Małgorzata Szereda-Przestaszewska

Reflex effects of chemical irritation of the upper airways on the laryngeal lumen in cats

Changes in airflow resistance of the larynx isolated in situ have been measured in spontaneously breathing cats, vagotomised in the chest, during chemical stimulation of the nose and larynx. Insufflation of ammonia vapour into the larynx inhibited breathing with a large increase in expiratory laryngeal resistance. These responses were abolished by cutting the superior laryngeal nerves, which established the afferent path for the reflex. Insufflation of ammonia into the nose caused sneezing or inhibition of breathing with expiratory increases in laryngeal resistance, which were smaller after sensory denervation of the larynx. The main afferent pathway for this reflex is probably in the trigeminal nerves. The laryngeal reflexes were generally more sensitive than those with the same stimuli affecting breathing.

Effects of vagal and laryngeal afferents on apnoeic response to serotonin in cats.

Intravenous serotonin (5-HT) elicits apnoea followed by subsequent, shallow tachypnoea. The present study was designed to ascertain whether laryngeal afferents play a role in the respiratory reflex response. Administration of 5-HT into the femoral vein (i.v.) or to the laryngeal artery (lar. art.) in anaesthetized, spontaneously breathing cats caused an expiratory apnoea that was significantly reduced (i.v.) or abolished (lar. art.) by bilateral midcervical vagotomy. Subsequent bilateral division of the superior laryngeal nerves (SLNs) did not affect the magnitude of apnoea on i.v. administration. Supranodose vagotomy abolished the occurrence of post-serotonin apnoea following i.v. injection, which is consistent with earlier results. During the phase of rapid, shallow breathing the peak respiratory airflows were significantly increased on i.v. 5-HT injection in all neural states of cats, whereas laryngeal artery administration failed to produce a significant change in respiration airflows from baseline. Serotonin significantly increased breathing frequency in the intact and denervated (vagus and SLN cut bilaterally) cats independent of the route of injection. The results show that serotonin effects the respiratory pattern with large contribution of pulmonary vagal but not laryngeal afferents. However, the occurrence of the expiratory apnoea was related to large extent to the integrity of the infranodose vagi.

Retrograde Degeneration within the Dorsal Motor Yagal Nucleus following Bilateral Vagotomy in Rabbits

The effects of unilateral and bilateral intrathoracic vagotomy on the neuronal structure of the dorsal motor nucleus of the vagus were studied in rabbits. Degeneration affected mainly the small neurones which disintegrated and vanished from dorsal motor nucleus relative to the survival time after operation. A substantial proportion of large neurones was lost or degenerated, but some were preserved unchanged. In unilaterally vagotomized rabbits the dorsal motor nucleus of the intact side showed scattered neurones with axonal reaction which stands up for peripheral crossing of the vagi. The degree of retrograde degeneration was largely determined by the survival time. The nucleus ambiguus was bilaterally preserved unchanged.

Peripheral 5-HT1A receptors are not essential for increased ventilation evoked by systemic 8-OH-DPAT challenge in anaesthetized rats.

The respiratory effects resulting from stimulation of 5‐HT1A receptors were studied in spontaneously breathing rats that were: (i) neurally intact and subsequently bilaterally vagotomized; (ii) subjected to bilateral midcervical vagotomy followed by supranodosal vagotomy; (iii) midcervically vagotomized and treated by carotid sinus/body denervation; or (iv) subjected to infra‐ and supranodosal vagotomy followed by pharmacological blockade of 5‐HT1A receptors. An intravenous bolus of the 5‐HT1A receptor agonist 8‐hydroxy‐dipropylaminotetralin (8‐OH‐DPAT, 10 μg kg−1) evoked increases in both breathing rate and tidal volume. After section of the midcervical and supranodosal vagi, 8‐OH‐DPAT challenge still increased the respiratory rate and tidal volume. Carotid sinus/body denervation did not reduce the augmentation of the tidal volume, but prevented the increase in breathing rate. Blockade of 5‐HT1A receptors with intravenous doses of 1‐(2‐metoxyphenyl)‐4‐[4‐(2‐phthalimido) butyl] piperazine (NAN 190; 20 μg kg−1) abolished all respiratory effects of 8‐OH‐DPAT challenge. In all the neural states, 8‐OH‐DPAT evoked a significant fall in mean arterial blood pressure. Pretreatment with NAN 190 reduced baseline values of mean arterial pressure and prevented 8‐OH‐DPAT‐induced hypotension. These results indicate that: (i) 8‐OH‐DPAT‐evoked activation of 5‐HT1A receptors increases breathing rate and tidal volume, which persists after section of the lung vagi and the nodose ganglia, but only the increase in breathing rate was abolished by carotid sinus/body denervation; and (ii) 8‐OH‐DPAT hyperventilatory and hypotensive responses result from the excitation of presumed 5‐HT1A carotid receptors and the central 5‐HT1A‐expressing neurones.

Clonidine-evoked respiratory effects in anaesthetized rats

The respiratory effects of stimulation of α2‐adrenergic receptors were studied in spontaneously breathing anaesthetized rats that were neurally intact, or bilaterally vagotomized, or subjected to bilateral combined midcervical vagotomy and section of the carotid sinus nerves. An intravenous clonidine bolus (15 μg kg−1) evoked a prolonged slowing of the respiratory rate in all the neural states explored. Vagotomy reduced the early clonidine‐evoked decline, but not the augmentation of tidal volume that followed the decline. After section of the carotid sinus nerves, clonidine challenge continued to decrease the respiratory rate, but not the tidal volume. Blockade of α2‐adrenergic receptors with intravenous doses of SKF 86466 (200 μg kg−1) abolished all respiratory effects of the clonidine challenge. In all the neural states studied, clonidine evoked a significant short‐lived rise in mean arterial blood pressure followed by a decrease below the respective prechallenge value. The SKF 86466 pretreatment lowered mean arterial blood pressure control values and reduced the magnitude of postclonidine changes. These results indicate that: (i) clonidine‐evoked activation of α2‐adrenergic receptors affects the two components of the breathing pattern differently, and this occurs beyond the lung vagi; and (ii) changes in tidal volume result from excitation of the carotid bodies and are coupled with centrally mediated slowing of the respiratory rhythm.

Supranodose Vagotomy Precludes Reflex Respiratory Responses to Serotonin in Cats

Mediation of the respiratory reflex effects of an exogenous serotonin challenge goes beyond the lung vagi and is suggested to involve the nodose ganglia. In the present experiments the effects of an intravenous serotonin challenge on breathing pattern were studied in 8 pentobarbitone-chloralose anaesthetised cats. Bolus injection of serotonin oxalate (50 microg/kg) into the right femoral vein evoked prompt apnoea of 19.2 (+/- 2.4)-second duration in all 8 cats while intact; the apnoea was much shorter after midcervical vagal section (8.1 +/- 0.9 s, p < 0.001), and was abolished by supranodose vagotomy. In post-apnoeic breaths, the tidal volume was reduced from a baseline of 34.1 +/- 4.0 to 13.5 +/- 1.1 ml (p < 0.001) prior to, and from a baseline of 43.9 +/- 5.4 to 33.8 +/- 6.6 ml (p < 0.01) after midcervical vagotomy; the serotonin challenge did not affect tidal volume following supranodose vagal section (p = 0.4). The increase in respiratory rate found in intact (p < 0.001) and midcervically vagotomised cats (p < 0.01) was eliminated by the neurotomy above the nodose ganglia. Supranodose vagotomy altered cardiovascular response to serotonin by replacing the fall in blood pressure with an increase. These data suggest that the sequelae of serotonin-induced pulmonary chemoreflex, i.e. respiratory arrest, cardiovascular changes and post-apnoeic pattern of breathing require intact nodose ganglia.

NPY Y1 receptors are involved in cardio-respiratory responses to intravenous injection of neuropeptide Y in anaesthetized rats

The respiratory effects evoked by systemic injection of neuropeptide Y (NPY) were studied in anaesthetized, spontaneously breathing rats that were (i) neurally intact; (ii) subjected to bilateral midcervical vagotomy (MC vagi cut); (iii) midcervically vagotomized and treated by supranodosal denervation (NG vagi cut); (iv) neurally intact, before and after pharmacological blockade of the NPY Y(1) and NPY Y(2) receptors. An intravenous (iv) bolus of NPY (100 μg/kg) induced slowing down of the respiratory rate, decreased tidal volume and heart rate, and increased mean arterial blood pressure. After section of midcervical vagi, NPY still evoked the cardio-respiratory changes. Supranodose vagotomy abolished the fall in respiratory rate and reduced significantly the decreases in tidal volume and minute ventilation. This level of vagotomy did not affect vasopressor and bradycardic effects of NPY. Blockade of NPY Y(1) receptors with an intravenous dose of 5 mg/kg of BMS 193885, reduced significantly the cardio-respiratory effects of NPY injection. Pre-treatment with BIIE 0246, NPY (2) receptor antagonist at a dose of 1-2.5 mg/kg was not effective in blocking the response to NPY. The results of this study indicate that NPY-evoked activation of NPY Y(1) receptors decreases both components of the breathing pattern, and this response is primarily mediated central to the cervical vagi. Bradycardia and hypertensive effect of NPY are attributed to the excitation of peripheral and central NPY Y(1) receptors and occur outside of the vagal pathways.

Cardio-respiratory effects of systemic neurotensin injection are mediated through activation of neurotensin NTS1 receptors

The purpose of our study was to determine the cardio-respiratory pattern exerted by the systemic injection of neurotensin, contribution of neurotensin NTS(1) receptors and the neural pathways mediating the responses. The effects of an intravenous injection (i.v.) of neurotensin were investigated in anaesthetized, spontaneously breathing rats in following experimental schemes: (i) control animals before and after midcervical vagotomy; (ii) in three separate subgroups of rats: neurally intact, vagotomized at supranodosal level and initially midcervically vagotomized exposed to section of the carotid sinus nerves (CSNs); (iii) in the intact rats 2 minutes after blockade of neurotensin NTS(1) receptors with SR 142948. Intravenous injection of 10 μg/kg of neurotensin in the intact rats evoked prompt increase in the respiratory rate followed by a prolonged slowing down coupled with augmented tidal volume. Midcervical vagotomy precluded the effects of neurotensin on the frequency of breathing, while CSNs section reduced the increase in tidal volume. In all the neural states neurotensin caused significant fall in mean arterial blood pressure preceded by prompt hypertensive response. The cardio-respiratory effects of neurotensin were blocked by pre-treatment with NTS(1) receptor antagonist. The results of this study showed that neurotensin acting through NTS(1) receptors augments the tidal component of the breathing pattern in a large portion via carotid body afferentation whereas the respiratory timing response to neurotensin depends entirely on the intact midcervical vagi. Blood pressure effects evoked by an intravenous neurotensin occur outside vagal and CSNs pathways and might result from activation of the peripheral vascular NTS(1) receptors.

Endogenous benzodiazepine system and regulation of respiration in the cat

Benzodiazepines, a class of drugs widely used as anxiolytics, can induce a depression of respiration. This study was designed to determine if endogenous benzodiazepine ligands could act in a similar fashion and exert a tonic inhibitory influence on respiration. Administration of a benzodiazepine antagonist should then facilitate respiration. This might be especially visible in hypoxia, the condition characterized by both central respiratory depression and potentially enhanced benzodiazepine expression. We addressed this issue by comparing the effects on the phrenic neurogram of the specific benzodiazepine antagonist flumazenil (200 micrograms i.v. boluses) in the contrasting conditions of hypoxia and hyperoxia in anesthetized, both spontaneously breathing and paralyzed ventilated cats. Contrary to our hypothesis, flumazenil showed a modest but definite inhibitory effect on respiration. Flumazenil also lengthened the duration of the Hering-Breuer inspiratory inhibition. The respiratory depression was neither related to chemical drive nor to the GABA receptor complex, for it was sustained after antagonism of GABA with picrotoxin and bicuculline. We conclude that the endogenous benzodiazepine system is unlikely to play an inhibitory role in the regulation of respiration. The physiologic role of this system remains to be established.

Peripheral cardiorespiratory effects of bombesin in anaesthetized rats

The respiratory effects evoked by systemic injection of bombesin were studied in spontaneously breathing rats that were (i) neurally intact and subsequently bilaterally vagotomized, (ii) intact, before and after pharmacological blockade of the bombesin BB(1) and BB(2) receptors. An intravenous bolus of bombesin (10 microg/kg) evoked sighs, decrease in the breathing rate, augmentation of tidal volume and an increase in mean arterial blood pressure. Midcervical vagotomy abolished all respiratory changes evoked by bombesin challenge, but did not prevent the increase in blood pressure. Blockade of BB(1) and BB(2) receptors with an intravenous dose of 50 microg/kg of [D-Phe](12)-bombesin, reduced significantly the cardio-respiratory effects due to bombesin administration. The BB(1) receptors antagonist, BIM 23127, at a dose of 100 microg/kg did not block the response to bombesin. These results indicate that bombesin given systemically stimulates ventilation by activation of BB(2) receptors affecting mainly the tidal component of the breathing pattern, and that the response is mediated by the lung vagi. The hypertensive effect of bombesin resulted from the excitation of BB(2) receptors, but occurred outside vagal afferentation from the lungs.