (cystic fibrosis)-associated chronic infections in the lung.