Browsing by Author "Diaz-Jara, Esteban"

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    Activation of Intra-nodose Ganglion P2X7 Receptors Elicit Increases in Neuronal Activity
    (2023) Alcayaga, Julio; Vera, Jorge; Reyna-Jeldes, Mauricio; Covarrubias, Alejandra A. A.; Coddou, Claudio; Diaz-Jara, Esteban; Del Rio, Rodrigo; Retamal, Mauricio A. A.
    Vagus nerve innervates several organs including the heart, stomach, and pancreas among others. Somas of sensory neurons that project through the vagal nerve are located in the nodose ganglion. The presence of purinergic receptors has been reported in neurons and satellite glial cells in several sensory ganglia. In the nodose ganglion, calcium depletion-induced increases in neuron activity can be partly reversed by P2X7 blockers applied directly into the ganglion. The later suggest a possible role of P2X7 receptors in the modulation of neuronal activity within this sensory ganglion. We aimed to characterize the response to P2X7 activation in nodose ganglion neurons under physiological conditions. Using an ex vivo preparation for electrophysiological recordings of the neural discharges of nodose ganglion neurons, we found that treatments with ATP induce transient neuronal activity increases. Also, we found a concentration-dependent increase in neural activity in response to Bz-ATP (ED50 = 0.62 mM, a selective P2X7 receptor agonist), with a clear desensitization pattern when applied every similar to 30 s. Electrophysiological recordings from isolated nodose ganglion neurons reveal no differences in the responses to Bz-ATP and ATP. Finally, we showed that the P2X7 receptor was expressed in the rat nodose ganglion, both in neurons and satellite glial cells. Additionally, a P2X7 receptor negative allosteric modulator decreased the duration of Bz-ATP-induced maximal responses without affecting their amplitude. Our results show the presence of functional P2X7 receptors under physiological conditions within the nodose ganglion of the rat, and suggest that ATP modulation of nodose ganglion activity may be in part mediated by the activation of P2X7 receptors.
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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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    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 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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    Inhibition of Brainstem Endoplasmic Reticulum Stress Rescues Cardiorespiratory Dysfunction in High Output Heart Failure
    (2021) Diaz, Hugo S.; Andrade, David C.; Toledo, Camilo; Schwarz, Karla G.; Pereyra, Katherin, V; Diaz-Jara, Esteban; Marcus, Noah J.; Del Rio, Rodrigo
    Recent evidence shows that chronic activation of catecholaminergic neurons of the rostral ventrolateral medulla is crucial in promoting autonomic imbalance and cardiorespiratory dysfunction in high output heart failure (HF). Brainstem endoplasmic reticulum stress (ERS) is known to promote cardiovascular dysfunction; however, no studies have addressed the potential role of brainstem ERS in cardiorespiratory dysfunction in high output HF. In this study, we assessed the presence of brainstem ERS and its potential role in cardiorespiratory dysfunction in an experimental model of HF induced by volume overload. High output HF was surgically induced via creation of an arterio-venous fistula in adult male Sprague-Dawley rats. Tauroursodeoxycholic acid (TUDCA), an inhibitor of ERS, or vehicle was administered intracerebroventricularly for 4 weeks post-HF induction. Compared with vehicle treatment, TUDCA improved cardiac autonomic balance (LFHRV/HFHRV ratio, 3.02 +/- 0.29 versus 1.14 +/- 0.24), reduced cardiac arrhythmia incidence (141.5 +/- 26.7 versus 35.67 +/- 12.5 events/h), and reduced abnormal respiratory patterns (Apneas: 11.83 +/- 2.26 versus 4.33 +/- 1.80 events/h). TUDCA administration (HF+Veh versus HF+TUDCA, P<0.05) attenuated cardiac hypertrophy (HW/BW 4.4 +/- 0.3 versus 4.0 +/- 0.1 mg/g) and diastolic dysfunction. Analysis of rostral ventrolateral medulla gene expression confirmed the presence of ERS, inflammation, and activation of renin-angiotensin system pathways in high output HF and showed that TUDCA treatment completely abolished ERS and ERS-related signaling. Taken together, these results support the notion that ERS plays a role in cardiorespiratory dysfunction in high output HF and more importantly that reducing brain ERS with TUDCA treatment has a potent salutary effect on cardiac function in this model.
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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.