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Background: A subset of patients with postural tachycardia syndrome (POTS) are thought to have a primary hyperadrenergic cause. We assessed clinical biomarkers to identify those that would benefit from sympatholytic therapy., Methods: We measured sympathetic function (supine muscle sympathetic nerve activity, upright plasma norepinephrine, and blood pressure responses to the Valsalva maneuver) in 28 patients with POTS (phenotyping cohort) to identify clinical biomarkers that are associated with responsiveness to the central sympatholytic guanfacine in a separate uncontrolled treatment cohort of 38 patients that had received guanfacine clinically for suspected hyperadrenergic POTS (HyperPOTS)., Results: In the phenotyping cohort, an increase in diastolic blood pressure (DBP) >17 mm Hg during late phase 2 of the Valsalva maneuver identified patients with the highest quartile of resting muscle sympathetic nerve activity (HyperPOTS) with 71% sensitivity and 85% specificity. In the treatment cohort, patients with HyperPOTS, identified by this clinical biomarker, more often reported clinical improvement (85% versus 44% in nonhyperadrenergic; P =0.016), had better orthostatic tolerance (∆Orthostatic Hypotension Daily Activities Scale: -1.9±0.9 versus 0.1±0.5; P =0.032), and reported less chronic fatigue (∆PROMIS Fatigue Short Form 7a: -12.9±2.7 versus -2.2±2.2; P =0.005) in response to guanfacine., Conclusions: These results are consistent with the concept that POTS is caused by a central sympathetic activation in a subset of patients, which can be identified clinically by an exaggerated DBP increase during phase 2 of the Valsalva maneuver and improved by central sympatholytic therapy. These results support further clinical trials to determine the safety and efficacy of guanfacine in patients with POTS enriched for the presence of this clinical biomarker., Competing Interests: I. Biaggioni has received consultant fees and research support from Lundbeck and Theravance Biopharma Inc for the development of therapies for orthostatic hypotension. I. Biaggioni, L.E. Okamoto, J.K. Shirey-Rice, and J.M. Pulley have submitted a patent application for the use of guanfacine for the treatment of CFS. The other authors report no conflicts.

Purpose: Ischemic preconditioning (IPC), a procedure that involves the cyclic induction of limb ischemia and reperfusion via tourniquet inflation, has been reported to improve exercise capacity and performance, but the underlying mechanisms remain unclear. During exercise, sympathetically mediated vasoconstriction is dampened in active skeletal muscle. This phenomenon, termed functional sympatholysis, plays a critical role in maintaining oxygen delivery to working skeletal muscle and may contribute to determining exercise capacity. Herein, we investigate the effects of IPC on functional sympatholysis in humans., Methods: In 20 (10M/10F) healthy young adults, forearm blood flow (Doppler ultrasound) and beat-to-beat arterial pressure (finger photoplethysmography) were measured during lower body negative pressure (LBNP; -20 mm Hg) applied at rest and simultaneously during rhythmic handgrip exercise (30% maximum contraction) before and after local IPC (4 × 5-min 220 mm Hg) or sham (4 × 5-min 20 mm Hg). Forearm vascular conductance (FVC) was calculated as forearm blood flow/mean arterial pressure and the magnitude of sympatholysis as the difference of LBNP-induced changes in FVC between handgrip and rest., Results: At baseline, LBNP decreased FVC (females [F] = ∆-41% ± 19%; males [M] = ∆-44% ± 10%), and these responses were attenuated during handgrip (F = ∆-8% ± 9%; M = ∆-8% ± 7%). After IPC, LBNP induced similar decreases in resting FVC (F = ∆-37% ± 19%; M = ∆-44% ± 13%). However, during handgrip, this response was further attenuated in males (∆-3% ± 9%, P = 0.02 vs pre) but not females (∆-5% ± 10%, P = 0.13 vs pre), which aligned with an IPC-mediated increase in sympatholysis (M-pre = 36% ± 10% vs post = 40% ± 9%, P = 0.01; F-pre = 32% ± 15% vs post = 32% ± 14%, P = 0.82). Sham IPC had no effect on any variables., Conclusions: These findings highlight a sex-specific effect of IPC on functional sympatholysis and provide evidence of a potential mechanism underlying the beneficial effects of IPC on human exercise performance., (Copyright © 2023 by the American College of Sports Medicine.)

Clinical evidence suggests that pain hypersensitivity develops in patients with attention-deficit/hyperactivity disorder (ADHD). However, the mechanisms and neural circuits involved in these interactions remain unknown because of the paucity of studies in animal models. We previously validated a mouse model of ADHD obtained by neonatal 6-hydroxydopamine (6-OHDA) injection. Here, we have demonstrated that 6-OHDA mice exhibit a marked sensitization to thermal and mechanical stimuli, suggesting that phenotypes associated with ADHD include increased nociception. Moreover, sensitization to pathological inflammatory stimulus is amplified in 6-OHDA mice as compared to shams. In this ADHD model, spinal dorsal horn neuron hyperexcitability was observed. Furthermore, ADHD-related hyperactivity and anxiety, but not inattention and impulsivity, are worsened in persistent inflammatory conditions. By combining in vivo electrophysiology, optogenetics, and behavioral analyses, we demonstrated that anterior cingulate cortex (ACC) hyperactivity alters the ACC-posterior insula circuit and triggers changes in spinal networks that underlie nociceptive sensitization. Altogether, our results point to shared mechanisms underlying the comorbidity between ADHD and nociceptive sensitization. This interaction reinforces nociceptive sensitization and hyperactivity, suggesting that overlapping ACC circuits may be targeted to develop better treatments.

The vasoconstrictive effect of sympathetic activity is attenuated in contracting skeletal muscle (functional sympatholysis), allowing increased blood supply to the working muscle but the underlying mechanisms are incompletely understood. The purpose of this study was to examine α-adrenergic receptor responsiveness in isolated artery segments from non-exercised and exercised mice, using wire myography. Isometric tension recordings performed on femoral artery segments from exercised mice showed decreased α-adrenergic receptor responsiveness compared to non-exercised mice (logEC 50 -5.2 ± 0.04 M vs. -5.7 ± 0.08 M, respectively). In contrast, mesenteric artery segments from exercised mice displayed similar α-adrenergic receptor responses compared to non-exercised mice. Responses to the vasoconstrictor serotonin (5-HT) and vasodilator isoprenaline, were similar in femoral artery segments from non-exercised and exercised mice. To study sarcoplasmic reticulum (SR) function, we examined arterial contractions induced by caffeine, which depletes SR Ca 2+ and thapsigargin, which inhibits SR Ca 2+ -ATPase (SERCA) and SR Ca 2+ uptake. Arterial contractions to both caffeine and thapsigargin were increased in femoral artery segment from exercised compared to non-exercised mice. Furthermore, 3D electron microscopy imaging of the arterial wall showed SR volume/length ratio increased 157% in smooth muscle cells of the femoral artery from the exercised mice, whereas there was no difference in SR volume/length ratio in mesenteric artery segments. These results show that in arteries surrounding exercising muscle, the α-adrenergic receptor constrictions are blunted, which can be attributed to swollen smooth muscle cell SR's, likely due to increased Ca 2+ content that is possibly reducing free intracellular Ca 2+ available for contraction. Overall, this study uncovers a previously unknown mechanism underlying functional sympatholysis., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Morbidity and mortality risks are enhanced in preeclamptic (PE) mothers and their offspring. Here, we asked if sexual dimorphism exists in (i) cardiovascular and renal damage evolved in offspring of PE mothers, and (ii) offspring responsiveness to antenatal therapies. PE was induced by administering N G -nitro-L-arginine methyl ester (L-NAME, 50 mg/kg/day, oral gavage) to pregnant rats for 7 days starting from gestational day 14. Three therapies were co-administered orally with L-NAME, atrasentan (endothelin ETA receptor antagonist), terutroban (thromboxane A2 receptor antagonist, TXA2), or α-methyldopa (α-MD, central sympatholytic drug). Cardiovascular and renal profiles were assessed in 3-month-old offspring. Compared with offspring of non-PE rats, PE offspring exhibited elevated systolic blood pressure and proteinuria and reduced heart rate and creatinine clearance (CrCl). Apart from a greater bradycardia in male offspring, similar PE effects were noted in male and female offspring. While terutroban, atrasentan, or α-MD partially and similarly blunted the PE-evoked changes in CrCl and proteinuria, terutroban was the only drug that virtually abolished PE hypertension. Rises in cardiorenal inflammatory (tumor necrosis factor alpha, TNFα) and oxidative (isoprostane) markers were mostly and equally eliminated by all therapies in the two sexes, except for a greater dampening action of atrasentan, compared with α-MD, on tissue TNFα in female offspring only. Histopathologically, antenatal terutroban or atrasentan was more effective than α-MD in rectifying cardiac structural damage, myofiber separation, and cytoplasmic alterations, in PE offspring. The repair by antenatal terutroban or atrasentan of cardiovascular and renal anomalies in PE offspring is mostly sex-independent and surpasses the protection offered by α-MD, the conventional PE therapy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Heart failure (HF) remains the leading cause of morbidity and death in the western world, and new therapeutic modalities are urgently needed to improve the lifespan and quality of life of HF patients. The sodium-glucose co-transporter-2 (SGLT2) inhibitors, originally developed and mainly indicated for diabetes mellitus treatment, have been increasingly shown to ameliorate heart disease, and specifically HF, in humans, regardless of diabetes co-existence. Indeed, dapagliflozin has been reported to reduce cardiovascular mortality and hospitalizations in patients with HF and reduced ejection fraction (HFrEF). This SGLT2 inhibitor demonstrates these benefits also in non-diabetic subjects, indicating that dapagliflozin's efficacy in HF is independent of blood glucose control. Evidence for the effectiveness of various SGLT2 inhibitors in providing cardiovascular benefits irrespective of their effects on blood glucose regulation have spurred the use of these agents in HFrEF treatment and resulted in FDA approvals for cardiovascular indications. The obvious question arising from all these studies is, of course, which molecular/pharmacological mechanisms underlie these cardiovascular benefits of the drugs in diabetics and non-diabetics alike. The fact that SGLT2 is not significantly expressed in cardiac myocytes (SGLT1 appears to be the dominant isoform) adds even greater perplexity to this answer. A variety of mechanisms have been proposed over the past few years and tested in cell and animal models and prominent among those is the potential for sympatholysis, i.e., reduction in sympathetic nervous system activity. The latter is known to be high in HF patients, contributing significantly to the morbidity and mortality of the disease. The present minireview first summarizes the current evidence in the literature supporting the notion that SGLT2 inhibitors, such as dapagliflozin and empagliflozin, exert sympatholysis, and also outlines the main putative underlying mechanisms for these sympatholytic effects. Then, we propose a novel hypothesis, centered on the adrenal medulla, for the sympatholytic effects specifically of dapagliflozin. Adrenal medulla is responsible for the production and secretion of almost the entire amount of circulating epinephrine and of a significant percentage of circulating norepinephrine in the human body. If proven true experimentally, this hypothesis, along with other emerging experimental evidence for sympatholytic effects in neurons, will shed new light on the pharmacological effects that mediate the cardiovascular benefits of SGLT2 inhibitor drugs, independently of their blood glucose-lowering effects.

Chlorisondamine (CSD) has been used to assess the neurogenic contribution to blood pressure (BP) and vasomotor sympathetic tone in animal models. It is assumed that the reduction in BP following CSD administration is associated to decreases in cardiac output (CO) and peripheral resistance, reflecting cardiac and vasomotor sympathetic tone, respectively. Surprisingly, this has not been characterized experimentally in mice, despite the extensive use of this animal model in cardiovascular research. We hypothesize that a specific dose of CSD can selectively block the sympathetic vasomotor tone. To test this hypothesis, we evaluated the effects of different doses of CSD (intraperitoneal) on BP and heart rate (HR) using telemetry, and on CO using echocardiography. BP and HR in normotensive C57Bl/6J mice reduced to a similar extent by all CSD doses tested (1-6 mg/kg). CSD at 6 mg/kg also reduced CO without affecting left ventricular stroke volume or fractional shortening. On the other hand, lower doses of CSD (1 and 2 mg/kg) produced significantly larger BP and HR reductions in DOCA-salt-induced hypertensive mice, indicating a greater neurogenic BP response. In addition, all doses of CSD reduced CO in hypertensive mice. Our data suggest that the BP response to CSD in mice likely reflects reduced CO and vasomotor sympathetic tone. We conclude that CSD can be used to assess the neurogenic contribution to BP in mice but may not be appropriate for specifically estimating vasomotor sympathetic tone., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

The acetylcholinesterase inhibitor, galantamine, has shown therapeutic effect in rat model of rheumatoid arthritis. Hence, the current study aims at determining the mode of action of galantamine by examining different synovium-derived microRNAs (miRs) and their related pathogenic pathways. The study also focuses on how parasympathetic and sympathetic pathways in the synovial tissue could affect the mode of action and anti-arthritic effect of galantamine. Chemical sympathectomy was initiated in 12 adjuvant arthritic rats by exposure to 6-hydroxydopamine (6-OHDA; 2 × 50 mg/kg) on day 9 after adjuvant injection and again (2 × 100 mg/kg) one week later. Six rats were treated with galantamine (2.5 mg/kg/day) to explore the influence of sympathetic impairment on galantamine effect. Another twelve additional adjuvant arthritic rats were exposed to the selective α7 nicotinic acetylcholine receptor blocker methylcaconitine citrate (MLA; 5.6 mg/kg/day), 15 min before galantamine treatment. As control, six adjuvant arthritic rats were treated with galantamine alone. Treatment proceeded for 5 days, from day 14 till day 18 post-adjuvant injection. Different miRs and their related pathogenic pathways were examined. Tyrosine hydroxylase (TH) expression was also measured in joint tissue. Galantamine affected the expression of the different miRs and their related parameters. Both, 6-OHDA and MLA, interrupted the anti-inflammatory/anti-arthritic effect of galantamine to different extent. Additionally, TH expression in the synovium was affected by galantamine, suggesting a novel pathogenic target in the treatment of rheumatoid arthritis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The α 2 adrenergic receptors (α 2 ARs) are G protein-coupled receptors (GPCRs) that respond to adrenaline and noradrenaline and couple to the Gi/o family of G proteins. α 2 ARs play important roles in regulating the sympathetic nervous system. Dexmedetomidine is a highly selective α 2 AR agonist used in post-operative patients as an anxiety-reducing, sedative medicine that decreases the requirement for opioids. As is typical for selective αAR agonists, dexmedetomidine consists of an imidazole ring and a substituted benzene moiety lacking polar groups, which is in contrast to βAR-selective agonists, which share an ethanolamine group and an aromatic system with polar, hydrogen-bonding substituents. To better understand the structural basis for the selectivity and efficacy of adrenergic agonists, we determined the structure of the α 2B AR in complex with dexmedetomidine and Go at a resolution of 2.9 Å by single-particle cryo-EM. The structure reveals the mechanism of α 2 AR-selective activation and provides insights into Gi/o coupling specificity.

Acute kidney injury (AKI) is frequently accompanied by activation of the sympathetic nervous system (SNS). This may result from pre-exisiting chronic diseases associated with sympathetic activation prior to AKI or it may be induced by stressors that ultimately lead to AKI such as endotoxins and arterial hypotension in circulatory shock. Conversely, sympathetic activation may also result from acute renal injury. Focusing on studies in experimental renal ischaemia and reperfusion (IR), this review summarizes the current knowledge on how the SNS is activated in IR-induced AKI and on the consequences of sympathetic activation for the development of acute renal damage. Experimental studies show beneficial effects of sympathoinhibitory interventions on renal structure and function in response to IR. However, few clinical trials obtained in scenarios that correspond to experimental IR, namely major elective surgery, showed that peri-operative treatment with centrally acting sympatholytics reduced the incidence of AKI. Apparently, discrepant findings on how sympathetic activation influences renal responses to acute IR-induced injury are discussed and future areas of research in this field are identified., (© 2019 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Background: Parkinson's disease (PD) is a common neurodegenerative disorder that is characterized by motor symptoms related to the deficiency in dopamine levels, and cognitive symptoms that are similar in nature to those manifested during Alzheimer's disease. Levosimendan, on the other hand, is a calcium sensitizer and phosphodiesterase inhibitor that was shown to possess neuroprotective, memoryenhancing, and anti-apoptotic properties., Objective: In the current study, the possible protective effect of levosimendan was investigated in two animal models of Parkinson's disease., Methods: Both intracerebral injection 6-hydroxydopamine (6-OHDA) and the direct injection of lipopolysaccharide (LPS) into the substantia nigra were used as models to induce Parkinson's-like behavior. Levosimendan (12 μg/kg intraperitoneally once weekly) was started 7 days before or 2 days after lesioning of the animals. At day 14 post-lesioning, animals were subjected to apomorphine challenge, which was correlated with dopamine levels in the striatum and tyrosine hydroxylase (TH)-positive nigral cells., Results: Results showed that levosimendan restored the number of rotations in the apomorphine challenge test, the levels of dopamine in the striatum, and the TH-positive nigral cells when administered 7 days before, but not two days after 6-OHDA lesioning. In the LPS model of PD, the number of rotations in the apomorphine challenge test, the levels of dopamine in the striatum, and the TH-positive nigral cells were restored when levosimendan was administered 7 days before as well as two days after lesioning., Conclusion: Levosimendan seems to provide a promising agent with potential clinical value for PD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The effect of chemical sympathectomy on cardiovascular parameters and the compensatory role of adrenal hormones, the renin-angiotensin system, and cardiovascular sensitivity to vasoconstrictors were studied in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. Sympathectomy was induced in 20-week-old rats by daily intraperitoneal guanethidine administration (30 mg/kg b.w.) for 2 weeks. Basal blood pressure (BP), heart rate (HR), and restraint stress-induced cardiovascular changes were measured by radiotelemetry. The BP response to catecholamines was determined in rats with implanted catheters. Sympathectomy decreased BP only transiently, and after 14-day guanethidine treatment, BP returned to basal values in both strains. Sympathectomy permanently lowered HR, improved baroreflex sensitivity, and decreased the low-frequency domain of systolic blood pressure variability (a marker of vascular sympathetic activity). Guanethidine also attenuated the BP and HR responses to restraint stress. On the other hand, the BP response to catecholamines was augmented in sympathectomized rats, and this was not due to the de novo synthesis of vascular adrenergic receptors. Sympathectomy caused adrenal enlargement, enhanced the expression of adrenal catecholamine biosynthetic enzymes, and elevated plasma adrenaline levels in both strains, especially in WKY rats. Guanethidine also increased the plasma levels of aldosterone and corticosterone in WKY rats only. In conclusion, sympathectomy produced a transient decrease in BP, a chronic decrease in HR and improvement in baroreflex sensitivity. The effect of sympathectomy on BP was counteracted by increased vascular sensitivity to catecholamines in WKY rats and SHRs and/or by the enhanced secretion of adrenal hormones, which was more pronounced in WKY rats.

The sympathoinhibitory mechanism of azilsartan was investigated in an adenine-induced chronic renal failure model. Azilsartan exerted an antihypertensive effect, though BP elevation induced by adenine was marginal. The creatinine value was significantly lower in the azilsartan group (AZ) than in the vehicle group (VEH); furthermore, proteinuria was suppressed, and sodium excretion was augmented in the AZ group. The low frequency (LF) of systolic BP was suppressed (VEH: 4.07 ± 2.67 mmHg 2 vs. AZ: 3.32 ± 1.93 mmHg 2 P < 0.001), and the spontaneous baroreflex gain (sBRG) was augmented (VEH: 1.04 ± 0.62ms/mmHg vs. AZ: 1.38 ± 0.69 ms/mmHg, P < 0.001) in AZ. There were no significant differences in ACE1 and ACE2 expression between the groups, which indicated that the action of azilsartan on these components of the intrarenal renin-angiotensin-aldosterone system was comparatively small. Although NHE3, NKCC, and ENaC expression was similar between the groups, NaCl cotransporter (NCC) expression was markedly suppressed by azilsartan (P < 0.05). Thus, in a mild chronic kidney disease (CKD) model with slight BP elevation, the sympatholytic effect of ARB might be expected, and azilsartan might exert its natriuretic effect by NCC suppression achieved by sympathoinhibitory activity.

N 6 -Methyladenosine (m6A) is the most prevalent internal modification that occurs in the mRNA of eukaryotes and plays a vital role in the post-transcriptional regulation. Recent studies highlighted the biological significance of m6A modification in the nervous system, and its dysregulation has been shown to be related to degenerative and neurodevelopmental diseases. Parkinson's disease (PD) is a common age-related neurological disorder with its pathogenesis still not fully elucidated. Reports have shown that epigenetic mechanisms including DNA methylation and histone acetylation, which alter gene expression, are associated with PD. In this study, we found that global m6A modification of mRNAs is down-regulated in 6-OHDA-induced PC12 cells and the striatum of PD rat brain. To further explore the relationship between m6A mRNA methylation and molecular mechanism of PD, we decreased m6A in dopaminergic cells by overexpressing a nucleic acid demethylase, FTO, or by m6A inhibitor. The results showed that m6A reduction could induce the expression of N-methyl-d-aspartate (NMDA) receptor 1, and elevate oxidative stress and Ca 2+ influx, resulting in dopaminergic neuron apoptosis. Collectively, m6A modification may play a vital role in the death of dopaminergic neuron, which provides a novel view of mRNA methylation to understand the epigenetic regulation of Parkinson's disease.

Background Whether chronic obstructive sleep apnea ( OSA ) could promote epicardial adipose tissue ( EAT ) secretion of profibrotic adipokines, and thereby contribute to atrial fibrosis, and the potential therapeutic effects of metoprolol remain unknown. Methods and Results A chronic OSA canine model was established by repeatedly clamping the endotracheal tube for and then reopening it for 4 hours every other day for 12 weeks. In a metoprolol treatment group, metoprolol succinate was administered daily for 12 weeks. The EAT infiltration and left atrial fibrosis were examined. The expressions of adipokines secreted by EAT and hypoxic 3T3-L1 adipocytes were detected. The changes in collagen synthesis, transforming growth factor-β1 expression, and cell differentiation and proliferation in cardiac fibroblasts induced by hypoxic 3T3-L1 adipocyte-derived conditioned medium were further analyzed. Chronic OSA induced infiltration of EAT into the left atrium. OSA enhanced the profibrotic effect of EAT on the adjacent atrial myocardium. Moreover, OSA induced profibrotic cytokine secretion from EAT . We also found that hypoxia induced adipokine secretion in cultured adipocytes, and the medium conditioned by the hypoxic adipocytes increased collagen and transforming growth factor-β1 protein expression and cell proliferation of cardiac fibroblasts. More importantly, metoprolol attenuated infiltration of EAT and alleviated the profibrotic effect of EAT by inhibiting adipokine secretion. Metoprolol also inhibited hypoxia-induced adipokine secretion in adipocytes and thereby blocked the hypoxic adipocyte-derived conditioned medium-induced fibrotic response of cardiac fibroblasts. Conclusions Chronic OSA enhanced the profibrotic effect of EAT on the neighboring atrial myocardium by stimulating the secretion of profibrotic adipokines from EAT , which was significantly attenuated by metoprolol. This study gives insights into mechanisms underlying OSA -induced atrial fibrillation and also provides experimental evidence for the protective effects of metoprolol.

We previously obtained evidence suggesting that physical exercise increases the release of L-carnosine (CAR) from muscles and that CAR affects autonomic neurotransmission and physiological phenomena in rats. It has also been reported that exercise elicits an increase in activity of the sympathetic nerve innervating the skeletal muscle. Therefore, in this study, we investigated the effect of CAR application, onto the surface of the right femoral muscle, on activity of the sympathetic nerve innervating the left femoral muscle, in urethane-anesthetized rats. Topical application of 10 pg (44.2 fmol) of CAR increased either skeletal muscle sympathetic nerve activity (skeletal muscle-SNA) or skeletal muscle blood flow (skeletal muscle-BF) of the contralateral skeletal muscle. Furthermore, thioperamide, a histamine H3-antagonist, inhibited the increase in skeletal muscle-SNA, and butoxamine, a β2-antagonist, abolished the increase in skeletal muscle-BF caused by topical application of CAR. The present results suggest that CAR released from muscles during physical exercise might affect skeletal muscle-SNA and skeletal muscle-BF on the opposite side of the body via a CAR evoked effect in muscles.

In Parkinson's disease, nigral dopamine neurons are lost and the structure of the striatum is progressively degraded. These events lead to a substantial neuronal loss in the striatum, changing spatial pattern of the neurons and glial cells, and associated cellular connections. Therefore, the aim of this study was to develop a new insight into whether the Parkinson's disease causes a change in the spatial arrangement of the neurons and glial cells in the striatum. Nigral injection of 6-hydroxydopamine led to a significant reduction in the total number of the neurons, an increase in the number of striatal glial cells, and disruption in the spatial arrangement of glial and neuronal cells in the Parkinson's disease-induced group, compared to the control group. The data support the idea that in Parkinson's disease, the function of the striatum is disturbed by both the loss of neurons and an increase in the number of glial cells, culminating in the disordered spatial distribution of these cells.

Although beta-blockade itself is not a first choice for chronic kidney disease (CKD) patients, alpha-beta-blockers (ABB) do improve their prognoses. This study's aim was to evaluate the effect of beta-selective-blockers (BSB) and ABB on circadian cardiac autonomic activity in CKD patients.The study consisted of 496 non-diabetic individuals who underwent 24-hour Holter monitoring (149 CKD patients and 347 controls without CKD). Using heart rate variability analysis, we evaluated the proportion of NN50 and the high-frequency component (reflecting parasympathetic activity), and low- to high-frequency ratio (reflecting sympathovagal balance). These indices were evaluated by regression analysis incorporating gender, age, related comorbidities, and medications. BSB increased vagal activity only in the day-time and not the night-time in controls. In CKD patients, BSB was significantly related to higher vagal activity throughout the day and with lower sympathovagal balance at night. The night sympathovagal balance of CKD patients taking ABB was significantly higher than that of CKD patients taking BSB, which was the only significant difference between the effects of BSB and ABB.The sympatholytic therapy effect is different depending on CKD presence and whether patients are treated with BSB or ABB. In CKD patients without severe heart failure, BSB could be associated with higher parasympathetic activity and lower sympathovagal balance compared to ABB.

Senescence of innate and adaptive responses and low-grade inflammation (inflammaging) hallmarks normal aging, which increases vulnerability to infectious diseases, autoimmunity and cancer. In normal aging, sympathetic dysregulation contributes to the dysregulation of innate and adaptive immunity and inflammaging. Sympathetic innervation of immune cells in secondary immune organs regulates immune responses. Previously in Fischer 344 (F344) rats, we reported an age-related increase in sympathetic tone and sympathetic dysfunction in beta-adrenergic receptor (AR) signaling of splenic lymphocytes that contributes to immune senescence, although the responsible mechanisms remains unexplored. In this study, we extend our previous findings using the much longer-lived Brown-Norway (BN) rats, whose behavior and immune response profile differ strikingly from F344 rats. Here, we investigated whether increased sympathetic nerve activity (SNA) in the aging spleen contributes to age-related sympathetic neuropathy and altered neurotransmission in splenic lymphocytes in BN rats. Fifteen-month male BN rats received 0, 0.5 or 1.5 μg/kg/day rilmenidine intraperitoneally for 90 days to lower sympathetic tone. Untreated young and age-matched rats controlled for effects of age. We found that elevated SNA in the aging BN rat spleen does not contribute significantly to sympathetic neuropathy or the aging-induced impairment of canonical β-AR signal transduction. Despite the rilmenidine-induced increase in β-AR expression, splenocyte c-AMP production was comparable with age-matched controls, thus dampening nerve activity had no effect on receptor coupling to adenylate cyclase. Understanding how aging affects neuroimmune regulation in healthy aging rodent models may eventually lead to strategies that improve health in aging populations vulnerable to immunosenescence and low-grade systemic inflammation., (Copyright © 2018. Published by Elsevier B.V.)

Background: A robust adrenergic response following stroke impairs lymphocyte function, which may prevent the development of autoimmune responses to brain antigens. We tested whether inhibition of the sympathetic response after stroke would increase the propensity for developing autoimmune responses to brain antigens., Methods: Male Lewis rats were treated with 6-hydroxydopamine (OHDA) prior to middle cerebral artery occlusion (MCAO), labetalol after MCAO, or appropriate controls. Behavior was assessed weekly and animals survived to 1 month at which time ELISPOT assays were done on lymphocytes from spleen and brain to determine the Th1 and Th17 responses to myelin basic protein (MBP), ovalbumin (OVA), and concanavalin A. A subset of animals was sacrificed 72 hours after MCAO for evaluation of infarct volume and lymphocyte responsiveness. Plasma C-reactive protein (CRP) was measured as a biomarker of systemic inflammation., Results: Despite similar initial stroke severity and infarct volumes, 6-OHDA-treated animals lost less weight and experienced less hyperthermia after stroke. 6-OHDA-treated animals also had decreased CRP in circulation early after stroke and experienced better neurological outcomes at 1 month. The Th1 and Th17 responses to MBP did not differ among treatment groups at 1 month, but the Th1 response to OVA in spleen was more robust in labetalol and less robust in 6-OHDA-treated animals., Conclusions: Chemical sympathectomy with 6-OHDA, but not treatment with labetalol, decreased systemic markers of inflammation early after stroke and improved long-term outcome. An increase in Th1 and Th17 responses to MBP was not seen with inhibition of the sympathetic response., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A stellate ganglion block (SGB) is a clinical sympathetic block which can inhibit the body systemic inflammatory response. However, whether and how SGB can attenuate the sepsis-induced acute lung injury remains unclear. Here, we evaluated the effect of SGB on sepsis-induced acute lung injury in rats. Ninety healthy Sprague Dawley (SD) male rats were divided into three groups: the sham operation group (S group), sepsis group (Sep group), and SGB group. The sepsis model rats were produced by cecum ligation and puncture (CLP), and blood samples were taken from the abdominal aorta of the rats at different time points for evaluating the concentration of TNF-α, IL-6, and IL-10 by enzyme-linked immunosorbent assay (ELISA). The rats were sacrificed, and lungs were collected to measure the wet/dry (W/D) lung tissue weight ratio, score the lung tissue pathological damage by microscopic examination, determine the myeloperoxidase (MPO) activity by spectrophotometry, and measure nuclear factor-kappa B (NF-κB) p65 expression by Western blot. The concentration of serum TNF-α, IL-6, and IL-10, lung tissue W/D ratio, pathological injury score, MPO activity, and expression of NF-κB p65 were higher in the Sep group compared with the S group at T 1-4 . Furthermore, the concentration of serum TNF-α and IL-6, lung tissue W/D ratio, pathological damage score, MPO activity, and expression of NF-κB p65 were reduced and the concentration of IL-10 was increased in the SGB group compared with the Sep group at T 1-4 . The successful sepsis model rats were induced by CLP, and SGB attenuated the sepsis-induced acute lung injury in rats.

Background: Elevated heart rate (HR) increases cardiovascular morbidity and mortality in hypertension. The impact of beta-blockers on patient prognosis in hypertension is controversial. This study examined the age-related effects of betaxolol on HR, muscle sympathetic nerve activity (MSNA), blood pressure (BP) and sympathovagal balance in untreated males with hypertension and tachycardia., Methods: Ten young (age 26 ± 1 years) and seven older (age 50 ± 4 years) males underwent measurement of BP, HR, HR variability (Poincare plot) and MSNA before and after 8 weeks treatment with betaxolol at the initial starting dose of 10 mg/day, which was increased to 20 mg/day once daily after 4 weeks in all subjects., Results: In younger subjects, betaxolol decreased systolic BP (-13 ± 4 mm Hg, p = .01) and HR (-29 ± 4 bpm, p < .001) but not MSNA (3 ± 3 burst/min., p = 0.47) after 8 weeks. In older subjects a pronounced reduction in BP (-27 ± 7, p = .007) was accompanied by a significant decrease in MSNA (-13 ± 5 burst/min., p < .05) and HR (-17 ± 4 bpm, p = .002). SD1/SD2 ratio of Poincare plot increased in younger (0.36 ± 0.03 vs 0.51 ± 0.05, p = .004), but not in older (0.43 ± 0.08 vs 0.54 ± 0.12, p = .50) subjects., Conclusion: Autonomic neural responses to betaxolol are age-dependent in hypertension-related tachycardia. Betaxolol reduces sympathetic drive to the heart, but not to the peripheral vessels confirming the contribution of augmented cardiac sympathetic activity to disease pathophysiology in younger adults. In older hypertensives, the sympathovagal balance is not influenced by betaxolol. The paradoxical reduction in MSNA despite lowering of BP and HR in older patients may suggest age-related functional decrements in autonomic control and/or inhibitory effects of betaxolol on the central nervous system.

Introduction: Insufficient microvascular oxygenation (μHBO2) of the intestinal mucosa worsens outcome of septic patients. Hypercapnia ameliorates μHBO2, mediated via endogenous vasopressin release. Under physiological conditions, blockade of the endogenous sympathetic nervous system abolishes this protective effect of hypercapnia. The aim of our study was therefore to evaluate the role of the endogenous sympathetic nervous system during hypercapnia on intestinal μHBO2 under septic conditions., Methods: We randomized 80 male Wistar rats into eight groups. Sepsis was induced via colon ascendens stent peritonitis. The animals were subjected to 120 min of normocapnic (pCO2 35 mm Hg-45 mm Hg) or moderate hypercapnic (pCO2 65 mm Hg-75 mm Hg) ventilation 24 h after surgery. Animals received sympathetic blockade (hexamethonium 15 mg · kg (bolus) followed by 15 mg · kg · h (infusion) intravenously) or the same volume as vehicle (NaCl 0.9%). Microcirculatory oxygenation (μHBO2) and perfusion (μflow) were recorded using tissue reflectance spectrophotometry and laser Doppler., Results: In septic animals, μHBO2 decreased during normocapnia (-8.9 ± 4%) and increased during hypercapnia (+7.8 ± 7.5%). The additional application of hexamethonium did not influence these effects. μHBO2 declined in normocapnic septic animals treated with hexamethonium similar to normocapnia alone (-6.1 ± 5.4%) and increased in hypercapnic animals treated with hexamethonium similar to hypercapnia alone (+7.9 ± 11.7%). Furthermore, hypercapnic ventilation ameliorated microcirculatory perfusion (μflow) irrespective of whether animals received hexamethonium (from 113 ± 54 [AU] to 206 ± 87 [AU]) or vehicle (from 97 ± 37 [AU]-169 ± 52 [AU])., Conclusion: The amelioration of the intestinal microcirculation during hypercapnia in sepsis is independent of the endogenous sympathetic nervous system.

Recently, the influence of adrenergic activity over ovarian function, and thus fertility, has begun to gain importance. Previous studies have shown that adrenergic activity through norepinephrine (NE) participates in the control of follicular development and steroidal secretion from the ovary, among other functions. To examine this phenomenon, the denervation of the gonad has been widely used to observe changes in the ovary's performance. Nevertheless, the effect of the absence of adrenergic nerves in the ovary has only been studied in short times periods. In the present work, we used guanethidine (a drug that produces an irreversible sympathectomy) during the infantile period of rats, and we observed its effects in the adult rat (6 months old). Our results indicate that ovarian NE content is recovered at 6 months old, alongside with an increase of the adrenal content of NE and a dysfunctional celiac ganglion. Together, these results suggest that the recovery of ovarian NE does not come from a neural origin. In addition, ovarian performance was impaired because the changes in follicular development and steroidal secretion are not recovered despite the recovery of ovarian NE content. In conclusion, these results suggest that the nerve-ovarian connections, which are established during infantile development, are necessary for the accurate response of the ovary to sympathetic stimulation., (© 2018 Society for Reproduction and Fertility.)

Angiotensin 1-7 (ANG-(1-7)), a derivative of angiotensin I or II, is involved in the propagation of sympathetic output to the heart and vasculature, and the receptor for ANG-(1-7), the Mas receptor, is expressed on astrocytes in the rostral ventrolateral medulla (RVLM). We recorded blood pressure (BP) and splanchnic sympathetic nerve activity (SSNA) before and after focal injection of ANG-(1-7) into the RVLM of rats. Unilateral injection of ANG-(1-7) into the RVLM, acting through the Mas receptor, increased SSNA and BP, and glutamate receptor antagonists, CNQX and D-AP5, partially reduced the ANG-(1-7) effect. ATP is often co-released with glutamate, and blocking ATP with PPADS also reduced the pressor response to microinjection of ANG-(1-7) within the RVLM. The effects of ANG-(1-7) were blocked by the MAS receptor antagonist, A-779 (which had no consistent effect on blood pressure or sympathetic nerve activity when injected on its own). We conclude that astrocytes in the RVLM participate in central, angiotensin-dependent regulation of blood pressure and sympathetic nerve activity, and the Mas receptor, when activated by ANG-(1-7), elicits the release of the gliotransmitters, glutamate and ATP. These gliotransmitters then cause an increase in sympathetic nerve activity and blood pressure by interacting with AMPA/kainate and P2X receptors in the RVLM., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Increased extracellular glutamate may contribute to l-dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l-dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at the time of nigrostriatal lesion can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT-1 expression in a rat 6-hydroxydopamine model. In this article, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to l-dopa, could reduce l-dopa-induced dyskinesia in an established dyskinesia model., Methods: Ceftriaxone (200 mg/kg, intraperitoneal, once daily, 7 consecutive days) was initiated 7 days post-6-hydroxydopamine lesion (days 7-13) and continued every other week (days 21-27, 35-39) until the end of the study (day 39 postlesion, 20 days of l-dopa)., Results: Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic l-dopa treatment. Partial recovery of motor impairment from nigrostriatal lesion by l-dopa was unaffected by ceftriaxone. The ceftriaxone-treated l-dopa group had significantly increased striatal GLT-1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different when compared with the l-dopa alone group., Conclusions: Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during l-dopa, may reduce dyskinesia severity without affecting l-dopa efficacy or the reduction of striatal tyrosine hydroxylase loss. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Existing experimental studies of the effect of sympathetic nerve fibers on bone marrow cells are based on the systemic administration of neurotoxic 6-hydroxydopamine. The method of global chemical sympathectomy has some serious disadvantages and could lead to questionable results. We describe a new method of local chemical sympathectomy of rat femoral bone marrow using guanethidine (Ismelin) delivery using an osmotic mini pump. Local guanethidine treatment for 14days led to complete elimination of sympathetic fibers in femoral bone marrow in contrast to bone marrow of contralateral or naïve femurs. Ablation of sympathetic fibers was associated with a loss of rat endothelial cell marker (RECA) indicating immunophenotype changes in blood vessel endothelial cells, but no significant effect of guanethidine was found on the survival of endothelial cells and mesenchymal stem cells in vitro. Moreover, local guanethidine treatment also elicited a significant reduction of Nestin+/SDF1+ mesenchymal stem cells and c-Kit+/CD90+ hematopoietic stem cells in femoral bone marrow. Tissue-specific chemical sympathectomy of rat bone marrow by guanethidine overcomes some of the drawbacks of systemic administration of neurotoxic compounds like 6-hydroxydopamine and delivers unequivocal evidence on the effects of sympathetic innervation on the cell content of bone marrow., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Several lines of evidence imply alterations in adenosine signaling in Parkinson's disease (PD). Here, we investigated cerebral changes in adenosine 2A receptor (A 2A R) availability in 6-hydroxydopamine (6-OHDA)-lesioned rats with and without levodopa-induced dyskinesia (LID) using positron-emission tomography (PET) with [ 11 C]preladenant. In parallel dopamine type 2 receptor (D 2 R) imaging with [ 11 C]raclopride PET and behavioral tests for motor and cognitive function were performed., Methods: Parametric A 2A R and D 2 R binding potential (BP ND ) images were reconstructed using reference tissue models with midbrain and cerebellum as reference tissue, respectively. All images were anatomically standardized to Paxinos space and analyzed using volume-of-interest (VOI) and voxel-based approaches. The behavioral alternations were assessed with the open field test, Y-maze, novel object recognition test, cylinder test, and abnormal involuntary movement (AIM) score. In total, 28 female Wistar rats were included., Results: On the behavioral level, 6-OHDA-lesioned rats showed asymmetry in forepaw use and deficits in spatial memory and explorative behavior as compared to the sham-operated animals. 15-Days of levodopa (L-DOPA) treatment induced dyskinesia but did not alleviate motor deficits in PD rats. Intranigral 6-OHDA injection significantly increased D 2 R binding in the lesioned striatum (BP ND : 2.69 ± 0.40 6-OHDA vs. 2.31 ± 0.18 sham, + 16.6%; p = 0.03), whereas L-DOPA treatment did not affect the D 2 R binding in the ipsilateral striatum of the PD rats. In addition, intranigral 6-OHDA injection tended to decrease the A 2A R availability in the lesioned striatum. The decrease became significant when data were normalized to the non-affected side (BP ND : 4.32 ± 0.41 6-OHDA vs. 4.58 ± 0.89 sham; NS, ratio: 0.94 ± 0.03 6-OHDA vs. 1.00 ± 0.02 sham; - 6.1%; p = 0.01). L-DOPA treatment significantly increased A 2A R binding in the affected striatum (BP ND : 6.02 ± 0.91 L-DOPA vs. 4.90 ± 0.76 saline; + 23.4%; p = 0.02). In PD rats with LID, positive correlations were found between D 2 R and A 2A R BP ND values in the ipsilateral striatum (r = 0.88, p peak = 8.56.10 -4 uncorr), and between AIM score and the D 2 R BP ND in the contralateral striatum (r = 0.98; p peak = 9.55.10 -5 uncorr)., Conclusion: A 2A R availability changed in drug-naïve and in L-DOPA-treated PD rats. The observed correlations of striatal D 2 R availability with A 2A R availability and with AIM score may provide new knowledge on striatal physiology and new possibilities to further unravel the functions of these targets in the pathophysiology of PD., (Copyright © 2017. Published by Elsevier Inc.)

Aim: Multiple interacting pathways contribute to progression of renal and cardiac damage in chronic kidney disease followed by chronic heart failure (renocardiac syndrome). We hypothesized that simultaneous pharmacological modulation of critical pathways implicated in renocardiac syndrome would effectively reduce fibrosis in and preserve function of heart and kidney., Methods: Rats were subjected to subtotal nephrectomy followed 9 weeks later by coronary artery ligation. From week 11 until week 16, rats received vehicle or losartan, or a combination of the NF-kB inhibitor PDTC, the NO donor molsidomine and superoxide dismutase mimetic tempol, or a combination of all four of these plus metoprolol together. At week 16, renal and cardiac structure, function and gene expression were assessed., Results: Individual and combined treatments were similarly effective in limiting cardiac fibrosis and further decline in systolic function. Combined treatment with all five drugs reduced renal fibrosis and CTGF gene expression more effectively than other strategies. Combining all five drugs reduced heart rate, inotropy and mean arterial pressure (MAP)., Conclusion: Thus, in our model of chronic renocardiac syndrome, combined treatments similarly decreased cardiac fibrosis and stabilized systolic function as losartan alone, perhaps suggesting a dominant role for a single factor such as angiotensin II type 1 (AT1) receptor activation or inflammation in the network of aberrant systems in the heart. However, tubulointerstitial fibrosis was most effectively reduced by a five-drug regimen, pointing to additive effects of multiple pathophysiological pathways in the kidney., (© 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Glucagon receptor (GcgR) blockade has been proposed as an alternative to insulin monotherapy for treating type 1 diabetes since deletion or inhibition of GcgRs corrects hyperglycemia in models of diabetes. The factors regulating glycemia in a setting devoid of insulin and glucagon function remain unclear but may include the hormone ghrelin. Not only is ghrelin release controlled by glucose but also ghrelin has many actions that can raise or reduce falls in blood glucose level. Here, we tested the hypothesis that ghrelin rises to prevent hypoglycemia in the absence of glucagon function. Both GcgR knockout ( Gcgr -/- ) mice and db / db mice that were administered GcgR monoclonal antibody displayed lower blood glucose levels accompanied by elevated plasma ghrelin levels. Although treatment with the pancreatic β-cell toxin streptozotocin induced hyperglycemia and raised plasma ghrelin levels in wild-type mice, hyperglycemia was averted in similarly treated Gcgr -/- mice and the plasma ghrelin level was further increased. Notably, administration of a ghrelin receptor antagonist further reduced blood glucose levels into the markedly hypoglycemic range in overnight-fasted, streptozotocin-treated Gcgr -/- mice. A lowered blood glucose level also was observed in overnight-fasted, streptozotocin-treated ghrelin receptor-null mice that were administered GcgR monoclonal antibody. These data suggest that when glucagon activity is blocked in the setting of type 1 diabetes, the plasma ghrelin level rises, preventing hypoglycemia., (© 2017 by the American Diabetes Association.)

Changes in the basal brain bilateral morphologic, neurochemical and/or functional patterns may be partly responsible for some brain disorders such as those involving mood. WKY and SHR strains as well as 6-hydroxydopamine (6-OHDA)-lesioned animals are validated models for the study of mood disorders. Because dopamine and enkephalins are involved in anxiety-related behaviors, the aim of our study was to analyze enkephalinase activity, assayed as aminopeptidase M activity, in the left and right medial prefrontal cortex (mPFC) of WKY and SHR treated with saline (sham group) or following left or right intrastriatal injections of the neurotoxic 6-OHDA. Sham left and sham right WKY exhibited a significant left predominance. Left 6-OHDA-lesioned rats inverted the left predominance of sham to right predominance. In right 6-OHDA-lesioned rats, the left predominance in sham right rats disappeared. Sham left as well as sham right SHR did not show any bilateral differences. In contrast, while the left lesion demonstrated a highly significant left predominance, the right lesion showed a slight but significant right predominance. A significant negative correlation between enkephalinase activity of the right mPFC and blood pressure and heart rate was observed only in left-lesioned SHR. Our results demonstrate that unilateral nigrostriatal injections of 6-OHDA influence the bilateral distribution of enkephalinase activity depending on both the side of the lesion and the strain analyzed. These results support the hypothesis that DA pathways may interact asymmetrically with enkephalins in the mPFC and that enkephalinase activity may play a role in the regulatory mechanisms underlying this interaction., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Analysis of heart rate variability (HRV) by nonlinear approaches has been gaining interest due to their ability to extract additional information from heart rate (HR) dynamics that are not detectable by traditional approaches. Nevertheless, the physiological interpretation of nonlinear approaches remains unclear. Therefore, we propose long-term (60 min) protocols involving selective blockade of cardiac autonomic receptors to investigate the contribution of sympathetic and parasympathetic function upon nonlinear dynamics of HRV. Conscious male Wistar rats had their electrocardiogram (ECG) recorded under three distinct conditions: basal, selective (atenolol or atropine), or combined (atenolol plus atropine) pharmacological blockade of autonomic muscarinic or β 1 -adrenergic receptors. Time series of RR interval were assessed by multiscale entropy (MSE) and detrended fluctuation analysis (DFA). Entropy over short (1 to 5, MSE 1-5 ) and long (6 to 30, MSE 6-30 ) time scales was computed, as well as DFA scaling exponents at short (α short , 5 ≤ n ≤ 15), mid (α mid , 30 ≤ n ≤ 200), and long (α long , 200 ≤ n ≤ 1,700) window sizes. The results show that MSE 1-5 is reduced under atropine blockade and MSE 6-30 is reduced under atropine, atenolol, or combined blockade. In addition, while atropine expressed its maximal effect at scale six, the effect of atenolol on MSE increased with scale. For DFA, α short decreased during atenolol blockade, while the α mid increased under atropine blockade. Double blockade decreased α short and increased α long Results with surrogate data show that the dynamics during combined blockade is not random. In summary, sympathetic and vagal control differently affect entropy (MSE) and fractal properties (DFA) of HRV. These findings are important to guide future studies. NEW & NOTEWORTHY Although multiscale entropy (MSE) and detrended fluctuation analysis (DFA) are recognizably useful prognostic/diagnostic methods, their physiological interpretation remains unclear. The present study clarifies the effect of the cardiac autonomic control on MSE and DFA, assessed during long periods (1 h). These findings are important to help the interpretation of future studies., (Copyright © 2017 the American Physiological Society.)

Background: We aimed to investigate the effects of chronic oral treatment with centrally acting antihypertensive drugs, such as clonidine (CLO), an α 2 -adrenoceptor agonist, or LNP599, a selective I 1 imidazoline receptor agonist, on brain microvascular function in rats with high-fat diet (HFD)-induced metabolic syndrome., Methods: Male Wistar Kyoto rats were maintained on a normal diet (CON) or a HFD for 20 weeks. After this period, the HFD group received oral CLO (0.1 mg/kg), LNP599 (20 mg/kg), or vehicle daily for 4 weeks. Systolic blood pressure and heart rate (HR) were evaluated by photoplethysmography. Functional capillary density, endothelial function, and endothelial-leukocyte interactions in the brain were investigated by intravital video microscopy. Cerebral microcirculatory flow was evaluated by laser speckle contrast imaging. Brain tissue endothelial nitric oxide synthase, oxidative enzyme, and inflammatory marker expression levels were analyzed., Results: Metabolic syndrome decreased brain functional capillary density and microvascular blood perfusion, changes accompanied by deficient brain microcirculation vasodilatory responses to acetylcholine. Significant numbers of rolling and adherent leukocytes were also observed in the brain venules. Chronic sympathetic inhibition with clonidine and LNP599 reduced blood pressure and HR. These effects were accompanied by reversals of cerebral capillary rarefaction, improvements in cerebral microvascular blood flow and endothelial function, and decreases in endothelial-leukocyte interactions in the cerebral venules., Conclusions: Our results suggest that central sympathetic inhibition exerts beneficial effects by increasing perfusion and reducing inflammatory marker expression and oxidative stress in the brains of rats with metabolic syndrome. Centrally acting antihypertensive drugs may be helpful in regulating cerebral microcirculatory function and vascular inflammation in metabolic syndrome.

Background: Clonidine effectively decreases perioperative mortality by reducing sympathetic tone. However, application of clonidine might also restrict anaemia tolerance due to impairment of compensatory mechanisms. Therefore, the influence of clonidine induced, short-term sympathicolysis on anaemia tolerance was assessed in anaesthetized pigs. We measured the effect of clonidine on anaemia tolerance and of the potential for macrohemodynamic alterations to constrain the acute anaemia compensatory mechanisms., Methods: After governmental approval, 14 anaesthetized pigs of either gender (Deutsche Landrasse, weight (mean ± SD) 24.1 ± 2.4 kg) were randomly assigned to intravenous saline or clonidine treatment (bolus: 20 μg · kg -1 , continuous infusion: 15 μg · kg -1  · h -1 ). Thereafter, the animals were hemodiluted by exchange of whole blood for 6 % hydroxyethyl starch (MW 130.000/0.4) until the individual critical haemoglobin concentration (Hb crit ) was reached. Primary outcome parameters were Hb crit and the exchangeable blood volume (EBV) until Hb crit was reached., Results: Hb crit did not differ between both groups (values are median [interquartile range]: saline: 2.2 (2.0-2.5) g · dL -1 vs. clonidine: 2.1 (2.1-2.4) g · dL -1 ; n.s.). Furthermore, there was no difference in exchangeable blood volume (EBV) between both groups (saline: 88 (76-106) mL · kg -1 vs. clonidine: 92 (85-95) mL · kg -1 ; n.s.)., Conclusion: Anaemia tolerance was not affected by clonidine induced sympathicolysis. Consequently, perioperative clonidine administration probably has not to be omitted in view of acute anaemia.

α -Terpineol is a monoterpene with smooth muscle relaxant properties. In this study, its effects on the gastric emptying rate of awake rats were evaluated with emphasis on the mode by which it induces gastrointestinal actions. Administered by gavage, α -terpineol (50 mg/kg) delayed gastric emptying of a liquid test meal at 10 min postprandial. Hexamethonium or guanethidine did not interfere with the retarding effect induced by α -terpineol, but atropine and L-N G -nitroarginine methyl ester abolished it. In vagotomized rats, α -terpineol did not delay gastric emptying. In isolated strips of gastric fundus, concentration-effect curves in response to carbamylcholine were higher in magnitude after treatment with the monoterpene. α -Terpineol (1 to 2000 µM) relaxed sustained contractions induced by carbamylcholine or a high K + concentration in a concentration-dependent manner. This relaxing effect was not affected by the presence of L-N G -nitroarginine methyl ester, 1 H-[1, 2, 4]oxadiazolo[4,3-a]quinoxalin-1-one, tetraethylammonium, or atropine. Smooth muscle contractions induced by electrical field stimulation were inhibited by α -terpineol. In conclusion, α -terpineol induced gastric retention in awake rats through mechanisms that depended on intact vagal innervation to the stomach, which involved cholinergic/nitrergic signalling. Such a retarding effect induced by α -terpineol appears not to result from a direct action of the monoterpene on gastric smooth muscle cells., (Georg Thieme Verlag KG Stuttgart · New York.)

Agmatine, a vasoactive metabolite of L-arginine, is widely distributed in mammalian tissues including blood vessels. Agmatine binding to imidazoline and α₂-adrenoceptors induces a variety of physiological and pharmacological effects. We investigated the effect of agmatine on contractile responses of the rat pulmonary artery and portal vein induced by electrical stimulation of perivascular nerves and by exogenous adrenergic substances. Experiments were performed on isolated segments of rat main pulmonary artery and its extralobular branches, and portal vein suspended in organ bath containing modified Krebs bicarbonate solution and connected to a force-displacement transducer for isometric tension recording. Electrical field stimulation (EFS) produced tetrodotoxin-sensitive contractile responses of pulmonary artery and portal vein. Besides the well known vasorelaxant actions, we found that agmatine also produced a concentration-dependent inhibition of neurogenic contractions induced by EFS in pulmonary arteries; however, the agmatine treatment did not influence the responses to exogenous noradrenaline. The inhibitory effect on EFS-induced contractions was not abolished by the α₂-adrenoceptor antagonist rauwolscine. In portal vein, in contrast, agmatine increased spontaneous mechanical contractions and enhanced the contractions induced by EFS. The results suggest that agmatine can significantly influence vascular function of pulmonary arteries and portal veins by modulating sympathetically mediated vascular contractions by pre- and postsynaptic mechanisms.

Cerebral autoregulation (CA) dampens transfer of blood pressure (BP)-fluctuations onto cerebral blood flow velocity (CBFV). Thus, CBFV-oscillations precede BP-oscillations. The phase angle (PA) between sympathetically mediated low-frequency (LF: 0.03-0.15Hz) BP- and CBFV-oscillations is a measure of CA quality. To evaluate whether PA depends on sympathetic modulation, we assessed PA-changes upon sympathetic stimulation with and without pharmacologic sympathetic blockade. In 10 healthy, young men, we monitored mean BP and CBFV before and during 120-second cold pressor stimulation (CPS) of one foot (0°C ice-water). We calculated mean values, standard deviations and sympathetic LF-powers of all signals, and PAs between LF-BP- and LF-CBFV-oscillations. We repeated measurements after ingestion of the adrenoceptor-blocker carvedilol (25mg). We compared parameters before and during CPS, without and after carvedilol (analysis of variance, post-hoc t-tests, significance: p<0.05). Without carvedilol, CPS increased BP, CBFV, BP-LF- and CBFV-LF-powers, and shortened PA. Carvedilol decreased resting BP, CBFV, BP-LF- and CBFV-LF-powers, while PAs remained unchanged. During CPS, BPs, CBFVs, BP-LF- and CBFV-LF-powers were lower, while PAs were longer with than without carvedilol. With carvedilol, CPS no longer shortened resting PA. Sympathetic activation shortens PA. Partial adrenoceptor blockade abolishes this PA-shortening. Thus, PA-measurements provide a subtle marker of sympathetic influences on CA and might refine CA evaluation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Neuroinflammatory signaling may contribute to the pathophysiology of chronic anxiety disorders. Previous work showed that repeated social defeat (RSD) in mice promoted stress-sensitization that was characterized by the recurrence of anxiety following subthreshold stress 24 days after RSD. Furthermore, splenectomy following RSD prevented the recurrence of anxiety in stress-sensitized mice. We hypothesize that the spleen of RSD-exposed mice became a reservoir of primed monocytes that were released following neuroendocrine activation by subthreshold stress., Methods: Mice were subjected to subthreshold stress (i.e., single cycle of social defeat) 24 days after RSD, and immune and behavioral measures were taken., Results: Subthreshold stress 24 days after RSD re-established anxiety-like behavior that was associated with egress of Ly6C(hi) monocytes from the spleen. Moreover, splenectomy before RSD blocked monocyte trafficking to the brain and prevented anxiety-like behavior following subthreshold stress. Splenectomy, however, had no effect on monocyte accumulation or anxiety when determined 14 hours after RSD. In addition, splenocytes cultured 24 days after RSD exhibited a primed inflammatory phenotype. Peripheral sympathetic inhibition before subthreshold stress blocked monocyte trafficking from the spleen to the brain and prevented the re-establishment of anxiety in RSD-sensitized mice. Last, β-adrenergic antagonism also prevented splenic monocyte egress after acute stress., Conclusions: The spleen served as a unique reservoir of primed monocytes that were readily released following sympathetic activation by subthreshold stress that promoted the re-establishment of anxiety. Collectively, the long-term storage of primed monocytes in the spleen may have a profound influence on recurring anxiety disorders., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: The objective of this study was to investigate the role of the SNS on hemodynamic, metabolic, and microvascular alterations in a rat model of HFD-induced MS with salt supplementation., Methods: In total, 40 adult male Wistar rats were fed normal chow (n = 10) or a HFD (n = 30) for 20 weeks. Thereafter, the HFD group received the centrally acting sympatho-modulatory drugs clonidine (0.1 mg/kg) or rilmenidine (1 mg/kg) or vehicle (n = 10/group) orally by gavage. FCD was evaluated using intravital video microscopy, and the SCD was evaluated using histochemical analysis., Results: The pharmacological modulation of the SNS induced concomitant reductions in SBP, HR and plasma catecholamine levels. These effects were accompanied by a reversal of functional and structural capillary rarefaction in the skeletal muscle in both treated groups and an increase in SCD in the left ventricle only in the rilmenidine group. Improvement of the lipid profile and of glucose intolerance was also obtained only with rilmenidine treatment., Conclusions: Modulation of sympathetic overactivity results in the reversal of microvascular rarefaction in the skeletal muscle and left ventricle and improves metabolic parameters in an experimental model of MS in rats., (© 2016 John Wiley & Sons Ltd.)

Cardiac autonomic tone can be assessed either by estimating separately vagal and sympathetic tones or by evaluating the net effect of their interaction, the so-called sympathovagal balance (SVB). To compare the most commonly used methods in rats, telemetric recordings of the electrocardiogram were performed in normotensive WKY rats, and in groups of spontaneously hypertensive (SHR) rats that were either untreated or chronically treated with the cholinesterase inhibitor, pyridostigmine, to enhance vagal tone. Cardiac autonomic blockers were administered alone and in combination, so that heart rate (HR) could be measured (1) under resting conditions, (2) with either autonomic branch blocked, and (3) with both branches blocked (which provided intrinsic HR, iHR). SVB was assessed as the ratio of resting HR to iHR. This calculation pointed to a sympathetic predominance in untreated SHRs and even more so in WKY rats, and to a marked vagal predominance in pyridostigmine-treated SHRs. By contrast, the ratio between low and high frequency components (LF/HF) of RR interval spectra did not significantly differ between the groups. Each autonomic tone was quantified as the HR change induced by its selective blocker or as the difference between iHR and HR after blockade of its counterpart. Both pharmacological methods indicated vagal enhancement in treated SHRs, but provided opposite results in terms of vagal vs. sympathetic predominance. These data seriously question the use of the LF/HF ratio as an index of SVB, and the possibility to reliably estimate vagal and sympathetic tones separately through current pharmacological approaches in conscious rats., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aims: Sympathetic activation during myocardial ischemia enhances arrhythmogenesis, but the underlying pathophysiologic mechanisms remain unclear. We investigated the central sympathetic effects on ventricular repolarization during the early-period post-coronary artery occlusion., Main Methods: We studied 12 Wistar rats (254±2 g) for 30 min following left coronary artery ligation, with (n=6) or without (n=6) pretreatment with the central sympatholytic agent clonidine. Mapping of left and right ventricular epicardial electrograms was performed with a 32-electrode array. As an index of sympathetic activation, heart rate variability in the frequency domain was calculated. Heart rate and repolarization duration were measured with a custom-made recording and analysis software, followed by calculation of intra- and inter-ventricular dispersion of repolarization., Key Findings: Heart rate and heart rate variability indicated lower sympathetic activation in clonidine-treated rats during ischemia. Repolarization duration in the left ventricle prolonged after clonidine at baseline, independently of heart rate, but no differences were present 30 min post-ligation. Dispersion of repolarization in the right ventricle remained stable during ischemia, whereas it increased in the left ventricle, equally in both groups. A similar trend was observed for inter-ventricular dispersion, without differences between groups., Significance: In addition to intra-ventricular repolarization-dispersion, anterior-wall myocardial ischemia may also increase inter-ventricular repolarization-dispersion. Progressive central sympathetic activation occurs during myocardial ischemia, but it does not affect intra- or inter-ventricular dispersion of ventricular repolarization during the early phase. Further research is warranted on the potential effects during subsequent time-periods., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: A high mortality rate occurs with silent myocardial infarction (MI), particularly in aging and diabetic populations due to defects in the transient receptor potential vanilloid (TRPV1)-positive sensory nerve function. We have previously shown that TRPV1 deficiency markedly enhances post-MI inflammation and remodeling. However, the mechanisms remain unknown. The objective of this study was to clarify whether calcitonin gene-related peptide (CGRP) release was associated with the protective role of TRPV1 against postmyocardial inflammation and apoptosis., Methods: TRPV1 gene knockout (TRPV1KO) and wild-type (WT) mice were subjected to left anterior descending ligation or sham operation. The concentration of CGRP in the myocardium was measured at 30 min, 1, 6 and 24 h post-MI. Mice received saline vehicle, CGRP or the CGRP antagonist CGRP8-37 before ligation. Inflammation was evaluated by ELISA assay and histological staining. Apoptosis was assessed by Western blot and TUNEL assay., Results: Post-MI, both TRPV1KO and WT mice displayed elevated CGRP levels in myocardium when compared to sham controls. However, the levels of CGRP were significantly lower in TRPV1KO mice than in WT mice at 30 min after MI. Exogenous CGRP downregulated the levels of tumor necrosis factor-α and interleukin-6 expression in TRPV1KO mice post-MI. Moreover, exogenous CGRP decreased the neutrophil infiltration in TRPV1KO mice, whereas inhibition of CGRP by CGRP8-37 increased the neutrophil infiltration in WT mice. Western blotting data indicated that CGRP attenuated caspase-3 and caspase-9 expression, and enhanced Bcl-2 expression in TRPV1KO mice post-MI. CGRP8-37 upregulated caspase-3 and caspase-9 expression and downregulated Bcl-2 expression in WT mice., Conclusion: Our data suggest a protective role of TRPV1 activation against inflammation and apoptosis in mice post-MI, possibly through CGRP release. These findings elucidate a neurogenic mechanism in mice post-MI, which may participate in sensory neurotransmitter-mediated protection in TRPV1 activation., (© 2016 S. Karger AG, Basel.)

Objective: Pre-exertion skeletal muscle glycogen content is an important physiological determinant of endurance exercise performance: low glycogen stores contribute to premature fatigue. In low-oxygen environments (hypoxia), the important contribution of carbohydrates to endurance performance is further enhanced as glucose and glycogen dependence is increased; however, the insulin sensitivity of healthy adult humans is decreased. In light of this insulin resistance, maintaining skeletal muscle glycogen in hypoxia becomes difficult, and subsequent endurance performance is impaired. Sympathetic inhibition promotes insulin sensitivity in hypoxia but may impair hypoxic exercise performance, in part due to suppression of cardiac output. Accordingly, we tested the hypothesis that hypoxic exercise performance after intravenous glucose feeding in a low-oxygen environment will be attenuated when feeding occurs during sympathetic inhibition., Methods: On 2 separate occasions, while breathing a hypoxic gas mixture, 10 healthy men received 1 hour of parenteral carbohydrate infusion (20% glucose solution in saline; 75 g), after which they performed stationary cycle ergometer exercise (~65% maximal oxygen uptake) until exhaustion. Forty-eight hours before 1 visit, chosen randomly, sympathetic inhibition via transdermal clonidine (0.2 mg/d) was initiated., Results: The mean time to exhaustion after glucose feeding both with and without sympathetic inhibition was not different (22.7 ± 5.4 minutes vs 23.5 ± 5.1 minutes; P = .73)., Conclusions: Sympathetic inhibition protects against hypoxia-mediated insulin resistance without influencing subsequent hypoxic endurance performance., (Copyright © 2015 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.)

The type 2 angiotensin receptor (AT2R) has been suggested to counterbalance the type 1 angiotensin receptor (AT1R) in the central regulation of blood pressure and sympathetic tone. In the present study we investigated the blood pressure responses to stimulation of central AT2Rs by the selective agonist Compound 21 in conscious spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (WKY rats). We also assessed the impact on noradrenaline [norepinephrine (NE)] plasma levels, autonomic function, spontaneous baroreflex sensitivity, and the possible involvement of the nitric oxide (NO) pathway and the AT1Rs. Chronic intracerebroventricular Compound 21 infusion lowered blood pressure and NE plasma levels in both rat strains. The night-time hypotensive effect was greater in SHRs compared with WKY rats. Compound 21 improved spontaneous baroreflex sensitivity more in SHRs than in WKY rats. These effects were abolished by co-administration of the AT2R antagonist PD123319 or the NO synthase inhibitor Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME). Central AT1R blockade did not enhance the hypotensive response to Compound 21. Chronic selective stimulation of central AT2Rs lowers blood pressure through sympathoinhibition, and improves spontaneous baroreflex sensitivity more in SHRs than in WKY rats. These responses appear to require a functioning central NO pathway, but are not modified by central AT1R blockade. Collectively, the data demonstrate specific beneficial effects of stimulation of central AT2Rs in hypertension associated with increased sympathetic tone, and suggest that central AT2Rs may represent a potential new therapeutic target for the treatment of neurogenic hypertension.

Rationale: Overeating beyond individuals' homeostatic needs critically contributes to obesity. The neurobehavioral mechanisms underlying the motivation to consume excessive foods with high calories are not fully understood., Objective: The present study examined whether a pharmacological stressor, yohimbine, enhances the motivation to procure food reward with an emphasis on comparisons between standard lab chow and high-fat foods. The effects of corticotropin-releasing factor (CRF) receptor blockade by a CRF1-selective antagonist NBI on the stress-enhanced motivation for food reward were also assessed., Methods: Male Sprague-Dawley rats with chow available ad libitum in their home cages were trained to press a lever under a progressive ratio schedule for deliveries of either standard or high-fat food pellets. For testing yohimbine stress effects, rats received an intraperitoneal administration of yohimbine 10 min before start of the test sessions. For testing effects of CRF1 receptor blockade on stress responses, NBI was administered 20 min prior to yohimbine challenge., Results: The rats emitted higher levels of lever responses to procure the high-fat food pellets compared with their counterparts on standard food pellets. Yohimbine challenge facilitated lever responses for the reward in all of the rats, whereas the effect was more robust in the rats on high-fat food pellets compared with their counterparts on standard food pellets. An inhibitory effect of pretreatment with NBI was observed on the enhancing effect of yohimbine challenge but not on the responses under baseline condition without yohimbine administration., Conclusions: Stress challenge significantly enhanced the motivation of satiated rats to procure extra food reward, especially the high-fat food pellets. Activation of CRF1 receptors is required for the stress-enhanced motivation for food reward. These results may have implications for our better understanding of the biobehavioral mechanisms of overeating and obesity.

New 2-aryliminopyrrolidines (1-18) were synthesized and tested for their binding properties on I1 imidazoline receptors vs α2-adrenergic receptors and their blood pressure effects after both systemic and intracerebral administrations. The purposes of this study were: (i) to analyze structure-activity and affinity relationships on I1 imdazoline receptors and (ii) to propose some leader compounds for the development of new sympatho-inhibitory drugs with potential applications in hypertension and/or metabolic syndrome, i.e., a cluster of cardiovascular (hypertension) and metabolic disorders. Our study highlights decisive arguments of SAR concerning both the affinity for I1Rs and the hypotensive activity of 2-aryliminopyrrolidines. Binding assays showed high affinity and selectivity of some compounds for I1 imidazoline receptors over α2-adreergic receptors. Compound 13 (laboratory reference LNP599; Ki = 3.2 nM on I1imidazoline receptors) is the prototype for the development of new centrally acting agents targeting specifically I1imidazoline receptors to be used in the management of hypertension and/or metabolic syndrome.

The sympathetic nervous system regulates many immune functions and modulates the anti-tumor immune defense response, too. Therefore, we studied the effect of 6-hydroxydopamine induced sympathectomy on selected hematological parameters and inflammatory markers in rats with Yoshida AH130 ascites hepatoma. We found that chemically sympathectomized tumor-bearing rats had significantly increased neutrophil-to-lymphocyte ratio, leukocyte-to-lymphocyte ratio, and plasma levels of tumor necrosis factor alpha. Although our findings showed that sympathetic denervation in tumor-bearing rats led to increased neutrophil-to-lymphocyte ratio, that is an indicator of the disease progression, we found no significant changes in tumor growth and survival of sympathectomized tumor-bearing rats., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Chronic stress causes hypothalamo-pituitary-adrenal (HPA) axis hyperactivity and cardiovascular dyshomeostasis. Noradrenergic (NA) neurons in the nucleus of the solitary tract (NTS) are considered to play a role in these changes. In this study, we tested the hypothesis that NTS NA A2 neurons are required for cardiovascular and HPA axis responses to both acute and chronic stress. Adult male rats received bilateral microinjection into the NTS of 6-hydroxydopamine (6-OHDA) to lesion A2 neurons [cardiovascular study, n = 5; HPA study, n = 5] or vehicle [cardiovascular study, n = 6; HPA study, n = 4]. Rats were exposed to acute restraint stress followed by 14 d of chronic variable stress (CVS). On the last day of testing, rats were placed in a novel elevated plus maze (EPM) to test post-CVS stress responses. Lesions of NTS A2 neurons reduced the tachycardic response to acute restraint, confirming that A2 neurons promote sympathetic activation following acute stress. In addition, CVS increased the ratio of low-frequency to high-frequency power for heart rate variability, indicative of sympathovagal imbalance, and this effect was significantly attenuated by 6-OHDA lesion. Lesions of NTS A2 neurons reduced acute restraint-induced corticosterone secretion, but did not affect the corticosterone response to the EPM, indicating that A2 neurons promote acute HPA axis responses, but are not involved in CVS-mediated HPA axis sensitization. Collectively, these data indicate that A2 neurons promote both cardiovascular and HPA axis responses to acute stress. Moreover, A2 catecholaminergic neurons may contribute to the potentially deleterious enhancement of sympathetic drive following chronic stress.

Background and Aims: Maternal undernutrition induces development of the arterial hypertension. We investigated the effects of a maternal low-protein diet on cardiovascular autonomic control in the offspring., Methods and Results: Male Wistar rats were divided into two groups according to the diets of their mothers during gestation and lactation: the control (normal protein, NP, 17% casein; n = 14) and low-protein (LP, 8% casein; n = 14) groups. Direct measurements of arterial pressure (AP) were recorded from wakeful 90-day-old male offspring. The LP offspring presented higher mean AP than did the NP rats (NP: 93 ± 4 vs. LP: 113 ± 2 mmHg; p < 0.05), whereas the heart rate (HR) was similar in the two groups. In the spectral analysis, the LP group showed higher power at low (NP: 1.98 ± 0.25 vs. LP: 3.7 ± 0.3 mmHg²; p < 0.05) and high (NP: 1.28 ± 0.18 vs. LP: 2.13 ± 0.42 mmHg²; p < 0.05) frequencies of systolic arterial pressure (SAP). In the pulse interval, the LP group presented an increase in the LF/HF ratio (NP: 0.32 vs. LP: 0.56; p < 0.05). After propranolol (4 mg/kg, intravenous (iv)), the bradycardia was higher in the LP group (NP: -36 ± 8 vs. LP: -94 ± 12 bpm; p < 0.05), after methylatropine (2 mg/kg, iv), the tachycardia was similar to NP group. After administration of the ganglionic blocker (hexamethonium; 25 mg/kg, iv), the LP animals showed larger delta variation in the AP (NP: -33.7 ± 5 vs. LP: -53.6 ± 4 mmHg; p < 0.05)., Conclusion: The rats subjected to protein malnutrition presented an increase in the cardiovascular sympathetic tone, which contributed to the elevated AP observed in these animals., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background and Purpose: Previous studies have demonstrated that nicotine releases protons from adrenergic nerves via stimulation of nicotinic ACh receptors and activates transient receptor potential vanilloid-1 (TRPV1) receptors located on calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves, resulting in vasodilatation. The present study investigated whether perivascular nerves release protons, which modulate axon-axonal neurotransmission., Experiment Approach: Perfusion pressure and pH levels of perfusate in rat-perfused mesenteric vascular beds without endothelium were measured with a pressure transducer and a pH meter respectively., Key Results: Periarterial nerve stimulation (PNS) initially induced vasoconstriction, which was followed by long-lasting vasodilatation and decreased pH levels in the perfusate. Cold-storage denervation of the preparation abolished the decreased pH and vascular responses to PNS. The adrenergic neuron blocker guanethidine inhibited PNS-induced vasoconstriction and effects on pH, but not PNS-induced vasodilatation. Capsaicin (CGRP depletor), capsazepine and ruthenium red (TRPV1 inhibitors) attenuated the PNS-induced decrease in pH and vasodilatation. In denuded preparations, ACh caused long-lasting vasodilatation and lowered pH; these effects were inhibited by capsaicin pretreatment and atropine, but not by guanethidine or mecamylamine. Capsaicin injection induced vasodilatation and a reduction in pH, which were abolished by ruthenium red. The use of a fluorescent pH indicator demonstrated that application of nicotine, ACh and capsaicin outside small mesenteric arteries reduced perivascular pH levels and these effects were abolished in a Ca(2+) -free medium., Conclusion and Implication: These results suggest that protons are released from perivascular adrenergic and CGRPergic nerves upon PNS and these protons modulate transmission in CGRPergic nerves., (© 2014 The British Pharmacological Society.)