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The underlying cause of respiratory impairments appearing in Parkinson’s disease (PD) is still far from being elucidated. To better understand the pathogenesis of respiratory disorders appearing in PD, we studied hypoglossal (HG) and phrenic (PHR) motoneuron dysfunction in a rat model evoked with reserpine administration. After reserpine, a decrease in the baseline amplitude and minute HG activity was noted, and no depressive phase of the hypoxic ventilatory response was observed. The pre-inspiratory time of HG activity along with the ratio of pre-inspiratory time to total respiratory cycle time and the ratio of pre-inspiratory to inspiratory amplitude were significantly reduced during normoxia, hypoxia, and recovery compared to sham rats. We suggest that the massive depletion of not only dopamine, but above all noradrenaline and serotonin in the brainstem observed in our study, has an impact on the pre-inspiratory activity of the HG. The shortening of the pre-inspiratory activity of the HG in the reserpine model may indicate a serious problem with maintaining the correct diameter of the upper airways in the preparation phase for inspiratory effort and explain the development of obstructive sleep apnea in some PD patients. Therapies involving the supplementation of amine depletion other than dopamine should be considered.

The opioid-induced analgesia is associated with a number of side effects such as addiction, tolerance and respiratory depression. The involvement of neuropeptide FF (NPFF) in modulation of pain perception, opioid-induced tolerance and dependence was well documented in contrast to respiratory depression. Therefore, the aim of the present study was to examine the potency of NPFF to block post-opioid respiratory depression, one of the main adverse effects of opioid therapy. Urethane-chloralose anaesthetized Wistar rats were injected either intravenously (iv) or intracerebroventricularly (icv) with various doses of NPFF prior to iv endomorphin-1 (EM-1) administration. Iv NPFF diminished the number of EM-1-induced apneas without affecting their length and without influence on the EM-1 induced blood pressure decline. Icv pretreatment with NPFF abolished the occurrence of post-EM-1 apneas and reduced also the maximal drop in blood pressure and heart rate. These effects were completely blocked by the NPFF receptor antagonist RF9, which was given as a mixture with NPFF before systemic EM-1 administration. In conclusion, our results showed that centrally administered neuropeptide FF is effective in preventing apnea evoked by stimulation of &mu, opioid receptors and the effect was due to activation of central NPFF receptors. Our finding indicates a potential target for reversal of opioid-induced respiratory depression.

Respiratory disturbances present in Parkinson’s disease (PD) are not well understood. Thus, studies in animal models aimed to link brain dopamine (DA) deficits with respiratory impairment are needed. Adult Wistar rats were lesioned with injection of 6-hydroxydopamine (6-OHDA) into the third cerebral ventricle. Two weeks after hypoxic test was performed in whole-body plethysmography chamber, phrenic (PHR) and hypoglossal (HG) nerve activities were recorded in normoxic and hypoxic conditions in anesthetized, vagotomized, paralyzed and mechanically ventilated rats. The effects of activation and blockade of dopaminergic carotid body receptors were investigated during normoxia in anesthetized spontaneously breathing rats. 6-OHDA injection affected resting respiratory pattern in awake animals: an increase in tidal volume and a decrease in respiratory rate had no effect on minute ventilation. Hypoxia magnified the amplitude and minute activity of the PHR and HG nerve of 6-OHDA rats. The ratio of pre-inspiratory to inspiratory HG burst amplitude was reduced in normoxic breathing. Yet, the ratio of pre-inspiratory time to total time of the respiratory cycle was increased during normoxia. 6-OHDA lesion had no impact on DA and domperidone effects on the respiratory pattern, which indicate that peripheral DA receptors are not affected in this model. Analysis of monoamines confirmed substantial striatal depletion of dopamine, serotonin and noradrenaline (NA) and reduction of NA content in the brainstem. In bilateral 6-OHDA model changes in activity of both nerves: HG (linked with increased apnea episodes) and PHR are present. Demonstrated respiratory effects could be related to specific depletion of DA and NA.

Aims Parkinson's disease (PD) patients apart from motor dysfunctions exhibit respiratory disturbances. Their mechanism is still unknown and requires investigation. Our research was designed to examine the activity of phrenic (PHR) and hypoglossal (HG) nerves activity during a hypoxic respiratory response in the 6-hydroxydopamine (6-OHDA) model of PD. Main methods Male adult Wistar rats were injected unilaterally with 6-OHDA (20 μg) or the vehicle into the right medial forebrain bundle (MFB). Two weeks after the surgery the activity of the phrenic and hypoglossal nerve was registered in anesthetized, vagotomized, paralyzed, and mechanically ventilated rats under normoxic and hypoxic conditions. Lesion effectiveness was confirmed by the cylinder test, performed before the MFB injection and 14 days after, before the respiratory experiment. Key findings 6-OHDA lesioned animals showed a significant increase in normoxic inspiratory time. Expiratory time and total time of the respiratory cycle were prolonged in PD rats after hypoxia. The amplitude of the PHR activity and its minute activity were increased in comparison to the sham group at recovery time and during 30 s of hypoxia. The amplitude of the HG activity was increased in response to hypoxia in 6-OHDA lesioned animals. The degeneration of dopaminergic neurons decreased the pre-inspiratory/inspiratory ratio of the hypoglossal burst amplitude during and after hypoxia. Significance Unilateral MFB lesion changed the activity of the phrenic and hypoglossal nerves. The altered pre-inspiratory hypoglossal nerve activity indicates modifications to the central mechanisms controlling the activity of the HG nerve and may explain respiratory disorders seen in PD, i.e. apnea.

Aim Chimeric compound – PK20 despite its therapeutic activity on nociceptive and inflammatory processes may affect respiration and blood pressure. Our objective was to evaluate influence of the hybrid composed of endomorphin-2 and neurotensin fragments on ventilation, heart rate and blood pressure in anesthetized and awake rats. Methods The effects of PK20 (1 mg/kg) were studied either after its intravenous administration in anesthetized rats or intraperitoneal injection in awake state. Tidal volume and the timing components of the breathing pattern, arterial blood pressure, and heart rate were recorded. Results Intravenous administration of PK20 in the neurally intact rats evoked a dose-dependent apnoea followed by a transient insignificant increase in tidal volume and breathing rate. The blood pressure changes were biphasic: transient increase was replaced by prolonged hypotension. Midcervical vagotomy abrogated all post-PK20 respiratory effects. Hypotension was eliminated after blockade of neurotensin NTS 1 receptor, while respiratory changes were reduced by blockade of both: NTS 1 and μ opioid receptors. After PK20 intraperitoneal injection awake rats did not show any significant changes in ventilation and blood pressure. Conclusion This chimeric peptide should be used with care via intravenous administration in anesthetized animals since PK20 may evoke respiratory apnoea and hypotension. Nevertheless, applied intraperitoneally in the same dose in conscious rats induced no adverse effects.

Breathing impairments, such as an alteration in breathing pattern, dyspnoea, and sleep apnoea, are common health deficits recognised in Parkinson’s disease (PD). The mechanism that underlies these disturbances, however, remains unclear. We investigated the effect of the unilateral damage to the rat nigrostriatal pathway on the central ventilatory response to hypercapnia, evoked by administering 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle (MFB). The respiratory experiments were carried out in conscious animals in the plethysmography chamber. The ventilatory parameters were studied in normocapnic and hyperoxic hypercapnia before and 14 days after the neurotoxin injection. Lesion with the 6-OHDA produced an increased tidal volume during normoxia. The magnified response of tidal volume and a decrease of breathing frequency to hypercapnia were observed in comparison to the pre-lesion and sham controls. Changes in both respiratory parameters resulted in an increase of minute ventilation of the response to CO(2) by 28% in comparison to the pre-lesion state at 60 s. Our results demonstrate that rats with implemented unilateral PD model presented an altered respiratory pattern most often during a ventilatory response to hypercapnia. Preserved noradrenaline and specific changes in dopamine and serotonin characteristic for this model could be responsible for the pattern of breathing observed during hypercapnia.

Neurokinin A (NKA) is a peptide neurotransmitter that participates in the regulation of breathing and the cardiovascular system. The purpose of the current study was to determine the cardiorespiratory pattern exerted by the systemic injection of NKA, to look at the contribution of neurokinin NK1 and NK2 receptors, and to establish the engagement of the vagal pathway in mediation of these responses. The effects of intravenous injections of NKA (50 μg/kg) were studied in anaesthetized, spontaneously breathing rats in the following experimental schemes: in neurally intact rats; and vagotomized at either midcervical or supranodosal level. Intravenous injections of NKA in the intact rats evoked sudden and short-lived increase in the respiratory rate concomitant with drop in tidal volume, followed by a prolonged depression, coupled with continuous augmentation of the tidal volume. Respiratory alterations were accompanied by transient tachycardia and prolonged hypotension. Midcervical vagotomy eliminated respiratory rate response and augmentation of tidal volume. Section of supranodosal vagi abrogated all respiratory reactions. NK2 receptor blockade abolished respiratory changes without affecting cardiovascular effects, whereas NK1 receptor blockade significantly reduced hypotension and increase in heart rate with no impact on the respiratory system. These results indicate that NKA induced changes in the breathing resulting from an excitation of the NK2 receptors on the vagal endings. A fall in blood pressure triggered by NKA occurs outside of the vagus nerve and is probably mediated via its direct action on vascular smooth muscles supplied with NK1 receptors.

Modified non-motor brainstem ventilatory control might be involved in Parkinson's disease. Our study was designed to investigate the impact of degeneration of the nigrostriatal dopaminergic pathway on resting breathing and hypoxic ventilatory response in conscious rats. The role of central and peripheral dopamine D2 receptors in the modulation of the hypoxic ventilatory response in conditions of dopamine shortage was examined. Adult Wistar rats received a unilateral double 6-hydroxydopamine lesion of the right medial forebrain bundle. After surgery, animals were placed in whole-body plethysmographic chamber and exposed to hypoxia (8% O2). One group of animals received inraperitoneal injections of either haloperidol or domperidone before hypoxia. Levels of dopamine and its metabolite in the brainstem and striatum were assessed. Neurotoxin treatment evoked limb use asymmetry. No effect on the resting normoxic respiration was observed. An increase in tidal volume and a decrease in respiratory rate during respiratory response to hypoxia with short magnification of minute ventilation were predominant effects. Domperidone treatment in intact animals evoked a significant increase in normoxic tidal volume, while haloperidol potentiated tidal volume increase in response to hypoxia. After the lesion, the effects of both antagonists were absent. In rats with Parkinson's, the content of dopamine and its metabolite decreased substantially in the injured striatum. Augmentation of a tidal volume response to hypoxia, and the absence of stimulatory effect of intraperitoneal domperidone on normoxic and haloperidol on hypoxic tidal volume, in lesioned rats indicated altered control of breathing. This could be the result of a dopamine deficiency in the striatum and an increased turnover of DOPAC/DA in the brainstem.

PK20M (Dmt-D-Lys-Phe-Phe-OH) is a novel modified endomorphin-2 (EM-2) peptide producing strong dose- and time-dependent antinociceptive activity. Yet its prototype, endogenous EM-2, has been reported to trigger respiratory and vascular effects such as apnea and hypotension. The purpose of this study was to investigate the potency of the PK20M to evoke respiratory and cardiovascular responses in comparison to endogenous endomorphins. The engagement of the vagal pathway and μ opioid receptors in mediation of these responses was investigated. The effects of intravenous injections of PK20M, EM-1, and EM-2 were studied in anaesthetized, spontaneously breathing rats. The main dose-dependent effect of all endomorphins in the intact rats was immediate apnea, blood pressure and heart rate decrease. PK20M produced apnea in at least half of the intact animals in a much smaller dose than EM-1 and EM-2. The effects of all compounds were abrogated by pre-treatment with MNLX, a peripherally acting μ receptor antagonist. Cervical vagotomy eliminated arrest of breathing in the case of each tested compound. Hypotension was reduced by vagi section only after EM-1 and EM-2 administration. Our results demonstrated that apnea and bradycardia caused by systemic injection of all endomorphins were mediated via activation of μ vagal opioid receptors. The hypotension depended on intact vagi nerves only in the case of EM-1 and EM-2, whereas PK20M decreased blood pressure via other mechanisms outside vagal innervation. Modified opioid agonist is more potent in evoking extended hypotension; at the same time, it produces an arrest of breathing less frequently than its prototype EM-2.

The study investigated the share of vagal input at infra- and supra-nodosal level and the contribution of CCK1 and CCK2 receptors to the cardiorespiratory responses produced by an intravenous injection of sulfated cholecystokinin octapeptide (CCK-8) in anesthetized rats. This compound administered intravenously at a dose of 50μg/kg induced short-lived decline in tidal volume and respiratory rate resulting in depression of minute ventilation. Midcervical vagotomy had no effect on CCK-8-evoked ventilatory changes, whereas supranodosal denervation abolished slowing down of breathing. Cardiovascular response to CCK challenge was characterized by a transient decrease followed by an augmentation in the mean blood pressure (MAP) in the intact animals. Vagotomy performed at both levels abrogated the declining phase of MAP. Blood pressure changes were associated with decreased heart rate present in all neural states. All cardiovascular and respiratory effects were antagonized by pre-treatment with devazepide-CCK1 receptors' antagonist, whereas CI988-antagonist of CCK2 receptors was ineffective. In conclusion, our results indicate that CCK-8 modulates slowing down of respiratory rhythm via CCK1 receptors located in the nodose ganglia (NG) and depresses tidal volume via central CCK1 dependent mechanism. CCK-8-evoked decline in blood pressure may be due to activation of vagal afferents, whereas pressor responses seem to be mediated by an activation of CCK1 receptors in the central nervous system. Bradycardia was probably induced by the direct action of CCK-8 on the heart pacemaker cells.

Fabrication of multifunctional smart vehicles for drug delivery is a fascinating challenge of multidisciplinary research at the crossroads of materials science, physics and biology. We demonstrate a prototypical microcapsule system that is capable of encapsulating hydrophobic molecules and at the same time reveals magnetic properties. The microcapsules are prepared using a templated synthesis approach where the molecules to be encapsulated (Nile Red) are present in the organic droplets that are suspended in the polymerization solution which also contains magnetic nanoparticles. The polymer (polypyrrole) grows on the surface of organic droplets encapsulating the fluorescent dye in the core of the formed microcapsule which incorporates the nanoparticles into its wall. For characterization of the resulting structures a range of complementary physicochemical methodology is used including optical and electron microscopy, magnetometry, 1H NMR and spectroscopy in the visible and X-ray spectral ranges. Moreover, the microcapsules have been examined in biological environment in in vitro and in vivo studies.

In the present research long-term pulmonary toxicity of lead was investigated in rats treated by intraperitoneal administration of lead acetate for three consecutive days (25 mg/kg per day). Five weeks after treatment average lead content in the whole blood was 0.41 μg/dL ± 0.05, in the lung homogenates it measured 3.35 μg/g ± 0.54, as compared to the control values of 0.13 ± 0.07 μg/dL and 1.03 μg/g ± 0.59, respectively. X-ray microanalysis of lung specimens displayed lead localized mainly within type II pneumocytes and macrophages. At the ultrastructural level the effects of lead toxicity were found in lung capillaries, interstitium, epithelial cells, and alveolar lining. Alveolar septa showed intense fibrosis, consisting of collagen, elastin, and fibroblasts. Thinned alveolar septa had emphysematous tissue with some revealing signs of angiogenesis. Type II pneumocytes contained lamellar bodies with features of laminar destruction. Fragments of the surfactant layer were often detached from the alveolar epithelium. These findings indicate that 5 weeks after exposure, lead provokes reconstruction of the alveolar septa including fibrosis and emphysematous changes in the lung tissue.

The respiratory effects of stimulation of NPYY 2 receptors were studied in spontaneously breathing rats that were either (i) neurally intact and subsequently bilaterally vagotomized in the neck, or (ii) neurally intact and subjected to supranodosal vagotomy or (iii) neurally intact treated with pharmacological blockade of NPY 1–2 receptors. Before neural interventions an intravenous (iv) bolus of the NPYY 2 receptor agonist NPY 13–36 (10 μg/kg) increased breathing rate, tidal volume and mean arterial blood pressure (MAP). Section of the midcervical vagi abrogated NPY 13–36-evoked increase in respiratory rate but had no effect on augmented tidal volume, minute ventilation and blood pressure. Supranodosal vagotomy prevented the increase in tidal volume and slightly reduced the pressor response. Blockade of NPYY 2 receptor with intravenous doses of BIIE 0246 eliminated cardio-respiratory effects of NPY 13–36 injection. BMS 193885 – an antagonist of NPYY 1 receptor-was not effective in abrogating cardio-respiratory response. The present study showed that (i) NPY 13–36 induced stimulation of breathing results from activation of NPYY 2 receptors associated with pulmonary vagal afferentation; (ii) the increase in the frequency of breathing is mediated by midcervical vagi and augmentation of tidal volume relies on the intact supranodosal trunks (iii) the pressor response results from the excitation of NPYY 2 receptors outside of the vagal pathway.

Pulmonary toxicity of lead was studied in rats after an intraperitoneal administration of lead acetate at a dose of 25 mg/kg. Three consecutive days of treatment increased lead content in the whole blood to 2.1 µg/dl and in lung homogenate it attained 9.62 µg/g w.w. versus control values of 0.17 µg/dl and 0.78 µg/g w.w., respectively. At the ultrastructural level, the effects of lead toxicity were observed in lung capillaries, interstitium, epithelial cells and alveolar lining layer. Accumulation of aggregated platelets, leucocytic elements and monocytes was found within capillaries. Interstitium comprised a substantial number of collagen, elastin filaments and lipofibroblasts. Lamellar bodies of type II pneumocytes contained phospolipid lamellae, which stratified into an irregular arrangement. Pulmonary alveoli were filled with macrophages. The extracellular lining layer of lung alveoli was partially destroyed. This study provided evidence that acute lead intoxication affects the whole lung parenchyma and by impairing production of the surfactant might disturb the regular respiratory function.

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 intravenous injection of somatostatin were investigated in anaesthetized, spontaneously breathing rats that were: (i) neurally intact and subsequently bilaterally vagotomized in the neck, or (ii) midcervically vagotomized with later vagotomized at the supranodosal level, or (iii) midcervically vagotomized and subjected to section of the carotid sinus nerves (CSNs). Intravenous injection of 100 μg/kg of somatostatin before and after midcervical vagotomy-induced immediate slowing down of the respiratory rate and decreased tidal volume, mean arterial blood pressure (MAP) and heart rate. Supranodose vagotomy did not abolish somatostatin-induced respiratory depression. CSNs section eliminated all respiratory effects of somatostatin challenge. In all the neural states, somatostatin caused significant falls in mean arterial blood pressure and heart rate. The results of this study suggest that hypoventilation induced by intravenous somatostatin administration occurs outside vagal afferentation to the medulla and is mediated via carotid body afferents. Sino-aortic chemoreceptors and baroreceptors do not contribute to bradycardia and a fall in blood pressure. These cardiovascular effects are presumably mediated due to excitation of somatostatin receptors within the heart and/or in the brain.

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.

Respiratory effects of NMDA injection into the right atrium were investigated in 11 urethane-chloralose anaesthetised and spontaneously breathing rats. The animals were initially vagotomised and six of them were subdued to the subsequent carotid sinus nerve section, and the other five were treated by NMDA antagonist. Bolus injection of NMDA (27 micromol/kg) induced the depression of ventilation in all rats, due to the decrease in tidal volume from a baseline of 2.98 +/- 0.4 to 2.63 +/- 0.3 ml (P < 0.01), and slowing down of the respiratory rate from a baseline of 56 +/- 2.6 to 27 +/- 2.0 breaths min(-1) (P < 0.0001). Section of the carotid sinus nerves (CSNs) precluded the respiratory depression. Prolongation of the expiratory time was reduced by this neurotomy from 5.07 +/- 2.6 to 1.04 +/- 0.03 (P < 0.05). In five rats the blockade of NMDA receptors with the selective antagonist (AP-7) was likewise efficient in eliminating the post-NMDA respiratory response. NMDA increased mean arterial blood pressure and this rise occurred beyond the afferentation from the carotid bodies and the blockade of NMDA receptors. Results of this study indicate that inhibition of the respiratory drive evoked by NMDA administered via the peripheral circulation requires intact carotid bodies and activation of NMDA receptors.

1. Experiments were performed to determine the effects of systemic application of N-methyl-d-aspartate (NMDA) on respiratory variables and blood pressure in 22 urethane/chloralose-anaesthetized, spontaneously breathing rats. 2. Bolus injection of NMDA at a dose of 27 micro mol/kg, i.v., in neurally intact rats evoked a depression of breathing, most apparent at 30 s, comprising a decrease in tidal volume (P < 0.001) and respiratory rate (P < 0.001). The expiratory apnoea appeared in three intact rats only. 3. The respiratory effects of NMDA were independent of the vagal integrity between lungs and the nodose ganglia. Elimination of supranodose connection to the medulla reduced the prolongation of the expiratory time (P < 0.01). 4. N-Methyl-d-aspartate induced an initial rise in blood pressure followed by hypotension in rats treated by infra- and supranodose vagotomy. 5. It is concluded that the respiratory response to systemic NMDA challenge occurs beyond lung vagi and indicates that neurons of the nodose ganglia contribute to NMDA inhibition of the expiratory time.

Ile(9)PK20 is a novel hybrid of opioid-neurotensin peptides synthesized from the C-terminal hexapeptide of neurotensin and endomorphin-2 pharmacophore. This chimeric compound shows potent central and peripheral antinociceptive activity in experimental animals, however nothing is known about its influence on the respiratory and cardiovascular parameters. The present study was designed to determine the cardiorespiratory effects exerted by an intravenous injection (i.v.) of [Ile(9)]PK20. Share of the vagal afferentation and the contribution of NTS1 neurotensin and opioid receptors were tested. Intravenous injection of the hybrid at a dose of 100 μg/kg in the intact, anaesthetized rats provoked an increase in tidal volume preceded by a prompt short-lived decrease. Immediately after the end of injection brief acceleration of the respiratory rhythm appeared, and was ensued by the slowing down of breathing. Changes in respiration were concomitant with a bi-phasic response of the blood pressure: an immediate increase was followed by a sustained hypotension. Midcervical vagotomy eliminated the increase in tidal volume and respiratory rate responses. Antagonist of opioid receptors - naloxone hydrochloride eliminated only [Ile(9)]PK20-evoked decline in tidal volume response. Blockade of NTS1 receptors with an intravenous dose of SR 142,948, lessened the remaining cardiorespiratory effects. This study depicts that [Ile(9)]PK20 acting through neurotensin NTS1 receptors augments the tidal component of the breathing pattern and activates respiratory timing response through the vagal pathway. Blood pressure effects occur outside vagal afferentation and might result from activation of the central and peripheral vascular NTS1 receptors. In summary the respiratory effects of the hybrid appeared not to be profound, but they were accompanied with unfavourable prolonged hypotension.

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.

The aim of the present study was to investigate the effects of aortic depressor nerve (ADN) transection, supranodosal vagi denervation (NG vagi cut) and adrenergic receptor blocker treatment on the cardiovascular responses evoked by systemic injection of bombesin. The cardiovascular effects were studied in spontaneously breathing rats that were (i) bilaterally, midcervically vagotomized (MC vagi cut) and subjected to section of the aortic depressor nerves, (ii) midcervically vagotomized and subsequently vagotomized at the supranodosal level or (iii) midcervically vagotomized before and after pharmacological blockade of α- or β-adrenergic receptors with phentolamine and propranolol, respectively. An intravenous bolus of bombesin (10 μg/kg) in midcervically vagotomized and ADN denervated animals increased mean arterial blood pressure (MAP) and heart rate (HR). An approximate 20% increase in blood pressure occurred immediately following bombesin injection and lasted for 2-3 min. Augmentation of the heart rate occurred 30-60 s after the bombesin challenge and persisted for more than 10 min. After section of the supranodosal vagi, bombesin failed to induce an increase in heart rate. Blockade of α-adrenergic receptors with an intravenous dose of phentolamine significantly reduced post-bombesin hypertension. These results indicate that bombesin-evoked increases in blood pressure do not require aortic depressor nerves and supranodosal vagi and are presumably mediated by the activation of peripheral α-adrenergic receptors. Bombesin-induced tachycardia was dependent on an intact supranodose pathway and was amplified by activation of β-adrenoceptors.

The respiratory effects resulting from stimulation of 5-HT(1A) 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-HT(1A) receptors. An intravenous bolus of the 5-HT(1A) receptor agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT, 10 microg 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-HT(1A) receptors with intravenous doses of 1-(2-metoxyphenyl)-4-[4-(2-phthalimido) butyl] piperazine (NAN 190; 20 microg 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-HT(1A) 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-HT(1A) carotid receptors and the central 5-HT(1A)-expressing neurones.

Respiratory effects of intracarotid injection of gamma-amino-butyric acid (GABA) were investigated in two groups of rats. In the first group of 12 rats the effects of GABA were checked in the intact state, following bilateral vagotomy and GABA receptor blockade. The second group consisted of five initially vagotomized rats, challenged with GABA prior to and after bilateral carotid chemodenervation (CSN-cut). All rats were urethane and chloralose anaesthetized and spontaneously breathing. Injection of 39 micromol/kg GABA prior to and after vagotomy induced an expiratory apnoea of, respectively 5.5+/-0.84 sec and 3.9+/-0.6 sec duration (mean+/-S.E.M.), P0.05 in all 12 rats. In breaths that followed the apnoea tidal volume increased above the control level by 23.3% (P0.01) and 25.6% (P0.01) pre- and post-vagotomy, respectively. Blockade of GABA receptors with bicuculline and picrotoxin abolished the inhibition of breathing. In five vagotomized rats with intact carotid sinus nerves (CSNs) intracarotid GABA challenge increased tidal volume by 39% compared with baseline breathing (P0.05). Section of the CSNs precluded the occurrence of apnoea and undergoing respiratory changes evoked by GABA. Intracarotid GABA caused significant decrease in the mean blood pressure independent of the neural state, but the fall was delayed by CSNs neurotomy. Results of this study indicate that GABA given systemically induces apnoea followed by post-apnoeic hyperventilation. Carotid bodies are required for the ventilatory response to GABA; vagal afferents are not involved in this response.

Respiratory effects of an intravenous injection of capsaicin were investigated in nine vagotomized and subsequently laryngeally deafferentated, urethane- and chloralose-anaesthetized and spontaneously breathing rats. Bolus injection of capsaicin (5 micrograms/kg) into the right femoral vein induced an expiratory apnoea of 4.23 +/- 0.63 s duration (mean +/- SEM). In post-apnoeic breathing, tidal volume increased by 14% from the control level (P0.05) in all nine rats treated by vagotomy. Section of the superior laryngeal nerves (SLNs) precluded the occurrence of apnoea. Results of this study indicate that in vagotomized rats sensory input from the larynx constitutes an important pathway to the nodose ganglia endowed with capsaicin receptors.