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Background: Dexmedetomidine, renowned for its sedative, anxiolytic, and opioid-sparing properties, exerts its effects primarily within the locus ceruleus of the brainstem. By diminishing sympathetic outflow, it effectively attenuates stress responses. Despite its growing popularity, optimal dosing remains uncertain, particularly within the Indian population. This study aimed to compare the hemodynamic response attenuation achieved by two dexmedetomidine doses: 0.5 mcg/kg and 1 mcg/kg during laryngoscopy and intubation. Materials and Methods: One hundred elective surgery cases were consecutively enrolled in this prospective study after obtaining informed consent. The patients were randomly allocated into two groups, each comprising 50 cases. Group A received intravenous dexmedetomidine at 0.5 mcg/kg, while Group B received 1 mcg/kg, both diluted with 20 ml of normal saline over a 10-minute infusion using a pump. Hemodynamic responses from both the groups were then recorded. Results: Baseline diastolic blood pressure was comparable between groups, and at 10 minutes post-drug administration, as well as during intubation and 1 minute post-intubation (p>0.05). However, post-intubation diastolic blood pressure was significantly lower in Group B compared to Group A at 3 minutes post-intubation and remained lower through subsequent readings until 10 minutes post-intubation. Similarly, mean arterial pressure was significantly lower in Group B compared to Group A for all readings up to 10 minutes postintubation. Conclusion: In the context of attenuating the hemodynamic response to laryngoscopy and intubation, this study establishes the superiority of intravenous dexmedetomidine at 1 mcg/kg over 0.5 mcg/kg dosing. The higher dose may be particularly beneficial for patients with a history of myocardial ischemia, hypertension, or cerebrovascular accidents, for whom excessive stress response during laryngoscopy and intubation is undesirable. Caution is advised when administering the 1 mcg/kg dose due to potential bradycardia during drug infusion. [ABSTRACT FROM AUTHOR]

Despite the increasing number of anti-hypertensive drugs have been developed and used in the clinical setting, persistent deficiencies persist, including issues such as lifelong dosage, combination therapy. Notwithstanding receiving the treatment under enduring these deficiencies, approximately 4 in 5 patients still fail to achieve reliable blood pressure (BP) control. The application of neuromodulation in the context of hypertension presents a pioneering strategy for addressing this condition, con-currently implying a potential central nervous mechanism underlying hypertension onset. We hypothesize that neurological networks, an essential component of maintaining appropriate neurological function, are involved in hypertension. Drawing on both peer-reviewed research and our laboratory investigations, we endeavor to investigate the underlying neural mechanisms involved in hypertension by identifying a close relationship between its onset of hypertension and an excitation and inhibition (E/I) imbalance. In addition to the involvement of excitatory glutamatergic and GABAergic inhibitory system, the pathogenesis of hypertension is also associated with Voltage-gated sodium channels (VGSCs, Nav)-mediated E/I balance. The overloading of glutamate or enhancement of glutamate receptors may be attributed to the E/I imbalance, ultimately triggering hypertension. GABA loss and GABA receptor dysfunction have also proven to be involved. Furthermore, we have identified that abnormalities in sodium channel expression and function alter neural excitability, thereby disturbing E/I balance and potentially serving as a mechanism underlying hypertension. These insights are expected to furnish potential strategies for the advancement of innovative anti-hypertensive therapies and a meaningful reference for the exploration of central nervous system (CNS) targets of anti-hypertensives.

Metabolic syndrome is associated with cardiovascular dysfunction, including elevated sympathetic outflow. However, the underlying brain mechanisms are unclear. The nucleus tractus solitarius (NTS) critically regulates autonomic reflexes related to cardiovascular function and contains neurons projecting to the caudal ventrolateral medulla (CVLM). Nitric oxide (NO) is a diffusible freeradical messenger in the vascular, immune, and nervous systems. In this study, we determine if NO in the NTS is involved in the synaptic plasticity underlying the elevated sympathetic outflow in fructose-induced hypertension. We retrogradely labeled CVLM-projecting NTS neurons through the injection of FluoSpheres into the CVLM in a fructose-fed rat model to determine the cellular mechanism involved in increased sympathetic outflow. Fructose feeding increased the blood pressure and glucose levels, which represent metabolic syndrome. We found that fructose feeding reduces the NO precursor L-arginine-induced increase in the firing activity of CVLM-projecting NTS neurons. Furthermore, fructose feeding reduces the L-arginine-induced increase in presynaptic spontaneous glutamatergic synaptic inputs to NTS neurons, while NO donor DEA/NO produces an increase in glutamatergic synaptic inputs in fructose-fed rats similar to that in vehicle-treated rats. In addition, fructose feeding reduces the NO-induced depressor response and sympathoinhibition. These data suggested that fructose feeding reduced NO production and, thus, the subsequent NOinduced glutamate releases in the NTS and depressor response. The findings of this study provide new insights into the central mechanisms involved in the neural control of cardiovascular and autonomic functions in the NTS in metabolic syndrome. [ABSTRACT FROM AUTHOR]

Objective: Hepatic steatosis is a key initiating event in the pathogenesis of alcohol-associated liver disease (ALD), the most detrimental organ damage resulting from alcohol use disorder. However, the mechanisms by which alcohol induces steatosis remain incompletely understood. We have previously found that alcohol binging impairs brain insulin action, resulting in increased adipose tissue lipolysis by unrestraining sympathetic nervous system (SNS) outflow. Here, we examined whether an impaired brain–SNS–adipose tissue axis drives hepatic steatosis through unrestrained adipose tissue lipolysis and increased lipid flux to the liver. Methods: We examined the role of lipolysis, and the brain–SNS–adipose tissue axis and stress in alcohol induced hepatic triglyceride accumulation in a series of rodent models: pharmacological inhibition of the negative regulator of insulin signaling protein-tyrosine phosphatase 1β (PTP1b) in the rat brain, tyrosine hydroxylase (TH) knockout mice as a pharmacogenetic model of sympathectomy, adipocyte specific adipose triglyceride lipase (ATGL) knockout mice, wildtype (WT) mice treated with β3 adrenergic agonist or undergoing restraint stress. Results: Intracerebral administration of a PTP1b inhibitor, inhibition of adipose tissue lipolysis and reduction of sympathetic outflow ameliorated alcohol induced steatosis. Conversely, induction of adipose tissue lipolysis through β3 adrenergic agonism or by restraint stress worsened alcohol induced steatosis. Conclusions: Brain insulin resistance through upregulation of PTP1b, increased sympathetic activity, and unrestrained adipose tissue lipolysis are key drivers of alcoholic steatosis. Targeting these drivers of steatosis may provide effective therapeutic strategies to ameliorate ALD.

Corticotropin-releasing hormone (CRH) is a neuropeptide regulating neuroendocrine and autonomic function. CRH mRNA and protein levels in the hypothalamic paraventricular nucleus (PVN) are increased in primary hypertension. However, the role of CRH in elevated sympathetic outflow in primary hypertension remains unclear. CRHR1 proteins were distributed in retrogradely labeled PVN presympathetic neurons with an increased level in the PVN tissue in adult spontaneously hypertensive rats (SHRs) compared with age-matched male Wistar--Kyoto (WKY) rats. CRH induced a more significant increase in the firing rate of PVN-rostral ventrolateral medulla (RVLM) neurons and sympathoexcitatory response in SHRs than in WKY rats, an effect that was blocked by preapplication of NMDA receptors (NMDARs) antagonist AP5 and PSD-95 inhibitor, Tat- N-dimer. Blocking CRHRs with astressin or CRHR1 with NBI35965 significantly decreased the firing rate of PVN-RVLM output neurons and reduced arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) in SHRs but not in WKY, whereas blocking CRHR2 with antisauvagine-30 did not. Furthermore, Immunocytochemistry staining revealed that CRHR1 colocalized with NMDARs in PVN presympathetic neurons. Blocking CRHRs significantly decreased the NMDA currents in labeled PVN neurons. PSD-95-bound CRHR1 and PSD-95-bound GluN2A in the PVN were increased in SHRs. These data suggested that the upregulation of CRHR1 in the PVN is critically involved in the hyperactivity of PVN presympathetic neurons and elevated sympathetic outflow in primary hypertension. [ABSTRACT FROM AUTHOR]

Background and objective: Emotional stress substantially increases the risk of ischemic cardiovascular diseases. Previous study indicates that sympathetic outflow is increased under emotional stress. We aim to investigate the role of increased sympathetic outflow induced by emotional stress in myocardial ischemia–reperfusion (I/R) injury, and explore the underlying mechanisms. Methods and Results: We used Designer Receptors Exclusively Activated by Designer Drugs technique to activate the ventromedial hypothalamus (VMH), a critical emotion-related nucleus. The results revealed that emotional stress stimulated by VMH activation increased sympathetic outflow, enhanced blood pressure, aggravated myocardial I/R injury, and exacerbated infarct size. The RNA-seq and molecular detection demonstrated that toll-like receptor 7 (TLR7), myeloid differentiation factor 88 (MyD88), interferon regulatory factor 5 (IRF5), and downstream inflammatory markers in cardiomyocytes were significantly upregulated. Emotional stress-induced sympathetic outflow further exacerbated the disorder of the TLR7/MyD88/IRF5 inflammatory signaling pathway. While inhibition of the signaling pathway partially alleviated myocardial I/R injury aggravated by emotional stress-induced sympathetic outflow. Conclusion: Increased sympathetic outflow induced by emotional stress activates TLR7/MyD88/IRF5 signaling pathway, ultimately aggravating I/R injury. [ABSTRACT FROM AUTHOR]

Despite the increasing number of anti-hypertensive drugs have been developed and used in the clinical setting, persistent deficiencies persist, including issues such as lifelong dosage, combination therapy. Notwithstanding receiving the treatment under enduring these deficiencies, approximately 4 in 5 patients still fail to achieve reliable blood pressure (BP) control. The application of neuromodulation in the context of hypertension presents a pioneering strategy for addressing this condition, con-currently implying a potential central nervous mechanism underlying hypertension onset. We hypothesize that neurological networks, an essential component of maintaining appropriate neurological function, are involved in hypertension. Drawing on both peer-reviewed research and our laboratory investigations, we endeavor to investigate the underlying neural mechanisms involved in hypertension by identifying a close relationship between its onset of hypertension and an excitation and inhibition (E/I) imbalance. In addition to the involvement of excitatory glutamatergic and GABAergic inhibitory system, the pathogenesis of hypertension is also associated with Voltage-gated sodium channels (VGSCs, Nav)-mediated E/I balance. The overloading of glutamate or enhancement of glutamate receptors may be attributed to the E/I imbalance, ultimately triggering hypertension. GABA loss and GABA receptor dysfunction have also proven to be involved. Furthermore, we have identified that abnormalities in sodium channel expression and function alter neural excitability, thereby disturbing E/I balance and potentially serving as a mechanism underlying hypertension. These insights are expected to furnish potential strategies for the advancement of innovative anti-hypertensive therapies and a meaningful reference for the exploration of central nervous system (CNS) targets of anti-hypertensives., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Xia, Wang, Wang, Hu, Chen and Wang.)

The rostral ventrolateral medulla (RVLM) is a pivotal region in the central regulation of blood pressure (BP). It has been documented that silent information regulator 2 homolog 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent multifunctional transcription regulatory factor, has many cardiovascular protective effects. However, the role and significance of SIRT1 in the central regulation of cardiovascular activity, especially in RVLM, remains unknown. Therefore, the aim of this study was to explore the role and underlying mechanism of SIRT1 in the central regulation of cardiovascular activity in hypertension. Spontaneously hypertensive rats (SHRs) were given resveratrol (RSV) via intracerebroventricular (ICV) infusion or injected with SIRT1-overexpressing lentiviral vectors into the RVLM. In vitro experiments, angiotensin II (Ang II)-induced rat pheochromocytoma cell line (PC12 cells) were transfected with forkhead box protein O1 (FOXO1) small interfering RNA (siRNA) before treatment with RSV. Our results showed that SIRT1 activation with RSV or overexpression in the RVLM significantly decreased BP and sympathetic outflow of SHRs. Furthermore, SIRT1 overexpression in the RVLM significantly decreased reactive oxygen species (ROS) production and facilitated the forkhead box protein O1 (FOXO1) activation, accompanied by upregulation of the ROS-detoxifying enzyme superoxide dismutases 1 (SOD1) in the RVLM of SHRs. In PC12 cells, it was found that Ang II could induce oxidative stress and downregulate the SIRT1-FOXO1-SOD1 signaling pathway, which indicated that the suppressed expression of SIRT1 in the RVLM of SHRs might relate to the elevated central Ang II level. Furthermore, the enhanced oxidative stress and decreased SIRT1-FOXO1-SOD1 axis induced by Ang II were restored by treatment with RSV. However, these favorable effects mediated by SIRT1 activation were blocked by FOXO1 knockdown. Based on these findings, we concluded that SIRT1 activation or overexpression in the RVLM exerts anti-hypertensive effect through reducing oxidative stress via SIRT1-FOXO1-SOD1 signaling pathway, which providing a new target for the prevention and intervention of hypertension. [Display omitted] • The RVLM is a pivotal region for blood pressure regulation and plays a key role in the central anti-hypertensive mechanism. • Activation or overexpression SIRT1 in the RVLM exerts anti-hypertensive effect. • The RVLM SIRT1 mediated its cardiovascular protective effect through reducing oxidative stress via SIRT1-FOXO1-SOD1 axis. [ABSTRACT FROM AUTHOR]

Metabolic syndrome is associated with cardiovascular dysfunction, including elevated sympathetic outflow. However, the underlying brain mechanisms are unclear. The nucleus tractus solitarius (NTS) critically regulates autonomic reflexes related to cardiovascular function and contains neurons projecting to the caudal ventrolateral medulla (CVLM). Nitric oxide (NO) is a diffusible free-radical messenger in the vascular, immune, and nervous systems. In this study, we determine if NO in the NTS is involved in the synaptic plasticity underlying the elevated sympathetic outflow in fructose-induced hypertension. We retrogradely labeled CVLM-projecting NTS neurons through the injection of FluoSpheres into the CVLM in a fructose-fed rat model to determine the cellular mechanism involved in increased sympathetic outflow. Fructose feeding increased the blood pressure and glucose levels, which represent metabolic syndrome. We found that fructose feeding reduces the NO precursor L-arginine-induced increase in the firing activity of CVLM-projecting NTS neurons. Furthermore, fructose feeding reduces the L-arginine-induced increase in presynaptic spontaneous glutamatergic synaptic inputs to NTS neurons, while NO donor DEA/NO produces an increase in glutamatergic synaptic inputs in fructose-fed rats similar to that in vehicle-treated rats. In addition, fructose feeding reduces the NO-induced depressor response and sympathoinhibition. These data suggested that fructose feeding reduced NO production and, thus, the subsequent NO-induced glutamate releases in the NTS and depressor response. The findings of this study provide new insights into the central mechanisms involved in the neural control of cardiovascular and autonomic functions in the NTS in metabolic syndrome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhu, Sun, Wang and Li.)

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as anti-diabetic drugs and are approved for obesity treatment. However, GLP-1RAs also affect heart rate (HR) and arterial blood pressure (ABP) in rodents and humans. Although the activation of GLP-1 receptors (GLP-1R) is known to increase HR, the circuits recruited are unclear, and in particular, it is unknown whether GLP-1RAs activate preproglucagon (PPG) neurons, the brain source of GLP-1, to elicit these effects. Methods: We investigated the effect of GLP-1RAs on heart rate in anaesthetized adult mice. In a separate study, we manipulated the activity of nucleus tractus solitarius (NTS) PPG neurons (PPGNTS) in awake, freely behaving transgenic Glu-Cre mice implanted with biotelemetry probes and injected with AAV-DIO-hM3Dq:mCherry or AAV-mCherry-FLEX-DTA. Results: Systemic administration of the GLP-1RA Ex-4 increased resting HR in anaesthetized or conscious mice, but had no effect on ABP in conscious mice. This effect was abolished by β-adrenoceptor blockade with atenolol, but unaffected by the muscarinic antagonist atropine. Furthermore, Ex-4-induced tachycardia persisted when PPGNTS neurons were ablated, and Ex-4 did not induce expression of the neuronal activity marker cFos in PPGNTS neurons. PPGNTS ablation or acute chemogenetic inhibition of these neurons via hM4Di receptors had no effect on resting HR. In contrast, chemogenetic activation of PPGNTS neurons increased resting HR. Furthermore, the application of GLP-1 within the subarachnoid space of the middle thoracic spinal cord, a major projection target of PPG neurons, increased HR. Conclusions: These results demonstrate that both systemic application of Ex-4 or GLP-1 and chemogenetic activation of PPGNTS neurons increases HR. Ex-4 increases the activity of cardiac sympathetic preganglionic neurons of the spinal cord without recruitment of PPGNTS neurons, and thus likely recapitulates the physiological effects of PPG neuron activation. These neurons therefore do not play a significant role in controlling resting HR and ABP but are capable of inducing tachycardia and so are likely involved in cardiovascular responses to acute stress.

Thyrotropin-releasing hormone (TRH) plays several roles as a hormone/neuropeptide. Diencephalic TRH (dTRH) participates in the regulation of blood pressure in diverse animal models, independently of the thyroid status. The present study aimed to evaluate whether chronic overexpression of TRH in mice affects cardiovascular and metabolic variables. We developed a transgenic (TG) mouse model that overexpresses dTrh. Despite having higher food consumption and water intake, TG mice showed significantly lower body weight respect to controls. Also, TG mice presented higher blood pressure, heart rate, and locomotor activity independently of thyroid hormone levels. These results and the higher urine noradrenaline excretion observed in TG mice suggest a higher metabolic rate mediated by sympathetic overflow. Cardiovascular changes were impeded by siRNA inhibition of the diencephalic Trh overexpression. Also, the silencing of dTRH in the TG mice normalized urine noradrenaline excretion, supporting the view that the cardiovascular effects of TRH involve the sympathetic system. Overall, we show that congenital dTrh overexpression leads to an increase in blood pressure accompanied by changes in body weight and food consumption mediated by a higher sympathetic overflow. These results provide new evidence confirming the participation of TRH in cardiovascular and body weight regulation. [ABSTRACT FROM AUTHOR]

Hepatic steatosis is a key initiating event in the pathogenesis of alcohol-associated liver disease (ALD), the most detrimental organ damage resulting from alcohol use disorder. However, the mechanisms by which alcohol induces steatosis remain incompletely understood. We have previously found that alcohol binging impairs brain insulin action, resulting in increased adipose tissue lipolysis by unrestraining sympathetic nervous system (SNS) outflow. Here, we examined whether an impaired brain–SNS–adipose tissue axis drives hepatic steatosis through unrestrained adipose tissue lipolysis and increased lipid flux to the liver. We examined the role of lipolysis, and the brain–SNS–adipose tissue axis and stress in alcohol induced hepatic triglyceride accumulation in a series of rodent models: pharmacological inhibition of the negative regulator of insulin signaling protein-tyrosine phosphatase 1β (PTP1b) in the rat brain, tyrosine hydroxylase (TH) knockout mice as a pharmacogenetic model of sympathectomy, adipocyte specific adipose triglyceride lipase (ATGL) knockout mice, wildtype (WT) mice treated with β3 adrenergic agonist or undergoing restraint stress. Intracerebral administration of a PTP1b inhibitor, inhibition of adipose tissue lipolysis and reduction of sympathetic outflow ameliorated alcohol induced steatosis. Conversely, induction of adipose tissue lipolysis through β3 adrenergic agonism or by restraint stress worsened alcohol induced steatosis. Brain insulin resistance through upregulation of PTP1b, increased sympathetic activity, and unrestrained adipose tissue lipolysis are key drivers of alcoholic steatosis. Targeting these drivers of steatosis may provide effective therapeutic strategies to ameliorate ALD. • Alcohol binging induced fatty liver is reduced by CNS inhibition of the negative regulator of insulin signaling PTP1b. • Reduction of adipose tissue lipolysis prevents alcohol induced hepatic steatosis. • Reducing sympathetic outflow improves alcohol induced fatty liver. • Stress and β3 adrenergic agonism synergize with alcohol in increasing lipolysis and driving hepatic triglyceride accumulation. [ABSTRACT FROM AUTHOR]

We have previously shown that the increase in muscle sympathetic nerve activity (MSNA) to contracting muscle during sustained isometric exercise is due primarily to central command and that contracting muscle does not express a metaboreceptor-driven increase in MSNA. Here we tested the hypothesis that MSNA increases to the contracting muscle also during rhythmic isotonic exercise, in which muscle metabolites will not accumulate because the contraction is performed without external load. MSNA was recorded from the common peroneal nerve in 10 participants, and negative-going sympathetic spikes were extracted during 50 cycles of sinusoidal (0.15 Hz) isotonic dorsiflexions of the ipsilateral or contralateral ankle. Electromyographic activity (EMG) was recorded from the tibialis anterior muscle on both sides. Cross-correlation analysis between MSNA and EMG revealed a marked cyclic modulation of MSNA to the contracting (ipsilateral) muscle. This modulation, in which MSNA increased during the contraction phase, was three times greater than that to the noncontracting muscle (modulation index = 27.4 ± 3.2% vs. 9.2 ± 1.5%; P < 0.002). There were no differences in either the intensity or the magnitude of modulation of EMG during ipsilateral and contralateral contractions. We conclude that central command increases MSNA to the contracting muscle during rhythmic isotonic exercise. [ABSTRACT FROM AUTHOR]

The protein kinase A (PKA) signaling system mediates the effects of numerous hormones, neurotransmitters, and other molecules to regulate metabolism, cardiac function, and more. PKA defects may lead to diverse phenotypes that largely depend on the unique expression profile of the affected subunit. Deletion of the Prkarcb gene, which codes for PKA catalytic subunit β (C β), protects against diet-induced obesity (DIO), yet the mechanism for this phenotype remains unclear. We hypothesized that metabolic rate would be increased in C β knockout (KO) mice, which could explain DIO resistance. Male, but not female, C β KO mice had increased energy expenditure, and female but not male C β KO mice had increased subcutaneous temperature and increased locomotor activity compared with wild-type (WT) littermates. Urinary norepinephrine (NE) and normetanephrine were elevated in female C β KO mice. C β KO mice had increased heart rate (HR); blocking central NE release normalized HR to that of untreated WT mice. Basal and stimulated PKA enzymatic activities were unchanged in adipose tissue and heart and varied in different brain regions, suggesting that Prkacb deletion may mediate signaling changes in specific brain nuclei and may be less important in the peripheral regulation of PKA expression and activity. This is a demonstration of a distinct effect of the PKA C β catalytic subunit on catecholamines and sympathetic nerve signaling. The data provide an unexpected explanation for the metabolic phenotype of C β KO mice. Finally, the sexual dimorphism is consistent with mouse models of other PKA subunits and adds to the importance of these findings regarding the PKA system in human metabolism. [ABSTRACT FROM AUTHOR]

To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside (NTP) and phenylephrine (PE) and measured action potential (AP) patterns with wavelet-based methodology. We hypothesized that 1) baroreflex unloading (NTP) would increase firing of low-threshold axons and recruitment of latent axons and 2) baroreflex loading (PE) would decrease firing of low-threshold axons. Heart rate (HR, ECG), arterial blood pressure (BP, brachial catheter), and muscle sympathetic nerve activity (MSNA, microneurography of peroneal nerve) were measured at baseline and during steady-state systemic, intravenous NTP (0.5–1.2 µg·kg−1·min−1, n = 13) or PE (0.2–1.0 µg·kg−1·min−1, n = 9) infusion. BP decreased and HR and integrated MSNA increased with NTP (P < 0.01). AP incidence (326 ± 66 to 579 ± 129 APs/100 heartbeats) and AP content per integrated burst (8 ± 1 to 11 ± 2 APs/burst) increased with NTP (P < 0.05). The firing probability of low-threshold axons increased with NTP, and recruitment of high-threshold axons was observed (22 ± 3 to 24 ± 3 max cluster number, 9 ± 1 to 11 ± 1 clusters/burst; P < 0.05). BP increased and HR and integrated MSNA decreased with PE (P < 0.05). PE decreased AP incidence (406 ± 128 to 166 ± 42 APs/100 heartbeats) and resulted in fewer unique clusters (15 ± 2 to 9 ± 1 max cluster number, P < 0.05); components of an integrated burst (APs or clusters per burst) were not altered (P > 0.05). These data support a hierarchical pattern of sympathetic neural activation during manipulation of baroreceptor afferent activity, with rate coding of active neurons playing the predominant role and recruitment/derecruitment of higher-threshold units occurring with steady-state hypotensive stress. [ABSTRACT FROM AUTHOR]

5-hydroxytryptamine (5- HT) modulates noradrenergic activity in different cardiovascular territories, but its effect on the mesenteric vasopressor outflow has not yet been clarified. This study investigated the in vivo serotonergic influence, characterizing 5- HT receptors implicated, in sympathetic innervation of mesenteric vasculature. Wistar rats were anaesthetised and prepared for the in situ autoperfused rat mesentery, monitoring systemic blood pressure ( SBP), heart rate ( HR) and mesenteric perfusion pressure ( MPP). Electrical stimulation of mesenteric sympathetic nerves resulted in frequency-dependent increases in MPP (9 ± 1.6, 25.7 ± 3.9 and 60.2 ± 5 mmHg for 2, 4 and 8 Hz, respectively), without altering SBP or HR. 5- HT (1-25 μg/kg), 5-carboxamidotryptamine (5- HT1/7 agonist; 25 μg/kg) or L-694,247 (5-HT1D agonist; 1-25 μg/kg) i.a. bolus inhibited vasopressor responses by mesenteric nerves electrical stimulation, unlike i.a. bolus of agonists 8- OH- DPAT (5- HT1A), CGS-12066B (5- HT1B), BRL 54443 (5- HT1e/1F), α-methyl-5- HT (5- HT2), 1- PBG (5- HT3), cisapride (5- HT4) or AS-19 (5- HT7) (25 μg/kg each). Interestingly, i.a. L-694,247 (25 μg/kg) also reduced the exogenous norepinephrine-induced vasoconstrictions. Pretreatment with selective 5- HT1D receptor antagonist, LY310762 (1 mg/kg, i.v.), completely abolished L-694,247- and 5- HT-induced mesenteric sympathoinhibition. Furthermore, ELISA analysis confirmed 5- HT1D receptors expression in mesenteric artery. These findings suggest that serotonergic mechanisms-induced sympathoinhibition of mesenteric noradrenergic outflow is mediated by pre and/or postjunctional 5- HT1D receptors. [ABSTRACT FROM AUTHOR]

The incidence of chronic kidney disease (CKD) is increasing worldwide, with more than 26 million people suffering from CKD in the United States alone. More patients with CKD die of cardiovascular complications than progress to dialysis. Over 80% of CKD patients have hypertension, which is associated with increased risk of cardiovascular morbidity and mortality. Another common, perhaps underappreciated, feature of CKD is an overactive sympathetic nervous system. This elevation in sympathetic nerve activity (SNA) not only contributes to hypertension but also plays a detrimental role in the progression of CKD independent of any increase in blood pressure. Indeed, high SNA is associated with poor prognosis and increased cardiovascular morbidity and mortality independent of its effect on blood pressure. This brief review will discuss some of the consequences of sympathetic overactivity and highlight some of the potential pathways contributing to chronically elevated SNA in CKD. Mechanisms leading to chronic sympathoexcitation in CKD are complex, multifactorial and to date, not completely understood. Identification of the mechanisms and/or signals leading to sympathetic overactivity in CKD are crucial for development of effective therapeutic targets to reduce the increased cardiovascular risk in this patient group. [ABSTRACT FROM AUTHOR]

Corticotropin-releasing hormone (CRH) is a neuropeptide regulating neuroendocrine and autonomic function. CRH mRNA and protein levels in the hypothalamic paraventricular nucleus (PVN) are increased in primary hypertension. However, the role of CRH in elevated sympathetic outflow in primary hypertension remains unclear. CRHR1 proteins were distributed in retrogradely labeled PVN presympathetic neurons with an increased level in the PVN tissue in adult spontaneously hypertensive rats (SHRs) compared with age-matched male Wistar-Kyoto (WKY) rats. CRH induced a more significant increase in the firing rate of PVN-rostral ventrolateral medulla (RVLM) neurons and sympathoexcitatory response in SHRs than in WKY rats, an effect that was blocked by preapplication of NMDA receptors (NMDARs) antagonist AP5 and PSD-95 inhibitor, Tat-N-dimer. Blocking CRHRs with astressin or CRHR1 with NBI35965 significantly decreased the firing rate of PVN-RVLM output neurons and reduced arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) in SHRs but not in WKY, whereas blocking CRHR2 with antisauvagine-30 did not. Furthermore, Immunocytochemistry staining revealed that CRHR1 colocalized with NMDARs in PVN presympathetic neurons. Blocking CRHRs significantly decreased the NMDA currents in labeled PVN neurons. PSD-95-bound CRHR1 and PSD-95-bound GluN2A in the PVN were increased in SHRs. These data suggested that the upregulation of CRHR1 in the PVN is critically involved in the hyperactivity of PVN presympathetic neurons and elevated sympathetic outflow in primary hypertension. SIGNIFICANCE STATEMENT Our study found that corticotropin-releasing hormone receptor (CRHR)1 protein levels were increased in the paraventricular nucleus (PVN), and CRHR1 interacts with NMDA receptors (NMDARs) through postsynaptic density protein (PSD)-95 in the PVN neurons in primary hypertension. The increased CRHR1 and CRHR1-NMDAR-PSD-95 complex in the PVN contribute to the hyperactivity of the PVN presympathetic neurons and elevated sympathetic vasomotor tone in hypertension in SHRs. Thus, the antagonism of CRHR1 decreases sympathetic outflow and blood pressure in hypertension. These findings determine a novel role of CRHR1 in elevated sympathetic vasomotor tone in hypertension, which is useful for developing novel therapeutics targeting CRHR1 to treat elevated sympathetic outflow in primary hypertension. The CRHR1 receptor antagonists, which are used to treat health consequences resulting from chronic stress, are candidates to treat primary hypertension., (Copyright © 2023 the authors.)

Hydrogen sulfide (H 2 S) is a unique signaling molecule that, along with carbon monoxide and nitric oxide, belongs to the gasotransmitters family. H 2 S is endogenously synthesized by enzymatic and non-enzymatic pathways. Three enzymatic pathways involving cystathionine-γ-lyase, cystathionine-β-synthetase, and 3-mercaptopyruvate sulfurtransferase are known as endogenous sources of H 2 S. This gaseous molecule has recently emerged as a regulator of many systems and physiological functions, including the cardiovascular system where it controls the vascular tone of small arteries. In this context, H 2 S leads to vasorelaxation by regulating the activity of vascular smooth muscle cells, endothelial cells, and perivascular nerves. Specifically, H 2 S modulates the functionality of different ion channels to inhibit the autonomic sympathetic outflow—by either central or peripheral mechanisms—or to stimulate perivascular sensory nerves. These mechanisms are particularly relevant for those pathological conditions associated with impaired neuromodulation of vascular tone. In this regard, exogenous H 2 S administration efficiently attenuates the increased activity of the sympathetic nervous system often seen in patients with certain pathologies. These effects of H 2 S on the autonomic sympathetic outflow will be the primary focus of this review. Thereafter, we will discuss the central and peripheral regulatory effects of H 2 S on vascular tone. Finally, we will provide the audience with a detailed summary of the current pathological implications of H 2 S modulation on the neural regulation of vascular tone. [ABSTRACT FROM AUTHOR]

It has been reported that i.v. administration of NaHS, a donor of H 2 S, elicited dose-dependent hypotension although the mechanisms are not completely understood. In this regard, several mechanisms could be involved including the inhibition of the vasopressor sympathetic outflow. Thus, this study was designed to determine the potential capability of NaHS to mediate inhibition of the vasopressor responses induced by preganglionic sympathetic stimulation. For this purpose, Wistar rats were anaesthetised, pithed and cannulated for drug administration. In animals pre-treated with gallamine, the effect of i.v. infusion of NaHS (310 and 560 μg/kg min) or its vehicle (phosphate buffer) was determined on the vasopressor responses induced by: (1) sympathetic stimulation (0.03–10 Hz); (2) i.v. bolus injections of exogenous noradrenaline (0.03–3 μg/kg); or (3) methoxamine (1–100 μg/kg). The vasopressor responses induced by preganglionic sympathetic stimulation were dose-dependently inhibited by i.v. infusion of NaHS (310 and 560 μg/kg min), but not by vehicle, particularly at high frequencies. In marked contrast, the vasopressor responses to exogenous noradrenaline or methoxamine were not inhibited by the above doses of NaHS or its vehicle. The above results, taken together, demonstrate that NaHS inhibited the vasopressor responses induced by preganglionic sympathetic outflow by a prejunctional mechanism. This is the first evidence demonstrating this effect by NaHS that may contribute, at least in part, to the hypotension induced by NaHS. [ABSTRACT FROM AUTHOR]