Search Results (9)

The carotid body (CB) senses arterial PO₂, PCO₂, and pH levels, eliciting reflex responses to maintain cardiorespiratory homeostasis. Chronic intermittent hypoxia (CIH), the hallmark of obstructive sleep apnea, elicits autonomic and cardiorespiratory alterations that are attributed to an enhanced CB chemosensory responsiveness to hypoxia, which in turn activates neurons and glial cells in the nucleus of the tractus solitarius (NTS). Although the CB contribution to the CIH-induced pathological alterations is well-known, the underlying mechanisms are not fully understood. A growing body of new evidence suggests a crucial role for ROS in acute CB oxygen sensing, as well as in the potentiation of chemosensory discharge and the activation of the central chemoreflex pathway in CIH. Indeed, it has been proposed that acute hypoxia disrupts mitochondrial electron transport, increasing ROS and NADH in the chemoreceptor cells, which inhibit voltage-gated K⁺ channels, producing cell depolarization, Ca²⁺ entry, and release of excitatory transmitters. In addition, new evidence supports that the enhanced CB afferent discharge contributes to persistent CIH-induced cardiorespiratory alterations, likely triggering neuroinflammation in the NTS. Thus, in this review, we will examine the experimental evidence that supports the involvement of ROS in the acute O₂ sensing process, and their role in the enhanced CB chemosensory discharges, the glial-related inflammation in the NTS, and the cardiorespiratory alterations induced by CIH. Full article

Background: A reduction in carotid artery blood flow (CABF) and ultimately in wall shear stress (WSS) is a major driver of heightened peripheral chemoreceptor (PCh) activity in animal models of heart failure. However, it is yet to be translated to humans. To provide more insight into this matter, we considered severe aortic stenosis (AS) before and after transcatheter aortic valve implantation (TAVI) as a human model of carotid and aortic body function under dramatically different hemodynamic conditions. Materials and Methods: A total of 26 severe AS patients (aged 77 ± 6 y, body mass index: 29.1 ± 5.1 kg/m², left ventricular ejection fraction (LVEF): 50 ± 15%) were subjected to a transient hypoxia test twice: immediately before vs. 1–4 months after TAVI (median follow-up: 95 days). PCh function was analyzed in terms of ventilatory (HVR, L/min/SpO₂%) and heart rate responses to hypoxia (HR slope, bpm/SpO₂%). Standard ultrasound (inc. aortic valve area [AVA], mean aortic valve gradient, peak aortic jet velocity, LVEF, and CABF), respiratory, hemodynamic, and blood parameters were collected at both visits. Pre- vs. post-TAVI data regarding HVR and HR slopes were available for N = 26 and N = 10 patients, respectively. Results: HVR did not change following TAVI (pre- vs. post-TAVI: 0.42 ± 0.29 vs. 0.39 ± 0.33 L/min/SpO₂%, p = 0.523). The HR slope increased after TAVI (pre- vs. post-TAVI: 0.26 ± 0.23 vs. 0.37 ± 0.30 bpm/SpO₂%, p = 0.019), and the magnitude of the increase was strongly associated with an increase in AVA (Spearman’s R = 0.80, p = 0.006). No other significant relations between pre- vs. post-TAVI changes in PCh activity measures vs. hemodynamic parameters were found (all p > 0.12). Conclusions: The ventilatory component of the PCh reflex (defined as HVR) in severe AS patients is not affected by TAVI, and pre-TAVI values in this group are fairly comparable to those reported previously for healthy subjects. On the contrary, HR responses to hypoxia are increased after TAVI, and pre-TAVI values appear to be lower compared to the healthy population. An extraordinarily strong correlation between post-TAVI increases in HR slope and AVA may suggest that hemodynamic repercussions of the surgery in the aortic body area (most likely reduced WSS) play a critical role in determining aortic body function with a negligible effect on the carotid bodies. However, caution is needed when interpreting the results of the HR response to hypoxia in our study due to the small sample size (N = 10). Full article

Lead exposure is a significant health concern, ranking among the top 10 most harmful substances for humans. There are no safe levels of lead exposure, and it affects multiple body systems, especially the cardiovascular and neurological systems, leading to problems such as hypertension, heart disease, cognitive deficits, and developmental delays, particularly in children. Gender differences are a crucial factor, with women’s reproductive systems being especially vulnerable, resulting in fertility issues, pregnancy complications, miscarriages, and premature births. The globalization of lead exposure presents new challenges in managing this issue. Therefore, understanding the gender-specific implications is essential for developing effective treatments and public health strategies to mitigate the impact of lead-related health problems. This study examined the effects of intermittent and permanent lead exposure on both male and female animals, assessing behaviours like anxiety, locomotor activity, and long-term memory, as well as molecular changes related to astrogliosis. Additionally, physiological and autonomic evaluations were performed, focusing on baro- and chemoreceptor reflexes. The study’s findings revealed that permanent lead exposure has more severe health consequences, including hypertension, anxiety, and reactive astrogliosis, affecting both genders. However, males exhibit greater cognitive, behavioural, and respiratory changes, while females are more susceptible to chemoreflex hypersensitivity. In contrast, intermittent lead exposure leads to hypertension and reactive astrogliosis in both genders. Still, females are more vulnerable to cognitive impairment, increased respiratory frequency, and chemoreflex hypersensitivity, while males show more reactive astrocytes in the hippocampus. Overall, this research emphasizes the importance of not only investigating different types of lead exposure but also considering gender differences in toxicity when addressing this public health concern. Full article

Introduction: Hypertension, a leading cause of death, was investigated in this study to understand the role of specific brain regions in regulating blood pressure. The lateral parabrachial nucleus (LPBN), Kolliker-fuse nucleus (KF), and periductal grey matter (PAG) were examined for their involvement in hypertension. Methods: Lentiviral vectors were used to alter the activity of these brain regions in hypertensive rats. Over a 75-day period, blood pressure, heart rate, reflex responses, and heart rate variability were measured. Results: Decreasing the activity in the LPBN resulted in a reduced sympathetic outflow, lowering the blood pressure and heart rate. In the KF, the sympathetic activity decreased and chemoreflex variation was attenuated, without affecting the blood pressure. Silencing the PAG had no significant impact on blood pressure or sympathetic tone, but decreased cardiac baroreflex gain. Discussion: These findings highlight the significant role of the LPBN in hypertension-related sympathetic activation. Additionally, LPBN and KF neurons appear to activate mechanisms that control respiration and sympathetic outflow during chemoreceptor activation. Conclusions: The study provided insights into the contribution of the midbrain and pontine regions to neurogenic hypertension and offers potential avenues for future genetic interventions and developing novel treatment approaches. Full article

The nervous system is the primary target for lead exposure and the developing brain appears to be especially susceptible, namely the hippocampus. The mechanisms of lead neurotoxicity remain unclear, but microgliosis and astrogliosis are potential candidates, leading to an inflammatory cascade and interrupting the pathways involved in hippocampal functions. Moreover, these molecular changes can be impactful as they may contribute to the pathophysiology of behavioral deficits and cardiovascular complications observed in chronic lead exposure. Nevertheless, the health effects and the underlying influence mechanism of intermittent lead exposure in the nervous and cardiovascular systems are still vague. Thus, we used a rat model of intermittent lead exposure to determine the systemic effects of lead and on microglial and astroglial activation in the hippocampal dentate gyrus throughout time. In this study, the intermittent group was exposed to lead from the fetal period until 12 weeks of age, no exposure (tap water) until 20 weeks, and a second exposure from 20 to 28 weeks of age. A control group (without lead exposure) matched in age and sex was used. At 12, 20 and 28 weeks of age, both groups were submitted to a physiological and behavioral evaluation. Behavioral tests were performed for the assessment of anxiety-like behavior and locomotor activity (open-field test), and memory (novel object recognition test). In the physiological evaluation, in an acute experiment, blood pressure, electrocardiogram, and heart and respiratory rates were recorded, and autonomic reflexes were evaluated. The expression of GFAP, Iba-1, NeuN and Synaptophysin in the hippocampal dentate gyrus was assessed. Intermittent lead exposure induced microgliosis and astrogliosis in the hippocampus of rats and changes in behavioral and cardiovascular function. We identified increases in GFAP and Iba1 markers together with presynaptic dysfunction in the hippocampus, concomitant with behavioral changes. This type of exposure produced significant long-term memory dysfunction. Regarding physiological changes, hypertension, tachypnea, baroreceptor reflex impairment and increased chemoreceptor reflex sensitivity were observed. In conclusion, the present study demonstrated the potential of lead intermittent exposure inducing reactive astrogliosis and microgliosis, along with a presynaptic loss that was accompanied by alterations of homeostatic mechanisms. This suggests that chronic neuroinflammation promoted by intermittent lead exposure since fetal period may increase the susceptibility to adverse events in individuals with pre-existing cardiovascular disease and/or in the elderly. Full article

Reflex increases in breathing in response to acute hypoxia are dependent on activation of the carotid body (CB)—A specialised peripheral chemoreceptor. Central to CB O₂-sensing is their unique mitochondria but the link between mitochondrial inhibition and cellular stimulation is unresolved. The objective of this study was to evaluate if ex vivo intact CB nerve activity and in vivo whole body ventilatory responses to hypoxia were modified by alterations in succinate metabolism and mitochondrial ROS (mitoROS) generation in the rat. Application of diethyl succinate (DESucc) caused concentration-dependent increases in chemoafferent frequency measuring approximately 10–30% of that induced by severe hypoxia. Inhibition of mitochondrial succinate metabolism by dimethyl malonate (DMM) evoked basal excitation and attenuated the rise in chemoafferent activity in hypoxia. However, approximately 50% of the response to hypoxia was preserved. MitoTEMPO (MitoT) and 10-(6′-plastoquinonyl) decyltriphenylphosphonium (SKQ1) (mitochondrial antioxidants) decreased chemoafferent activity in hypoxia by approximately 20–50%. In awake animals, MitoT and SKQ1 attenuated the rise in respiratory frequency during hypoxia, and SKQ1 also significantly blunted the overall hypoxic ventilatory response (HVR) by approximately 20%. Thus, whilst the data support a role for succinate and mitoROS in CB and whole body O₂-sensing in the rat, they are not the sole mediators. Treatment of the CB with mitochondrial selective antioxidants may offer a new approach for treating CB-related cardiovascular–respiratory disorders. Full article

Carotid bodies (CBs) are peripheral chemoreceptors that sense changes in blood O₂, CO₂, and pH levels. Apart from ventilatory control, these organs are deeply involved in the homeostatic regulation of carbohydrates and lipid metabolism and inflammation. It has been described that CB dysfunction is involved in the genesis of metabolic diseases and that CB overactivation is present in animal models of metabolic disease and in prediabetes patients. Additionally, resection of the CB-sensitive nerve, the carotid sinus nerve (CSN), or CB ablation in animals prevents and reverses diet-induced insulin resistance and glucose intolerance as well as sympathoadrenal overactivity, meaning that the beneficial effects of decreasing CB activity on glucose homeostasis are modulated by target-related efferent sympathetic nerves, through a reflex initiated in the CBs. In agreement with our pre-clinical data, hyperbaric oxygen therapy, which reduces CB activity, improves glucose homeostasis in type 2 diabetes patients. Insulin, leptin, and pro-inflammatory cytokines activate the CB. In this manuscript, we review in a concise manner the putative pathways linking CB chemoreceptor deregulation with the pathogenesis of metabolic diseases and discuss and present new data that highlight the roles of hyperinsulinemia, hyperleptinemia, and chronic inflammation as major factors contributing to CB dysfunction in metabolic disorders. Full article

Sleep apnea is very common in patients with cardiovascular disease, especially in patients with hypertension. Over the last few decades a number of discoveries have helped support a causal relationship between the two and even resistant hypertension. The role neurogenic mechanisms play has gathered more attention in the recent past due to their immediate bedside utility. Several innovative discoveries in pathogenesis including those exploring the role of baroreflex gain, cardiovascular variability, chemoreceptor reflex activation and the sympathetic nervous system have emerged. In this review, we discuss the epidemiology of sleep apnea and hypertension and the pathogenic mechanisms contributing to neurogenic hypertension. Furthermore, recent management strategies in addition to continuous positive airway pressure (CPAP), such as upper airway stimulation and renal denervation that target these pathogenic mechanisms, are also discussed. Full article

Carotid bodies (CBs) are secondary sensory receptors in which the sensing elements, chemoreceptor cells, are activated by decreases in arterial PO₂ (hypoxic hypoxia). Upon activation, chemoreceptor cells (also known as Type I and glomus cells) increase their rate of release of neurotransmitters that drive the sensory activity in the carotid sinus nerve (CSN) which ends in the brain stem where reflex responses are coordinated. When challenged with hypoxic hypoxia, the physiopathologically most relevant stimulus to the CBs, they are activated and initiate ventilatory and cardiocirculatory reflexes. Reflex increase in minute volume ventilation promotes CO₂ removal from alveoli and a decrease in alveolar PCO₂ ensues. Reduced alveolar PCO₂ makes possible alveolar and arterial PO₂ to increase minimizing the intensity of hypoxia. The ventilatory effect, in conjunction the cardiocirculatory components of the CB chemoreflex, tend to maintain an adequate supply of oxygen to the tissues. The CB has been the focus of attention since the discovery of its nature as a sensory organ by de Castro (1928) and the discovery of its function as the origin of ventilatory reflexes by Heymans group (1930). A great deal of effort has been focused on the study of the mechanisms involved in O₂ detection. This review is devoted to this topic, mechanisms of oxygen sensing. Starting from a summary of the main theories evolving through the years, we will emphasize the nature and significance of the findings obtained with veratridine and tetrodotoxin (TTX) in the genesis of current models of O₂-sensing. Full article