Browsing by Author "Río Troncoso, Rodrigo Andre del"

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    Astrocytes from the retrotrapezoid nucleus drives chemoreceptor neuron hyper-responsiveness to hypercapnia in heart failure: role of oxidative stress and glutamate spill-over
    (2024) Díaz Jara, Esteban; Río Troncoso, Rodrigo Andre del; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas
    La insuficiencia cardiaca con fracción de eyección preservada (ICFEP) es una enfermedad crónica caracterizada por una alta prevalencia de desórdenes respiratorios e irregularidades en el patrón ventilatorio, las cuales están estrechamente asociados con la potenciación del quimiorreflejo central. El principal núcleo quimiorreceptor central es el núcleo retrotrapezoide (RTN), ubicado en la superficie del tronco encefálico, que contiene neuronas que frente a un estímulo hipercápnico propagan potenciales de acción excitatorios hacia los centros respiratorios, modulando el patrón respiratorio. En modelos preclínicos de ICFEP, la eliminación selectiva de las neuronas quimiorreceptoras del RTN normaliza la quimiorrefleja central y elimina la irregularidad en el patrón respiratorio. Sin embargo, los mecanismos celulares que potencian la función del RTN durante la ICFEP no se han estudiado previamente. En los últimos años, se ha demostrado que, además de las neuronas quimiorreceptoras, los astrocitos ubicados en el RTN desempeñan un papel clave en la regulación de la quimiorrecepción en condiciones normales. Sin embargo, se desconoce el rol de estas células en el control de la quimiorecepción central durante la ICFEP. Por lo tanto, propuse como hipótesis que "El estrés oxidativo aumenta el impulso del quimioreflejo central en la ICFEP al reducir la captación de glutamato mediada por los astrocitos en el núcleo retrotrapezoide". Los objetivos principales de esta tesis doctoral fueron: i) Determinar los niveles de estrés oxidativo y glutamato en el RTN y estudiar la contribución del estrés oxidativo en las respuestas exageradas del quimiorreflejo central en ratas con ICFEP; ii) Determinar las alteraciones en la morfología de los astrocitos y la localización y expresión del transportador de glutamato-1 (GLT-1) en el RTN de ratas con ICFEP; iii) Determinar la actividad neuronal en secciones del tronco encefálico que contienen el RTN de ratas con ICFEP; y iv) Determinar si la sobre-expresión de GLT-1 en los astrocitos del RTN de ratas con ICFEP restaura la respuesta normal de las neuronas quimiorreceptoras a la hipercapnia. La ICFEP fue inducida en ratas Sprague Dawley machos adultos (~250 g) mediante una fístula arteriovenosa. Se utilizó pletismografía de cuerpo entero para evaluar tanto la respuesta ventilatoria a la hipercapnia (FiCO2 7%), como el patrón respiratorio en reposo. Los niveles del anión superóxido y de superóxido dismutasa 2 en el RTN se determinaron por tinción con dihidroetidio (DHE) y Western Blot, respectivamente. La morfología de los astrocitos y los niveles de GLT-1 en el RTN se determinaron mediante inmunofluorescencia y RNAscope, respectivamente. La localización celular de SOD2 y de GLT-1 se realizó mediante análisis bioinformáticos. Los niveles de glutamato extracelular en el RTN se midieron en animales anestesiados, y posteriormente mediante Cromatografía líquida de alta eficacia (HPLC). Para evaluar la actividad de las neuronas quimiorreceptoras RTN, se realizaron inyecciones estereotáxicas de un adenovirus que permitió la expresión de un sensor de calcio citoplasmático (GCaMP6s) en las neuronas. Posteriormente se analizaron los cambios de fluorescencia en las secciones del tronco encefálico que contenían el RTN mediante microscopía confocal. Finalmente, la sobreexpresión de GLT-1 en astrocitos RTN fue realizada por la inyección estereotáxica de un adenovirus que permitió la expresión del transportador de glutamato-1 bajo el promotor específico de astrocitos, la proteína ácida fibrilar glial (GFAP). Los animales con ICFEP presentaron un aumento en los niveles del anión superóxido en el RTN, los cuales están estrechamente relacionados con la potenciación del quimiorreflejo central en animales ICFEP. El aumento de los niveles de superóxido en el RTN se asoció con la disminución en los niveles de expresión de SOD2, tanto a nivel de mRNA y proteína, en los animales con ICFEP. En paralelo, animales con una disminución parcial de SOD2 presentan un aumento en los niveles de superóxido en el RTN los cuales se correlacionan con la potenciación del quimiorreflejo central, similar a lo observado en animales con ICFEP. Análisis de co-localización y bioinformáticos demostraron que SOD2 se expresa preferentemente en los astrocitos del RTN en lugar de en las neuronas quimiorreceptoras. Las ratas con ICFEP presentan un aumento en los niveles de glutamato extracelular en el RTN tanto en condiciones basales como durante el estímulo hipercápnico comparado con animales Sham. Tanto las ratas con ICFEP como en animales con una disminución parcial de SOD2 presentan una disminución en la morfología de los astrocitos del RTN. Interesantemente se observó que los animales con ICFEP presentan una disminución en la tinción de NMB, el marcador de neuronas quimiorreceptoras del RTN. Análisis de co-localización y bioinformáticos demostraron que GLT-1 se expresa preferentemente en los astrocitos del RTN y no en las neuronas quimiorreceptoras, y que en los animales con ICFEP, existe una disminución en los niveles de GLT-1 en el RTN. Las neuronas quimiorreceptoras del RTN de animales con ICFEP presentan un aumento de actividad tanto en condiciones basales como al ser expuestas a un medio ácido. Finalmente, la sobre-expresión de GLT-1 en los astrocitos del RTN de animales con ICFEP normaliza la actividad de las neuronas quimiorreceptoras del RTN. Además, la sobreexpresión de GLT-1 normaliza los niveles extracelulares de glutamato en el RTN, el quimiorreflejo central y el patrón respiratorio en animales con ICFEP. Estos resultados sugieren que el aumento del estrés oxidativo y la disfunción de los astrocitos en el RTN juegan un rol clave en la potenciación del quimiorreflejo y en la progresión de la ICFEP, principalmente a través la recaptación del glutamato extracelular.
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    Cardioventilatory Acclimatization Induced by Chronic Intermittent Hypoxia
    (2009) Iturriaga Agüera, Rodrigo; Rey Keim, Sergio; Río Troncoso, Rodrigo Andre del; Moya Céspedes, Esteban Alexis.
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    Carotid body and cardiorespiratory alterations in intermittent hypoxia: the oxidative link
    (2010) Río Troncoso, Rodrigo Andre del; Moya Céspedes, Esteban Alexis.; Iturriaga Agüera, Rodrigo
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    Carotid body chemoreceptors, sympathetic neural activation, and cardiometabolic disease
    (2016) Iturriaga Agüera, Rodrigo; Río Troncoso, Rodrigo Andre del; Idiaquez, Juan.; Somers, Virend K.
    Abstract The carotid body (CB) is the main peripheral chemoreceptor that senses the arterial PO2, PCO2 and pH. In response to hypoxemia, hypercapnia and acidosis, carotid chemosensory discharge elicits reflex respiratory, autonomic and cardiovascular adjustments. The classical construct considers the CB as the main peripheral oxygen sensor, triggering reflex physiological responses to acute hypoxemia and facilitating the ventilatory acclimation to chronic hypoxemia at high altitude. However, a growing body of experimental evidence supports the novel concept that an abnormally enhanced CB chemosensory input to the brainstem contributes to overactivation of the sympathetic nervous system, and consequent pathology. Indeed, the CB has been implicated in several diseases associated with increases in central sympathetic outflow. These include hypertension, heart failure, sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome. Indeed, ablation of the CB has been proposed for the treatment of severe and resistant hypertension in humans. In this review, we will analyze and discuss new evidence supporting an important role for the CB chemoreceptor in the progression of autonomic and cardiorespiratory alterations induced by heart failure, obstructive sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome.Abstract The carotid body (CB) is the main peripheral chemoreceptor that senses the arterial PO2, PCO2 and pH. In response to hypoxemia, hypercapnia and acidosis, carotid chemosensory discharge elicits reflex respiratory, autonomic and cardiovascular adjustments. The classical construct considers the CB as the main peripheral oxygen sensor, triggering reflex physiological responses to acute hypoxemia and facilitating the ventilatory acclimation to chronic hypoxemia at high altitude. However, a growing body of experimental evidence supports the novel concept that an abnormally enhanced CB chemosensory input to the brainstem contributes to overactivation of the sympathetic nervous system, and consequent pathology. Indeed, the CB has been implicated in several diseases associated with increases in central sympathetic outflow. These include hypertension, heart failure, sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome. Indeed, ablation of the CB has been proposed for the treatment of severe and resistant hypertension in humans. In this review, we will analyze and discuss new evidence supporting an important role for the CB chemoreceptor in the progression of autonomic and cardiorespiratory alterations induced by heart failure, obstructive sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome.
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    Carotid body potentiation during chronic intermittent hypoxia: implication for hypertension
    (2014) Río Troncoso, Rodrigo Andre del; Moya Céspedes, Esteban Alexis.; Iturriaga Agüera, Rodrigo
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    Carotid body potentiation induced by intermittent hypoxia: Implications for cardiorespiratory changes induced by sleep apnoea
    (2009) Iturriaga Agüera, Rodrigo; Moya Céspedes, Esteban Alexis.; Río Troncoso, Rodrigo Andre del
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    Chemogenetic inhibition of NTS astrocytes normalizes cardiac autonomic control and ameliorate hypertension during chronic intermittent hypoxia
    (2023) Pereyra Florián, Katherin Vanessa; Las Heras, Alexandra; Toledo, Camilo; Díaz-Jara, Esteban; Iturriaga, Rodrigo; Río Troncoso, Rodrigo Andre del
    Abstract Background Obstructive sleep apnea (OSA) is characterized by recurrent episodes of chronic intermittent hypoxia (CIH), which has been linked to the development of sympathoexcitation and hypertension. Furthermore, it has been shown that CIH induced inflammation and neuronal hyperactivation in the nucleus of the solitary tract (NTS), a key brainstem region involved in sympathetic and cardiovascular regulation. Since several studies have proposed that NTS astrocytes may mediate neuroinflammation, we aimed to determine the potential contribution of NTS-astrocytes on the pathogenesis of CIH-induced hypertension. Results Twenty-one days of CIH induced autonomic imbalance and hypertension in rats. Notably, acute chemogenetic inhibition (CNO) of medullary NTS astrocytes using Designer Receptors Exclusively Activated by Designers Drugs (DREADD) restored normal cardiac variability (LF/HF: 1.1 ± 0.2 vs. 2.4 ± 0.2 vs. 1.4 ± 0.3, Sham vs. CIH vs. CIH + CNO, respectively) and markedly reduced arterial blood pressure in rats exposed to CIH (MABP: 82.7 ± 1.2 vs. 104.8 ± 4.4 vs. 89.6 ± 0.9 mmHg, Sham vs. CIH vs. CIH + CNO, respectively). In addition, the potentiated sympathoexcitation elicit by acute hypoxic chemoreflex activation in rats exposed to CIH was also completely abolished by chemogenetic inhibition of NTS astrocytes using DREADDs. Conclusion Our results support a role for NTS astrocytes in the maintenance of heightened sympathetic drive and hypertension during chronic exposure to intermittent hypoxia mimicking OSA.
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    Comparative respiratory strategies of subterranean and fossorial octodontid rodents to cope with hypoxic and hypercapnic atmospheres
    (2010) Tomasco, I. H.; Río Troncoso, Rodrigo Andre del; Iturriaga Agüera, Rodrigo; Bozinovic Kuscevic, Francisco
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    Contribution of inflammation on carotid body chemosensory potentiation induced by intermittent hypoxia
    (2012) Río Troncoso, Rodrigo Andre del; Moya Céspedes, Esteban Alexis.; Iturriaga Agüera, Rodrigo
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    Contribution of medullary pre-sympathetic neurons on cardiovascular dysfunction during transition to menopause
    (2025) Schwarz Flores, Karla Gabriele; Río Troncoso, Rodrigo Andre del; Inestrosa Cantín, Nibaldo; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas
    Cardiovascular disease is a highly prevalent condition in middle-aged women and are among the leading cause of poor patient’s quality of life and is recognized as the woman’s greatest health threat. Importantly, recent evidence suggests the existence of an intimate crosstalk between the heart and the brain, resulting from a complex network of neurohumoral circuits. From a pathophysiological perspective, the higher prevalence of heart disease in elderly women, may be explained in part by sex-related differences in cardiovascular disease’s risk factors. The autonomic nervous system is a major physiological actor affecting heart-brain axis in health and disease. Importantly, accumulating evidence support the negative impact of decreased estrogen due to menopause transition as a risk factor for adverse cardiovascular events, possibly contributing to autonomic imbalance in middle-aged women, however this hypothesis has not been comprehensive tested before. Central autonomic nuclei, such as the rostral ventrolateral medulla (RVLM) encompasses a pivotal circuit of control of sympathetic flow and blood pressure. Overactivity of sympathetic tone is a hallmark of cardiovascular disorders, including hypertension, stroke and HF. In fact, it was suggested that estrogens exert direct effects on RVLM through estrogen receptors (ERα and ERβ), thereby leading to sympathoinhibitory effects, which may be crucial for cardiovascular protection. While a strong causal-association between sympathetic overactivity and development of cardiovascular diseases has been previously established, further interdisciplinary studies are needed to better understand the underlying cellular/molecular and physiological mechanisms, particularly in the perimenopausal and postmenopausal women. If a reduced estrogen signaling through neuronal ERs contributes to aberrant pre-sympathetic neural activity during menopause leads to autonomic imbalance, cardiovascular disorders and exercise capacity remains totally unknown. My underlying hypothesis is that normalizing autonomic nervous function during perimenopause will have a positive impact on cardiac function in experimentally healthy menopause. I proposed an integrative approach by combining freely moving animal recordings, chemogenetic and hormone treatment to assess cardiovascular/autonomic function in a preclinical model of menopause transition using 4-vinylcyclohexane- mediated accelerated ovarian failure. Furthermore, cellular and molecular mechanisms associated with ERs signaling were elucidated using in vitro model of menopause. In this proposal, I determined, for the first time that, i) estrogen decrease during perimenopause triggers brainstem pre-sympathetic neurons (RVLM C1) overactivity WT mice, leading to cardiac autonomic imbalance, arrhythmogenesis and cardiac diastolic and systolic dysfunction; ii) RVLM C1 neurons contribute to cardiac sympathetic overactivity, cardiac arrythmias and cardiac impairment in postmenopausal mice; iii) long-term 17β-estradiol treatment during perimenopause decrease RVLM C1 activity, improving cardiac function in postmenopausal stage. Together, the results suggest that RVLM C1 neurons play a major role in cardiovascular remodeling during female reproductive senescence.
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    Contribution of TASK-like potassium channels to the enhanced rat carotid body responsiveness to hypoxia.
    (2012) Ortiz Cisternas, Fernando Andrés.; Río Troncoso, Rodrigo Andre del; Varas Orozco, Rodrigo; Iturriaga Agüera, Rodrigo
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    Contribution of the Inflammasome on Carotid Body Potentiation in Heart Failure with Preserved Ejection Fraction: Role in Disease Progression
    (2025) Pereyra Florián, Katherin Vanessa; Río Troncoso, Rodrigo Andre del; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas
    Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent pathological condition in the elderly population characterized by impaired cardiac function. Several compensatory mechanisms get activated to support the failing heart; however, some of them became maladaptive and hastens disease progression. Recently, we found that the carotid body (CB)-mediated chemoreflex was enhanced in experimental HFpEF and that increases in chemoreflex drive was closely associated with a high incidence of breathing disorders (i.e. apneas, hypopneas) ultimately adding more stress to the failing heart. However, the precise mechanisms underpinning carotid body potentiation in the setting of HFpEF has never been studied. Interestingly, HFpEF has been characterized as an inflammatory disease since HFpEF patients shown increased circulating levels of pro-inflammatory cytokines that positively and significantly correlates with a worsening in functional class, increased rate of hospitalizations and poor survival. Although the role of inflammation in cardiac function regulation has been widely studied the potential role of carotid body inflammation on hemodynamic and respiratory distress in the setting of HFpEF has never been addressed. Previous investigations described that glomus cell, the functional unit of CB, express all the molecular machinery necessary to transduce inflammatory signals. Indeed, constitutive expression of functional interleukin receptors type 1 (IL-R1) and TNF-α receptor (TNFR) within the CB tissue has been described. Indeed, pro-inflammatory cytokines increases intracellular calcium in glomus cells and stimulate catecholamine release upon afferent terminals from petrosal ganglion neurons leading to an increase in the firing rate of afferent fibers. Importantly, it is well known that chronic inflammatory states result in inflammasome activation. The inflammasome is a cytosolic multiprotein oligomer that mediates the cleavage of inactive pro-inflammatory cytokines (among other functions) that perpetuates the inflammatory niche in several tissues. The role of the inflammasome in CB function and its contribution, if any, to the potentiation of CB activity in HFpEF are completely unknown. Accordingly, we hypothesized that activation of the inflammasome in CBs of HFpEF mice contributes to the potentiation of the peripheral chemoreflex through the regulation of cytokine release within the CB tissue being the outcome the maintenance of cardiorespiratory disorders in HFpEF. We expect that this PhD thesis provides first evidence of the role of the inflammasome pathway in CB function in health and disease conditions, particularly in the setting of HFpEF.
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    Differential expression of pro-inflammatory cytokines, endothelin-1 and nitric oxide synthases in the rat carotid body exposed to intermittent hypoxia
    (2011) Río Troncoso, Rodrigo Andre del; Moya Céspedes, Esteban Alexis.; Iturriaga Agüera, Rodrigo
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    Effects of vagotomy on cardiovascular and heart rate variability alterations following chronic normobaric hypoxia in adult rabbits
    (2018) Alcayaga Urbina, Julio Andrés; Río Troncoso, Rodrigo Andre del; Moya Céspedes, Esteban Alexis.; Freire, Matías.; Iturriaga Agüera, Rodrigo
    Abstract Background chronic hypoxia increases basal ventilation and pulmonary vascular resistance, with variable changes in arterial blood pressure and heart rate, but it’s impact on heart rate variability and autonomic regulation have been less well examined. We studied changes in arterial blood pressure, heart rate and heart rate variability (HRV) in rabbits subjected to chronic normobaric hypoxia (CNH; PB ~ 719 mmHg; FIO2 ~ 9.2%) for 14 days and assess the effect of autonomic control by acute bilateral vagal denervation. Results exposure to CNH stalled animal weight gain and increased the hematocrit, without affecting heart rate or arterial blood pressure. Nevertheless, Poincaré plots of the electrocardiographic R–R intervals showed a reduced distribution parallel to the line of identity, which interpreted as reduced long-term HRV. In the frequency domain, CNH reduced the very-low- (< 0.2 Hz) and high-frequency components (> 0.8 Hz) of the R–R spectrograms and produced a prominent component in the low-frequency component (0.2–0.5 Hz) of the power spectrum. In control and CNH exposed rabbits, bilateral vagotomy had no apparent effect on the short- and long-term HRV in the Poincaré plots. However, bilateral vagotomy differentially affected higher-frequency components (> 0.8 Hz); reducing it in control animals without modifying it in CNH-exposed rabbits. Conclusions These results suggest that CNH exposure shifts the autonomic balance of heart rate towards a sympathetic predominance without modifying resting heart rate or arterial blood pressure.
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    Evidence for Histamine as a New Modulator of Carotid Body Chemoreception
    (2009) Río Troncoso, Rodrigo Andre del; Moya Céspedes, Esteban Alexis.; Iturriaga Agüera, Rodrigo
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    Heart rate and cardiac autonomic responses to concomitant deep breathing, hand grip exercise, and circulatory occlusion in healthy young adult men and women
    (2021) Andrade Andrade, David Cristóbal; Melipillan, Claudia; Toledo, Camilo; Rios-Gallardo, Angélica; Marcus, Noah J.; Ortiz, Fernando C.; Martinez, Gonzalo; Muñoz Venturelli, Paula; Río Troncoso, Rodrigo Andre del
    Background: Deep breathing (DB) and handgrip (HG) exercise -with and without circulatory occlusion (OC) in muscle-, have been shown to have beneficial effects on cardiovascular function; however, the combination of these maneuvers on heart rate (HR) and cardiac sympathovagal balance have not been previously investigated. Therefore, the aim of the present study was to evaluate the effect of simultaneous DB, HG, and OC maneuvers on the sympathovagal balance in healthy women and men subjects. Methods and results: Electrocardiogram and ventilation were measured in 20 healthy subjects (Women: n = 10; age = 27 ± 4 years; weight = 67.1 ± 8.4 kg; and height = 1.6 ± 0.1 m. Men: n = 10; age = 27 ± 3 years; weight = 77.5 ± 10.1 kg; and height = 1.7 ± 0.1 m) at baseline and during DB, DB + HG, or DB + HG + OC protocols. Heart rate (HR) and respiratory rate were continuously recorded, and spectral analysis of heart rate variability (HRV) were calculated to indirectly estimate cardiac autonomic function. Men and women showed similar HR responses to DB, DB + HG and DB + HG + OC. Men exhibited a significant HR decrease following DB + HG + OC protocol which was accompanied by an improvement in cardiac autonomic control evidenced by spectral changes in HRV towards parasympathetic predominance (HRV High frequency: 83.95 ± 1.45 vs. 81.87 ± 1.50 n.u., DB + HG + OC vs. baseline; p < 0.05). In women, there was a marked decrease in HR after completion of both DB + HG and DB + HG + OC tests which was accompanied by a significant increase in cardiac vagal tone (HRV High frequency: 85.29 ± 1.19 vs. 77.93 ± 0.92 n.u., DB + HG vs. baseline; p < 0.05). No adverse effects or discomfort were reported by men or women during experimental procedures. Independent of sex, combination of DB, HG, and OC was tolerable and resulted in decreases in resting HR and elevations in cardiac parasympathetic tone. Conclusions: These data indicate that combined DB, HG and OC are effective in altering cardiac sympathovagal balance and reducing resting HR in healthy men and women.
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    Inflammation and oxidative stress during intermittent hypoxia: the impact on chemoreception
    (2015) Iturriaga Agüera, Rodrigo; Moya Céspedes, Esteban Alexis.; Río Troncoso, Rodrigo Andre del
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    Inhibition of rat carotid body glomus cells TASK-like channels by acute hypoxia is enhanced by chronic intermittent hypoxia
    (2013) Ortiz Cisternas, Fernando Andrés.; Río Troncoso, Rodrigo Andre del; Varas Orozco, Rodrigo; Iturriaga Agüera, Rodrigo
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    Intranasal oxytocin increases respiratory rate and reduces obstructive event duration and oxygen desaturation in obstructive sleep apnea patients : a randomized double blinded placebo controlled study
    (2020) Jain, V.; Kimbro, S.; Kowalik, G.; Milojevic, I.; Dowling, N. Maritza; Hunley, A. L.; Hauser, K.; Andrade Andrade, David Cristóbal; Río Troncoso, Rodrigo Andre del; Kay, M. W.; Mendelowitz D.
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    Modulatory effects of histamine on cat carotid body chemoreception
    (2008) Río Troncoso, Rodrigo Andre del; Moya Céspedes, Esteban Alexis.; Iturriaga Agüera, Rodrigo