Browsing by Author "Toledo C."

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    Acute Chemogenetic Inhibition of Caudal NTS Astrocytes Reduced Systemic Blood Pressure in Rats Exposed to Chronic Intermittent Hypoxia-mimicking Sleep Apnea Syndrome
    (NLM (Medline), 2022) Iturriaga R.; Toledo C.; Ortolani D.; Del Rio R.
    © FASEB.Chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea, enhances carotid body (CB) discharges, leading to heightened sympathetic outflow and systemic hypertension. Previously, we found that CBs play a pivotal role in the hyperactivation of central nervous system (CNS) autonomic nuclei following CIH, particularly at the level of the caudal portion of the nucleus of the tractus solitary (NTS). Indeed, increased CB afferent activity during CIH increases the expression of pro-inflammatory cytokines in the NTS, suggesting that CBs may drive neuroinflammation at key cardiorespiratory regulatory areas. Astrocytes has been implicated in inflammatory processes at the CNS. However, the contribution of NTS astrocytes on the cardiorespiratory abnormalities following CIH has not been studied. Accordingly, we assessed the role of astrocytes residing within the NTS on the maintenance of hypertension following CIH. Male Sprague-Dawley rats (200 g) were exposed to CIH (5-6% inspired O2 for 20s, followed by room air for 280s, 12 times/h, 8 h/day, for 28 days). Arterial blood pressure (BP) was measured by indwelling telemetry. At 7 days of CIH exposure, rats were anesthetized and an adeno-associated virus (AAV; 450 nL, 1*10-12 vg) containing an inhibitory (Gi) Designer Receptor Exclusively Activated by Designer Drugs (DREADD) expressed under the control of the GFAP promoter was bilaterally injected into the caudal portion of the NTS using stereotaxic coordinates (-14.3 mm to bregma). At day 28 of CIH, hemodynamic and respiratory parameters were recorded before and after inhibition of NTS astrocytes with clozapine N-oxide (CNO, 1mg/kg, ip.). At the end of the experiments rats were transcardially perfused with 4% buffered paraformaldehyde, brains extracted and sectioned to assess astrocyte activation within the NTS. Twenty-eight days of CIH resulted in a significant 2-fold increase in NTS astrocyte activation as evidenced by enhanced reactivity of GFAP. Additionally, resting BP was markedly elevated compared to Sham conditions (MABP, 98±2 vs. 84±2 mmHg, CIH vs. Sham; p<0.05). Acute chemogenetic inhibition of NTS astrocytes following 28 days of CIH results in a significant reduction in BP (⁓10 mmHg; p<0.05). In addition, the exacerbated hemodynamic response triggered by acute hypoxic stimulation (Fi O2 10%) in rats exposed to CIH for 28 days was also reduced by NTS astrocyte inhibition ΔMABP, 30±2 vs. 15±2 mmHg, pre vs. post CNO; p<0.05). No cardiovascular effects of CNO alone were found in control rats that did not underwent AAV-DREADD-Gi injection into the NTS. Taken together, our results support a role for NTS astrocyte activation on the maintenance of hypertension following chronic CIH and suggest that activation of NTS astrocytes may participate in the CB-mediated cardiovascular reflex response during hypoxic stimulation.
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    Carotid Body-Mediated Chemoreflex Function in Aging and the Role of Receptor-Interacting Protein Kinase
    (Springer, 2023) Diaz-Jara E.; Schwarz K.G.; Rios-Gallardo A.; Toledo C.; Alcayaga J.A.; Court F.A.; Del Rio R.; CEDEUS (Chile)
    © 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.Ventilatory impairment during aging has been linked to carotid body (CB) dysfunction. Anatomical/morphological studies evidenced CB degeneration and reductions in the number of CB chemoreceptor cells during aging. The mechanism(s) related to CB degeneration in aging remains elusive. Programmed cell death encompasses both apoptosis and necroptosis. Interestingly, necroptosis can be driven by molecular pathways related to low-grade inflammation, one hallmark of the aging process. Accordingly, we hypothesized that necrotic cell death dependent on receptor-interacting protein kinase-3 (RIPK3) may contribute, at least in part, to impair CB function during aging. Adult (3 months) and aged (24 months) wild type (WT) and RIPK3-/- mice were used to study chemoreflex function. Aging results in significant reductions in both the hypoxic (HVR) and hypercapnic ventilatory responses (HCVR). Adult RIPK3-/- mice showed normal HVR and HCVR compared to adult WT mice. Remarkable, aged RIPK3-/- mice displayed no reductions in HVR nor in HCVR. Indeed, chemoreflex responses obtained in aged RIPK3-/- KO mice were undistinguishable from the ones obtained in adult WT mice. Lastly, we found high prevalence of breathing disorders during aging and this was absent in aged RIPK3-/- mice. Together our results support a role for RIPK3-mediated necroptosis in CB dysfunction during aging.
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    Enhanced Peripheral Chemoreflex Drive Is Associated with Cardiorespiratory Disorders in Mice with Coronary Heart Disease
    (Springer, 2023) Bravo L.; Pereyra K.V.; Diaz H.S.; Flores M.; Schwarz K.G.; Toledo C.; Diaz-Jara E.; Gonzalez L.; Andia M.E.; Del Rio R.; CEDEUS (Chile)
    © 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.Coronary heart disease (CHD) is a prevalent cardiovascular disease characterized by coronary artery blood flow reductions caused by lipid deposition and oxidation within the coronary arteries. Dyslipidemia is associated with local tissue damage by oxidative stress/inflammation and carotid bodies (CB) peripheral chemoreceptors are heavily modulated by both reactive oxygen species and pro-inflammatory molecules (i.e., cytokines). Despite this, it is not know whether CB-mediated chemoreflex drive may be affected in CHD. In the present study, we evaluated peripheral CB-mediated chemoreflex drive, cardiac autonomic function, and the incidence of breathing disorders in a murine model of CHD. Compared to age-matched control mice, CHD mice showed enhanced CB-chemoreflex drive (twofold increase in the hypoxic ventilatory response), cardiac sympathoexcitation, and irregular breathing disorders. Remarkably, all these were closely linked to the enhanced CB-mediated chemoreflex drive. Our results showed that mice with CHD displayed an enhanced CB chemoreflex, sympathoexcitation, and disordered breathing and suggest that CBs may be involved in chronic cardiorespiratory alterations in the setting of CHD.
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    Role of Peripheral Chemoreceptors on Enhanced Central Chemoreflex Drive in Nonischemic Heart Failure
    (Springer, 2023) Pereyra K.; Diaz-Jara E.; Arias P.; Bravo L.; Toledo C.; Schwarz K.; Del Rio R.; CEDEUS (Chile)
    © 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.Heart failure (HF) is a prevalent disease in elderly population. Potentiation of the ventilatory chemoreflex drive plays a pivotal role in disease progression, at least in part, through their contribution to the generation/maintenance of breathing disorders. Peripheral and central chemoreflexes are mainly regulated by carotid body (CB) and the retrotrapezoid nuclei (RTN), respectively. Recent evidence showed an enhanced central chemoreflex drive in rats with nonischemic HF along with breathing disorders. Importantly, increase activity from RTN chemoreceptors contribute to the potentiation of central chemoreflex response to hypercapnia. The precise mechanism driving RTN potentiation in HF is still elusive. Since interdependency of RTN and CB chemoreceptors has been described, we hypothesized that CB afferent activity is required to increase RTN chemosensitivity in the setting of HF. Accordingly, we studied central/peripheral chemoreflex drive and breathing disorders in HF rats with and without functional CBs (CB denervation). We found that CB afferent activity was required to increase central chemoreflex drive in HF. Indeed, CB denervation restored normal central chemoreflex drive and reduced the incidence of apneas by twofold. Our results support the notion that CB afferent activity plays an important role in central chemoreflex potentiation in rats with HF.