Sympathetic Neurotransmission Research Articles

Assessment of the Association between Neuropeptide Y and Chronic Kidney Disease Progression

Background: Neuropeptide Y (NPY) is a sympathetic neurotransmitter with wide-ranging effects in various organ systems, from the central nervous system (CNS) to the cardiovascular system, the bone and the renal system. There is a strong association between serum concentration of NPY and deterioration of eGFR and proteinuria as suggested by recent studies, however, its real effect on chronic kidney disease (CKD) progression is uncertain. Objective: This study was conducted to assess the relationship between serum NPY and CKD progression. Materials and Methods: In this observational case-control study all participants were subjected to renal function tests and calculation of estimated glomerular filtration rate, urinary protein/creatinine ratio, serum NPY and pelviabdominal ultrasonography at baseline and repeated for the patients only after six months as follow up. Results: Serum NPY increased with a statistically significant difference in the patients group after six months follow up, the same as serum creatinine which increased significantly after six months and eGFR decreased with statistically significant difference. Also there was high statistically significant rise in the blood urea. There was no statistically significant difference rise in protein creatinine ratio after six months. The ROC curve determined the sensitivity and specificity of serum NPY as a marker of progression in CKD patients and the best cut off point to detect CKD status was calculated with NPY greater than 110 ng/L with sensitivity 100% and specificity 93.33%. Conclusion: Serum NPY could be a useful sensitive and specific marker that can be used as diagnostic and progression predictor for CKD.

Assessment of the Association between Neuropeptide Y and Chronic Kidney Disease Progression

Background: Neuropeptide Y (NPY) is a sympathetic neurotransmitter with wide-ranging effects in various organ systems, from the central nervous system (CNS) to the cardiovascular system, the bone and the renal system. There is a strong association between serum concentration of NPY and deterioration of eGFR and proteinuria as suggested by recent studies, however, its real effect on chronic kidney disease (CKD) progression is uncertain. Objective: This study was conducted to assess the relationship between serum NPY and CKD progression. Materials and Methods: In this observational case-control study all participants were subjected to renal function tests and calculation of estimated glomerular filtration rate, urinary protein/creatinine ratio, serum NPY and pelviabdominal ultrasonography at baseline and repeated for the patients only after six months as follow up. Results: Serum NPY increased with a statistically significant difference in the patients group after six months follow up, the same as serum creatinine which increased significantly after six months and eGFR decreased with statistically significant difference. Also there was high statistically significant rise in the blood urea. There was no statistically significant difference rise in protein creatinine ratio after six months. The ROC curve determined the sensitivity and specificity of serum NPY as a marker of progression in CKD patients and the best cut off point to detect CKD status was calculated with NPY greater than 110 ng/L with sensitivity 100% and specificity 93.33%. Conclusion: Serum NPY could be a useful sensitive and specific marker that can be used as diagnostic and progression predictor for CKD.

Brown adipocyte-derived exosomal miR-132-3p suppress hepatic Srebf1 expression and thereby attenuate expression of lipogenic genes

Recent evidence has revealed a novel signaling mechanism through which brown adipose tissue (BAT)-derived exosomal microRNAs (miRNAs) influence hepatic gene expression. Here, we uncover neuronal control of these miRNAs and identify exosomal miR-132-3p as a regulator of hepatic lipogenesis under cold stress conditions. Norepinephrine, a sympathetic nervous system neurotransmitter mediating cold-induced BAT activation, altered the composition of brown adipocyte (BAC)-derived exosomal miRNAs; among them, miR-132-3p was significantly induced. The isolated BAC-derived exosomes suppressed expression of hepatic Srebf1, a predicted target of miR-132-3p. In an indirect co-culture system, BACs suppressed expression of hepatic Srebf1 and its target lipogenic genes; this effect was not seen with miR-132-3p–inhibited BACs. Srebf1 was experimentally validated as an miR-132-3p target. Cold stimuli consistently induced miR-132-3p expression in BAT and attenuated Srebf1 expression in the liver. Our results suggest that BAT-derived exosomal miR-132-3p acts as an endocrine factor that regulates hepatic lipogenesis for cold adaptation.

Neurotoxicity of Tityus bahiensis (brown scorpion) venom in sympathetic vas deferens preparations and neuronal cells

Systemic scorpion envenomation is characterized by massive neurotransmitter release from peripheral nerves mediated primarily by scorpion venoms neurotoxins. Tityus bahiensis is one of the medically most important species in Brazil, but its venom pharmacology, especially regarding to peripheral nervous system, is poorly understood. Here, we evaluated the T. bahiensis venom activity on autonomic (sympathetic) neurotransmission by using a variety of approaches, including vas deferens twitch-tension recordings, electrophysiological measurements (resting membrane potentials, spontaneous excitatory junctional potentials and whole-cell patch-clamp), calcium imaging and histomorphological analysis. Low concentrations of venom (≤ 3 μg/mL) facilitated the electrically stimulated vas deferens contractions without affecting postsynaptic receptors or damaging the smooth muscle cells. Transient TTX-sensitive sustained contractions and resting membrane depolarization were mediated mainly by massive spontaneous ATP release. High venom concentrations (≥ 10 μg/mL) blocked the muscle contractions and induced membrane depolarization. In neuronal cells (ND7-23wt), the venom increased the peak sodium current, modified the current-voltage relationship by left-shifting the Nav-channel activation curve, thereby facilitating the opening of these channels. The venom also caused a time-dependent increase in neuronal calcium influx. These results indicate that the sympathetic hyperstimulation observed in systemic envenomation is presynaptically driven, probably through the interaction of α- and β-toxins with neuronal sodium channels.

Norepinephrine Inhibits the Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells via β2-Adrenoceptor-Mediated ERK1/2 and PKA Phosphorylation.

Bone marrow-derived mesenchymal stem cells (BMSCs) represent an alternative to chondrocytes to support cartilage regeneration in osteoarthritis (OA). The sympathetic neurotransmitter norepinephrine (NE) has been shown to inhibit their chondrogenic potential; however, their proliferation capacity under NE influence has not been studied yet. Therefore, we used BMSCs obtained from trauma and OA donors and compared the expression of adrenergic receptors (AR). Then, BMSCs from both donor groups were treated with NE, as well as with combinations of NE and α1-, α2- or β1/2-AR antagonists (doxazosin, yohimbine or propranolol). Activation of AR-coupled signaling was investigated by analyzing ERK1/2 and protein kinase A (PKA) phosphorylation. A similar but not identical subset of ARs was expressed in trauma (α2B-, α2C- and β2-AR) and OA BMSCs (α2A-, α2B-, and β2-AR). NE in high concentrations inhibited the proliferation of both trauma and OA BMCSs significantly. NE in low concentrations did not influence proliferation. ERK1/2 as well as PKA were activated after NE treatment in both BMSC types. These effects were abolished only by propranolol. Our results demonstrate that NE inhibits the proliferation and accordingly lowers the regenerative capacity of human BMSCs likely via β2-AR-mediated ERK1/2 and PKA phosphorylation. Therefore, targeting β2-AR-signaling might provide novel OA therapeutic options.

Nitrergic perivascular innervation in health and diseases: Focus on vascular tone regulation.

For a long time, the vascular tone was considered to be regulated exclusively by tonic innervation of vasoconstrictor adrenergic nerves. However, accumulating experimental evidence has revealed the existence of nerves mediating vasodilatation, including perivascular nitrergic nerves (PNN), in a wide variety of mammalian species. Functioning of nitrergic vasodilator nerves is evidenced in several territories, including cerebral, mesenteric, pulmonary, renal, penile, uterine and cutaneous arteries. Nitric oxide (NO) is the main neurogenic vasodilator in cerebral arteries and acts as a counter-regulatory mechanism for adrenergic vasoconstriction in other vascular territories. In the penis, NO relaxes the vascular and cavernous smooth muscles leading to penile erection. Furthermore, when interacting with other perivascular nerves, NO can act as a neuromodulator. PNN dysfunction is involved in the genesis and maintenance of vascular disorders associated with arterial and portal hypertension, diabetes, ageing, obesity, cirrhosis and hormonal changes. For example defective nitrergic function contributes to enhanced sympathetic neurotransmission, vasoconstriction and blood pressure in some animal models of hypertension. In diabetic animals and humans, dysfunctional nitrergic neurotransmission in the corpus cavernosum is associated with erectile dysfunction. However, in some vascular beds of hypertensive and diabetic animals, an increased PNN function has been described as a compensatory mechanism to the increased vascular resistance. The present review summarizes current understanding on the role of PNN in control of vascular tone, its alterations under different conditions and the associated mechanisms. The knowledge of these changes can serve to better understand the mechanisms involved in these disorders and help in planning new treatments.

Ion currents, action potentials, and noradrenergic responses in rat pulmonary vein and left atrial cardiomyocytes.

The electrophysiological properties of pulmonary vein (PV)‐cardiomyocytes, and their responses to the sympathetic neurotransmitter, noradrenaline (NA), are thought to differ from those of the left atrium (LA) and contribute to atrial ectopy. The aim of this study was to examine rat PV cardiomyocyte electrophysiology and responses to NA in comparison with LA cells. LA and PV cardiomyocytes were isolated from adult male Wistar rat hearts, and membrane potentials and ion currents recorded at 36°C using whole‐cell patch‐clamp techniques. PV and LA cardiomyocytes did not differ in size. In control, there were no differences between the two cell‐types in zero‐current potential or action potential duration (APD) at 1 Hz, although the incidence of early afterdepolarizations (EADs) was greater in PV than LA cardiomyocytes. The L‐type Ca2+ current (I CaL) was ~×1.5 smaller (p = .0029, Student's t test) and the steady‐state K+ current (I Kss) was ~×1.4 larger (p = .0028, Student's t test) in PV than in LA cardiomyocytes. PV cardiomyocyte inward‐rectifier current (I K1) was slightly smaller than LA cardiomyocyte I K1. In LA cardiomyocytes, NA significantly prolonged APD30. In PV cells, APD30 responses to 1 μM NA were heterogeneous: while the mean percentage change in APD30 was not different from 0 (16.5 ± 9.7%, n cells/N animals = 12/10, p = .1177, one‐sample t test), three cells showed shortening (‐18.8 ± 6.0%) whereas nine showed prolongation (28.3 ± 10.1%, p = .008, Student's t test). NA had no effect on I K1 in either cell‐type but inhibited PV I Kss by 41.9 ± 4.1% (n/N = 23/11 p < .0001), similar to LA cells. NA increased I CaL in most PV cardiomyocytes (median × 2.2‐increase, p < .0001, n/N = 32/14, Wilcoxon‐signed‐rank test), although in 7/32 PV cells I CaL was decreased following NA. PV cardiomyocytes differ from LA cells and respond heterogeneously to NA.

α 2-Adrenoceptors: Challenges and Opportunities-Enlightenment from the Kidney.

It was indeed a Don Quixote-like pursuit of the mechanism of essential hypertension when we serendipitously discovered α2-adrenoceptors (α2-ARs) in skin-lightening experiments in the frog. Now α2-ARs lurk on the horizon involving hypertension causality, renal denervation for hypertension, injury from falling in the elderly and prazosin's mechanism of action in anxiety states such as posttraumatic stress disorder (PTSD). Our goal here is to focus on this horizon and bring into clear view the role of α2-AR-mediated mechanisms in these seemingly unrelated conditions. Our narrative begins with an explanation of how experiments in isolated perfused kidneys led to the discovery of a sodium-retaining process, a fundamental mechanism of hypertension, mediated by α2-ARs. In this model system and in the setting of furosemide-induced sodium excretion, α2-AR activation inhibited adenylate cyclase, suppressed cAMP formation, and caused sodium retention. Further investigations led to the realization that renal α2-AR expression in hypertensive animals is elevated, thus supporting a key role for kidney α2-ARs in the pathophysiology of essential hypertension. Subsequent studies clarified the molecular pathways by which α2-ARs activate prohypertensive biochemical systems. While investigating the role of α1-adrenoceptors (α1-ARs) versus α2-ARs in renal sympathetic neurotransmission, we noted an astonishing result: in the kidney α1-ARs suppress the postjunctional expression of α2-ARs. Here, we describe how this finding relates to a broader understanding of the role of α2-ARs in diverse disease states. Because of the capacity for qualitative and quantitative monitoring of α2-AR-induced regulatory mechanisms in the kidney, we looked to the kidney and found enlightenment.

The sympathetic transmitter norepinephrine inhibits VSMC proliferation induced by TGFβ by suppressing theexpression of the TGFβ receptor ALK5 in aorta remodeling.

The sympathetic system is involved in the arterial diseases, but its mechanism remains poorly understood. The present study aimed to explore the impact of the sympathetic neurotransmitter norepinephrine (NE) on transforming growth factor (TGF) β signaling and the role of NE in aortic remodeling. Guanethidine was used to induce a regional chemical sympathetic denervation (CSD) in angiotensin II (AngII) and β-aminopropionitrile (BAPN)-induced aortic aneurysm models. The diameter of the aorta was measured, and elastic fiber staining was performed. TGFβ type I receptor kinase (ALK5) expression in rat aortic NE-treated vascular smooth muscle cells (VSMCs) was detected by reverse transcription-quantitative PCR and western blotting. The effects of NE and ALK5 overexpression on migration, proliferation, apoptosis and TGFβ signaling were also evaluated. Furthermore, adrenergic receptor blockers were used to determine which receptor was involved in the modulation on TGFβ signaling by NE. The results of the present study demonstrated that CSD protected rats from AngII+BAPN-induced aortic remodeling and aneurysm formation. Compared with the control group, NE inhibited VSMC proliferation and migration, but promoted apoptosis by suppressing ALK5 expression, reversing the effects of TGFβ signaling through the suppression of the SMAD-dependent canonical pathway and promotion of the non-canonical pathway. These effects were prevented by ALK5 overexpression. The inhibition of α- or β-adrenergic receptors alleviated the NE-mediated suppression of ALK5 expression. In conclusion, regional CSD protected rats from aortic aneurysm. NE inhibited SMAD2/3-dependent TGFβ signaling by suppressing ALK5 expression, which may serve an important role in VSMC biological functions. Both α- and β-adrenergic receptors were involved in the regulation of ALK5 expression by NE. Abnormal sympathetic innervation of the aorta may be used as a therapeutic target in aortic diseases.

Serum Neuropeptide Y Levels Are Associated with TNF-α Levels and Disease Activity in Rheumatoid Arthritis.

Background Neuropeptide Y (NPY) is a sympathetic neurotransmitter with effects on the regulation of inflammatory cells. The role of NPY on autoimmune inflammatory diseases such as rheumatoid arthritis (RA) is not completely understood. Therefore, we evaluate if NPY levels are markers of disease activity in RA and if there is a correlation between NPY levels and tumor necrosis factor-alpha (TNF-α), leptin, and interleukin 6 (IL-6) levels. Methods Cross-sectional design, including 108 women with RA. We assessed disease activity by DAS28-ESR (considering active disease a score of ≥2.6). Serum NPY levels and anti-CCP2 antibody, TNF-α, IL-6, and leptin levels were quantified (ELISA). Results Sixty-eight RA had an active disease (RA-active), and 40 were in remission (RA-remission). RA-active patients had higher NPY levels vs. RA-remission (22.8 ± 13.6 vs. 17.8 ± 10.3; p = 0.04). NPY levels correlated with increased TNF-α levels (r = 0.32, p = 0.001). Leptin or IL-6 did not correlate with NPY levels. In the logistic regression analysis, NPY increased the risk of disease activity (OR: 1.04, 95% CI 1.006-1.09, and p = 0.03). Conclusion Higher NPY levels are an independent marker of disease activity in RA. This study encourages the quantification of NPY levels as a surrogate marker for RA-active. Future studies evaluating the role of NPY levels interacting with other proinflammatory cytokines are required.

A positive feedback loop between alpha1-adrenoceptors and inflammatory cytokines in keratinocytes

A positive feedback loop between inflammatory cytokines and alpha1-adrenoceptors (α1-AR) (a target of the sympathetic nervous system neurotransmitter norepinephrine) influences inflammatory responses in immune cells. This cross-talk between the sympathetic nervous system and immune system may play a role in promoting chronic inflammation. Emerging evidence shows that α1-AR interact with inflammatory cytokines in keratinocytes, and this epidermal adrenergic signalling may contribute to skin inflammatory responses following injury, disease or stress. In this study, utilizing an in vitro approach, we hypothesized that α1-AR interact in a positive feedback loop with inflammatory mediators in keratinocytes. The pro-inflammatory cytokine tumor necrosis factor α (TNFα) was used to induce an inflammatory state in cultured keratinocytes. TNFα increased interleukin (IL)-1β, IL-6, IL-8 and nerve growth factor (NGF) production and gene expression levels of α1-AR subtype B (α1B-AR). Additional stimulation of α1-AR further increased IL-6 levels, while maintaining high levels of IL-8 and decreasing levels of IL-1β and NGF. Our results suggest that reciprocal influences between α1-ARs and inflammatory cytokines may play a role in normal inflammatory responses. However, if unchecked, this cycle could contribute to pathology (e.g. chronic inflammatory diseases, chronic pain conditions, and stress-induced cancer progression).

Sympathicus exhibits differential effects on articular cartilage, synovium and subchondral bone during osteoarthritis development

Purpose: Osteoarthritis (OA) is a disease of the whole joint, since its pathogenesis involves articular cartilage, synovial tissue and subchondral bone. OA is characterized by progressive degradation of cartilage, synovial inflammation, osteophyte formation and subchondral bone sclerosis. In contrast to cartilage, its surrounding tissues are innervated by tyrosine hydroxylase(TH)-positive sympathetic nerve fibers and the most important sympathetic neurotransmitter norepinephrine (NE) was detected in the synovial fluid of OA patients.

Comparison of Neurotransmitter Release from Perivascular Nerves in C57BL/6J Mice and Wistar Rats

It is thought that sympathetic nerve activation stimulates arterial constriction predominately through the release of three neurotransmitters: norepinephrine (NE), adenosine triphosphate (ATP) and neuropeptide Y (NPY). The aim of the current study was to examine the composition of neurotransmitter released in response to sympathetic nerve stimulation in mesenteric arteries of two commonly used wild‐type animal models. Isolated mesenteric arteries from male C57BL/6J mice and Wistar rats were mounted in a Danish Myotechnology 2‐Channel Wire Myograph System and isometric force measurements were recorded. Electrical field stimulation (EFS) was used to stimulate sympathetic perivascular nerves (PVNs) to release neurotransmitters in the presence and absence of the adrenergic receptor blocker phentolamine and/or purinergic receptor blocker NF449. Phentolamine alone blocked a significant proportion of the contractile response evoked by EFS in both mice and rats, suggesting that NE is the main sympathetic neurotransmitter in both species. Treatment with NF449 alone blocked a small proportion of the contractile response evoked by EFS in mice but did not have a significant effect in rat, suggesting that ATP may play a more important role in mice. The application of both phentolamine and NF449 nearly completely blocked the contractile response to EFS in mouse mesenteric arteries; however, in rat, a proportion of the contractile response, roughly equivalent to the response obtained in the presence of phentolamine alone, was still observed. These data suggest that the neurotransmitter composition is different between mice and rats, in particular mouse mesenteric sympathetic PVNs release NE and ATP while rat mesenteric sympathetic PVNs release NE and another non‐purinergic neurotransmitter(s).

Neuropeptide Y and Pial Artery Vasomotor Control: An Ordered Affair

Evidence indicates sympathetic neurotransmitters influence cerebral vasomotor tone in a branch order‐dependent manner. Further, in addition to eliciting vasoconstriction, sympathetic co‐transmitter neuropeptide Y (NPY) may also elicit dilation in the cererbrovasculature depending on whether it acts on vascular smooth muscle or the endothelium. Herein, we investigated vasomotor responses to NPY in pial arteries (intracranial arteries on the surface of the brain) along the cerebrovascular tree. Female pigs (n=15, total arteries=88; age=2±0 months) were euthanized and their brains were harvested. First order (1A; n=7–8 per experiment), second order (2A; n=7–8 per experiment), and third order (3A; n=7–8 per experiment) pial arterial branches from the middle cerebral artery were dissected for pressure myography experiments. Following stabilization, NPY was administered either extra‐luminally (1e‐10 ‐‐to 1e‐6 M; half log doses, n=8 pigs) or intra‐luminally (1e‐9 M, n=7 pigs). To evaluate the contribution of nitric oxide (NO) on vasomotor responses to NPY, a subset of arteries were pre‐treated with a NO synthase (NOS) inhibitor (L‐NAME 3e‐4 M) 30 minutes prior to NPY administration. Whereas extra‐luminal NPY elicited vasoconstriction (24/24 arteries), intra‐luminal NPY tended to elicit vasodilation (16/21 arteries). Maximal vasoconstriction (% of baseline diameter) in response to extra‐luminal NPY was greater in 3a vs. 2a and 1a pial arteries (1a=13±1%; 2a=15±2%; *3a=23±4%; p≤0.01). Differences between 1a and 2a pial arteries were not significant (p=0.17). Pre‐treatment with a NOS inhibitor enhanced the maximal vasoconstriction in 1a, 2a and 3a pial arteries (grouped data; untreated=17±1%; *following NOS inhibition=29±1%; p&lt;0.01). Dilation (% of baseline diameter) in response to intra‐luminal NPY was greater in 1a and 3a vs. 2a pial arteries (*1a=4±4%; 2a=−3±6%; *3a=9±4%; p≤0.01). Of note, whereas 86% of 1a and 3a pial arteries dilated, only 57% of 2a pial arteries dilated following transient exposure to intra‐luminal NPY. NOS inhibition abolished NPY‐induced dilation and promoted an NPY‐mediated vasoconstriction (grouped data; untreated=4±3%; *following NOS inhibition=−15±3%; p&lt;0.01). In summary, NPY regulates cerebral vasomotor control through both vasoconstriction and dilation. These results indicate vasomotor responses to NPY are branch order‐dependent and most apparent in 3a pial arteries. NOS inhibition exacerbated NPY‐induced constriction and ablated NPY‐induced dilation, implicating NO signaling as a regulator of NPY‐dependent effects on cerebrovascular tone.Support or Funding InformationThis work was supported by a MU CVM COR grant and a SHRF Establishment grant (#4522).

Aging alters spontaneous and neurotransmitter-mediated Ca2+ signaling in smooth muscle cells of mouse mesenteric arteries.

Aging impairs MA dilation by reducing the ability of sensory nerves to counteract sympathetic vasoconstriction. This study tested whether altered SMC Ca2+ signals to sympathetic (NE) and sensory (CGRP) neurotransmitters underlie aging-related deficits in vasodilation. MAs from young and old mice were pressurized and loaded with Fluo-4 dye for confocal measurement of SMC Ca2+ sparks and waves. Endothelial denudation resolved the influence of ECs. SMCs were immunolabeled for RyR isoforms and compared with transcript levels for RyRs and CGRP receptor components. SMCs from young vs old mice exhibited more spontaneous Ca2+ spark sites with no difference in Ca2+ waves. NE reduced spark sites and increased waves for both groups; addition of CGRP restored sparks and reduced waves only for young mice. Endothelial denudation attenuated Ca2+ responses to CGRP for young but not old mice, which were already attenuated, suggesting a diminished role for ECs with aging. CGRP receptor expression was similar between ages with increased serum CGRP in old mice, where RyR1 expression was replaced by RyR3. With aging, we suggest that altered RyR expression in SMCs contributes to impaired ability of sensory neurotransmission to restore Ca2+ signaling underlying vasomotor control during sympathetic activation.

Phenylethanolamine N-methyltransferase gene polymorphisms associate with crisis pain in sickle cell disease patients.

Aim: Phenylethanolamine N-methyltransferase (PNMT) catalyzes the conversion of sympathetic neurotransmitter norepinephrine to epinephrine. We examined the association of PNMT polymorphisms with acute and chronic pain in sickle cell disease (SCD). Methods: Utilization of emergency care owing to painful crisis was used as a marker for acute pain in 131 patients with SCD. Results: rs876493 A allele, rs2934965 T allele and rs2941523 G allele were significantly associated with decreased utilization (p≤0.05). rs876493 A allele showed association with utilization in females (p=0.003), not males (p=0.803). rs2934965 T allele and rs2941523 G allele were predicted to cause loss of putative transcription factor binding sites. This is the first report of the association of PNMT polymorphisms with acute crisis pain in SCD. Together with our previous findings in catechol-o-methyltransferase, polymorphisms in catecholamine metabolizing enzymes appear to primarily influence acute pain in SCD.

α2A-Adrenoceptors Modulate Renal Sympathetic Neurotransmission and Protect against Hypertensive Kidney Disease.

Increased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α2A-adrenoceptors on sympathetic nerves, and α2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown. We investigated effects of α2A-adrenoceptor-regulated renal NE release on the development of angiotensin II-dependent hypertension and kidney disease. In uninephrectomized wild-type and α2A-adrenoceptor-knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days. Urinary NE excretion and BP did not differ between normotensive α2A-adrenoceptor-knockout mice and wild-type mice at baseline. However, NE excretion increased during AngII treatment, with the knockout mice displaying NE levels that were significantly higher than those of wild-type mice. Accordingly, the α2A-adrenoceptor-knockout mice exhibited a systolic BP increase, which was about 40 mm Hg higher than that found in wild-type mice, and more extensive kidney damage. In isolated kidneys, AngII-enhanced renal nerve stimulation induced NE release and pressor responses to a greater extent in kidneys from α2A-adrenoceptor-knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α2A-adrenoceptor-deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α2A-adrenoceptor-knockout mice after renal denervation. Our findings reveal a protective role of prejunctional inhibitory α2A-adrenoceptors in pathophysiologic conditions with an activated renin-angiotensin system, such as hypertensive kidney disease, and support the concept of sympatholytic therapy as a treatment.

The autonomic nervous system and ventricular arrhythmias in myocardial infarction and heart failure

Ventricular arrhythmias (VA) can range in presentation from asymptomatic to cardiac arrest and sudden cardiac death (SCD). Sustained ventricular tachycardias/ventricular fibrillation (VT/VF) are a common cause of SCD in the setting of myocardial infarction (MI) and heart failure. A particularly arrhythmogenic cardiac syncytia in these conditions can be attributed to both sympathetic activation and parasympathetic dysfunction, while appropriate neuromodulation has the potential to reduce occurrence of VT/VF. In this review, we outline the components of the autonomic nervous system that play an important role in normal cardiac electrophysiology and function. In addition, we discuss changes that occur in the setting of cardiac disease including adverse neural remodeling and neurohormonal activation which significantly contribute to propensity for VT/VF. Finally, we review neuromodulation strategies to mitigate VT/VF which predominantly rely on increasing parasympathetic drive and blockade of sympathetic neurotransmission.

Neuropeptide Y enhances proliferation and chondrogenic differentiation of ATDC5 cells

In recent years, emerging evidence has illustrated the indispensable role of sympathetic neurotransmitters and their receptors in cartilage mediation. The presence of neuropeptide Y (NPY)-positive sympathetic nerve fibres in cartilage and NPY-secretion function in chondrocytes raises the possibility of NPY directly regulating the function of chondrocytes. Therefore, this study intended to evaluate the effect of NPY and its receptors on the proliferation and chondrogenic differentiation of ATDC5 cells. Results showed NPY, especially at a concentration of 10−10 M, to significantly enhance proliferation of ATDC5 cells. Moreover, NPY effectively facilitated early chondrogenesis and late hypertrophy/mineralisation of ATDC5 cells via Y1 receptor signalling, rather than via Y2 receptor signalling. Taken together, the results help us to understand how NPY and its receptors affect the function of chondrocytes.

Macrophages and brown adipocytes cross-communicate to modulate a thermogenic program following methamphetamine exposure

Hyperthermia is a potentially lethal side-effect of Methamphetamine (Meth), a stimulant drug. Activation of non-shivering thermogenesis in brown adipose tissue (BAT) is partly responsible for Meth-induced rise in temperature, with contributing sympathetic neurotransmitters, such as norepinephrine (NE), and reactive oxygen species (ROS). However, the mechanisms controlling the development of a molecular thermogenic program in brown adipocytes (BA) following Meth are unknown. We hypothesize that Meth and NE affect BAT cells, BA and macrophages, to modify their physiology and interactions, with consequences to thermogenic genes. We also hypothesize that ROS play a critical role in signaling transcription of thermogenic genes and their regulatory components. Using primary BA and macrophage cultures, we measured Meth and NE interference with physiological and phenotypic measures that are relevant to thermogenesis in BAT. Meth caused both BA and macrophages to decrease mitochondrial maximal capacity and increase ROS. In BA, the thermogenic genes UCP1, PPARγ, PGC1α and GADD45γ were transcriptionally increased by Meth in a ROS-dependent manner. In macrophages, Meth increased oxidative stress response and caused a predominance of M2 subset markers. BA transcriptional changes in response to Meth and NE were significantly controlled by macrophages. The results suggest that BA and macrophages respond to Meth and NE, with effects on mitochondrial functions and transcription of genes involved in thermogenesis. ROS-dependent signals in BA and cellular interactions between BA and macrophages synergize to regulate the BAT environment and control critical pathways leading to Meth-hyperthermia.