Effect of 6-OHDA on hypercapnic ventilatory response in the rat model of Parkinson's disease.

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.

Hypoxic ventilatory response after dopamine D2 receptor blockade in unilateral rat model of Parkinson's disease.

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.

Nodose ganglia-modulatory effects on respiration.

The key role of the vagus nerves in the reflex control of breathing is generally accepted. Cardiopulmonary vagal receptors and their afferent connection with the medullary respiratory centers secures the proper regulatory feedback. Section of the vagi at the midcervical level interrupts primary vagal reflexes and those due to activation of lung afferents by neuroactive substances. In this context the present review focuses on the reflex contribution of the inferior (nodose) vagal ganglia to the respiratory pattern, considering that this structure contains perikarya of vagal afferent neurons which house neurotransmitters, neuropeptides and neurochemical substances. In experimental animals with removed sensory input from the lungs (midcervical vagotomy) the following evidence was reported. Transient respiratory suppression in the form of apnoea, occurring after systemic injection of serotonin, adenosine triphosphate and anandamide (N-arachidonoyl-ethanolamine-endogenous cannabinoid neurotransmitter), which was abrogated by nodose ganglionectomy. Preserved nodose-NTS connection conditioned respiratory depression affecting the timing component of the breathing pattern evoked by N-6-cyclopentyl-adenosine (CPA) and inhibition of both respiratory constituents induced by NPY. Stimulatory effect of NPY13-36 on tidal volume required nodosal connection. The cardiovascular effects of majority of the tested substances occurred beyond the nodose ganglia (with exclusion of serotonin and anandamide).

Macroanatomical investigation of the aorticorenal ganglion in 1-day-old infant sheep.

The aorticorenal gland belongs to the paired splanchnic ganglion, which is the main component of the coeliac plexus. It lies near the renal artery and suprarenal gland. The research was conducted on 13 1-day-old infant sheep - eight males and five females. Based on the conducted studies, it was concluded that the aorticorenal ganglion is characterized by the variable location in relation to the abdominal aorta, renal artery, caudal vena cava and suprarenal gland (holotopy), the thoracic and lumbar segment of the vertebral column (skeletotopy) (between L(1) and L(3)) and also a different shape (elongated, round, triangular, oval) as well as variable length (the aorticorenal ganglion is longer on the left side of the body; 2.72 mm) and distance from the caudal end of the suprarenal gland (longer on the left side of the body; 8.34 mm). With regard to the sex of the animal, the ganglion is the longest on the left side in ewes (3.02 mm), while in rams it is the longest on the right side (2.68 mm). Regarding the division according to sex, the longest segment was observed on the right side in ewes (9.27 mm), and the shortest segment in rams was also on the right side (6.84 mm).

The potential role of the nodose ganglion adenosine A1 receptor in regulation of breathing in anaesthetized rats.

The respiratory effects of stimulation of adenosine A(1) receptors were studied in spontaneously breathing rats that were either (1) neurally intact and subsequently bilaterally vagotomized in the neck, or (2) neurally intact and subjected to supranodosal vagotomy or (3) midcervically vagotomized before and after pharmacological blockade of A(1) receptors. Before neural interventions an intravenous bolus of the A(1) receptor agonist N6-cyclopentyladenosine (CPA, 5 microg kg(-1)) decreased breathing rate, tidal volume, mean arterial blood pressure (MAP) and heart rate. After section of the midcervical vagi, CPA still decreased respiratory rate and tidal volume. Supranodose vagotomy abolished the fall in respiratory rate but did not affect the depression of tidal volume. Blockade of A(1) receptors with intravenous doses of DPCPX (100 microg kg(-1)) eliminated all respiratory effects of CPA challenge. In all the neural states, CPA caused significant falls in mean arterial blood pressure and heart rate. DPCPX pre-treatment prevented these cardiovascular effects. The present data suggest that: (1) CPA-evoked activation of A(1) receptors decreases breathing rate and tidal volume and this occurs central to the cervical vagi; (2) supranodosal vagotomy prevents the decrease in breathing rate, which is presumably due to stimulation of nodosal A(1) receptor; and (3) depression of tidal volume and the hypotensive response result from the excitation of central nervous A(1) expressing neurones.

Topical application of F991, an immunoglobulin free light chain antagonist, prevents development of contact sensitivity in mice.

BACKGROUND: Exposure to reactive chemicals or environmental allergens can lead to hypersensitivity reactions in the skin of predisposed people. Most of these reactions are of atopic origin, but a subgroup of patients exhibits skin hypersensitivity reactions without features of atopy. OBJECTIVE: This study was undertaken to examine the effect of inhibiting the action of Ig-free light chains in a murine model for non-atopic skin hypersensitivity by dermal application of the free light chain antagonist F991. METHODS: To study the efficacy of F991, BALB/c mice were either passively immunized with trinitrophenyl (TNP)-specific immunoglobulin light chains (IgLC) and challenged with the hapten picryl chloride (PCl) or actively skin-sensitized and challenged with dinitrofluorobenzene (DNFB). The effect of F991 or control treatment was investigated by measuring local edema formation and the production of pro-inflammatory cytokines. RESULTS: Passive immunization with TNP-specific IgLC resulted in an increase in ear swelling 2 h after PCl challenge. F991 inhibited this enhanced ear swelling in a dose-dependent manner when applied 4 h before the sensitization with IgLC. F991 also inhibited DNFB-induced contact hypersensitivity reaction in the mouse skin 2 and 24 h after challenge when applied before challenge. Besides the prophylactic action, F991 when applied 2 h after DNFB-challenge, it was also able to attenuate symptoms of the DNFB-induced hypersensitivity reaction at 24 h after challenge. We showed that the beneficial effects of F991 are restricted to the side of application. CONCLUSION: F991 is able to effectively alleviate symptoms of contact sensitivity in mice. Our study suggests that local interference with IgLC-induced allergic symptoms may be attractive in the treatment of hypersensitivity responses.

Involvement of vagal opioid receptors in respiratory effects of morphine in anaesthetized rats.

Respiratory effects of morphine injection to the femoral vein were investigated in urethane and chloralose anaesthetized and spontaneously breathing rats, prior to and after midcervical vagotomy. Bolus injection of morphine HCl at a dose of 2 mg/kg of body weight induced depression of ventilation in all rats, due to the significant decrease in tidal volume and to the decline in respiratory rate both pre- and post-vagotomy. Expiratory apnoea of mean duration of 10.0+/-3.4 s was present in the vagally intact rats only. Bilateral midcervical section of the vagus nerve precluded the occurrence of apnoea. Prolongation of the expiratory time (T(E morphine) / T(E control)), which amounted to 10.7+/-2.2-fold in the intact state, was apparently reduced to 1.5+/-0.3-fold after division of the vagi. Morphine significantly decreased mean arterial pressure (MAP) at 30 s after the challenge, the effect persisted for not less than 1 minute and was absent in vagotomized rats. The respiratory changes evoked by morphine reverted to the control level after intravenous injection of naloxone at a dose of 1 mg/kg. Results of this study indicate that opioid receptors on vagal afferents are responsible for the occurrence of apnoea and hypotension evoked by morphine.

Diverging respiratory effects of serotonin and nicotine in vagotomised cats prior to and after section of carotid sinus nerves.

Respiratory effects of intravenous serotonin and nicotine were investigated prior to and after bilateral neurotomy of the carotid sinus nerves (CSNs) in eight pentobarbitone/chloralose-anaesthetised, bilaterally vagotomised and superior laryngeal nerves-sectioned cats. Injection of 188 nmol kg(-1) serotonin (hydrogen oxalate salt, 50 microg x kg(-1)) prior to and after CSNs section induced an expiratory apnoea of, respectively, 7.9 +/- 1.25 s and 8.3 +/- 1.6 s duration (mean +/- S.E.M.) in, respectively, five and three of those cats. In all cats, the serotonin challenge produced a period of accelerated breathing (P < 0.05) both prior to and after section of CSNs. Injection of a 433 nmol nicotine bolus (hydrogen tartrate salt, 200 microg) increased tidal volume by 25 +/- 8% in cats with intact CSNs (P < 0.01), but decreased it by 13 + 10% (P < 0.05) after CSNs section. Nicotine, but not serotonin, transiently increased mean arterial blood pressure in our cats, which rise was delayed by CSNs cut. Results of this study indicate that the respiratory response to serotonin occurs beyond carotid body chemoreceptors in vagotomised cats, and suggest that the volume response to intravenous nicotine depends qualitatively on carotid body chemoreceptor input in this experimental model.

Respiratory effects of capsaicin occur beyond the lung vagi in anaesthetized rats.

The effects of an intravenous capsaicin challenge on the respiratory pattern and ventilation were studied in 15 urethane/chloralose-anaesthetized, spontaneously breathing rats. Bolus injection of capsaicin at a dose of 5 micrograms/kg into the right femoral vein evoked respiratory arrest in all animals (both prior to and after bilateral midcervical vagotomy), which effect was abolished by ruthenium red pretreatment. Breathing that followed the apnoea was of enlarged tidal volume and initially increased respiratory rate, which resulted in an augmented ventilation. The capsaicin-induced respiratory changes were independent of vagal integrity and may depend on stimulation of vanilloid receptors within the nodose ganglia.