Browsing by Author "Ortolani, Domiziana"

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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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    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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    Sleep dysregulation in sympathetic-mediated diseases: implications for disease progression
    (2022) Jose Olivares, Maria; Toledo, Camilo; Ortolani, Domiziana; Ortiz, Fernando C.; Diaz, Hugo S.; Iturriaga, Rodrigo; Del Rio, Rodrigo
    The autonomic nervous system (ANS) plays an important role in the coordination of several physiological functions including sleep/wake process. Significant changes in ANS activity occur during wake-to-sleep transition maintaining the adequate cardiorespiratory regulation and brain activity. Since sleep is a complex homeostatic function, partly regulated by the ANS, it is not surprising that sleep disruption trigger and/or evidence symptoms of ANS impairment. Indeed, several studies suggest a bidirectional relationship between impaired ANS function (i.e. enhanced sympathetic drive), and the emergence/development of sleep disorders. Furthermore, several epidemiological studies described a strong association between sympathetic-mediated diseases and the development and maintenance of sleep disorders resulting in a vicious cycle with adverse outcomes and increased mortality risk. However, which and how the sleep/wake control and ANS circuitry becomes affected during the progression of ANS-related diseases remains poorly understood. Thus, understanding the physiological mechanisms underpinning sleep/wake-dependent sympathetic modulation could provide insights into diseases involving autonomic dysfunction. The purpose of this review is to explore potential neural mechanisms involved in both the onset/maintenance of sympathetic-mediated diseases (Rett syndrome, congenital central hypoventilation syndrome, obstructive sleep apnoea, type 2 diabetes, obesity, heart failure, hypertension, and neurodegenerative diseases) and their plausible contribution to the generation of sleep disorders in order to review evidence that may serve to establish a causal link between sleep disorders and heightened sympathetic activity.