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Sympathetic Overactivity in Chronic Kidney Disease: Consequences and Mechanisms

Jasdeep Kaur, Benjamin Young, Paul Fadel

International Journal of Molecular Sciences · 2017 · Review · CC BY

doi:10.3390/ijms18081682

Abstract

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

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 26, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

More than 26 million people in the United States suffer from chronic kidney disease (CKD) with thousands of new cases diagnosed each year. CKD has poor prognosis and health outcomes with very high health care costs. In the US alone, the cost of treatment for CKD has exceeded 49 billion dollars per year. There are five stages of CKD defined by progressive decreases in renal function as quantified by estimated glomerular filtration rate (eGFR) and/or kidney damage (proteinuria, albuminuria). Stage 1 CKD constitutes kidney damage with normal or reduced eGFR (≥90 mL/min/1.73 m2). Stages 2, 3 and 4 show progressive renal dysfunction with an eGFR of 60–89, 30–59 and 15–29 mL/min/1.73 m2, respectively. Stage 5 CKD is renal failure or end-stage renal disease which is characterized by eGFR of <15 mL/min/1.73 m2 or dialysis. Moderate to severe CKD (stage 3–5) is associated with a significantly higher risk of cardiovascular (CV) morbidity and mortality. In fact, over 50% of deaths in renal failure patients occur due to myocardial infarction, stroke, heart failure, and sudden cardiac death, the latter accounting for 25% of deaths in these patients alone. There is growing evidence that sympathetic overactivity, a characteristic feature of CKD, is one of the major mechanisms leading to higher CV risk in this patient population. This brief review will discuss some of the consequences of chronically elevated sympathetic nerve activity (SNA) and highlight some of the potential pathways contributing to elevated SNA in CKD.

A multitude of studies have shown elevated SNA in CKD. Early observations of exaggerated SNA in renal failure patients came from studies showing significantly elevated plasma norepinephrine, the primary neurotransmitter released by sympathetic nerves. Several studies have also used the technique of microneurography to directly record from post-ganglionic sympathetic nerve fibers innervating blood vessels that supply skeletal muscle (i.e., muscle sympathetic nerve activity (MSNA)). Converse et al. was the first to report elevated resting MSNA in renal failure patients on hemodialysis (Figure 1). However, of note, sympathoexcitation is not confined to renal failure, but is also detectable in earlier stages of CKD. Indeed, Grassi et al. studied mild-to-moderate CKD patients who were divided into four groups based on their eGFR, with highest quartile of eGFR (95.4 ± 1.6 mL/min/1.73 m2) in group I and lowest quartile of eGFR (31.4 ± 1.8 mL/min/1.73 m2) in group IV. There was a significant and progressive increase in resting MSNA from the highest quartile to the lowest quartile of eGFR (Figure 2). Other studies have reported elevated MSNA even in patients with polycystic kidney disease and no impairment in renal function. Collectively, these findings demonstrate two important points: (1) SNA is augmented early in CKD; and (2) SNA increases progressively with declining renal function.

2. Consequences of Sympathetic Overactivity

Sympathetic overactivity is associated with various diseases and accelerates the progression of cardiovascular, metabolic and renal pathology. The most common detrimental consequence of elevated SNA is hypertension, which is observed in 80% of CKD patients. Hypertension, in turn, leads to structural and functional abnormalities such as left ventricular hypertrophy, increased vascular smooth muscle cell hyperplasia and hypertrophy, and endothelial dysfunction. More importantly, chronic sympathoexcitation independent of hypertension has detrimental effects. For example, administration of sub-hypertensive doses of norepinephrine has been shown to cause myocardial cell hypertrophy and left ventricular hypertrophy. Moreover, elevated SNA without increases in blood pressure has been shown to cause vascular smooth muscle cell hypertrophy and proliferation. In addition, other deleterious effects of elevated SNA, independent of increased blood pressure, include, but are not limited to, exaggerated coronary vasoconstriction, arrythmogenicity, impaired renal function, glomerular podocyte injury, metabolic impairment, increased arterial stiffness, endothelial dysfunction and subsequent development of atherosclerosis, all of which lead to increased risk of CV events.

On the other hand, reducing SNA without any lowering of blood pressure has been shown to be protective, in particular to the kidney. In this regard, treatment of partially nephrectomized rats (an animal model of CKD) with non-hypotensive doses of the sympatholytic agent moxonidine, resulted in reduced glomerulosclerosis and urinary albumin excretion compared to untreated nephrectomized animals. Furthermore, low doses of moxonidine that did not change blood pressure were shown to elicit an antialbuminuric effect in diabetic patients. Collectively, these data provide strong evidence that sympathetic overactivity, independent of increases in blood pressure, can cause detrimental cardiovascular, metabolic, and renal effects. Although there is clear evidence of sympathetic overactivity in CKD, the mechanisms leading to chronic sympathoexcitation in CKD are complex, multifactorial and not completely understood. The remainder of this review will focus on some of the potential mechanisms contributing to elevated SNA in CKD.

3.1. Renin–Angiotensin System

It is well known that the renin–angiotensin system is activated in CKD. Renin is secreted from the kidney and converts angiotensinogen to angiotensin I, which in turn is converted to angiotensin II (Ang II) by angiotensin-converting enzyme (ACE). Activation of renin–angiotensin system increases renin secretion ultimately leading to high circulating plasma concentrations of Ang II, a common feature of CKD. Ang II is a potent vasoconstrictor with a multitude of peripheral and central actions as previously described in detail (for review see). Briefly, in addition to causing direct peripheral vasoconstriction, Ang II also modulates peripheral SNA by potentiating norepinephrine release from sympathetic nerve terminals. Ang II also plays an important role in regulating sympathetic outflow from the brainstem. For example, microinjection of Ang II into the rostral ventrolateral medulla (RVLM) activates vasomotor sympathetic neurons resulting in elevated SNA while microinjection of an Ang II receptor blocker, losartan, into the RVLM causes sympathoinhibition. These findings and others provide clear evidence for a direct role of Ang II in regulating central sympathetic outflow. Although Ang II receptor blockers and ACE inhibitors are a first-line choice of treatment in CKD patients, chronic treatment with these drugs only reduces MSNA but does not normalize it. In other words, MSNA in CKD patients following chronic treatment with Ang II receptor blockers and ACE inhibitors is still higher than in healthy individuals. Therefore, mechanisms other than the renin–angiotensin system are also involved in causing sympathetic overactivity in CKD.

3.2. Renal Afferents

The kidneys are richly innervated by chemoreceptors and baroreceptors which send feedback to the brain to regulate sympathetic outflow and systemic blood pressure. Evidence from both animal and human studies indicates that neural signals originating from the kidney play a role in increasing sympathetic outflow in CKD. Rats subjected to 5/6th nephrectomy, an animal model of CKD, develop hypertension with elevated norepinephrine turnover in various hypothalamic nuclei involved in the regulation of sympathetic outflow. Selective removal of afferent nerves (dorsal rhizotomy) in these animals prevents both the development of hypertension and increase in norepinephrine turnover in hypothalamic nuclei in the brain. Furthermore, renal injury without a reduction in renal function also leads to augmented sympathetic outflow. Animal studies have shown that renal injury via intrarenal phenol injection, which does not decrease renal function, causes increases in renal SNA, plasma norepinephrine concentrations, blood pressure, and norepinephrine secretion in the posterior hypothalamus. In addition, ligands such as urea and adenosine, which are elevated in CKD, can stimulate renal nerves, also contributing to increases in SNA. Renal ischemia enhances adenosine production, which not only stimulates renal afferent nerves but also causes vasoconstriction of afferent arterioles leading to reduced GFR. Interestingly, Hausberg et al. observed that MSNA in renal transplant patients with intact native kidneys was similar to that in dialysis patients (stage 5 CKD). However, transplant patients who underwent bilateral native kidney nephrectomy exhibited a significant reduction in MSNA, to values not that different from control subjects. Thus, signals arising from the native kidney can contribute to heightened MSNA in renal disease. Moreover, recent studies have suggested reduced renalase levels as a potential contributing factor in elevated SNA in CKD. Renalase is a monoamine oxidase produced by the kidneys that circulates in the blood in its inactive form prorenalase. Once activated, renalase degrades catecholamines and can decrease blood pressure. CKD and renal failure patients have significantly reduced levels of renalase, which would lead to less breakdown of catecholamines and contribute to the higher SNA in these patients.

3.3. Nitric Oxide Pathway

Another potential mechanism for chronic sympathoexcitation in CKD is reduced nitric oxide (NO) bioavailability. NO is produced by nitric oxide synthase (NOS) during oxidation of l-arginine to l-citrulline. There are three isoforms of NOS: endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS). While eNOS and nNOS are constitutively expressed in all cells and contribute to the regulation of vascular tone and blood pressure, iNOS is activated by macrophages and cytokines during inflammation. NO produced by eNOS diffuses into smooth muscle cells and causes vasodilation via stimulation of guanylate cyclase. Indeed, systemic NOS inhibition in healthy individuals causes an immediate increase in arterial blood pressure by reducing NO and endothelium-mediated vasodilation. In addition to its action as a vasodilator, NO also plays a key role in maintaining vascular homeostasis by inhibiting platelet aggregation, atherogenesis, smooth muscle cell proliferation and leukocyte adhesion to the endothelium. Thus, endothelium-derived NO not only regulates vascular tone and thereby, arterial blood pressure but it also plays an essential role in maintaining a healthy vasculature. While the role of peripheral NO in endothelium-mediated vasodilation and blood pressure regulation is well known, much less appreciated is the potential central effect of NO.

There is increasing evidence that suggests NO is a key signaling molecule involved in regulation of sympathetic outflow from the brainstem. Shapoval et al. performed the first in vivo study to demonstrate a direct effect of central NO on sympathetic outflow. They showed that microinjection of the NOS inhibitor NG-monomethyl l-arginine (l-NMMA) directly into the RVLM of anesthetized animals increased renal SNA and consequently, blood pressure, while microinjections of l-arginine and sodium nitroprusside (NO donor) reduced renal SNA and blood pressure. Microinjection of l-NMMA into the nucleus tractus solitarius (NTS) showed similar changes in renal SNA and blood pressure. Tagawa and colleagues used rat brainstem slices to show that l-arginine causes a dose-dependent increase in neuronal activity of ~40% of NTS neurons, and this response is attenuated by l-NMMA. Hemoglobin, which endogenously binds to NO, blocks the increase in neuronal activity evoked by l-arginine, suggesting that NO diffuses out into the extracellular space to excite the adjacent neurons from which the neural activity was measured. They further extended their findings by using methylene blue, a guanylate cyclase blocker, to investigate whether these effects of l-arginine were mediated by cyclic guanosine monophosphate (cGMP). Methylene blue inhibits the increase in neuronal activity in the NTS elicited by both l-arginine and sodium nitroprusside. These data indicate that NO produced from l-arginine in the NTS neurons diffuses out to nearby target neurons where it increases neuronal activity through cGMP. Other animal studies involved intravenous infusion, interacisternal injection or microinjection of NOS inhibitors into the paraventricular nucleus (PVN) and the NTS, demonstrating acute increases in renal SNA and blood pressure. Furthermore, overexpression of NOS in the RVLM via adenovirus transfection results in elevated NO levels in the RVLM, which reduced urinary norepinephrine excretion along with a lowering of blood pressure. Together, these studies indicate that centrally-derived NO is a key signaling molecule involved in the tonic restraint of sympathetic outflow from the brainstem.

Initial studies performed to extrapolate these findings from direct central injections to systemic infusions of NOS inhibitors observed a reduction in SNA. Indeed, when NOS inhibitors were infused systemically in animals and humans, there was a rapid and large increase in blood pressure along with a decrease in SNA. The rapid increase in blood pressure occurred due to inhibition of NO-mediated, endothelium-dependent vasodilation in the peripheral vasculature. This increase in blood pressure activated the arterial baroreflex resulting in a reflex-mediated decrease in SNA. Thus, baroreflex-mediated reductions in SNA masked any increases in sympathetic outflow that might have occurred due to reduced central NO. To eliminate the influence of the arterial baroreflex, the effect of systemic NOS inhibition was compared between barointact and barodenervated animals. Administration of the NOS inhibitor l-nitroarginine methyl ester (l-NAME) in barointact animals caused a biphasic response in renal SNA, an initial decrease followed by an increase in renal SNA. In barodenervated animals, NOS inhibition caused a progressive and significant increase in renal SNA uncovering the role of central NO in restraining sympathetic outflow. Our laboratory has also provided evidence for NO in central sympathetic control in humans. To overcome the confounding inhibitory influence of the arterial baroreflex on SNA, we directly measured skin SNA, which is not under baroreceptor control. Systemic l-NAME infusion in healthy adults caused progressive and sustained increases in skin SNA.

Another consideration with systemic infusion of NOS inhibitors to examine effects of central NO on SNA is the time needed for the inhibitors to cross the blood brain barrier. In this regard, systemic infusion of l-NAME in animals with and without sympathectomy showed that both groups had a similar increase in blood pressure during the first hour of infusion primarily due to inhibition of peripheral endothelial NO production. Importantly, blood pressure in the sympathectomized animals after 8 h and after 6 days of l-NAME infusion was significantly lower than the control group, indicating a delayed but significant role of the sympathetic nervous system in the blood pressure-raising effect of NOS inhibition (Figure 3). In agreement with a time delay in sympathetic activation via systemic NOS inhibition, when phentolamine (α-adrenergic blocker) was infused immediately and 90 min after l-NAME infusion in humans, there was little effect on the initial hypertensive response but phentolamine significantly attenuated the subsequent further increase in blood pressure. These results indicate that the initial increase in blood pressure occurred due to diminished peripheral NO causing inhibition of endothelium-mediated vasodilation while the later increase in blood pressure was caused by sympathetic adrenergic vasoconstriction. This would also explain the results observed in initial studies where NOS inhibition caused a reduction in SNA, as SNA was only measured for 40 min after l-NAME infusion, which may not have been long enough to observe central effects of systemic NOS inhibition. Taken together, these data indicate the role of central NO in tonically restraining sympathetic outflow from the brainstem in healthy rodents and humans. Thus, it is plausible that in CKD, reduced central NO concentrations potentially contribute to chronically elevated SNA in these patients.

One of the major mechanisms causing reduced NO concentrations in CKD is elevated levels of asymmetric dimethylarginine (ADMA), the primary endogenous NOS inhibitor. Plasma concentrations of ADMA are significantly elevated in mild CKD and increase progressively as renal function declines. Importantly, numerous studies have shown ADMA to be a strong, independent predictor of future CV risk in CKD patients. In fact, Zoccali et al. reported that in renal failure patients, plasma ADMA concentrations are the second strongest predictor of all-cause and CV mortality (after age). ADMA concentrations also predict CV risk and mortality in earlier stages of CKD. For example, in a large cohort of stage 3 to 4 CKD patients, elevated ADMA was shown to have a strong association with CV disease and a modest association with all-cause and CV mortality. While it is clear that high ADMA levels are associated with CV risk, to date the majority of work with ADMA has been correlational in nature with a focus on the well-known vascular endothelial properties of NO. Given the increasing functional evidence described above that indicates NO is also a key signaling molecule involved in the tonic restraint of central sympathetic outflow, a role for ADMA in contributing to sympathetic overactivity in CKD warrants consideration.

ADMA is produced in all cell types and can pass the blood–brain barrier. It is produced by post-translational methylation of proteins via the enzyme arginine methyltransferase type I and it is either metabolized by the dimethylarginine dimethylaminohydrolase (DDAH) enzyme or excreted by the kidneys. Although reduced renal clearance of ADMA in CKD contributes to elevated plasma levels, the major pathway for elimination of ADMA is its metabolism by DDAH. It is estimated that the human body produces about 300 µmol of ADMA every day, of which 250 µmol is metabolized by DDAH and only a small amount is excreted by the kidneys. In terms of sympathetic activation and ADMA, Augustyniak et al. investigated the potential effects of ADMA on sympathetic outflow by systemic ADMA infusions in barointact and barodenervated animals. In barointact animals, ADMA infusion caused an initial decrease in renal SNA followed by an increase, causing renal SNA to go back to baseline values. In contrast, in barodenervated animals, systemic ADMA infusion caused a frank sympathoexcitation as indicated by ~50% increase in renal SNA at the end of ADMA infusion (Figure 4). Thus, elevated ADMA levels can cause inhibition of central NOS, thereby reducing NO bioavailability and increasing SNA. These data support the idea that elevated ADMA reduces central NO in CKD patients, potentially contributing to elevated sympathetic outflow from the brainstem (Figure 5). Along these lines, ADMA levels and resting muscle SNA were inversely related to eGFR in stage 2 to 4 CKD patients such that patients with higher ADMA levels had higher resting SNA and lower renal function (i.e., lower eGFR).

3.4. Oxidative Stress

CKD patients are reported to have higher oxidative stress, which could be another potential mechanism that results in chronic sympathoexcitation in CKD. Oxidative stress in the central nervous system has an important role in regulating sympathetic outflow from the brainstem. Reactive oxygen species (ROS) such as superoxide ion, hydroxyl radical and hydrogen peroxide play an important role as intracellular messengers however, overproduction of ROS can be harmful. Various animal studies have indicated that elevated oxidative stress in the brain contributes to enhanced central sympathetic outflow, either directly or by scavenging NO. Elevated levels of Ang II also contribute to overproduction of ROS as Ang II is a potent activator of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, the primary source of superoxide. Reductions in oxidative stress in the brain using the superoxide dismutase (SOD; an enzyme that catalyzes superoxide ion) mimetic tempol or overexpression of SOD reverses the elevated central sympathetic outflow. In addition, tempol administration through drinking water and systemic tempol infusion have both been shown to normalize SNA and reduce neuronal activity of presympathetic neurons in the PVN and the RVLM. These studies provide clear evidence that oxidative stress can cause chronic sympathoexcitation. In addition to its direct effects, elevated oxidative stress also inhibits DDAH, the primary mechanism for breakdown of ADMA. This may contribute to ADMA-induced increases in central sympathetic activation. Collectively, these studies indicate that oxidative stress is one of the mechanisms that increases sympathetic outflow from the brainstem and may be involved in elevated SNA in CKD.

4. Therapeutic Strategies

Sympathetic overactivity is a hallmark of CKD and therapeutic strategies to reduce this heightened sympathetic activation are needed. In this review we have identified some of the potential pathways contributing to elevated SNA in CKD that warrant consideration when discussing therapeutic targets to reduce SNA in this high risk population. Ang II receptor blockers and ACE inhibitors have been shown to lower resting MSNA and blood pressure but neither normalizes MSNA in CKD and thus, other therapeutic strategies are needed. Sympatholytic agents such as moxonidine have been shown to be effective in reducing MSNA in patients however, the side-effects limit their clinical application. Statins are another potential therapeutic strategy that has been shown to reduce SNA and oxidative stress in addition to lowering cholesterol. In fact, statins have been shown to downregulate Ang II receptors and upregulate nNOS in the brain. Even short-term statin therapy has been shown to reduce sympathetic overactivity, making it a potentially beneficial therapy for CKD patients. Indeed, statin therapy in predialysis CKD patients reduced MSNA, delayed the start of dialysis, and decreased the risk of CV events and all-cause mortality. In addition, reduction of oxidative stress is another potential mechanism for decreasing sympathetic overactivity in CKD. Although numerous animal studies have shown significant reductions in SNA after reducing oxidative stress, studies in patients have provided mixed results. This could be, in part, due to the antioxidant used in the study (vitamin C vs. vitamin E), the duration of treatment (acute vs. chronic treatment), the dose of antioxidant and the efficacy of antioxidant in reducing oxidative stress. Furthermore, pioglitazone treatment may also be beneficial in CKD as it has been reported to reduce circulating ADMA levels. Reductions in plasma ADMA concentrations can increase central NO and inhibit sympathetic outflow from the brainstem. Thus, pioglitazone treatment could be a promising therapy for reducing ADMA and sympathetic overactivity in CKD. In general, further research is warranted to identify viable pharmacological therapies to reduce sympathetic overactivity in CKD along with its deleterious consequences.

Aside from the aforementioned pharmacological strategies, there are therapeutic interventions such as renal denervation and carotid baroreflex stimulation that may also be used to reduce SNA in CKD. Renal denervation has been primarily utilized to treat resistant hypertension. Several studies in hypertensive patients and experimental animal disease models showed a significant reduction in blood pressure following renal denervation. Interestingly, in a large controlled clinical trial (SYMPLICITY HTN-3), although hypertensive patients had a reduction in blood pressure following renal denervation, this decrease was not different from a sham control group. Since bilateral nephrectomy in hemodialysis patients has been shown to reduce resting MSNA, renal denervation might be beneficial for the CKD population. Indeed, pilot studies have shown promising results: besides reducing blood pressure, renal denervation has also been shown to lower renin production, enhance GFR and reduce albuminuria. Nevertheless, despite the advantages, some factors must be considered before performing renal denervation in CKD patients such as: contrast-induced nephropathy in CKD, non-optimal diameter of renal artery and complications due to low renal blood flow. Another therapeutic intervention to potentially reduce sympathetic overactivity in CKD patients is carotid baroreceptor stimulation. With this intervention, a device is surgically implanted to chronically stimulate carotid baroreceptors. This technique has been shown to cause sympatho-inhibition and reduce blood pressure in hypertensive patients. However, further studies are required to investigate the potential beneficial effects of chronic carotid baroreflex stimulation in CKD patients.

5. Conclusions

Chronic sympathoexcitation is a major contributor to increased CV risk and mortality in CKD. Despite recent advances in research, our understanding of the mechanisms causing sympathetic overactivity in CKD is still incomplete. As discussed in this review, various studies have proposed a role for the renin–angiotensin system, renal afferent stimulation, reduced NO concentrations due to elevated ADMA, and increased oxidative stress in contributing to chronic sympathoexcitation in CKD. Further research is needed to better clarify the individual and interactive roles of each of the aforementioned pathways in contributing to sympathetic overactivity in CKD patients.

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    Not in our library10.1152/physrev.1982.62.2.347

  30. 30.
    Left Ventricular Hypertrophy: Major Risk Factor in Patients with Hypertension: Update and Practical Clinical Applications · 2011
    No notice
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    Simpson P. Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an alpha 1 adrenergic response. J. Clin. Investig. 1983;72:732-738.

    Not in our library10.1172/jci111023

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    Raum W.J., Laks M.M., Garner D., Ikuhara M.H., Swerdloff R.S. Norepinephrine increases β-receptors and adenylate cyclase in canine myocardium. Am. J. Physiol. 1984;246:H31-H36.

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    Laks M.M., Morady F., Swan H.J. Myocardial hypertrophy produced by chronic infusion of subhypertensive doses of norepinephrine in the dog. Chest. 1973;64:75-78.

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    Bevan R.D. Effect of sympathetic denervation on smooth muscle cell proliferation in the growing rabbit ear artery. Circ. Res. 1975;37:14-19.

    Not in our library10.1161/01.res.37.1.14

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    Bevan R.D. Trophic effects of peripheral adrenergic nerves on vascular structure. Hypertension. 1984;6:19-26.

    Not in our library10.1161/01.hyp.6.6_pt_2.iii19

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    Coutsos M., Sala-Mercado J.A., Ichinose M., Li Z., Dawe E.J., O’Leary D.S. Muscle metaboreflex-induced coronary vasoconstriction limits ventricular contractility during dynamic exercise in heart failure. Am. J. Physiol. Heart Circ. Physiol. 2013;304:1029-1037.

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  37. 37.

    Volders P.G. Novel insights into the role of the sympathetic nervous system in cardiac arrhythmogenesis. Heart Rhythm. 2010;7:1900-1906.

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  38. 38.

    DiBona G.F. Sympathetic nervous system and the kidney in hypertension. Curr. Opin. Nephrol. Hypertens. 2002;11:197-200.

    Not in our library10.1097/00041552-200203000-00011

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    Rafiq K., Noma T., Fujisawa Y., Ishihara Y., Arai Y., Nabi A.H., Suzuki F., Nagai Y., Nakano D., Hitomi H., et al. Renal sympathetic denervation suppresses de novo podocyte injury and albuminuria in rats with aortic regurgitation. Circulation. 2012;125:1402-1413.

    Not in our library10.1161/circulationaha.111.064097

  40. 40.

    Jamerson K.A., Julius S., Gudbrandsson T., Andersson O., Brant D.O. Reflex sympathetic activation induces acute insulin resistance in the human forearm. Hypertension. 1993;21:618-623.

    Not in our library10.1161/01.hyp.21.5.618

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    Salzer D.A., Medeiros P.J., Craen R., Shoemaker J.K. Neurogenic-nitric oxide interactions affecting brachial artery mechanics in humans: Roles of vessel distensibility vs. diameter. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008;295:R1181-R1187.

    Not in our library10.1152/ajpregu.90333.2008

  42. 42.

    Boutouyrie P., Lacolley P., Girerd X., Beck L., Safar M., Laurent S. Sympathetic activation decreases medium-sized arterial compliance in humans. Am. J. Physiol. 1994;267:H1368-H1376.

    Not in our library10.1152/ajpheart.1994.267.4.h1368

  43. 43.

    Failla M., Grappiolo A., Emanuelli G., Vitale G., Fraschini N., Bigoni M., Grieco N., Denti M., Giannattasio C., Mancia G. Sympathetic tone restrains arterial distensibility of healthy and atherosclerotic subjects. J. Hypertens. 1999;17:1117-1123.

    Not in our library10.1097/00004872-199917080-00011

  44. 44.

    Thijssen D.H., de G.P., Kooijman M., Smits P., Hopman M.T. Sympathetic nervous system contributes to the age-related impairment of flow-mediated dilation of the superficial femoral artery. Am. J. Physiol. Heart Circ. Physiol. 2006;291:3122-3129.

    Not in our library10.1152/ajpheart.00240.2006

  45. 45.

    Hijmering M.L., Stroes E.S., Olijhoek J., Hutten B.A., Blankestijn P.J., Rabelink T.J. Sympathetic activation markedly reduces endothelium-dependent, flow-mediated vasodilation. J. Am. Coll. Cardiol. 2002;39:683-688.

    Not in our library10.1016/s0735-1097(01)01786-7

  46. 46.

    Santos A.C., Alves M.J., Rondon M.U., Barretto A.C., Middlekauff H.R., Negrao C.E. Sympathetic activation restrains endothelium-mediated muscle vasodilatation in heart failure patients. Am. J. Physiol. Heart Circ. Physiol. 2005;289:593-599.

    Not in our library10.1152/ajpheart.01240.2004

  47. 47.

    Kaplan J.R., Manuck S.B. Using ethological principles to study psychosocial influences on coronary atherosclerosis in monkeys. Acta Physiol. Scand. Suppl. 1997;640:96-99.

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  48. 48.

    Kaplan J.R., Manuck S.B., Clarkson T.B., Lusso F.M., Taub D.M., Miller E.W. Social stress and atherosclerosis in normocholesterolemic monkeys. Science. 1983;220:733-735.

    Not in our library10.1126/science.6836311

  49. 49.

    Strojek K., Grzeszczak W., Gorska J., Leschinger M.I., Ritz E. Lowering of microalbuminuria in diabetic patients by a sympathicoplegic agent: Novel approach to prevent progression of diabetic nephropathy? J. Am. Soc. Nephrol. 2001;12:602-605.

    Not in our library10.1681/asn.v123602

  50. 50.

    Anguiano L., Riera M., Pascual J., Valdivielso J.M., Barrios C., Betriu A., Clotet S., Mojal S., Fernandez E., Soler M.J. Circulating angiotensin converting enzyme 2 activity as a biomarker of silent atherosclerosis in patients with chronic kidney disease. Atherosclerosis. 2016;253:135-143.

    Not in our library10.1016/j.atherosclerosis.2016.08.032

  51. 51.

    Medina A., Bell P.R., Briggs J.D., Brown J.J., Fine A., Lever A.F., Morton J.J., Paton A.M., Robertson J.I., Tree M., et al. Changes of blood pressure, renin, and angiotensin after bilateral nephrectomy in patients with chronic renal failure. Br. Med. J. 1972;4:694-696.

    Not in our library10.1136/bmj.4.5842.694

  52. 52.

    Ibrahim H.N., Rosenberg M.E., Hostetter T.H. Role of the renin-angiotensin-aldosterone system in the progression of renal disease: A critical review. Semin. Nephrol. 1997;17:431-440.

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  53. 53.

    Reid I.A. Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am. J. Physiol. 1992;262:E763-E778.

    Not in our library10.1152/ajpendo.1992.262.6.e763

  54. 54.

    Siddiqi L., Joles J.A., Grassi G., Blankestijn P.J. Is kidney ischemia the central mechanism in parallel activation of the renin and sympathetic system? J. Hypertens. 2009;27:1341-1349.

    Not in our library10.1097/hjh.0b013e32832b521b

  55. 55.

    Hu L., Zhu D.N., Yu Z., Wang J.Q., Sun Z.J., Yao T. Expression of angiotensin II type 1 (AT1) receptor in the rostral ventrolateral medulla in rats. J. Appl. Physiol. 2002;92:2153-2161.

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  56. 56.

    Muratani H., Averill D.B., Ferrario C.M. Effect of angiotensin II in ventrolateral medulla of spontaneously hypertensive rats. Am. J. Physiol. 1991;260:977-984.

    Not in our library10.1152/ajpregu.1991.260.5.r977

  57. 57.

    Hirooka Y., Potts P.D., Dampney R.A. Role of angiotensin II receptor subtypes in mediating the sympathoexcitatory effects of exogenous and endogenous angiotensin peptides in the rostral ventrolateral medulla of the rabbit. Brain Res. 1997;772:107-114.

    Not in our library10.1016/s0006-8993(97)00861-5

  58. 58.

    Allen A.M. Blockade of angiotensin AT1-receptors in the rostral ventrolateral medulla of spontaneously hypertensive rats reduces blood pressure and sympathetic nerve discharge. J. Renin Angiotensin Aldosterone Syst. 2001;2:120-124.

    Not in our library10.1177/14703203010020012101

  59. 59.

    Allen A.M., Moeller I., Jenkins T.A., Zhuo J., Aldred G.P., Chai S.Y., Mendelsohn F.A. Angiotensin receptors in the nervous system. Brain Res. Bull. 1998;47:17-28.

    Not in our library10.1016/s0361-9230(98)00039-2

  60. 60.

    Davisson R.L. Physiological genomic analysis of the brain renin-angiotensin system. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003;285:498-511.

    Not in our library10.1152/ajpregu.00190.2003

  61. 61.

    Campese V.M., Kogosov E. Renal afferent denervation prevents hypertension in rats with chronic renal failure. Hypertension. 1995;25:878-882.

    Not in our library10.1161/01.hyp.25.4.878

  62. 62.

    Ye S., Zhong H., Yanamadala V., Campese V.M. Renal injury caused by intrarenal injection of phenol increases afferent and efferent renal sympathetic nerve activity. Am. J. Hypertens. 2002;15:717-724.

    Not in our library10.1016/s0895-7061(02)02959-x

  63. 63.

    Ye S., Ozgur B., Campese V.M. Renal afferent impulses, the posterior hypothalamus, and hypertension in rats with chronic renal failure. Kidney Int. 1997;51:722-727.

    Not in our library10.1038/ki.1997.103

  64. 64.

    Ye S., Zhong H., Yanamadala S., Campese V.M. Oxidative stress mediates the stimulation of sympathetic nerve activity in the phenol renal injury model of hypertension. Hypertension. 2006;48:309-315.

    Not in our library10.1161/01.hyp.0000231307.69761.2e

  65. 65.

    Katholi R.E., Whitlow P.L., Hageman G.R., Woods W.T. Intrarenal adenosine produces hypertension by activating the sympathetic nervous system via the renal nerves in the dog. J. Hypertens. 1984;2:349-359.

    Not in our library10.1097/00004872-198402040-00005

  66. 66.

    Recordati G., Moss N.G., Genovesi S., Rogenes P. Renal chemoreceptors. J. Auton. Nerv. Syst. 1981;3:237-251.

    Not in our library10.1016/0165-1838(81)90066-7

  67. 67.

    Vallon V., Muhlbauer B., Osswald H. Adenosine and kidney function. Physiol. Rev. 2006;86:901-940.

    Not in our library10.1152/physrev.00031.2005

  68. 68.

    Hausberg M., Kosch M., Harmelink P., Barenbrock M., Hohage H., Kisters K., Dietl K.H., Rahn K.H. Sympathetic nerve activity in end-stage renal disease. Circulation. 2002;106:1974-1979.

    Not in our library10.1161/01.cir.0000034043.16664.96

  69. 69.

    Desir G.V., Peixoto A.J. Renalase in hypertension and kidney disease. Nephrol. Dial. Transplant. 2014;29:22-28.

    Not in our library10.1093/ndt/gft083

  70. 70.

    Xu J., Li G., Wang P., Velazquez H., Yao X., Li Y., Wu Y., Peixoto A., Crowley S., Desir G.V. Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure. J. Clin. Investig. 2005;115:1275-1280.

    Not in our library10.1172/jci24066

  71. 71.

    Desir G.V. Renalase deficiency in chronic kidney disease, and its contribution to hypertension and cardiovascular disease. Curr. Opin. Nephrol. Hypertens. 2008;17:181-185.

    Not in our library10.1097/mnh.0b013e3282f521ba

  72. 72.

    Li G., Xu J., Wang P., Velazquez H., Li Y., Wu Y., Desir G.V. Catecholamines regulate the activity, secretion, and synthesis of renalase. Circulation. 2008;117:1277-1282.

    Not in our library10.1161/circulationaha.107.732032

  73. 73.

    Mungrue I.N., Bredt D.S., Stewart D.J., Husain M. From molecules to mammals: What’s NOS got to do with it? Acta Physiol. Scand. 2003;179:123-135.

    Not in our library10.1046/j.1365-201x.2003.01182.x

  74. 74.

    Sakuma I., Togashi H., Yoshioka M., Saito H., Yanagida M., Tamura M., Kobayashi T., Yasuda H., Gross S.S., Levi R. NG-methyl-l-arginine, an inhibitor of l-arginine-derived nitric oxide synthesis, stimulates renal sympathetic nerve activity in vivo. A role for nitric oxide in the central regulation of sympathetic tone? Circ. Res. 1992;70:607-611.

    Not in our library10.1161/01.res.70.3.607

  75. 75.

    Sander M., Hansen J., Victor R.G. The sympathetic nervous system is involved in the maintenance but not initiation of the hypertension induced by N(omega)-nitro-l-arginine methyl ester. Hypertension. 1997;30:64-70.

    Not in our library10.1161/01.hyp.30.1.64

  76. 76.

    Sander M., Chavoshan B., Victor R.G. A large blood pressure-raising effect of nitric oxide synthase inhibition in humans. Hypertension. 1999;33:937-942.

    Not in our library10.1161/01.hyp.33.4.937

  77. 77.

    Cannon R.O. Role of nitric oxide in cardiovascular disease: Focus on the endothelium. Clin. Chem. 1998;44:1809-1819.

    Not in our library

  78. 78.

    Cooke J.P., Dzau V.J. Nitric oxide synthase: Role in the genesis of vascular disease. Annu. Rev. Med. 1997;48:489-509.

    Not in our library10.1146/annurev.med.48.1.489

  79. 79.

    Shapoval L.N., Sagach V.F., Pobegailo L.S. Nitric oxide influences ventrolateral medullary mechanisms of vasomotor control in the cat. Neurosci. Lett. 1991;132:47-50.

    Not in our library10.1016/0304-3940(91)90430-2

  80. 80.

    Harada S., Tokunaga S., Momohara M., Masaki H., Tagawa T., Imaizumi T., Takeshita A. Inhibition of nitric oxide formation in the nucleus tractus solitarius increases renal sympathetic nerve activity in rabbits. Circ. Res. 1993;72:511-516.

    Not in our library10.1161/01.res.72.3.511

  81. 81.

    Tagawa T., Imaizumi T., Harada S., Endo T., Shiramoto M., Hirooka Y., Takeshita A. Nitric oxide influences neuronal activity in the nucleus tractus solitarius of rat brainstem slices. Circ. Res. 1994;75:70-76.

    Not in our library10.1161/01.res.75.1.70

  82. 82.

    Togashi H., Sakuma I., Yoshioka M., Kobayashi T., Yasuda H., Kitabatake A., Saito H., Gross S.S., Levi R. A central nervous system action of nitric oxide in blood pressure regulation. J. Pharmacol. Exp. Ther. 1992;262:343-347.

    Not in our library

  83. 83.

    Kishi T., Hirooka Y., Sakai K., Shigematsu H., Shimokawa H., Takeshita A. Overexpression of eNOS in the RVLM causes hypotension and bradycardia via GABA release. Hypertension. 2001;38:896-901.

    Not in our library

  84. 84.

    Kishi T., Hirooka Y., Ito K., Sakai K., Shimokawa H., Takeshita A. Cardiovascular effects of overexpression of endothelial nitric oxide synthase in the rostral ventrolateral medulla in stroke-prone spontaneously hypertensive rats. Hypertension. 2002;39:264-268.

    Not in our library10.1161/hy0202.102701

  85. 85.

    Kumagai H., Averill D.B., Khosla M.C., Ferrario C.M. Role of nitric oxide and angiotensin II in the regulation of sympathetic nerve activity in spontaneously hypertensive rats. Hypertension. 1993;21:476-484.

    Not in our library10.1161/01.hyp.21.4.476

  86. 86.

    Hansen J., Jacobsen T.N., Victor R.G. Is nitric oxide involved in the tonic inhibition of central sympathetic outflow in humans? Hypertension. 1994;24:439-444.

    Not in our library10.1161/01.hyp.24.4.439

  87. 87.

    Augustyniak R.A., Victor R.G., Morgan D.A., Zhang W. l-NAME and ADMA-induced sympathetic neural activation in conscious rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2006;290:R726-R732.

    Not in our library10.1152/ajpregu.00768.2004

  88. 88.

    Young C.N., Fisher J.P., Gallagher K.M., Whaley-Connell A., Chaudhary K., Victor R.G., Thomas G.D., Fadel P.J. Inhibition of nitric oxide synthase evokes central sympatho-excitation in healthy humans. J. Physiol. 2009;587:4977-4986.

    Not in our library10.1113/jphysiol.2009.177204

  89. 89.

    Xiao S., Wagner L., Schmidt R.J., Baylis C. Circulating endothelial nitric oxide synthase inhibitory factor in some patients with chronic renal disease. Kidney Int. 2001;59:1466-1472.

    Not in our library10.1046/j.1523-1755.2001.0590041466.x

  90. 90.

    Kielstein J.T., Boger R.H., Bode-Boger S.M., Frolich J.C., Haller H., Ritz E., Fliser D. Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J. Am. Soc. Nephrol. 2002;13:170-176.

    Not in our library10.1681/asn.v131170

  91. 91.

    Ravani P., Tripepi G., Malberti F., Testa S., Mallamaci F., Zoccali C. Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: A competing risks modeling approach. J. Am. Soc. Nephrol. 2005;16:2449-2455.

    Not in our library10.1681/asn.2005010076

  92. 92.

    Ueda S., Yamagishi S., Kaida Y., Okuda S. Asymmetric dimethylarginine may be a missing link between cardiovascular disease and chronic kidney disease. Nephrology. 2007;12:582-590.

    Not in our library10.1111/j.1440-1797.2007.00840.x

  93. 93.

    Zoccali C. Asymmetric dimethylarginine (ADMA): A cardiovascular and renal risk factor on the move. J. Hypertens. 2006;24:611-619.

    Not in our library10.1097/01.hjh.0000217839.26971.8d

  94. 94.

    Zoccali C., Bode-Boger S., Mallamaci F., Benedetto F., Tripepi G., Malatino L., Cataliotti A., Bellanuova I., Fermo I., Frolich J., et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: A prospective study. Lancet. 2001;358:2113-2117.

    Not in our library10.1016/s0140-6736(01)07217-8

  95. 95.

    Fliser D., Kronenberg F., Kielstein J.T., Morath C., Bode-Boger S.M., Haller H., Ritz E. Asymmetric dimethylarginine and progression of chronic kidney disease: The mild to moderate kidney disease study. J. Am. Soc. Nephrol. 2005;16:2456-2461.

    Not in our library10.1681/asn.2005020179

  96. 96.

    Boger R.H., Bode-Boger S.M., Szuba A., Tsao P.S., Chan J.R., Tangphao O., Blaschke T.F., Cooke J.P. Asymmetric dimethylarginine (ADMA): A novel risk factor for endothelial dysfunction: Its role in hypercholesterolemia. Circulation. 1998;98:1842-1847.

    Not in our library10.1161/01.cir.98.18.1842

  97. 97.

    Young J.M., Terrin N., Wang X., Greene T., Beck G.J., Kusek J.W., Collins A.J., Sarnak M.J., Menon V. Asymmetric dimethylarginine and mortality in stages 3 to 4 chronic kidney disease. Clin. J. Am. Soc. Nephrol. 2009;4:1115-1120.

    Not in our library10.2215/cjn.06671208

  98. 98.

    Watson C.P., Pazarentzos E., Fidanboylu M., Padilla B., Brown R., Thomas S.A. The transporter and permeability interactions of asymmetric dimethylarginine (ADMA) and l-arginine with the human blood-brain barrier in vitro. Brain Res. 2016;1648:232-242.

    Not in our library10.1016/j.brainres.2016.07.026

  99. 99.

    Vallance P., Leiper J. Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler. Thromb. Vasc. Biol. 2004;24:1023-1030.

    Not in our library10.1161/01.atv.0000128897.54893.26

  100. 100.

    Tran C.T., Leiper J.M., Vallance P. The DDAH/ADMA/NOS pathway. Atheroscler. Suppl. 2003;4:33-40.

    Not in our library10.1016/s1567-5688(03)00032-1

  101. 101.

    Achan V., Broadhead M., Malaki M., Whitley G., Leiper J., MacAllister R., Vallance P. Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler. Thromb. Vasc. Biol. 2003;23:1455-1459.

    Not in our library10.1161/01.atv.0000081742.92006.59

  102. 102.

    Dounousi E., Papavasiliou E., Makedou A., Ioannou K., Katopodis K.P., Tselepis A., Siamopoulos K.C., Tsakiris D. Oxidative stress is progressively enhanced with advancing stages of CKD. Am. J. Kidney Dis. 2006;48:752-760.

    Not in our library10.1053/j.ajkd.2006.08.015

  103. 103.

    Oberg B.P., McMenamin E., Lucas F.L., McMonagle E., Morrow J., Ikizler T.A., Himmelfarb J. Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney Int. 2004;65:1009-1016.

    Not in our library10.1111/j.1523-1755.2004.00465.x

  104. 104.

    Himmelfarb J., Stenvinkel P., Ikizler T.A., Hakim R.M. The elephant in uremia: Oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int. 2002;62:1524-1538.

    Not in our library10.1046/j.1523-1755.2002.00600.x

  105. 105.

    Martinez Cantarin M.P., Whitaker-Menezes D., Lin Z., Falkner B. Uremia induces adipose tissue inflammation and muscle mitochondrial dysfunction. Nephrol. Dial. Transplant. 2017;32:943-951.

    Not in our library10.1093/ndt/gfx050

  106. 106.

    Takahashi N., Morimoto S., Okigaki M., Seo M., Someya K., Morita T., Matsubara H., Sugiura T., Iwasaka T. Decreased plasma level of vitamin C in chronic kidney disease: Comparison between diabetic and non-diabetic patients. Nephrol. Dial. Transplant. 2011;26:1252-1257.

    Not in our library10.1093/ndt/gfq547

  107. 107.

    Hirooka Y., Kishi T., Sakai K., Takeshita A., Sunagawa K. Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2011;300:R818-R826.

    Not in our library10.1152/ajpregu.00426.2010

  108. 108.

    Oliveira-Sales E.B., Nishi E.E., Carillo B.A., Boim M.A., Dolnikoff M.S., Bergamaschi C.T., Campos R.R. Oxidative stress in the sympathetic premotor neurons contributes to sympathetic activation in renovascular hypertension. Am. J. Hypertens. 2009;22:484-492.

    Not in our library10.1038/ajh.2009.17

  109. 109.

    Nishihara M., Hirooka Y., Matsukawa R., Kishi T., Sunagawa K. Oxidative stress in the rostral ventrolateral medulla modulates excitatory and inhibitory inputs in spontaneously hypertensive rats. J. Hypertens. 2012;30:97-106.

    Not in our library10.1097/hjh.0b013e32834e1df4

  110. 110.

    Kishi T., Hirooka Y., Kimura Y., Ito K., Shimokawa H., Takeshita A. Increased reactive oxygen species in rostral ventrolateral medulla contribute to neural mechanisms of hypertension in stroke-prone spontaneously hypertensive rats. Circulation. 2004;109:2357-2362.

    Not in our library10.1161/01.cir.0000128695.49900.12

  111. 111.

    Campese V.M., Ye S., Zhong H., Yanamadala V., Ye Z., Chiu J. Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity. Am. J. Physiol. Heart Circ. Physiol. 2004;287:695-703.

    Not in our library10.1152/ajpheart.00619.2003

  112. 112.

    Griendling K.K., Minieri C.A., Ollerenshaw J.D., Alexander R.W. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ. Res. 1994;74:1141-1148.

    Not in our library10.1161/01.res.74.6.1141

  113. 113.

    Campese V.M., Shaohua Y., Huiquin Z. Oxidative stress mediates angiotensin II-dependent stimulation of sympathetic nerve activity. Hypertension. 2005;46:533-539.

    Not in our library10.1161/01.hyp.0000179088.57586.26

  114. 114.

    Chan S.H., Hsu K.S., Huang C.C., Wang L.L., Ou C.C., Chan J.Y. NADPH oxidase-derived superoxide anion mediates angiotensin II-induced pressor effect via activation of p38 mitogen-activated protein kinase in the rostral ventrolateral medulla. Circ. Res. 2005;97:772-780.

    Not in our library10.1161/01.res.0000185804.79157.c0

  115. 115.

    Patel K.P., Mayhan W.G., Bidasee K.R., Zheng H. Enhanced angiotensin II-mediated central sympathoexcitation in streptozotocin-induced diabetes: Role of superoxide anion. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2011;300:R311-R320.

    Not in our library10.1152/ajpregu.00246.2010

  116. 116.

    Zimmerman M.C., Lazartigues E., Lang J.A., Sinnayah P., Ahmad I.M., Spitz D.R., Davisson R.L. Superoxide mediates the actions of angiotensin II in the central nervous system. Circ. Res. 2002;91:1038-1045.

    Not in our library10.1161/01.res.0000043501.47934.fa

  117. 117.

    Shi Z., Chen A.D., Xu Y., Chen Q., Gao X.Y., Wang W., Zhu G.Q. Long-term administration of tempol attenuates postinfarct ventricular dysfunction and sympathetic activity in rats. Pflug. Arch. 2009;458:247-257.

    Not in our library10.1007/s00424-008-0627-x

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    Wei S.G., Zhang Z.H., Yu Y., Felder R.B. Systemically administered tempol reduces neuronal activity in paraventricular nucleus of hypothalamus and rostral ventrolateral medulla in rats. J. Hypertens. 2009;27:543-550.

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