Systemic 8-OH-DPAT challenge causes hyperventilation largely via activating pre-botzinger complex 5-HT1A receptors.

Systemic 8-OH-DPAT (a 5-HT1A receptor agonist) challenge evokes hyperventilation independent of peripheral 5-HT1A receptors. Though the pre-Botzinger Complex (PBC) is critical in generating respiratory rhythm and activation of local 5-HT1A receptors induces tachypnea via disinhibition of local GABAA neurons, its role in the respiratory response to systemic 8-OH-DPAT challenge is still unclear. In anesthetized rats, 8-OH-DPAT (100 µg/kg, iv) was injected twice to confirm the reproducibility of the evoked responses. The same challenges were performed after bilateral microinjections of (S)-WAY-100135 (a 5-HT1A receptor antagonist) or gabazine (a GABAA receptor antagonist) into the PBC. Our results showed that: 1) 8-OH-DPAT caused reproducible hyperventilation associated with hypotension and bradycardia; 2) microinjections of (S)-WAY-100135 into the PBC attenuated the hyperventilation by ˜60 % without effect on the evoked hypotension and bradycardia; and 3) the same hyperventilatory attenuation was also observed after microinjections of gabazine into the PBC. Our data suggest that PBC 5-HT1A receptors play a key role in the respiratory response to systemic 8-OH-DPAT challenge likely via disinhibiting local GABAergic neurons.

Hyperventilation and Respiratory Alkalosis After Olanzapine for Insomnia: A Case Report.

Olanzapine is increasingly used as a sleep aid in hospitalized patients. Although thought to have less extrapyramidal effects, known side effects include oversedation, arrythmias, and hypotension. We present the unusual case of hyperventilation with respiratory alkalosis after the administration of olanzapine for insomnia in an elderly postoperative patient. This led to a second admission to the intensive care unit with invasive interventions including mechanical ventilation and vasopressor support. Caution must be exercised in prescribing antipsychotics for off-label use, especially in a population whose baseline characteristics can affect the pharmacokinetics of second-generation antipsychotics.

The involvement of the central cholinergic system in the hyperventilation effect of centrally injected nesfatin-1 in rats.

We recently demonstrated that peripheral and central administration of nesfatin-1 in fasting and satiety states generate hyperventilation activity by increasing tidal volume (TV), respiratory rate (RR), and respiratory minute ventilation (RVM). The present study aimed to investigate the mediation of central cholinergic receptors effective in respiratory control in the hyperventilation activity of nesfatin-1. Besides this, we intended to determine possible changes in blood gases due to hyperventilation activity caused by nesfatin-1 and investigate the mediation of central cholinergic receptors in these changes. Intracerebroventricular (ICV) administration of nesfatin-1 revealed a hyperventilation response with an increase in TV, RR, RMV, and pO2 and a decrease in pCO2 in saturated Sprague Dawley rats. ICV pretreatment with the muscarinic receptor antagonist atropine partially blocked the RR, RMV, pO2, and pCO2 responses produced by nesfatin-1 while completely blocking the TV response. However, central pretreatment with nicotinic receptor antagonist mecamylamine blocked the respiratory and blood gas responses induced by nesfatin-1. The study's conclusion demonstrated that nesfatin-1 had active hyperventilation effects resulting in an increase in pO2 and a decrease in pCO2. The critical finding of the study was that activation of central cholinergic receptors was involved in nesfatin-1-evoked hyperventilation and blood gas responses.

Ipsilateral somatic nerves mediate histamine-induced vasosensory reflex responses involving perivascular afferents in rat models.

Reflex cardiorespiratory alterations elicited after instillation of nociceptive agents intra-arterially (i.a) are termed as 'vasosensory reflex responses'. The present study was designed to evaluate such responses produced after i.a. instillation of histamine (1 mM; 10 mM; 100 mM) and to delineate the pathways i.e. the afferents and efferents mediating these responses. Blood pressure, electrocardiogram and respiratory excursions were recorded before and after injecting saline/histamine, in a local segment of femoral artery in urethane anesthetized rats. Paw edema and latencies of responses were also estimated. Separate groups of experiments were conducted to demonstrate the involvement of somatic nerves in mediating histamine-induced responses after ipsilateral femoral and sciatic nerve sectioning (+NX) and lignocaine pre-treatment (+Ligno). In addition, another set of experiments was performed after bilateral vagotomy (+VagX) and the responses after histamine instillation were studied. Histamine produced concentration-dependent hypotensive, bradycardiac, tachypnoeic and hyperventilatory responses of shorter latencies (2-7 s) favouring the neural mechanisms in eliciting the responses. Instillation of saline (time matched control) in a similar fashion produced no response, excluding the possibilities of ischemic/stretch effects. Paw edema was absent in both hind limbs indicating that the histamine did not reach the paws and did not spill out into the systemic circulation. +NX, +VagX, +Ligno attenuated histamine-induced cardiorespiratory responses significantly. These observations conclude that instillation of 10 mM of histamine produces optimal vasosensory reflex responses originating from the local vascular bed; afferents and efferents of which are mostly located in ipsilateral somatic and vagus nerves respectively.

Centrally and peripherally injected nesfatin-1-evoked respiratory responses.

Nesfatin-1, which is an anorexiogenic peptide, plays a crucial role as a neurotransmitter and/or neuromodulator in the central nervous system for cardiovascular control and energy balance etc. It is expressed abundantly in multiple brain nuclei including central respiratory control areas such as nucleus tractus solitarius, nucleus ambiguous, dorsal vagal complex, dorsal motor nucleus of the vagus nerve, and hypothalamus. To date, no previous studies have been found to report nesfatin-1-evoked respiratory effects. Therefore, the present study was designed to investigate the possible impacts of centrally and/or peripherally injected nesfatin-1 on respiratory parameters in either 12h-fasted or fed-ad libitum rats. Intracerebroventricular (ICV) administration of nesfatin-1 provoked significant hyperventilation by increasing tidal volume (TV), respiratory rate (RR) and respiratory minute ventilation (RMV) in both the 12h-fasted and the fed-ad libitum Spraque Dawley rats in dose- and time- dependent manner. Moreover, the hyperventilatory effects of centrally injected nesfatin-1 were more potent in the fed-ad libitum rats. Intravenous injection of nesfatin-1 induced a significant rise in RR and RMV, but not in TV, in the fed-ad libitum rats. In conclusion, these findings plainly report that both centrally and/or peripherally injected nesfatin-1 induces significant hyperventilatory effects in the 12h-fasted and the fed-ad libitum rats. These hyperventilatory effects of nesfatin-1 might show a discrepancy according to the food intake of the rats and the delivery method of the peptide.

An advanced recording and analysis system for the differentiation of guinea pig cough responses to citric acid and prostaglandin E2 in real time.

Cough number and/or sound have been used to assess cough sensitivity/intensity and to discriminate cough patterns in clinical settings. However, to date, only manual counting of cough number in an offline manner is applied in animal cough studies, which diminishes the efficiency of cough identification and hinders the diagnostic discrimination of cough patterns, especially in animals with pulmonary diseases. This study aims to validate a novel recording/analysis system by which cough numbers are automatically counted and cough patterns are comprehensively differentiated in real time. The experiment was carried out in conscious guinea pigs exposed to aerosolized citric acid (CA, 150 mM) and prostaglandin E2 (PGE2, 0.43 mM). Animal body posture (video), respiratory flow, and cough acoustics (audio) were simultaneously monitored and recorded. Cough number was counted automatically, and cough sound parameters including waveform, duration, power spectral density, spectrogram, and intensity, were analyzed in real time. Our results showed that CA- and PGE2-evoked coughs had the same cough numbers but completely different patterns [individual coughs vs. bout(s) of coughs]. Compared to CA-evoked coughs, PGE2-evoked coughs possess a longer latency, higher cough rate (coughs/min), shorter cough sound duration, lower cough sound intensity, and distinct cough waveforms and spectrograms. A few mucus- and wheeze-like coughs were noted in response to CA but not to PGE2. In conclusion, our recording/analysis system is capable of automatically counting the cough number and successfully differentiating the cough pattern by using valuable cough sound indexes in real time. Our system enhances the objectivity, accuracy, and efficiency of cough identification and count, improves the intensity evaluation, and offers ability for pattern discrimination compared to traditional types of cough identification. Importantly, this approach is beneficial for assessing the efficacy of putative antitussive drugs in animals without or with pulmonary diseases, particularly in cases without significant change in cough number.

Levofloxacin-associated Encephalopathy with Severe Hyperventilation.

A 64-year-old woman with no previous mental illness took a single 500 mg tablet of levofloxacin for cystitis. Two hours later, she developed psychosis with involuntary movement and severe hyperventilation with respiratory alkalosis. Cranial magnetic resonance imaging findings were unremarkable, and an electroencephalogram revealed no epileptiform discharge. Her symptoms improved on the third day after levofloxacin was discontinued. Levofloxacin-associated encephalopathy with psychotic features is a rare adverse event. Disturbance of gamma-aminobutyric acid-ergic (GABAergic) interneurons by levofloxacin may lead to hyperventilation via dysfunction of the brainstem respiratory network. Physicians should be aware of hyperventilation as an additional serious symptom of levofloxacin-associated encephalopathy in acute settings.

Respiratory dysfunction progresses with age in Kcna1-null mice, a model of sudden unexpected death in epilepsy.

OBJECTIVE: Increased breathing rate, apnea, and respiratory failure are associated with sudden unexpected death in epilepsy (SUDEP). We recently demonstrated the progressive nature of epilepsy and mortality in Kcna1-/- mice, a model of temporal lobe epilepsy and SUDEP. Here we tested the hypothesis that respiratory dysfunction progresses with age in Kcna1-/- mice, thereby increasing risk of respiratory failure and sudden death (SD). METHODS: Respiratory parameters were determined in conscious mice at baseline and following increasing doses of methacholine (MCh) using noninvasive airway mechanics (NAM) systems. Kcna1+/+ , Kcna1+/- , and Kcna1-/- littermates were assessed during 3 age ranges when up to ~30%, ~55%, and ~90% of Kcna1-/- mice have succumbed to SUDEP: postnatal day (P) 32-36, P40-46, and P48-56, respectively. Saturated arterial O2 (SaO2 ) was determined with pulse oximetry. Lung and brain tissues were isolated and Kcna1 gene and protein expression were evaluated by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blot techniques. Airway smooth muscle responsiveness was assessed in isolated trachea exposed to MCh. RESULTS: Kcna1-/- mice experienced an increase in basal respiratory drive, chronic oxygen desaturation, frequent apnea-hypopnea (A-H), an atypical breathing sequence of A-H-tachypnea-A-H, increased tidal volume, and hyperventilation induced by MCh. The MCh-provoked hyperventilation was dramatically attenuated with age. Of interest, only Kcna1-/- mice developed seizures following exposure to MCh. Seizures were provoked by lower concentrations of MCh as Kcna1-/- mice approached SD. MCh-induced seizures experienced by a subset of younger Kcna1-/- mice triggered death. Respiratory parameters of these younger Kcna1-/- mice resembled older near-SD Kcna1-/- mice. Kcna1 gene and protein were not expressed in Kcna1+/+ and Kcna1+/- lungs, and MCh-mediated airway smooth muscle contractions exhibited similar half-maximal effective concentration( EC50 ) in isolated Kcna1+/+ and Kcna1-/- trachea. SIGNIFICANCE: The Kcna1-/- model of SUDEP exhibits progressive respiratory dysfunction, which suggests a potential increased susceptibility for respiratory failure during severe seizures that may result in sudden death.

Effects of Moderate Hyperventilation on Jugular Bulb Gases under Propofol or Isoflurane Anesthesia during Supratentorial Craniotomy.

BACKGROUND: The optimal ventilated status under total intravenous or inhalation anesthesia in neurosurgical patients with a supratentorial tumor has not been ascertained. The purpose of this study was to intraoperatively compare the effects of moderate hyperventilation on the jugular bulb oxygen saturation (SjO 2 ), cerebral oxygen extraction ratio (O 2 ER), mean arterial blood pressure (MAP), and heart rate (HR) in patients with a supratentorial tumor under different anesthetic regimens. METHODS: Twenty adult patients suffered from supratentorial tumors were randomly assigned to receive a propofol infusion followed by isoflurane anesthesia after a 30-min stabilization period or isoflurane followed by propofol. The patients were randomized to one of the following two treatment sequences: hyperventilation followed by normoventilation or normoventilation followed by hyperventilation during isoflurane or propofol anesthesia, respectively. The ventilation and end-tidal CO 2 tension were maintained at a constant level for 20 min. Radial arterial and jugular bulb catheters were inserted for the blood gas sampling. At the end of each study period, we measured the change in the arterial and jugular bulb blood gases. RESULTS: The mean value of the jugular bulb oxygen saturation (SjO 2 ) significantly decreased, and the oxygen extraction ratio (O 2 ER) significantly increased under isoflurane or propofol anesthesia during hyperventilation compared with those during normoventilation (SjO 2 : t = -2.728, P = 0.011 or t = -3.504, P = 0.001; O 2 ER: t = 2.484, P = 0.020 or t = 2.892, P = 0.009). The SjO 2 significantly decreased, and the O 2 ER significantly increased under propofol anesthesia compared with those values under isoflurane anesthesia during moderate hyperventilation (SjO 2 : t = -2.769, P = 0.012; O 2 ER: t = 2.719, P = 0.013). In the study, no significant changes in the SjO 2 and the O 2 ER were observed under propofol compared with those values under isoflurane during normoventilation. CONCLUSIONS: Our results suggest that the optimal ventilated status under propofol or isoflurane anesthesia in neurosurgical patients varies. Hyperventilation under propofol anesthesia should be cautiously performed in neurosurgery to maintain an improved balance between the cerebral oxygen supply and demand.

Prenatal nicotine exposure increases hyperventilation in α4-knock-out mice during mild asphyxia.

Prenatal nicotine exposure alters breathing and ventilatory responses to stress through stimulation of nicotine acetylcholine receptors (nAChRs). We tested the hypothesis that α4-containing nAChRs are involved in mediating the effects of prenatal nicotine exposure on ventilatory and metabolic responses to intermittent mild asphyxia (MA). Using open-flow plethysmography, we measured ventilation (V̇(E)) and rate of O2 consumption ( V̇(O2)) of wild-type (WT) and α4-knock-out (KO) mice, at postnatal (P) days 1-2 and 7-8, with and without prenatal nicotine exposure (6 mg kg(-1) day(-1) beginning on embryonic day 14). Mice were exposed to seven 2 min cycles of mild asphyxia (10% O2 and 5% CO2), each interspersed with 2 min of air. Compared to WT, α4 KO mice had increased air V̇(E) and V̇(O2) at P7-8, but not P1-2. Irrespective of age, genotype had no effect on the hyperventilatory response (increase in V̇(E)/V̇(O2)) to MA. At P1-2, nicotine suppressed air V̇(E) and V̇(O2) in both genotypes but did not affect the hyperventilatory response to MA. At P7-8 nicotine suppressed air V̇(E) and V̇(O2) of only α4 KO's but also significantly enhanced V̇(E) during MA (nearly double that of WT; p<0.001). This study has revealed complex effects of α4 nAChR deficiency and prenatal nicotine exposure on ventilatory and metabolic interactions and responses to stress.

Does ammonia trigger hyperventilation in the elasmobranch, Squalus acanthias suckleyi?

We examined the ventilatory response of the spiny dogfish, to elevated internal or environmental ammonia. Sharks were injected via arterial catheters with ammonia solutions or their Na salt equivalents sufficient to increase plasma total ammonia concentration [TAmm]a by 3-5 fold from 145±21µM to 447±150µM using NH4HCO3 and a maximum of 766±100µM using (NH4)2SO4. (NH4)2SO4 caused a small increase in ventilation frequency (+14%) and a large increase in amplitude (+69%), while Na2SO4 did not. However, CO2 partial pressure (PaCO2) also increased and arterial pHa and plasma bicarbonate concentration ([HCO3(-)]a) decreased. NH4HCO3 caused a smaller increase in plasma ammonia resulting in a smaller but significant, short lived increases in ventilation frequency (+6%) and amplitude (36%), together with a rise in PaCO2 and [HCO3(-)]a. Injection with NaHCO3 which increased pHa and [HCO3(-)]a did not change ventilation. Plasma ammonia concentration correlated significantly with ventilation amplitude, while ventilation frequency showed a (negative) correlation with pHa. Exposure to high environmental ammonia (1500µM NH4HCO3) did not induce changes in ventilation until plasma [TAmm]a increased and ventilation amplitude (but not frequency) increased in parallel. We conclude that internal ammonia stimulates ventilation in spiny dogfish, especially amplitude or stroke volume, while environmental ammonia only stimulates ventilation after ammonia diffuses into the bloodstream.

The effect of centrally injected CDP-choline on respiratory system; involvement of phospholipase to thromboxane signaling pathway.

CDP-choline is an endogenous metabolite in phosphatidylcholine biosynthesis. Exogenous administration of CDP-choline has been shown to affect brain metabolism and to exhibit cardiovascular, neuroendocrine neuroprotective actions. On the other hand, little is known regarding its respiratory actions and/or central mechanism of its respiratory effect. Therefore the current study was designed to investigate the possible effects of centrally injected CDP-choline on respiratory system and the mediation of the central cholinergic receptors and phospholipase to thromboxane signaling pathway on CDP-choline-induced respiratory effects in anaesthetized rats. Intracerebroventricularly (i.c.v.) administration of CDP-choline induced dose- and time-dependent increased respiratory rates, tidal volume and minute ventilation of male anaesthetized Spraque Dawley rats. I.c.v. pretreatment with atropine failed to alter the hyperventilation responses to CDP-choline whereas mecamylamine, cholinergic nicotinic receptor antagonist, mepacrine, phospholipase A2 inhibitor, and neomycin phospholipase C inhibitor, blocked completely the hyperventilation induced by CDP-choline. In addition, central pretreatment with furegrelate, thromboxane A2 synthesis inhibitor, also partially blocked CDP-choline-evoked hyperventilation effects. These data show that centrally administered CDP-choline induces hyperventilation which is mediated by activation of central nicotinic receptors and phospholipase to thromboxane signaling pathway.

Inhibitory effects of hyperoxia and methemoglobinemia on H(2)S induced ventilatory stimulation in the rat.

The aim of this study was to clarify, using in vitro and in vivo approaches in the rat, the site of mediation of the inhibition of H(2)S induced arterial chemoreceptor stimulation, by hyperoxia and methemoglobinemia. We first determined the ventilatory dose-response curves during intravenous injections of H(2)S. A very high dose of NaHS, i.e. 0.4 µmol (concentration: 800 µM), was needed to stimulate breathing within 1s following i.v. injection. Above this level (and up to 2.4 µmol, with a concentration of 4800 µM), a dose-dependent effect of H(2)S injection was observed. NaHS injection into the thoracic aorta produced the same effect, suggesting that within one circulatory time, H(2)S pulmonary exchange does not dramatically reduce H(2)S concentrations in the arterial blood. The ventilatory response to H(2)S was abolished in the presence of MetHb (12.8%) and was significantly depressed in hyperoxia and, surprisingly, in 10% hypoxia. MetHb per se did not affect the ventilatory response to hypoxia or hyperoxia, but dramatically enhanced the oxidation of H(2)S in vitro, with very fast kinetics. These findings suggest that, the decrease/oxidation of exogenous H(2)S in the blood is the primary effect of MetHb in vivo. In contrast, the in vitro oxidative properties of blood for H(2)S were not affected by the level of [Formula: see text] between 23 and >760 mmHg. This suggests that the inhibition of the ventilatory response to H(2)S by hyperoxia during aortic or venous injection originates within the CB and not in the blood. The implications of these results on the role of endogenous H(2)S in the arterial chemoreflex are discussed.

Influence of CO2 on upper airway muscles and chest wall/diaphragm corticomotor responses assessed by transcranial magnetic stimulation in awake healthy subjects.

RATIONALE: Functional interaction between upper airway (UA) dilator muscles and the diaphragm is crucial in the maintenance of UA patency. This interaction could be altered by increasing respiratory drive. The aim of our study was to compare the effects of hypercapnic stimulation on diaphragm and genioglossus corticomotor responses to transcranial magnetic stimulation (TMS). METHODS: 10 self-reported healthy men (32 ± 9 yr; body mass index = 24 ± 3 kg/m(-2)) breathed, in random order, room air or 5% and then 7% Fi(CO(2)), both balanced with pure O(2). Assessments included ventilatory variables, isoflow UA resistance (at 300 ml/s), measurement of lower chest wall/diaphragm (LCW/diaphragm), and genioglossus motor threshold (MT) and motor-evoked potential (MEP) characteristics. TMS twitches were applied during early inspiration and end expiration at stimulation intensity 30% above LCW/diaphragm and genioglossus MT. RESULTS: Compared with room air, CO(2) inhalation significantly augmented minute ventilation, maximal inspiratory flow, tidal volume, and tidal volume/respiratory time ratio. UA resistance was unchanged with CO(2) inhalation. During 7% CO(2) breathing, LCW/diaphragm MT decreased by 9.6 ± 10.1% whereas genioglossus MT increased by 7.2 ± 9%. CO(2)-induced ventilatory stimulation led to elevation of LCW/diaphragm MEP amplitudes during inspiration but not during expiration. LCW/diaphragm MEP latencies remained unaltered both during inspiration and expiration. Genioglossus MEP latencies and amplitudes were unchanged with CO(2). CONCLUSION: In awake, healthy subjects, CO(2)-induced hyperventilation is associated with heightened LCW/diaphragm corticomotor activation without modulating genioglossus MEP responses. This imbalance may promote UA instability during increased respiratory drive.

Quetiapine-induced hyperventilation and dyspnea.

OBJECTIVES: Quetiapine is an atypical antipsychotic with favorable properties in the treatment of bipolar disorder, but it has recently been associated with respiratory dysfunction. METHODS: In this case report, we describe a patient who developed quetiapine-induced hyperventilation and dyspnea after being treated with quetiapine. RESULTS: To our knowledge, this is the first case presented with quetiapine-induced hyperventilation in a patient with bipolar disorder. CONCLUSIONS: We recommend a quick reduction of the quetiapine dosage and a change to an alternative antipsychotic for patients treated with quetiapine, who report such respiratory symptoms without a somatic cause for the symptoms.

A 19-month-old boy with recurrent respiratory distress.

We present a 19-month-old boy with a history of asthma who presented to the pediatric emergency department with noisy breathing and tachypnea partially responsive to albuterol. He was discharged to routine care at home. His parents brought him back the next day for persistent respiratory distress despite routine home albuterol. A check of electrolytes showed a low bicarbonate level.

Intraoperative hyperventilation vs remifentanil during electrocorticography for epilepsy surgery - a case report.

BACKGROUND: Traditionally, intraoperative intracranial electroen-cephalography-recordings are limited to the detection of the irritative zone defined by interictal spikes. However, seizure patterns revealing the seizure onset zone are thought to give better localizing information, but are impractical due to the waiting time for spontaneous seizures. Therefore, provocation by seizure precipitants may be used with the precaution that spontaneous and provoked seizures may not be identical. OBJECTIVE: We present evidence that hyperventilation induced and drug induced focal seizures may arise from different brain regions in the same patient. METHODS: Hyperventilation and ultra short acting opioid remifentanil were used separately as intraoperative precipitatants of seizure patterns, while recording from subdural and intraventricular electrodes in a patient with temporal lobe epilepsy. Two different ictal onset zones appeared in response to hyperventilation and remifentanil. Both zones were resected and the patient has remained essentially seizure free for 1 year. Furthermore, this is the first description of hyperventilation used as an intraoperative seizure precipitant in human focal epilepsy.

[Isocapnic hyperpnea--new method of treatment in clinical toxicology?]. / Hiperwentylacja z izokapnia--nowa metoda terapii w toksykologii klinicznej?

We presented the method of treatment of acute poisoning with some substances which is based on izocapnic hyperpnea. It seems that this method may be useful in the treatment of poisoning with various xenobiotics.

Respiratory safety pharmacology: positive control drug responses in Sprague-Dawley rats, Beagle dogs and cynomolgus monkeys.

Rats are most frequently used to fulfill ICH S7A requirements for respiratory safety pharmacology. We hypothesized that the models used to assess respiratory safety pharmacology present different ventilatory responses to bronchoconstriction, bronchodilation and respiratory depression. Respiratory monitoring was performed with head-out plethysmographs for rats, masks for dogs and bias airflow helmets for monkeys. Respiratory rate (RR), tidal volume (TV) and minute volume (MV) were recorded. Forty rats, 18 dogs and 8 monkeys were acclimated to the respiratory monitoring equipment. Animals received saline (IV), albuterol (inhalation), methacholine (IV) and remifentanil (IV). Albuterol increased TV in all species. Methacholine decreased TV and MV in monkeys. In dogs, methacholine increased TV, RR and MV. In rats, methacholine increased TV and decreased RR. Remifentanil induced central respiratory depression in all species with decreased MV, except in rats. Dogs presented a biphasic response to remifentanil with hypoventilation followed by delayed hyperventilation. The monkeys presented similar responses to humans which may be due to biologic similarities. Dogs and rats presented clinically significant ventilatory alterations following positive control drugs. Although, the response to bronchoconstriction in dogs and rats was different from humans, the two species presented ventilatory changes that highlight the potential adverse effect of test articles.