Intracerebroventricular serotonin reduces the degree of acute hypoxic ventilatory depression in peripherally chemodenervated rabbits.

Hypoxia causes changes in the rate of synthesis or release of neurotransmitters in the brain. The accumulation of serotonin (5-HT) in the central nervous system might cause hypoxic respiratory depression. In the present study, we aimed to examine the role of central 5-HT on normoxic and acute hypoxic ventilatory depression (AHVD) in peripheral chemoreceptors denervated rabbits. All experiments were performed in peripherally chemodenervated rabbits anesthetized with intravenous injection of urethane (400 mg/kg) and alpha-chloralose (40 mg/kg). For intracerebroventricular (ICV) administration of 5-HT (20 microg/kg) and ketanserin (10 microg/kg), a cannula was placed in left lateral ventricle by stereotaxic method. Respiratory frequency (fR), tidal volume (VT), ventilation minute volume (VE) and systemic arterial bood pressure (BP) were recorded in each experimental phases and mean arterial pressure was calculated (MAP). Heart rate (HR) was also determined from the pulsation of BP. The effects of ICV serotonin and ICV ketanserin on the indicated parameters during air breathing (normoxia) and breathing of hypoxia (8% O2--92% N2) were investigated. During hypoxia, fR, VT, VE, MAP and HR decreased, and AHVD was thus obtained. ICV injection of 5-HT during normoxia caused significant increases in VT (P < 0.001) and in VE (P < 0.01). On the other hand, ICV 5-HT injection reduced the degree of AHVD in peripherally chemodenervated rabbits during hypoxia (fR; P < 0.05, VT; P < 0.05 and VE; P < 0.01). After ICV injection of ketanserin, the enhancement of 5-HT on VE was prevented during normoxia. On the breathing of hypoxic gas after ICV ketanserin, the degree of AHVD was augmented. In conclusion, our findings suggested that central 5-HT increases normoxic ventilation and reduces the degree of AHVD during hypoxia and that ICV ketanserin prevents the stimulatory effect of 5-HT on respiration and augments AHVD.

The reflex effects on the respiratory regulation of the CO2 at the different flow rate and concentration.

PURPOSE: The purpose of this study was to investigate the activation of the respiratory centers during insufflation of the larynx with CO2 at different flow rates and concentrations. MATERIALS AND METHODS: The experiments were carried out in spontaneous air breathing rabbits, anesthetized with thiopental sodium (25 mg kg(-1) i.v.). The larynx was separated from the oropharyngeal cavity and the trachea. The tidal volume (VT) and respiratory frequency (f min(-1)) were recorded from the lower tracheal cannula. The respiratory minute volume (VE) was calculated, the action potentials from the right phrenic nerve were recorded and the inspiratory (TI) and expiratory (TE) periods and the mean inspiratory flow rate (VT/TI) were calculated. The larynx was insufflated at flow rates of 500 mL min(-1) and 750 mL min(-1), with 7 and 12% CO2-Air by means of a respiratory pump. RESULTS: Insufflation of the larynx, with both gas mixtures, decreased the f and VT significantly. The TI and TE were found to increase significantly due to the decreasing in f. There was a significant decrease in VT/TI ratio. Following bilateral midcervical vagotomy, on the passing of both gas mixtures, significant decreases were observed in the VT, and the responses of f, TI and TE were abolished. After cutting the superior laryngeal nerve, the responses of the VT to both gas mixtures were abolished. CONCLUSION: In conclusion, the results of this study purpose that the stimulation of the laryngeal mechanoreceptors by the effect of hypercapnia decreases the activation of the respiratory center.

Respiratory alterations due to chronic long-term intermittent hypobaric hypoxia in rabbits: importance of peripheral chemoreceptors.

BACKGROUND: None of the studies carried out so far investigated the effect of denervation of peripheral chemoreceptors on basal ventilation and respiratory responses to acute hypoxia in subjects exposed to chronic long-term intermittent hypobaric hypoxia (CLTIHH). We aimed to research (i) the effect of CLTIHH (430 mmHg, 5 h/day, 5 days/week, 5 weeks) on basal ventilation and respiratory responses to hypoxia and (ii) the effects of CLTIHH on central respiratory mechanisms after peripheral chemodenervation. METHODS: Sixteen adult albino rabbits were divided into two groups: CLTIHH (n = 8) and control (n = 8). The tidal volume (V(T)) and respiratory frequency (f/min) were initially recorded in both groups and respiratory minute volume (V(E)) was calculated. PaO(2), PaCO(2), and pHa values were determined. RESULTS: The initial values of f/min and V(E) in CLTIHH group were significantly higher than that of control group. After exposure to hypoxic gas mixture (8% O(2)-92% N(2)), the elevations in f/min, V(T), and V(E) in CLTIHH group were significantly higher than those of control group. After denervation of peripheral chemoreceptors, the decrease in V(E) in CLTIHH group was found to be significantly less than that of control group. When the animals in control group were allowed to breathe hypoxic gas mixture, f/min, V(T,) and V(E) decreased significantly and hypoxic depression was obtained. In contrast, hypoxic depression did not occur in the CLTIHH group. CONCLUSIONS: Our results suggested that CLTIHH increases the basal ventilation and hypoxic respiratory responses and that enhanced ventilatory responses were due not only to the augmentation of peripheral chemoreceptor activity but also to the augmentation of central respiratory activity.

The role of peripheral chemoreceptor activity on the respiratory responses to hypoxia and hypercapnia in anaesthetised rabbits with induced hypothyroidism.

The purpose of this study was to investigate the role of peripheral chemoreceptor activity on the hypoxic and hypercapnic ventilatory drives in rabbits with induced hypothyroidism. Experiments were carried out in control and hypothyroid rabbits. Hypothyroidism was induced by an administration of an iodide-blocker, methimazole in food (75 mg/100 g food) for ten weeks. At the end of the tenth week, triiodothyronine (T3) and thyroxine (T4) levels significantly decreased (P<0.001) while thyroid stimulating hormone (TSH) increased (P<0.001). Tidal volume (VT), respiratory frequency (f/min), ventilation minute volume (VE) and systemic arterial blood pressure (BP) were recorded during the breathing of the normoxic, hypoxic (8% O2-92% N2) and hypercapnic (6% CO2-Air) gas mixtures, in the anaesthetised rabbits of both groups. At the end of each experimental phase, PaO2, PaCO2, and pHa were measured. The same experimental procedure was repeated after peripheral chemoreceptor denervation in both groups. VT significantly decreased in some of the rabbits with hypothyroidism during the breathing of the hypoxic gas mixture (nonresponsive subgroup) (P<0.05). After chemodenervation, a decrease in VT was observed in this nonresponsive subgroup during normoxia (P<0.05). The percent decrease in VT in nonresponsive subgroup of hypothyroid rabbits after chemodenervation was lower than that of the chemodenervated control animals (P<0.01). When these rabbits with hypothyroidism were allowed to breath the hypercapnic gas mixtures, increases in VT and VE were not significant. In conclusion, although there is a decrease in peripheral chemoreceptor activity in hypothyroidism, it does not seem to be the only cause of decrease in ventilatory drive during hypoxia and hypercapnia.

The effects of vagal stimulation on laryngeal vascular resistance and intraluminal pressure in the dog.

In anaesthetized dogs (sodium pentobarbitone 30 mg/kg, i.v.) laryngeal vascular resistance was measured by unilateral perfusion at constant flow of the branch of the cranial superior thyroid artery that supplies the larynx. Arterial perfusion was at constant flow and inflow pressure was divided by flow to give laryngeal vascular resistance (R(LV)). Intraluminal laryngeal pressure (P(L)) and systemic arterial blood pressure (BP) were also measured. Stimulation (20 V, 20 Hz, 0.2 milliseconds) of the central end of cervical vagus caused an increase in R(LV) (+22.9+/-6.1%) and a decrease in P(L) (-12.1+/-4.4%). Stimulation (10 V, 10 Hz, 0.2 milliseconds) of the central end of the recurrent laryngeal nerve (RLN) reduced RLV (-3.4+/-0.8%) and P(L) (-7.5+/-4.1%). Stimulation of the peripheral end of the RLN decreased R(LV) (-7.1+/-1.9%) and increased PL (+21.6+/-7.7%). Stimulation of the central end of the superior laryngeal nerve (SLN) increased R(LV) (+17.9+/-3.2%) and P(L) (+59.8+/-2.7%), whereas stimulation of the peripheral end of the SLN decreased R(LV) (-4.8+/-1.6%) and P(L) (-4.1+/-2.4%). After treatment with alpha-adrenoreceptor antagonist phentolamine (0.5 mg/kg, i.v.), stimulation of the central end of cervical vagus nerve reduced R(LV) by 25% and decreased BP. Phentolamine caused a decrease in BP and reduced the magnitude of increase in R(LV) in response to stimulation of central end of SLN. After atropine sulphate (0.5-2.0 mg/kg, i.v.), the stimulation of both central and peripheral ends of RLN reduced R(LV). The decrease in R(LV) during stimulation of peripheral end of SLN was reduced by atropine. Thereafter, pancuronium bromide (0.06-0.1 mg/kg, i.v.) was given and dogs were artifically ventilated. After paralyzed, stimulation of the central end of the SLN decreased R(LV) (+26.0+/-4.5%) but produced no change in P(L), It is concluded that parasympathetic motor fibers in the RLN and SLN are effective for the laryngeal vascularity and non-adrenergic system may be responsible for laryngeal vasoconstriction. laryngeal vasculature; vagal stimulation; phentolamine; atropine

Hypoxic initiation of pulmonary hypertension is mediated by serotonin secretion from neuroepithelial bodies in chemodenervated dogs.

The purpose of this study was to investigate the stimulatory effect of hypoxia on the secretion of serotonin by neuroepithelial bodies (NEB) as well as to determine the relation between its level and changes in pulmonary arterial pressure (PAP) and also to determinate the effect of serotonin antagonists (pizotifen and methysergide) on the responses of pulmonary and systemic arterial pressures. The experiments were carried out in peripheral chemoreceptor-denervated dogs anesthetized with Na penthabarbital (30 mg/kg i.v.). On the breathing of normoxic and hypoxic (7% O2-93% N2) gas mixtures and on the injection of KCN (80 microg/kg i.v.), PAP, systemic arterial blood pressure (BP), tidal volume (VT), respiratory frequency (f/min), ventilation minute volume (VE) were determined. Also PAP and BP were recorded before and after the injection of pizotifen (0.5 mg/kg i.v.) and methysergide (1 mg/kg i.v.) during normoxic or hypoxic gas mixture breathing. At the end of each experimantal phase, serotonin level, PaO2, PaCO2 and pHa values in blood samples obtained from left ventricle and femoral artery were determined. On the breathing of the hypoxic gas mixture of the chemodenervated dogs, VT, VE and BP significantly decreased (P < 0.001, P < 0.001, P < 0.01). The mean value of PAP and serotonin levels (ventricular and femoral) were found significantly increased when compared with the corresponding normoxic values (P < 0.001, P < 0.05). On the other hand, injection of KCN produced no significant changes in PAP, serotonin levels, BP and respiratory parameters. After the injection of pizotifen, PAP was significantly increased in hypoxia (P < 0.01). After the injection of methysergide, the response of PAP was completely abolished during the breathing of hypoxic gas mixture. The finding of the abolition of response of PAP to hypoxia after the injection of methysergide indicates that serotonin release from NEB may be responsible for the elevation of PAP in hypoxic hypoxia.

The effect of intracerebroventricular dopamine administration on the respiratory response to hypoxia.

Acute hypoxia produces an increase in ventilation. When the hypoxia is sustained, the initial increase in ventilation is followed a decrease in ventilation. The precise mechanism of this decline in ventilation during sustained hypoxia is unknown. Recent studies hypothesized that the accumulation of dopamine in the central nervous system might have a major role in production of hypoxic respiratory depression. The purpose of this study was to examine whether dopamine has an effect on occurance of central ventilatory depression which is seen in acute hypoxia in peripheral chemoreceptors denervated animals. The experiment were conducted in rabbits anesthetized with Na-pentobarbital (25 mg x kg(-1) i.v.). For intracerebroventricular (i.c.v.) injections of dopamine (1 microg) in each animal, canula was placed in left lateral cerebral ventricle by stereotaxic method. Respiratory frequency (f x min(-1)), tidal volume (V(T)) ventilation minute volume (V(E)) and systemic arterial blood pressure (BP) were recorded during air and 3 minutes hypoxic gas mixture (8%O2-92%N2) breathing. I.c.v. administration of dopamine during normoxia decreased V(T), f, V(E) and BP, significantly. When rabbits were injected with an i.c.v. dopamine on hypoxic gas mixture breathing in control animals, there was depression of hypoxic ventilatory responses. After i.c.v. administration of dopamine antagonists haloperidol (0.1 mg) and domperidone (0.07 mg) in chemodenervated rabbits, the significant increases in V(T), V(E) and BP were observed. On the breathing of hypoxic gas mixture of chemodenervated and i.c.v. dopamine antagonists administrated rabbits, hypoxic depression was completely abolished. These results of this study show that accumulation of dopamine in the brain seems to reduce the response of the central control mechanisms to chemoreceptor impulses during normoxia and hypoxia. In conclusion present study suggests important role played by central dopaminergic pathways in the occurence of acute hypoxic ventilatory depression.