Search Results (8)

Background/Objectives: Increasing evidence reveals the likely peripheral etiology of Parkinson’s disease; however, the mechanistic insight into α-Synuclein aggregation in the periphery remains unclear. This study aimed to explore the effect of abnormal expression of renalase on dopamine metabolism, toxic DOPAL generation, and subsequently, α-Synuclein aggregation. Methods: Blood pressure (BP) was monitored while changing the body position of rats; the serum level of renalase was detected by ELISA; the mRNA/protein of renalase and α-Synuclein were determined by qRT-PCR/Western blot; DOPAL was measured using HPLC; renalase distribution was explored by immunostaining; cell viability and ultrastructure were examined by TUNEL and electron microscopy, respectively. Results: The results showed that, in PD model rats, the serum level of renalase was increased time-dependently with up-regulated renalase gene/protein expression in the nodose ganglia, nucleus tractus solitarius, and heart; a reduced dopamine content was also detected by the renalase overexpression in PC12 cells. Strikingly, up-regulated renalase and orthostatic BP changes were observed before the behavioral changes in the model rats. Meanwhile, the levels of DOPAL and α-Synuclein were increased time-dependently. Intriguingly, the low molecular weight of α-Synuclein declined coordinately with the increase in the higher molecular weight of α-Synuclein. Clear ultrastructure damage at the cellular level supported the notion of molecular findings. Notably, the α-Synuclein aggregation-induced impairment of the axonal transport function predates neuronal degeneration mediated by renalase overexpression. Conclusions: Our results demonstrate that abnormal peripheral dopamine metabolism mediated by overexpressed renalase promotes the DOPAL-induced α-Synuclein and leads to baroreflex afferent neuronal degeneration and early autonomic failure. Full article

Background: Cardiovascular disease (CVD) is the leading cause of mortality and disability worldwide. While sex differences in CVD have been well documented, the physiological mechanisms of those sex differences remain unclear. As important components of the cardiovascular system, cardiac vagal control and baroreflex serve as mechanisms of sex differences in CVD and are modifiable factors for gender-specific CVD preventions. Methods: Ninety-four healthy adults (18–44 years of age; M_age = 21.09 years; 46 female) were recruited to complete the assessments of heart rate variability (HRV) at a resting baseline and the cardiac timing effect on an R-wave-locked reaction time (RT) task, which were used as the indicator of cardiac vagal control and a novel behavioral measure of baroreflex activity, respectively. HRV metrics (including the root mean square of successive R-R interval differences, high frequency and low frequency heart rate variability, and low frequency-to-high frequency ratio), the cardiac timing effect (the inhibition of RT response at the phase of cardiac systole compared to diastole), and their associations were compared between female and male participants. Results: Female participants showed higher levels of vagally mediated HRV after adjusting for basal resting heart rate. Importantly, the cardiac timing effect on RT responses was positively correlated with vagally mediated HRV among males but not among females. Conclusions: Females and males exhibited different physiological processes to regulate cardiovascular functions and behavioral outcomes. The present findings will help to reduce gender disparities in the preventive care of CVD and improve cardiovascular health for both women and men. Full article

Multi-drug therapies are common in cardiovascular disease intervention; however, io channel/pump coordination has not been tested electrophysiologically. Apparently, inward currents were not elicited by Yoda1/10 nM or Dobutamine/100 nM alone in Ah-type baroreceptor neurons, but were by their combination. To verify this, electroneurography and the whole-cell patch-clamp technique were performed. The results showed that Ah- and C-volley were dramatically increased by the combination at 0.5 V and 5 V, in contrast to A-volley, as consistent with repetitive discharge elicited by step and ramp with markedly reduced current injection/stimulus intensity. Notably, a frequency-dependent action potential (AP) duration was increased with Iberiotoxin-sensitive K⁺ component. Furthermore, an increased peak in AP measured in phase plots suggested enhanced Na⁺ influx, cytoplasmic Ca²⁺ accumulation through reverse mode of Na⁺/Ca²⁺ exchanger, and, consequently, functional KCa1.1 up-regulation. Strikingly, the Yoda1- or Dbtm-mediated small/transient Na⁺/K⁺-pump currents were robustly increased by their combination, implying a quick ion equilibration that may also be synchronized by hyperpolarization-induced voltage-sag, enabling faster repetitive firing. These novel findings demonstrate multi-channel/pump collaboration together to integrate neurotransmission at the cellular level for baroreflex, providing an afferent explanation in sexual dimorphic blood pressure regulation, and raising the caution regarding the individual drug concentration in multi-drug therapies to optimize efficacy and minimize toxicity. Full article

Heart rate variability is a useful measure for monitoring the autonomic nervous system. Heart rate variability measurements have gained significant demand not only in science, but also in the public due to the fairly low price and wide accessibility of the Internet of things. The scientific debate about one of the measures of heart rate variability, i.e., what low-frequency power is reflecting, has been ongoing for decades. Some schools reason that it represents the sympathetic loading, while an even more compelling reasoning is that it measures how the baroreflex modulates the cardiac autonomic outflow. However, the current opinion manuscript proposes that the discovery of the more precise molecular characteristics of baroreceptors, i.e., that the Piezo2 ion channel containing vagal afferents could invoke the baroreflex, may possibly resolve this debate. It is long known that medium- to high-intensity exercise diminishes low-frequency power to almost undetectable values. Moreover, it is also demonstrated that the stretch- and force-gated Piezo2 ion channels are inactivated in a prolonged hyperexcited state in order to prevent pathological hyperexcitation. Accordingly, the current author suggests that the almost undetectable value of low-frequency power at medium- to high-intensity exercise reflects the inactivation of Piezo2 from vagal afferents in the baroreceptors with some Piezo1 residual activity contribution. Consequently, this opinion paper highlights how low-frequency power of the heart rate variability could represent the activity level of Piezo2 in baroreceptors. Full article

Purpose: The goal of this study on Spinal Cord Injury (SCI) patients with cervical or thoracic lesion was to assess whether disturbances of ANS control, according to location, might differently affect vagal and sympatho-vagal markers during sleep and orthostatic challenge. We analyzed with linear and nonlinear techniques beat-by-beat RR and arterial pressure (and respiration) variability signals, extracted from a polysomnographic study and a rest–tilt test. We considered spontaneous or induced sympathetic excitation, as obtained shifting from non-REM to REM sleep or from rest to passive tilt. We obtained evidence of ANS cardiac (dys)regulation, of greater importance for gradually proximal location (i.e., cervical) SCI, compatible with a progressive loss of modulatory role of sympathetic afferents to the spinal cord. Furthermore, in accordance with the dual, vagal and sympathetic bidirectional innervation, the results suggest that vagally mediated negative feedback baroreflexes were substantially maintained in all cases. Conversely, the LF and HF balance (expressed specifically by normalized units) appeared to be negatively affected by SCI, particularly in the case of cervical lesion (group p = 0.006, interaction p = 0.011). Multivariate analysis of cardiovascular variability may be a convenient technique to assess autonomic responsiveness and alteration of functionality in patients with SCI addressing selectively vagal or sympathetic alterations and injury location. This contention requires confirmatory studies with a larger population. Full article

Natriuretic peptides (NPs) induce vasodilation, natriuresis, and diuresis, counteract the renin–angiotensin–aldosterone system and autonomic nervous system, and are key regulators of cardiovascular volume and pressure homeostasis. Baroreflex afferent pathway is an important reflex loop in the neuroregulation of blood pressure (BP), including nodose ganglion (NG) and nucleus tractus solitarius (NTS). Dysfunction of baroreflex would lead to various hypertensions. Here, we carried out functional experiments to explore the effects of NPs on baroreflex afferent function. Under physiological and hypertensive condition (high-fructose drinking-induced hypertension, HFD), BP was reduced by NPs through NG microinjection and baroreflex sensitivity (BRS) was enhanced via acute intravenous NPs injection. These anti-hypertensive effects were more obvious in female rats with the higher expression of NPs and its receptor A/B (NPRA/NPRB) and lower expression of its receptor C (NPRC). However, these effects were not as obvious as those in HFD rats compared with the same gender control group, which is likely to be explained by the abnormal expression of NPs and NPRs in the hypertensive condition. Our data provide additional evidence showing that NPs play a crucial role in neurocontrol of BP regulation via baroreflex afferent function and may be potential targets for clinical management of metabolic-related hypertension. Full article

The arterial baroreflex is a key autonomic regulator of blood pressure whose dysfunction has been related to several cardiovascular diseases. Changes in blood pressure are sensed by specific mechanosensory proteins, called baroreceptors, particularly located in the outer layer of the carotid sinus and the inner curvature of the aortic arch. The signal is propagated along the afferent nerves to the central nervous system and serves as negative feedback of the heart rate. Despite extensive research, the precise molecular nature of baroreceptors remains elusive. Current knowledge assumes that baroreceptors are ion channels at the nerve endings within the outer layer of the arteries. However, the evidence is based mainly on animal experiments, and the specific types of mechanosensitive receptors responsible for the signal transduction are still unknown. Only a few studies have investigated mechanosensory transmission in the aortic arch. In addition, although aortic dissection, and particularly type A involving the aortic arch, is one of the most life-threatening cardiovascular disorders, there is no knowledge about the impact of aortic dissection on baroreceptor function. In this review, we aim not to highlight the regulation of the heart rate but what mechanical stimuli and what possible ion channels transfer the corresponding signal within the aortic arch, summarizing and updating the current knowledge about baroreceptors, specifically in the aortic arch, and the impact of aortic pathologies on their function. Full article

Sodium salicylate (SA), a cyclooxygenase inhibitor, has been shown to increase insulin sensitivity and to suppress inflammation in obese patients and animal models. Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel expressed in afferent nerve fibers. Cyclooxygenase-derived prostaglandins are involved in the activation and sensitization of TRPV1. This study tested whether the metabolic and renal effects of SA were mediated by the TRPV1 channel. Wild-type (WT) and TRPV1^−/− mice were fed a Western diet (WD) for 4 months and received SA infusion (120mg/kg/day) or vehicle for the last 4 weeks of WD feeding. SA treatment significantly increased blood pressure in WD-fed TRPV1^−/− mice (p < 0.05) but not in WD-fed WT mice. Similarly, SA impaired renal blood flow in TRPV1^−/− mice (p < 0.05) but not in WT mice. SA improved insulin and glucose tolerance in both WT and TRPV1^−/− mice on WD (all p < 0.05). In addition, SA reduced renal p65 and urinary prostaglandin E2, prostaglandin F1α, and interleukin-6 in both WT and TRPV1^−/− mice (all p < 0.05). SA decreased urine noradrenaline levels, increased afferent renal nerve activity, and improved baroreflex sensitivity in WT mice (all p < 0.05) but not in TRPV1^−/− mice. Importantly, SA increased serum creatinine and urine kidney injury molecule-1 levels and decreased the glomerular filtration rate in obese WT mice (all p < 0.05), and these detrimental effects were significantly exacerbated in obese TRPV1^−/− mice (all p < 0.05). Lastly, SA treatment increased urine albumin levels in TRPV1^−/− mice (p < 0.05) but not in WT mice. Taken together, SA-elicited metabolic benefits and anti-inflammatory effects are independent of TRPV1, while SA-induced sympathetic suppression is dependent on TRPV1 channels. SA-induced renal dysfunction is dependent on intact TRPV1 channels. These findings suggest that SA needs to be cautiously used in patients with obesity or diabetes, as SA-induced renal dysfunction may be exacerbated due to impaired TRPV1 in obese and diabetic patients. Full article