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Obstructive apnea due to laryngospasm during seizures, but not central apnea, causes hypoxic cardiac derangements in rats
Abstracts / Autonomic Neuroscience: Basic and Clinical 192 (2015) 56–141
vs. 70 ± 4 cm/s; p b 0.05). During hypercapnia cerebral blood flow velocity was lower in older adults compared with young adults (79 ± 8 vs. 96 ± 6 cm/s; p b 0.05). MAP was not different between groups at baseline (96 ± 4 mmHg in young vs. 103 ± 3 mmHg in older; p N 0.05), however MAP was higher in older adults compared with young adults (110 ± 3 vs.101 ± 3 mmHg; p b 0.05). MSNA was higher in older adults compared with young adults at baseline (28 ± 4 vs.16 ± 1 bursts/min; p b 0.01) and during hypercapnia (31 ± 4 vs. 20 ± 2 bursts/min; p b 0.01). However, the percent increase in MSNA during hypercapnia was not different between groups (24 ± 6% in young vs. 20 ± 9% in older adults; p N 0.05). Additionally, there were no correlations between cerebral blood flow velocity or MAP responses and sympathetic activation during hypercapnia (p N 0.05 for all). Taken together, these results suggest that hypercapnia-induced sympathoexcitation is not altered with advancing age. Funding: NIH grant HL118154. doi:10.1016/j.autneu.2015.07.043
P4.5 Obstructive apnea due to laryngospasm during seizures, but not central apnea, causes hypoxic cardiac derangements in rats K. Nakase, R. Kollmar, K. Sundaram, J. Silverman, R. Orman, M. Stewart Departments of Physiology & Pharmacology, Cell Biology, Otolaryngology, and Neurology, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY,USA Sudden Unexplained Death in Epilepsy (SUDEP) accounts for up to 17% of deaths in epileptic persons where disturbances of cardiovascular and respiratory function are almost certainly the link between seizure activity and death. With our urethane/kainate rat model, which uses the glutamate receptor agonist, kainic acid, as a convulsant in rats anesthetized with urethane, we are able to monitor invasively and non-invasively systemic physiology DURING seizures. Rats were studied in a plethysmogragh with simultaneous continuous recordings of ECG, EEG, and video laryngoscopy. Periods of central apnea, determined by abrupt cessation of breathing at the end of expiration for periods up to 20 seconds and video evidence of an open airway, occurred in all groups with similar incidence, including animals that were intubated. Obstructive apnea, determined by progressive decreases in tidal volume until flow stopped and video evidence of a closed glottis, was associated with hypoxic cardiac derangements as evidenced by ST segment elevation and progressive bradyarrhythmia, ending in death in 8/9 animals. We conclude that severe laryngospasm represents a likely contributor to the seizure and hypoxemia-induced conditions that result in death. doi:10.1016/j.autneu.2015.07.044
P4.6 Antioxidant treatment with N-acetyl cysteine reduced the hypertension induced by intermittent hypoxia in a rat model of obstructive sleep apnoea R. Iturriagaa, B. Krauseb, P. Casanellob, R. Del Rioc a Lab. Neurobiology, Faculty of Biological Sciences b Division of Obstetrics & Gynaecology and Division of Paediatrics, Faculty of Medicine, Pontificia Universidad Católica de Chile c Lab Cardiorespiratory Control, Universidad Autónoma de Chile, Santiago, Chile Background/Aims: Chronic intermittent hypoxia (CIH), a main feature of obstructive sleep apnoea (OSA) led to endothelial
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dysfunction and hypertension. Sympathetic hyperactivation due to an enhanced carotid body (CB) drive produced by oxidative stress has been associated to hypertension. Administration of antioxidants prevents the enhanced CB discharges and the hypertension. We tested if oxidative stress is involved in the endothelial dysfunction and hypertension in rats exposed to CIH. Accordingly, we studied if the antioxidant N-acetyl cysteine (NAC) was able to revert the hypertension and endothelial dysfunction induced by CIH. Methods: Male Sprague-Dawley rats (200 g) were exposed to CIH (5% O2, 12 times/h 8 h/day) or sham condition for 28 days. After 14 days of CIH, rats were treated with NAC (100 mg/day in drinking water) until day 28 of the protocol. Arterial blood pressure (BP) was measured by radiotelemetry (PA-C40, DSI, USA) in conscious rats, and external carotid arteries (2 mm) were isolated to measure vasoactive responses to KCl (37.5 mM) and acetylcholine (Ach, 10− 10-10− 5 M) using wire-myography. Results: CIH increased mean BP (10 mm Hg) after 3 days of exposure. NAC markedly decreases the elevated BP toward normal values in 6-8 days despite of CIH exposure. External carotid arteries from CIH- rats showed higher active contraction induced by KCl than sham rats (3.8 ± 0.3 N/m2 vs. 2.3 ± 0.4 N/m2, respectively) and decreased maximal relaxation to ACh related to sham (12.8 ± 1.5% vs 24.8 ± 3.7%, respectively). NAC did not reverse the increased vessel contraction (3.9 ± 0.6 N/m2) induced by KCl, and failed to restore the impaired ACh-induced relaxation in the carotid arteries (10.7 ± 0.8%). Conclusion: Our results suggest that oral NAC administration is a suitable treatment for the CIH-induced hypertension, but did not restored the endothelial dysfunction displayed by rats exposed to CIH. Supported by FONDEF D11I1098. doi:10.1016/j.autneu.2015.07.045
P4.7 Maintenance of ventilation under a hypoxic condition requires activated astrocytes I. Fukushia,b, K. Takedab,c, Y. Hasebeb,d, J. Horiuchia, Y. Okadab a Department of Biomedical Engineering, Graduate School of Science & Engineering, Toyo University, Japan b Clinical Research Center, National Hospital Organization Murayama Medical Center, Japan c Fujita Memorial Nanakuri Institute, Fujita Health University, Japan d Department of Pediatrics, School of Medicine, University of Yamanashi, Japan Although mild hypoxia increases ventilation, severe hypoxia decreases ventilation. The mechanism of this phenomenon, hypoxic ventilatory depression, has not been fully understood. Maintenance of ventilation and its response to hypoxia are dependent on the conditions of not only the brainstem but the higher brain. Recently, it has been elucidated that astrocytes play active roles in various brain functions. Therefore, we hypothesized that the maintenance of ventilation under a hypoxic condition is dependent on the function of astrocytes. In the present study, we intended to clarify the role of astrocytes in the maintenance of brain function and ventilation under a hypoxic condition. Experiments were performed in unanesthetized adult mice (n = 12). We measured respiratory parameters by whole body plethysmography, and recorded EEG. Two levels of hypoxia (mild 12% and severe 6% O2 in N2) were loaded. Each hypoxic exposure was conducted before and after pharmacological blockade of astrocytic activation (arundic acid; 100 and 300 mg/kg, i.p. administration). EEG signals were subjected to a frequency analysis by spectrography. When exposed to mild hypoxia, ventilation was increased but an apparent change was not detected in EEG. On the other hand, severe hypoxia induced initial augmentation
vs. 70 ± 4 cm/s; p b 0.05). During hypercapnia cerebral blood flow velocity was lower in older adults compared with young adults (79 ± 8 vs. 96 ± 6 cm/s; p b 0.05). MAP was not different between groups at baseline (96 ± 4 mmHg in young vs. 103 ± 3 mmHg in older; p N 0.05), however MAP was higher in older adults compared with young adults (110 ± 3 vs.101 ± 3 mmHg; p b 0.05). MSNA was higher in older adults compared with young adults at baseline (28 ± 4 vs.16 ± 1 bursts/min; p b 0.01) and during hypercapnia (31 ± 4 vs. 20 ± 2 bursts/min; p b 0.01). However, the percent increase in MSNA during hypercapnia was not different between groups (24 ± 6% in young vs. 20 ± 9% in older adults; p N 0.05). Additionally, there were no correlations between cerebral blood flow velocity or MAP responses and sympathetic activation during hypercapnia (p N 0.05 for all). Taken together, these results suggest that hypercapnia-induced sympathoexcitation is not altered with advancing age. Funding: NIH grant HL118154. doi:10.1016/j.autneu.2015.07.043
P4.5 Obstructive apnea due to laryngospasm during seizures, but not central apnea, causes hypoxic cardiac derangements in rats K. Nakase, R. Kollmar, K. Sundaram, J. Silverman, R. Orman, M. Stewart Departments of Physiology & Pharmacology, Cell Biology, Otolaryngology, and Neurology, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY,USA Sudden Unexplained Death in Epilepsy (SUDEP) accounts for up to 17% of deaths in epileptic persons where disturbances of cardiovascular and respiratory function are almost certainly the link between seizure activity and death. With our urethane/kainate rat model, which uses the glutamate receptor agonist, kainic acid, as a convulsant in rats anesthetized with urethane, we are able to monitor invasively and non-invasively systemic physiology DURING seizures. Rats were studied in a plethysmogragh with simultaneous continuous recordings of ECG, EEG, and video laryngoscopy. Periods of central apnea, determined by abrupt cessation of breathing at the end of expiration for periods up to 20 seconds and video evidence of an open airway, occurred in all groups with similar incidence, including animals that were intubated. Obstructive apnea, determined by progressive decreases in tidal volume until flow stopped and video evidence of a closed glottis, was associated with hypoxic cardiac derangements as evidenced by ST segment elevation and progressive bradyarrhythmia, ending in death in 8/9 animals. We conclude that severe laryngospasm represents a likely contributor to the seizure and hypoxemia-induced conditions that result in death. doi:10.1016/j.autneu.2015.07.044
P4.6 Antioxidant treatment with N-acetyl cysteine reduced the hypertension induced by intermittent hypoxia in a rat model of obstructive sleep apnoea R. Iturriagaa, B. Krauseb, P. Casanellob, R. Del Rioc a Lab. Neurobiology, Faculty of Biological Sciences b Division of Obstetrics & Gynaecology and Division of Paediatrics, Faculty of Medicine, Pontificia Universidad Católica de Chile c Lab Cardiorespiratory Control, Universidad Autónoma de Chile, Santiago, Chile Background/Aims: Chronic intermittent hypoxia (CIH), a main feature of obstructive sleep apnoea (OSA) led to endothelial
67
dysfunction and hypertension. Sympathetic hyperactivation due to an enhanced carotid body (CB) drive produced by oxidative stress has been associated to hypertension. Administration of antioxidants prevents the enhanced CB discharges and the hypertension. We tested if oxidative stress is involved in the endothelial dysfunction and hypertension in rats exposed to CIH. Accordingly, we studied if the antioxidant N-acetyl cysteine (NAC) was able to revert the hypertension and endothelial dysfunction induced by CIH. Methods: Male Sprague-Dawley rats (200 g) were exposed to CIH (5% O2, 12 times/h 8 h/day) or sham condition for 28 days. After 14 days of CIH, rats were treated with NAC (100 mg/day in drinking water) until day 28 of the protocol. Arterial blood pressure (BP) was measured by radiotelemetry (PA-C40, DSI, USA) in conscious rats, and external carotid arteries (2 mm) were isolated to measure vasoactive responses to KCl (37.5 mM) and acetylcholine (Ach, 10− 10-10− 5 M) using wire-myography. Results: CIH increased mean BP (10 mm Hg) after 3 days of exposure. NAC markedly decreases the elevated BP toward normal values in 6-8 days despite of CIH exposure. External carotid arteries from CIH- rats showed higher active contraction induced by KCl than sham rats (3.8 ± 0.3 N/m2 vs. 2.3 ± 0.4 N/m2, respectively) and decreased maximal relaxation to ACh related to sham (12.8 ± 1.5% vs 24.8 ± 3.7%, respectively). NAC did not reverse the increased vessel contraction (3.9 ± 0.6 N/m2) induced by KCl, and failed to restore the impaired ACh-induced relaxation in the carotid arteries (10.7 ± 0.8%). Conclusion: Our results suggest that oral NAC administration is a suitable treatment for the CIH-induced hypertension, but did not restored the endothelial dysfunction displayed by rats exposed to CIH. Supported by FONDEF D11I1098. doi:10.1016/j.autneu.2015.07.045
P4.7 Maintenance of ventilation under a hypoxic condition requires activated astrocytes I. Fukushia,b, K. Takedab,c, Y. Hasebeb,d, J. Horiuchia, Y. Okadab a Department of Biomedical Engineering, Graduate School of Science & Engineering, Toyo University, Japan b Clinical Research Center, National Hospital Organization Murayama Medical Center, Japan c Fujita Memorial Nanakuri Institute, Fujita Health University, Japan d Department of Pediatrics, School of Medicine, University of Yamanashi, Japan Although mild hypoxia increases ventilation, severe hypoxia decreases ventilation. The mechanism of this phenomenon, hypoxic ventilatory depression, has not been fully understood. Maintenance of ventilation and its response to hypoxia are dependent on the conditions of not only the brainstem but the higher brain. Recently, it has been elucidated that astrocytes play active roles in various brain functions. Therefore, we hypothesized that the maintenance of ventilation under a hypoxic condition is dependent on the function of astrocytes. In the present study, we intended to clarify the role of astrocytes in the maintenance of brain function and ventilation under a hypoxic condition. Experiments were performed in unanesthetized adult mice (n = 12). We measured respiratory parameters by whole body plethysmography, and recorded EEG. Two levels of hypoxia (mild 12% and severe 6% O2 in N2) were loaded. Each hypoxic exposure was conducted before and after pharmacological blockade of astrocytic activation (arundic acid; 100 and 300 mg/kg, i.p. administration). EEG signals were subjected to a frequency analysis by spectrography. When exposed to mild hypoxia, ventilation was increased but an apparent change was not detected in EEG. On the other hand, severe hypoxia induced initial augmentation