Browsing by Author "Toledo, Camilo"

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    Ablation of brainstem C1 neurons improves cardiac function in volume overload heart failure
    (2019) Andrade Andrade, David Cristóbal; Toledo, Camilo; Díaz, Hugo S.; Lucero, Claudia; Arce Álvarez, Alexis; Oliveira, Luis M.; Takakura, Ana C.; Moreira, Thiago S.; Schultz, Harold D.; Del Rio, Rodrigo; Marcus, Noah J.; Alcayaga Urbina, Julio Andrés
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    Carbamylated form of human erythropoietin normalizes cardiorespiratory disorders triggered by intermittent hypoxia mimicking sleep apnea syndrome
    (LIPPINCOTT WILLIAMS & WILKINS, 2021) Andrade, David C.; Toledo, Camilo; Diaz, Hugo S.; Pereyra, Katherin, V; Schwarz, Karla G.; Diaz Jara, Esteban; Melipillan, Claudia; Rios Gallardo, Angelica P.; Uribe Ojeda, Atenea; Alcayaga, Julio; Quintanilla, Rodrigo A.; Iturriaga, Rodrigo; Richalet, Jean Paul; Voituron, Nicolas; Del Rio, Rodrigo
    Background and objective: Chronic intermittent hypoxia (CIH), one of the main features of obstructive sleep apnea (OSA), enhances carotid body-mediated chemoreflex and induces hypertension and breathing disorders. The carbamylated form of erythropoietin (cEpo) may have beneficial effects as it retains its antioxidant/anti-inflammatory and neuroprotective profile without increasing red blood cells number. However, no studies have evaluated the potential therapeutic effect of cEpo on CIH-related cardiorespiratory disorders. We aimed to determine whether cEpo normalized the CIH-enhanced carotid body ventilatory chemoreflex, the hypertension and ventilatory disorders in rats. Methods: Male Sprague-Dawley rats (250 g) were exposed to CIH (5% O-2, 12/h, 8 h/day) for 28 days. cEPO (20 mu g/kg, i.p) was administrated from day 21 every other day for one more week. Cardiovascular and respiratory function were assessed in freely moving animals. Results: Twenty-one days of CIH increased carotid body-mediated chemoreflex responses as evidenced by a significant increase in the hypoxic ventilatory response (FiO2 10%) and triggered irregular eupneic breathing, active expiration, and produced hypertension. cEpo treatment significantly reduced the carotid body--chemoreflex responses, normalizes breathing patterns and the hypertension in CIH. In addition, cEpo treatment effectively normalized carotid body chemosensory responses evoked by acute hypoxic stimulation in CIH rats. Conclusion: Present results strongly support beneficial cardiorespiratory therapeutic effects of cEpo during CIH exposure.
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    Cardiorespiratory alterations following intermittent photostimulation of RVLM C1 neurons: Implications for long-term blood pressure, breathing and sleep regulation in freely moving rats
    (2022) Toledo, Camilo; Andrade, David C.; Diaz-Jara, Esteban; Ortolani, Domiziana; Bernal-Santander, Ignacio; Schwarz, Karla G.; Ortiz, Fernando C.; Marcus, Noah J.; Oliveira, Luiz M.; Takakura, Ana C.; Moreira, Thiago S.; Del Rio, Rodrigo
    Aim Sympathoexcitation and sleep-disordered breathing are common contributors for disease progression. Catecholaminergic neurons from the rostral ventrolateral medulla (RVLM-C1) modulate sympathetic outflow and have anatomical projections to respiratory neurons; however, the contribution of highly selective activation of RVLM-C1 neurons on long-term autonomic and breathing (dys)regulation remains to be understood. Methods To explore this relationship, a lentiviral vector carrying the light-sensitive cation channel channelrhodopsin-2 (LVV-PRSX8-ChR2-YFP) was unilaterally injected into the RVLM of healthy rats. On the contralateral side, LVV-PRSX8-ChR2-YFP was co-injected with a specific immunotoxin (D beta H-SAP) targeted to eliminate C1 neurons. Results Intermittent photostimulation of RVLM-C1 in vivo, in unrestrained freely moving rats, elicited long-term facilitation of the sympathetic drive, a rise in blood pressure and sympatho-respiratory coupling. In addition, photoactivation of RVLM-C1 induced long-lasting ventilatory instability, characterized by oscillations in tidal volume and increased breathing variability, but only during non-rapid eye movement sleep. These effects were not observed when photostimulation of the RVLM was performed in the presence of D beta H-SAP toxin. Conclusions The finding that intermittent activation of RVLM-C1 neurons induces autonomic and breathing dysfunction suggest that episodic stimulation of RVLM-C1 may serve as a pathological substrate for the long-term development of cardiorespiratory disorders.
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    Cardiorespiratory optimal point as a submaximal evaluation tool in endurance athletes: An exploratory study
    (2023) Oyarzo-Aravena, Alexis; Arce-Alvarez, Alexis; Salazar-Ardiles, Camila; Ramirez-Campillo, Rodrigo; Alvarez, Cristian; Toledo, Camilo; Izquierdo, Mikel; Andrade, David C.
    Introduction: The cardiorespiratory optimal point (COP) represents the lowest minute ventilation to oxygen consumption ratio (VE/VO2) and can be estimated during a CPET at submaximal intensity when an exercise test until volitional fatigue is not always advisable (i.e., a conflict zone where you cannot be confident of the security because near-competition, off-season, among other). COP's physiological components have not been wholly described yet. Therefore, this study seeks to identify the determinants of COP in highly trained athletes and its influence on maximum and sub-maximum variables during CPET through principal c omponent analysis (PCA) (explains the dataset's variance).Methods: Female (n = 9; age, 17.4 +/- 3.1 y; maximal VO2 [VO2max]), 46.2 +/- 5.9 mL/kg/min) and male (n = 24; age, 19.7 +/- 4.0 y; VO2max, 56.1 +/- 7.6 mL/kg/min) athletes performed a CPET to determine the COP, ventilatory threshold 1 (VT1) and 2 (VT2), and VO2max. The PCA was used to determine the relationship between variables and COP, explaining their variance.Results: Our data revealed that females and males displayed different COP values. Indeed, males showed a significant diminished COP compared to the female group (22.6 +/- 2.9 vs. 27.2 +/- 3.4 VE/VO2, respectively); nevertheless, COP was allocated before VT1 in both groups.Discussion: PC analysis revealed that the COP variance was mainly explained (75.6%) by PC1 (expired CO2 at VO2max) and PC2 (VE at VT2), possibly influencing cardiorespiratory efficiency at VO2max and VT2. Our data suggest that COP could be used as a submaximal index to monitor and assess cardiorespiratory system efficiency in endurance athletes. The COP could be particularly useful during the offseason and competitive periods and the return to the sports continuum.
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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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    Exercise intolerance in volume overload heart failure is associated with low carotid body mediated chemoreflex drive
    (2021) Andrade, David C.; Diaz-Jara, Esteban; Toledo, Camilo; Schwarz, Karla G.; Pereyra, Katherin V.; Diaz, Hugo S.; Marcus, Noah J.; Ortiz, Fernando C.; Rios-Gallardo, Angelica P.; Ortolani, Domiziana; Del Rio, Rodrigo
    Mounting an appropriate ventilatory response to exercise is crucial to meeting metabolic demands, and abnormal ventilatory responses may contribute to exercise-intolerance (EX-inT) in heart failure (HF) patients. We sought to determine if abnormal ventilatory chemoreflex control contributes to EX-inT in volume-overload HF rats. Cardiac function, hypercapnic (HCVR) and hypoxic (HVR) ventilatory responses, and exercise tolerance were assessed at the end of a 6 week exercise training program. At the conclusion of the training program, exercise tolerant HF rats (HF+EX-T) exhibited improvements in cardiac systolic function and reductions in HCVR, sympathetic tone, and arrhythmias. In contrast, HF rats that were exercise intolerant (HF+EX-inT) exhibited worse diastolic dysfunction, and showed no improvements in cardiac systolic function, HCVR, sympathetic tone, or arrhythmias at the conclusion of the training program. In addition, HF+EX-inT rats had impaired HVR which was associated with increased arrhythmia susceptibility and mortality during hypoxic challenges (similar to 60% survival). Finally, we observed that exercise tolerance in HF rats was related to carotid body (CB) function as CB ablation resulted in impaired exercise capacity in HF+EX-T rats. Our results indicate that: (i) exercise may have detrimental effects on cardiac function in HF-EX-inT, and (ii) loss of CB chemoreflex sensitivity contributes to EX-inT in HF.
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    Exercise training improves cardiac autonomic control, cardiac function, and arrhythmogenesis in rats with preserved-ejection fraction heart failure
    (2017) Andrade Andrade, David Cristóbal; Arce-Alvarez Alexis; Toledo, Camilo; Díaz, Hugo S.; Lucero, Claudia; Schultz, Harold D.; Marcus, Noah J.; Del Rio, Rodrigo
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    Exercise training reduces brainstem oxidative stress and restores normal breathing function in heart failure
    (2021) Diaz-Jara, Esteban; Diaz, Hugo S.; Rios-Gallardo, Angelica; Ortolani, Domiziana; Andrade, David C.; Toledo, Camilo; V. Pereyra, Katherin; Schwarz, Karla; Ramirez, Gigliola; Ortiz, Fernando C.; Andia, Marcelo E.; Del Rio, Rodrigo
    Enhanced central chemoreflex drive and irregular breathing are both hallmarks in heart failure (HF) and closely related to disease progression. Central chemoreceptor neurons located within the retrotrapezoid nucleus (RTN) are known to play a role in breathing alterations in HF. It has been shown that exercise (EX) effectively reduced reactive oxygen species (ROS) in HF rats. However, the link between EX and ROS, particularly at the RTN, with breathing alterations in HF has not been previously addressed. Accordingly, we aimed to determine: i) ROS levels in the RTN in HF and its association with chemoreflex drive, ii) whether EX improves chemoreflex/breathing function by reducing ROS levels, and iii) determine molecular alterations associated with ROS generation within the RTN of HF rats and study EX effects on these pathways. Adult male Sprague-Dawley rats were allocated into 3 experimental groups: Sham (n = 5), volume overloaded HF (n = 6) and HF (n = 8) rats that underwent EX training for 6 weeks (60 min/day, 25 m/min, 10% inclination). At 8 weeks post-HF induction, breathing patterns and chemoreflex function were analyzed by unrestrained plethysmography. ROS levels and anti/pro-oxidant enzymes gene expression were analyzed in the RTN. Our results showed that HF rats have high ROS levels in the RTN which were closely linked to the enhanced central chemoreflex and breathing disorders. Also, HF rats displayed decreased expression of antioxidant genes in the RTN compared with control rats. EX training increases antioxidant defense in the RTN, reduces ROS formation and restores normal central chemoreflex drive and breathing regularity in HF rats. This study provides evidence for a role of ROS in central chemoreception in the setting of HF and support the use of EX to reduce ROS in the brainstem of HF animals and reveal its potential as an effective mean to normalize chemoreflex and breathing function in HF.
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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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    Medullary astrocytes mediate irregular breathing patterns generation in chronic heart failure through purinergic P2X7 receptor signalling
    (2022) Toledo, Camilo; Diaz-Jara, Esteban; Diaz, Hugo S.; Schwarz, Karla G.; Pereyra, Katherin, V; Las Heras, Alexandra; Rios-Gallardo, Angelica; Andrade, David C.; Moreira, Thiago; Takakura, Ana; Marcus, Noah J.; Del Rio, Rodrigo
    Background Breathing disorders (BD) (apnoeas/hypopneas, periodic breathing) are highly prevalent in chronic heart failure (CHF) and are associated with altered central respiratory control. Ample evidence identifies the retrotrapezoid nucleus (RTN) as an important chemosensitivity region for ventilatory control and generation of BD in CHF, however little is known about the cellular mechanisms underlying the RTN/BD relationship. Within the RTN, astrocyte-mediated purinergic signalling modulates respiration, but the potential contribution of RTN astrocytes to BD in CHF has not been explored.
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    Paraquat herbicide diminishes chemoreflex sensitivity, induces cardiac autonomic imbalance and impair cardiac function in rats
    (2021) Pereyra, Katherin, V; Schwarz, Karla G.; Andrade, David C.; Toledo, Camilo; Rios-Gallardo, Angelica; Diaz-Jara, Esteban; Bastias, Sussy S.; Ortiz, Fernando C.; Ortolani, Domiziana; Del Rio, Rodrigo
    Paraquat (PQT) herbicide is widely used in agricultural practices despite being highly toxic to humans. It has been proposed that PQT exposure may promote cardiorespiratory impairment. However, the physiological mechanisms involved in cardiorespiratory dysfunction following PQT exposure are poorly known. We aimed to determine the effects of PQT on ventilatory chemoreflex control, cardiac autonomic control, and cardiac function in rats. Male Sprague-Dawley rats received two injections/week of PQT (5 mg.kg(-1) ip) for 4 wk. Cardiac function was assessed through echocardiography and pressure-volume loops. Ventilatory function was evaluated using whole body plethysmography. Autonomic control was indirectly evaluated by heart rate variability (HRV). Cardiac electrophysiology (EKG) and exercise capacity were also measured. Four weeks of PQT administration markedly enlarged the heart as evidenced by increases in ventricular volumes and induced cardiac diastolic dysfunction. Indeed, end-diastolic pressure was significantly higher in PQT rats compared with control (2.42 +/- 0.90 vs. 4.01 +/- 0.92 mmHg, PQT vs. control, P < 0.05). In addition, PQT significantly reduced both the hypercapnic and hypoxic ventilatory chemoreflex response and induced irregular breathing. Also, PQT induced autonomic imbalance and reductions in the amplitude of EKG waves. Finally, PQT administration impaired exercise capacity in rats as evidenced by a similar to 2-fold decrease in times-to-fatigue compared with control rats. Our results showed that 4 wk of PQT treatment induces cardiorespiratory dysfunction in rats and suggests that repetitive exposure to PQT may induce harmful mid/long-term cardiovascular, respiratory, and cardiac consequences.
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    Rostral ventrolateral medullary catecholaminergic neurones mediate irregular breathing pattern in volume overload heart failure rats
    (2019) Toledo, Camilo; Andrade, David C.; Diaz, Hugo S.; Pereyra, Katherin V.; Schwarz, Karla G.; Diaz-Jara, Esteban; Oliveira, Luiz M.; Takakura, Ana C.; Moreira, Thiago S.; Schultz, Harold D.; Marcus, Noah J.; Del Rio, Rodrigo
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    Superoxide dismutase 2 deficiency is associated with enhanced central chemoreception in mice: Implications for breathing regulation
    (2024) Diaz-Jara, Esteban; Pereyra, Katherine; Vicencio, Sinay; Olesen, Margrethe A.; Schwarz, Karla G.; Toledo, Camilo; Diaz, Hugo S.; Quintanilla, Rodrigo A.; Del Rio, Rodrigo
    Aims: In mammals, central chemoreception plays a crucial role in the regulation of breathing function in both health and disease conditions. Recently, a correlation between high levels of superoxide anion (O2.-) in the Retrotrapezoid nucleus (RTN), a main brain chemoreceptor area, and enhanced central chemoreception has been found in rodents. Interestingly, deficiency in superoxide dismutase 2 (SOD2) expression, a pivotal antioxidant enzyme, has been linked to the development/progression of several diseases. Despite, the contribution of SOD2 on O2.-regulation on central chemoreceptor function is unknown. Accordingly, we sought to determine the impact of partial deletion of SOD2 expression on i) O2.-accumulation in the RTN, ii) central ventilatory chemoreflex function, and iii) disordered-breathing. Finally, we study cellular localization of SOD2 in the RTN of healthy mice.Methods: Central chemoreflex drive and breathing function were assessed in freely moving heterozygous SOD2 knockout mice (SOD2+/-mice) and age-matched control wild type (WT) mice by whole-body plethysmography. O2.-levels were determined in RTN brainstem sections and brain isolated mitochondria, while SOD2 protein expression and tissue localization were determined by immunoblot, RNAseq and immunofluorescent staining, respectively.Results: Our results showed that SOD2+/-mice displayed reductions in SOD2 levels and high O2.-formation and mitochondrial dysfunction within the RTN compared to WT. Additionally, SOD2+/-mice displayed a heightened ventilatory response to hypercapnia and exhibited overt signs of altered breathing patterns. Both, RNAseq analysis and immunofluorescence co-localization studies showed that SOD2 expression was confined to RTN astrocytes but not to RTN chemoreceptor neurons. Finally, we found that SOD2+/-mice displayed alterations in RTN astrocyte morphology compared to RTN astrocytes from WT mice.Innovation & conclusion: These findings provide first evidence of the role of SOD2 in the regulation of O2.-levels in the RTN and its potential contribution on the regulation of central chemoreflex function. Our results suggest that reductions in the expression of SOD2 in the brain may contribute to increase O2.-levels in the RTN being the outcome a chronic surge in central chemoreflex drive and the development/maintenance of altered breathing patterns. Overall, dysregulation of SOD2 and the resulting increase in O2.-levels in brainstem respiratory areas can disrupt normal respiratory control mechanisms and contribute to breathing dysfunction seen in certain disease conditions characterized by high oxidative stress.
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    Topical Application of Connexin43 Hemichannel Blocker Reduces Carotid Body-Mediated Chemoreflex Drive in Rats
    (2018) Andrade Andrade, David Cristóbal; Iturriaga Agüera, Rodrigo; Toledo, Camilo; Lucero, Claudia M.; Diaz, Hugo S.; Arce-Alvarez, Alexis; Retamal, Mauricio A.; Marcus, Noah J.; Alcayaga Urbina, Julio Andrés; Del Rio, Rodrigo
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    Ventilatory and Autonomic Regulation in Sleep Apnea Syndrome: A Potential Protective Role for Erythropoietin?
    (2018) Andrade Andrade, David Cristóbal; Haine, Liasmine; Toledo, Camilo; Diaz, Hugo S.; Quintanilla, Rodrigo A.; Marcus, Noah J.; Iturriaga Agüera, Rodrigo; Richalet, Jean-Paul; Voituron, Nicolas; Del Rio, Rodrigo