Apnea In Rats Research Articles

Hemoglobin Vesicles prolong the time to circulatory collapse in rats during apnea

BackgroundHemoglobin vesicles (HbV) are hemoglobin-based oxygen carriers manufactured by liposome encapsulation of hemoglobin molecules. We hypothesised that the infusion of oxygenated HbV could prolong the time to circulatory collapse during apnea in rats.MethodsTwenty-four Sprague-Dawley rats were randomly divided into four groups (Air, Oxy, NS and HbV). The rats were anaesthetized with isoflurane and the trachea was intubated using 14-gauge intravenous catheters. Rats in the Air group were mechanically ventilated with 1.5% isoflurane in room air, and those in other groups received 1.5% isoflurane in 100% oxygen. Mechanical ventilation was withdrawn 1 min after the administration of rocuronium bromide to induce apnea. After 30 s, 6 mL saline and HbV boluses were infused at a rate of 0.1 mL/s in the NS and HbV groups, respectively. Circulatory collapse was defined as a pulse pressure < 20 mmHg and the time to reach this point (PP20) was compared between the groups. The results were analysed via a one-way analysis of variance and post-hoc Holm–Sidak test.ResultsPP20 times were 30.4 ± 4.2 s, 67.5 ± 9.7 s, 95 ± 17.3 s and 135 ± 38.2 s for the Air (ventilated in room air with no fluid bolus), Oxy (ventilated with 100% oxygen with no fluid bolus), NS (ventilated with 100% oxygen with a normal saline bolus), and HbV (ventilated in 100% oxygen with an HbV bolus) groups, respectively, and differed significantly between the four groups (P = 0.0001). The PP20 times in the HbV group were significantly greater than in the Air (P = 0.0001), Oxy (P = 0.007) and NS (P = 0.04) groups.ConclusionInfusion of oxygenated HbV prolongs the time to circulatory collapse during apnea in rats.

Role of the peripheral chemoreceptor reflex on cardiovascular and sympathetic responses to obstructive sleep apnea in rats

The potential contribution of peripheral chemoreceptors to the responses of systemic arterial pressure, heart rate, and sympathetic nerve activity (SNA) to obstructive sleep apnea was studied. Male Wistar rats had a tracheal balloon inserted to allow induction of apnea, with electrodes for measurement of renal SNA (RSNA) and lumbar SNA (LSNA), and a catheter for measurement of systemic arterial pressure. Electroencephalogram, electromyogram, and electrocardiogram records were also obtained. The tracheal balloon was inflated for 40 seconds during non‐rapid eye movement sleep. Systemic arterial pressure, RSNA, and LSNA increased after onset of tracheal balloon inflation while heart rate decreased. Bilateral carotid body section significantly attenuated the magnitude of the decrease in heart rate observed in intact rats, but had only minor effects on the responses of systemic arterial pressure, RSNA, and LSNA to obstructive sleep apnea. These data suggest that peripheral chemoreceptors may play a critical role in bradycardia in response to obstructive sleep apnea, and a minor role in the increases in systemic arterial pressure, RSNA, and LSNA in conscious rats. JSPS Grant.

The lateral habenular nucleus mediates signal transduction from the insular cortex in OSA rats

The insular cortex (Ic) and habenular nuclei (Hb) of the limbic system are associated with human and animal dyspnea by regulating 5-hydroxytryptamine (5-HT) release in the raphe nuclei (RN). However, the Hb are composed of the medial habenular nucleus (MHb) and the lateral habenular nucleus (LHb). Therefore, it is still unclear whether the Ic signal is conducted through the MHb or LHb. This study aimed to investigate the role of the Hb and Ic in obstructive sleep apnea syndrome (OSA) and the functional relationship between these two structures. We monitored multiple indicators, including the respiration movement curve, neuronal activity in the MHb and LHb, and arterial blood gas, when stimulating the anterior Ic of Wistar rats. We compared the results with the control group (stimulating the surrounding cortex). Electrical stimulation of the Ic in the rat brain caused respiratory disturbances, apnea, reduced blood pH, and aggravated base deficit (more negative base excess value) compared to control animals (p < 0.05). It also reduced the spontaneous firing of the MHb neurons but increased that of the LHb neurons. Electrical stimulation of the Ic induces apnea in rats in a similar manner to human OSA. The Ic and the Hb are functionally linked. Stimulation of the Ic inhibits the MHb, but activates the LHb. It induces OSA-like symptoms by enhancing LHb-mediated inhibition of the RN. This study illustrates the mechanism by which an animal model of OSA is created by stimulating the Ic and promotes understanding of OSA pathogenesis.

Sympathetic nerve activity and systemic arterial pressure during obstructive sleep apnea in conscious rats

This study investigated sympathetic nerve activity responses in obstructive sleep apnea. Wistar male rats were chronically instrumented for measurements of renal (RSNA) and lumbar (LSNA) sympathetic nerve activity, as well as for an electroencephalogram, electromyogram, and electrocardiogram and systemic arterial pressure, and with a tracheal balloon for induction of apnea. At least 3 days after the surgery, rats were subjected to sleep apnea by inflating the tracheal balloon for 40 seconds during non‐rapid eye movement sleep. RSNA and LSNA increased immediately after the onset of tracheal balloon inflation and by approximately 3 – 4 fold compared with those at pre‐inflation levels. Heart rate decreased in a biphasic manner; it began to fall gradually during the initial several seconds and then it fell abruptly by approximately 200 beats/min. Systemic arterial pressure increased because of the tracheal balloon inflation. We conclude that sympathetic nerve activity plays a critical role in increasing systemic arterial pressure during obstructive sleep apnea in rats. JSPS Grant.

Injection of l-glutamate into the insular cortex produces sleep apnea and serotonin reduction in rats

Obstructive sleep apnea (OSA) is primarily characterized by repetitive episodes of complete or partial obstruction of airflow during sleep. The neuronal and cellular mechanisms underlying this process are not fully understood, although the focus of some studies is on putative serotonin (5-HT) mechanisms, and serotonergic therapy may be beneficial to OSA patients. This study aimed to demonstrate possible changes in 5-HT associated with induction of OSA in a rat model. Apnea was induced in rats by injection of L-glutamate (L-Glu) into the insular cortex. We examined changes in: (1) simultaneous genioglossus and diaphragm EMG activity; and (2) peripheral and cerebral levels of 5-HT, by histology. Injection of L-glutamate (L-Glu) into the insular cortex induced apnea in the rats. L-Glu stimulation of the insular cortex also produced significant reductions in plasma 5-HT levels and the expression of 5-HT in the brainstem. In addition, lower activity was observed in the GG and a higher activity was observed in the diaphragm, as compared to controls. Data indicate that L-Glu stimulation of the insular cortex simulates the electrical activity of the genioglossus muscle and diaphragm in sleep apnea, and contributes to reduced peripheral and cerebral 5-HT levels in rats. The results of our study suggest that 5-HT may play a role in the pathogenesis of OSA.

The role of respiratory effort and peripheral chemoreceptors in cardiovascular responses induced by obstructive apnea in rats

Background/aims: Apnea in awake rats induces a pressor response and intense bradycardia. These responses do not depend on carotid chemoreceptors. We studied the mechanisms involved in these responses in decerebrated rats, which, unlike anesthetized rats, show responses to apnea similar to those seen in awake rats.

Age dependent changes in A 2A receptor expression in PreBotzinger Complex

Adenosine is a modulator of respiratory output, and can both increase and decrease respiratory frequency in an age and receptor dependent manner. We have shown an in vivo, age dependent, effect of A2A receptor activation on apneas in rats which is attenuated from postnatal day (P)14 to P21 through adulthood. We hypothesized that the attenuated response to A2A activation was due to decreased A2A receptor expression in the PreBötzinger complex (pBc). To test this hypothesis, we used unbiased stereology to quantify changes in A2A expression in pBc over the first three weeks of life. Sprague Dawley rat pups were perfused at P0, 4, 7, 14, and 21. The brains were cryosectioned and 4 identical sets of slides made from each brain. These slides were immunostained for NK-1R and somatostatin to deliniate the pBc. The remaining slides were stained with A2A, NeuN or S100β antibodies. The number of immunopositive cells in the pBc and the pBc volume were quantified using unbiased stereology (n=5 for each antibody at each age). The number of cells immunopositive for A2A per 1X105μm3 of pBc decreased significantly between P0 and P7 (p < 0.006), and rose again by P21 (P < 0.2). The number of NeuN and S100β immunopositive cells per 1X105μm3 decreased significantly between P0 and P21 (p < 0.001 for both). We conclude that A2A expression changes with age, but these changes are not correlated with the pattern of A2A dependent apneas seen in vivo.

Habituation without NMDA Receptor-Dependent Desensitization of Hering–Breuer Apnea Reflex in a Mecp2+/− Mutant Mouse Model of Rett Syndrome

Non-associative learning is a basic neuroadaptive behavior exhibited in almost all animal species and sensory modalities but its functions and mechanisms in the mammalian brain are poorly understood. Previous studies have identified two distinct forms of non-associative learning in the classic Hering–Breuer inflation reflex (HBIR) induced apnea in rats: NMDA receptor (NMDAR)-independent habituation in a primary vagal pathway and NMDAR-dependent desensitization in a secondary pontine pathway. Here, we show that abnormal non-associative learning of the HBIR may underlie the endophenotypic tachypnea in an animal model of Rett syndrome (RTT), an autism-spectrum disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2). Mecp2+/− symptomatic mice on a mixed-strain background demonstrated significantly increased resting respiratory frequency with shortened expiration and normal inspiratory duration compared with asymptomatic mutants and wild-type controls, a phenotype that is characteristic of girls with RTT. Low-intensity electrical stimulation of the vagus nerve elicited fictive HBIR with time-dependent habituation in both Mecp2+/− and wild-type mice. However, time-dependent desensitization of the HBIR was evidenced only in wild-type controls and asymptomatic mutant mice but was absent or suppressed in Mecp2+/− symptomatic mice or in wild-type mice after blockade of NMDAR with dizocilpine. Remarkably, ∼50% of the Mecp2+/− mice developed these X-linked phenotypes despite somatic mosaicism. Such RTT-like respiratory endophenotypes in mixed-strain Mecp2+/− mice differed from those previously reported in Mecp2-/y mice on pure C57BL/6J background. These findings provide the first evidence indicating that impaired NMDAR-dependent desensitization of the HBIR may contribute to the endophenotypic tachypnea in RTT.

Ampakine CX717 Protects against Fentanyl-induced Respiratory Depression and Lethal Apnea in Rats

The use of fentanyl as a potent analgesic is contradicted by marked respiratory depression among a subpopulation of patients. The commonly used approach of reversing fentanyl-induced respiratory depression with mu-opiate receptor antagonists such as naloxone has the undesirable effect of blocking analgesia. Here, the authors report a clinically feasible pharmacological solution for countering fentanyl-induced respiratory depression via a mechanism that does not interfere with analgesia. Specifically, to determine if the ampakine CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from severe fentanyl-induced apnea. Plethsymographic recordings were performed from young and adult rats. Varying doses of fentanyl were administered either intraperitoneally or intravenously to induce moderate to life-threatening apneas. CX717 was administered either before or after fentanyl administration. In addition, phrenic nerve recordings were performed from in situ working heart brainstem preparations from juvenile rats. Preadministration of CX717 markedly attenuated fentanyl-induced respiratory depression. Postadministration of CX717 rescued animals from a lethal dose of fentanyl. Significantly, CX717 countered fentanyl-induced depression of respiratory frequency without suppressing analgesia. The effective dose of CX717 was in the range deemed safe on the basis of clinical trials examining its efficacy for cognitive disorders. In situ, fentanyl-induced depression in respiratory frequency and amplitude was alleviated by CX717. CX717 is an agent that enhances the safety of using opiate drugs while preserving the analgesic effects. This advancement could significantly improve pain management in a variety of clinical settings.

Influence of renal denervation on blood pressure, sodium and water excretion in acute total obstructive apnea in rats

Obstructive apnea (OA) can exert significant effects on renal sympathetic nerve activity (RSNA) and hemodynamic parameters. The present study focuses on the modulatory actions of RSNA on OA-induced sodium and water retention. The experiments were performed in renal-denervated rats (D; N = 9), which were compared to sham (S; N = 9) rats. Mean arterial pressure (MAP) and heart rate (HR) were assessed via an intrafemoral catheter. A catheter was inserted into the bladder for urinary measurements. OA episodes were induced via occlusion of the catheter inserted into the trachea. After an equilibration period, OA was induced for 20 s every 2 min and the changes in urine, MAP, HR and RSNA were recorded. Renal denervation did not alter resting MAP (S: 113 +/- 4 vs D: 115 +/- 4 mmHg) or HR (S: 340 +/- 12 vs D: 368 +/- 11 bpm). An OA episode resulted in decreased HR and MAP in both groups, but D rats showed exacerbated hypotension and attenuated bradycardia (S: -12 +/- 1 mmHg and -16 +/- 2 bpm vs D: -16 +/- 1 mmHg and 9 +/- 2 bpm; P < 0.01). The basal urinary parameters did not change during or after OA in S rats. However, D rats showed significant increases both during and after OA. Renal sympathetic nerve activity in S rats increased (34 +/- 9%) during apnea episodes. These results indicate that renal denervation induces elevations of sodium content and urine volume and alters bradycardia and hypotension patterns during total OA in unconscious rats.

Expression of TASK-1 in brainstem and the occurrence of central sleep apnea in rats

Recent studies revealed that unstable ventilation control is one of mechanisms underlying the occurrence of sleep apnea. Thus, we investigated whether TASK-1, an acid-sensitive potassium channel, plays a role in the occurrence of sleep apnea. First, the expression of TASK-1 transcriptions on brainstem was checked by in situ hybridization. Then, the correlation between the central apneic episodes and protein contents of TASK-1 measured by western blot was analyzed from 27 male rats. Results showed that TASK-1 mRNAs were widely distributed on the putative central chemoreceptors such as locus coeruleus, nucleus tractus solitarius and medullary raphe, etc. Both the total spontaneous apnea index (TSAI) and spontaneous apnea index in NREM sleep (NSAI) were positively correlated with TASK-1 protein contents (r=0.547 and 0.601, respectively, p<0.01). However, the post-sigh sleep apnea index (PAI) had no relationship with TASK-1 protein. Thus, we concluded that TASK-1 channels may function as central chemoreceptors that play a role in spontaneous sleep apneas in rats.

Influence of adenosine A1-receptor blockade and vagotomy on the gasping and heart rate response to hypoxia in rats during early postnatal maturation

Failure to autoresuscitate from apnea has been suggested to play a role in sudden infant death. Little is known, however, about factors that influence the gasping and heart rate response to severe hypoxia that are fundamental to successful autoresuscitation in the newborn. The present experiments were carried out on 184 rat pups to investigate the influence of the parasympathetic nervous system, as well as adenosine, in mediating the profound bradycardia that occurs with the onset of hypoxic-induced primary apnea and in modulating hypoxic gasping. On days 1 to 2, days 5 to 6, and days 10 to 11 postpartum and following bilateral cervical vagotomy (VAG) or administration of a selective adenosine A(1) receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine; DPCPX), each pup was exposed to a single period of severe hypoxia produced by breathing an anoxic gas mixture (97% N(2)-3% CO(2)). Exposure to severe hypoxia resulted in an age-dependent decrease in heart rate (P < 0.001), accentuated with increasing postnatal age, that was attenuated in all age groups by DPCPX but not by VAG. Furthermore, DPCPX but not VAG decreased the time to last gasp but increased the total number of gasps in the 1- to 2-day-old and 5- to 6-day-old pups but not in the 10- to 11-day-old pups during exposure to severe hypoxia. Thus our data provide evidence that adenosine acting via adenosine A(1) receptors plays a role in modulating hypoxic gasping and in mediating the profound bradycardia that occurs coincident with hypoxic-induced primary apnea in rats during early postnatal life.

Effects of intertrigeminal region NMDA and non-NMDA receptors on respiratory responses in rats

Respiratory disturbance, including apnea, can be induced by microinjection of glutamate into the intertrigeminal region (ITR) of the lateral pons, a region that is anatomically coupled to both the dorsal and ventral respiratory groups of the medulla. We showed that the ITR plays a functional role in regulating both vagal reflex apnea and spontaneous sleep-related apnea in rats, but the mechanisms have not been determined. This study shows that functional NMDA receptors are expressed in the ITR since the blockade of these receptors by AP5, a specific NMDA receptor antagonist, was fully effective in blocking apnea induced by glutamate injection within this region. Selective blockade of ITR NMDA receptors had no effect on the immediate apnea evoked by an intravenous 5-HT bolus, whereas the nonspecific glutamate receptor antagonist kynurenic acid significantly increased the duration of this vagal reflex apnea. These findings are of interest because pontine NMDA receptors participate in inspiratory off-switch mechanisms and have been implicated in various short- and long-term potentiation and depression phenomena. These data support the involvement of ITR non-NMDA receptors in modulation of reflex apnea per se, whereas NMDA receptors play a role in damping respiratory responses to transient disturbances.

Time course of cardiovascular neural regulation during programmed 20-sec apnea in rats

Long-term hypoxia results in hemodynamic breakdown in patients in the intensive care unit; however, intermittent hypoxia causes hypertension in individuals with sleep apnea. The objective of this study was to explore the sequential cardiovascular neural alterations in response to acute hypoxic apnea. The authors conducted a prospective, randomized animal study. The study was conducted in a university animal laboratory. A programmable apnea model was developed in anesthetized rats, in which a 20-sec period of apnea was produced and subsequently divided into the early (2.0 to 7.9 secs), middle (8.0 to 13.9 secs), and late apneic phases (14.0 to 19.9 secs) and immediate reventilatory phase (20.0 to 25.9 secs). Evident hypoxia developed during 20-sec apnea. Arterial pressure increased in the early apneic phase and returned to control level in the middle phase. Significant hypotension developed in the late apneic phase and deteriorated in the reventilatory phase. Interbeat interval increased mildly along the apneic event. The increase of pressure in the early and middle phases was inhibited by propranolol (1.0 mg/kg intravenously [iv]) but was provoked by phentolamine (2.5 mg/kg iv). The decrease of pressure in the late and reventilatory phases was reversed, at least in part, by phentolamine. Atropine (0.5 mg/kg iv) did not produce discernible effects in the arterial pressure. The increase of interbeat interval was suppressed by propranolol. Power spectral analysis of arterial pressure variability demonstrated significant increases of the low-frequency (sympathetic vasomotor activity) and normalized high-frequency (cardiac sympathetic modulation) power after reventilation. Although the sympathetic activity is excited during and after a hypoxic apnea, the immediate pressor effect is related to an inotropic response of cardiac sympathetic regulation, whereas the negative chronotropic and subsequent depressor effect is associated with a failure in the cardiovascular response to sympathetic excitation.

Effect of high-fat diet and metformin treatment on ventilation and sleep apnea in non-obese rats

We investigated the effect of insulin resistance on ventilation and the incidence of sleep apnea in non-obese rats and determined whether metformin could change ventilation and occurrence of sleep apneas. Five groups of rats were studied: (1) standard chow; (2) high-fat groups, with 1 with metformin; (2) had type 2 diabetes induced by streptozotocin, with 1 with metformin. Compared to standard rats, ventilatory parameters remained unchanged in the high-fat fed diet as well as in diabetic rats. However, their oxygen consumption was reduced (p<or=0.01). They had a lower ventilatory response to CO2 challenge (p<or=0.01), and their sleep apnea scores increased markedly (p<or=0.001). These results suggest that insulin resistance could impair the ventilation control. Metformin treatment, known to reduce insulin resistance, got sleep apnea scores back to their basic levels, reinforcing the idea that insulin resistance is a major factor in the occurrence of apneas in this rat model.

Augmented Endothelin Vasoconstriction in Intermittent Hypoxia-Induced Hypertension

We reported previously that simulating sleep apnea in rats by exposing them 7 hours per day to intermittent hypoxia/hypercapnia (IH) elevates plasma endothelin-1 and causes hypertension, which is reversed by an endothelin-1 antagonist. We hypothesized that in this model of sleep apnea-induced hypertension, vascular sensitivity to endothelin-1 is increased in combination with the elevated plasma endothelin-1 to cause the endothelin-1-dependent hypertension. In small mesenteric arteries with endothelial function disabled by passing air through the lumen, diameter and vessel wall [Ca2+] were recorded simultaneously. IH arteries demonstrated increased constrictor sensitivity to endothelin-1 (percentage max constriction 100+/-0% IH versus 80+/-10% Sham; P<0.05). This was accompanied by increased calcium sensitivity of IH arteries. In contrast, constrictor sensitivity and increases in vessel wall [Ca2+] to KCl and phenylephrine were not different between IH and Sham arteries. We have shown previously that endothelin-1 constriction in mesenteric arteries is mediated by endothelin A receptors. In the current study, the selective increase in endothelin-1 constriction in IH resistance arteries was accompanied by increased expression of endothelin A receptor expression (densitometry units 271+/-23 IH versus 158+/-25 Sham; P<0.05). Thus, IH hypertension appears to cause alterations in signaling components unique to endothelin-1 at the receptor level and in postreceptor signaling that increases calcium sensitivity during endothelin A activation. Future studies will determine the specific changes in vascular smooth muscle signaling in IH hypertension causing this augmented contractile phenotype.

Modulation of reflex and sleep related apnea by pedunculopontine tegmental and intertrigeminal neurons

We describe and summarize here our recent findings about the role in respiration of two pontine structures that are not classically included in the pontine respiratory group: the pedunculopontine tegmental nucleus (PPT) and the intertrigeminal region (ITR). We also discuss significant contributions of other workers in the field, especially, S. Datta [Cell. Mol. Neurobiol. 17: 341-365, 1997], R. Lydic and H. Baghdoyan [Sleep, 25: 617-622, 2002], and N. Chamberlin and C. Saper [J. Neurosci. 18: 6048-6056, 1998], who postulated a role for the ITR in modulating reflex apnea. In anesthetized and freely moving rats we have consistently documented that PPT and ITR have a role in respiration. Neurochemical manipulations of each area affected the brainstem respiratory pattern generator and respiratory pattern variability,observed as spontaneous disturbances during sleep or as induced reflex apnea. Although the exact central mechanisms of apnea cannot be determined from our studies to date, we postulate that reflex and sleep-related apneas in rats share some common brainstem pathways, which may include PPT and ITR.

C-fiber activation exacerbates sleep-disordered breathing in rats.

We reported previously that activation of vagal feedback by protoveratrines or serotonin exacerbates sleep apnea in rats, but each of these agents activates multiple afferent fiber types. To elucidate the specific impact of C-fiber activity on sleep apnea, the present study utilized capsaicin (CAP), which stimulates C-fibers via the CAP receptor. Nine adult Sprague-Dawley rats were instrumented for chronic polysomnography and recorded for 6 hours on four occasions. Prior to each recording, the animals received an intraperitoneal injection of either saline (control), or CAP 0.1, 1.0, or 10.0 mg/kg. Respiration was monitored by single-chamber plethysmography and apneas were scored as breaths longer than 2.5 seconds not preceded by a sigh. CAP increased apneas during non-rapid eye movement (NREM) sleep (p < 0.05 vs control) and reduced respiratory minute ventilation by about 15% in all behavioral states (waking, NREM, and REM sleep). We conclude that selective pharmacological activation of C-fibers produces a diathesis of sleep-disordered breathing specific to NREM sleep in rats.

Effect of anesthesia on CBF, MAP and fMRI-BOLD signal in response to apnea

Systemic effects of anesthesia on the dynamics of the apnea-induced Blood Oxygen Level Dependent (BOLD) signal is still not clear. In the present study, the dynamics of the fMRI-BOLD signal and blood flow using laser Doppler flowmetry (LDF) was studied in rats in response to apnea. Two anesthetics namely pentobarbital and urethane, hypothesized to have distinct effects on the mean arterial blood pressure (MAP) were used. During normoxic baseline conditions, MAP decreased in response to apnea in rats anesthetized with pentobarbital but increased with urethane. However, MAP did not change significantly in response to apnea during hyperoxic or hypercapnic baseline conditions with both anesthetics. LDF increased in response to apnea during normoxia, hyperoxia or hypercapnia and was influenced by MAP during normoxia. Apnea-induced BOLD signal dynamics was similar with both anesthetics, dominated by an alteration in arterial blood oxygenation and independent of changes in MAP. Our results suggest that anesthesia-dependent MAP change modulates the apnea-induced cerebral blood flow (CBF) response but has a minimal effect on the fMRI-BOLD signal probably due to uncoupling of CBF and oxygen consumption.

Pontine intertrigeminal region attenuates sleep apneas in rats.

To determine whether the pontine intertrigeminal region (ITR), with recently described anatomic connections and an effect on vagally induced reflex apnea, has an impact on spontaneous sleep apneas in rats. Respiration, electroencephalogram (EEG), and electromyogram (EMG) were recorded in rats with lesions of the pontine ITR and in control animals. 9 adult male Sprague-Dawley rats. Rats were implanted with EEG and EMG electrodes and were polygraphically recorded for 6 hours, and their respiration was monitored by placing each animal inside a single-chamber plethysmograph. Subsequently, a respiratory-related intertrigeminal site was identified by probing on dorsoventral tracks with 2 to 5 nL glutamate (10 nL, 10 mmol) injections from a multibarrel glass pipette. This site was then lesioned by injecting ibotenic acid (10 nL, 50 mmol) from a second pipette barrel. Animals were again recorded for 6 hours on days 2, 7, and 14 after the lesion. ITR lesions exerted no impact on mean respiratory pattern during any sleep-wake state, compared to baseline recordings. In contrast, apnea frequency during non-rapid eye movement sleep increased following ITR lesion, more than doubling by day 14. This study demonstrates that a small and well-localized unilateral lesion of the ITR region in the lateral pons can increase sleep apnea expression in freely moving rats over a 2-week period. The present findings are in agreement with the general modulatory role of pontine structures in activities including respiration, heart rate, and regulation of blood pressure.