Norepinephrine Spillover Research Articles

The sympathetic nervous system in polycystic ovary syndrome: a novel therapeutic target?

Polycystic ovary syndrome (PCOS) is a common endocrine condition associated with long-term health risks, including type 2 diabetes and vascular dysfunction in addition to reproductive sequelae. Many of the common features of PCOS, such as central obesity, hyperinsulinaemia and obstructive sleep apnoea (OSA), are associated with chronic sympathetic overactivity, suggesting that sympathoexcitation may be involved in the pathogenesis of this condition. Rodent models of polycystic ovaries have shown that ovarian sympathetic outflow may be increased, accompanied by elevated intra-ovarian synthesis of nerve growth factor (NGF) which may be involved in initiation of ovarian pathology. Patients with PCOS have evidence of increased muscle sympathetic nerve activity (MSNA), altered heart rate variability and attenuated heart rate recovery postexercise, compared with age- and BMI-matched controls, suggesting a generalized increase in sympathetic nerve activity. Active weight loss can reduce MSNA and whole body noradrenaline spillover, whereas low-frequency electroacupuncture decreased MSNA in overweight women with PCOS. Treatment of OSA with continuous positive airways pressure may reduce plasma noradrenaline levels and diastolic blood pressure and improve cardiac sympathovagal balance. Renal sympathetic denervation also reduced MSNA, noradrenaline spillover and blood pressure in two PCOS subjects with hypertension, accompanied by improved insulin sensitivity. The sympathetic nervous system may thus offer a new therapeutic target in PCOS but larger and longer-term studies are needed before these treatments can be considered in clinical practice.

Effects of renal sympathetic denervation on inducibility of atrial fibrillation during rapid atrial pacing

Background Atrial fibrillation (AF) is associated with activity of renin–angiotensin–aldosterone system (RAAS). Reduction in renal noradrenaline spillover could be achieved after renal sympathetic denervation (RSD). The relationship between RSD and AF is unknown.

Assessing the activity of cardiac sympathetic innervation with a novel PET tracer

When he was awarded the Nobel Prize in 1970, Ulf vonEuler described cardiac adrenergic neurotransmission asfollows: “Section of the adrenergic nerves to the heart andsome other organs and subsequent degeneration caused thenoradrenaline content to fall to very low values, or to dis-appear, which also indicated that it was normally bound tothe nerves in the organs”…“With the aid of radioactivelylabelled noradrenaline it could be shown that uptake oftransmitter occurred in the particles concomitantly with therelease”. His seminal work in 1946 was the foundation forthe noninvasive study of cardiac sympathetic activity [1].Thesympatheticoutflowtotheheartistonicallyandphasi-cally modulated both in health and disease by the continuousinteraction between central neural integration and peripheralinhibitory and excitatory reflexes. The importance of themeasurement of neurotransmitter concentrations as an indica-tion of neural activity directed to the heart was highlighted in1982byHaskingetal.[2].Thetenetatthattime,derivedfromassays on atrial tissue or papillary muscle samples, was thatthefailingheartshowedaprofounddepletionofnoradrenalinestores. The finding that noradrenaline spillover was increasedby540%abovenormalvaluesrevealedtheoveractivityofthesympathetic outflow directed to the heart. A few years laterBohm et al. using tissue samples of the left ventricle provedthat there is a presynaptic defect leading to reduced uptake-1activity in the failing heart. This unpaired mechanism ispharmacologically mimicked by the effects of uptakeblocking agents in the normal heart [3]. The consequence isan increased synaptic concentration of noradrenaline predis-posingto adenylyl cyclase desensitization[3]. Dr. Esler in hisrecent Paton lecture pointed out that at that time he had “toprovide a spirited defence of the research ethics” to carry outinvasive noradrenaline spillover measurements in healthyvolunteers.In the last three decades two tracers have been used toassess the function of the reuptake-1 mechanism noninva-sively in humans:

Neuroadrenergic Dysfunction Along the Diabetes Continuum

Neuroadrenergic function in type 2 diabetic (T2D) patients without neuropathy is poorly characterized. We therefore compared sympathetic nervous system activity at rest and during an oral glucose tolerance test in obese metabolic syndrome (MetS) subjects classified as glucose intolerant (impaired glucose tolerance [IGT]; n = 17) or treatment-naive T2D (n = 17). Untreated subjects, matched for age (mean 59 ± 1 year), sex, BMI (32.4 ± 0.6 kg/m2), and family history of diabetes were studied. We measured resting muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine kinetics by isotope dilution, insulin sensitivity by euglycemic-hyperinsulinemic clamp (steady-state glucose utilization adjusted for fat-free mass and steady-state insulin concentration [M/I]), and MetS components. T2D subjects had higher resting MSNA burst incidence (67 ± 4 versus 55 ± 3 bursts per 100 heartbeats; P = 0.05) and arterial norepinephrine levels (264 ± 33 versus 167 ± 16 pg/mL; P = 0.02), lower plasma norepinephrine clearance (by 17%; P = 0.03), and reduced neuronal reuptake compared with IGT subjects (by 46%; P = 0.04). Moreover, norepinephrine spillover responses to glucose ingestion were blunted in T2D subjects. The M/I value independently predicted whole-body norepinephrine spillover (r = −0.47; P = 0.008), whereas fasting insulin level related to neuronal norepinephrine reuptake (r = −0.35, P = 0.047). These findings demonstrate that progression to T2D is associated with increased central sympathetic drive, blunted sympathetic responsiveness, and altered norepinephrine disposition.

Hard‐wired for hypertension? The sympathetic nervous system causing havoc to non‐responders’ blood pressure

Hard‐wired for hypertension? The sympathetic nervous system causing havoc to non‐responders’ blood pressure

489 Activation by Human Heart Failure of a Sympathoexcitatory Cardiopulmonary Reflex

Functionally specific efferent renal sympathetic nerve fibers fire in response to discrete afferent stimuli. We hypothesize that individual efferent sympathetic fibers directed at other vascular beds also may be activated reflexively by specific afferent inputs. Previous work from our group, involving quantification of cardiac norepinephrine spillover, detected activation in heart failure (HF) by high atrial pressure of a normally quiescent cardio-cardiac sympatho-excitatory reflex. Whether individual vasoconstrictor neurons directed at skeletal muscle vessels respond concordantly or differentially to changes in atrial pressure is unknown.

787 EFFECTS OF TRANSCATHETER RENAL NERVE ABLATION ON SYMPATHETIC AND NEUROHORMONAL ACTIVITY IN PATIENTS WITH RESISTANT HYPERTENSION

Background: Transcatheter renal nerve ablation is a novel treatment modality to directly and selectively target efferent sympathetic and afferent sensory nerves. Initial clinical trials have demonstrated favorable effects not only on blood pressure control but also on other conditions commonly characterized by sympathetic overdrive, such as insulin resistance, sleep apnea and others. The effects of renal denervation on regional sympathetic nerve activity and neurohormonal activation have not yet been described in detail. Design and methods: A total of 40 patients with resistant hypertension (mean age: 60 ± 8yrs) underwent assessment of regional sympathetic nerve activity using microneurography and/or renal and whole body noradrenaline spillover before and after staged or single session bilateral renal denervation. Renal blood flow and markers of neurohormonal activation were also measured. Results: Renal and muscle sympathetic nerve activity were substantially elevated at baseline and reduced in most patients after renal denervation which was associated with a significant reduction in blood pressure and renovascular resistance. Complementing the reduction in renal NA spillover, plasma renin activity was reduced by 24% and renal plasma flow increased by 11.2%. Data from 10 patients who underwent a staged renal nerve ablation procedure revealed a distinct sympathetic response pattern with an immediate ipsilateral reduction and contralateral increase in renal NA spillover. Prior to the second procedure, renal NA spillover was already reduced bilaterally with the effect being more pronounced after the second procedure. Conclusions: Transcatheter renal nerve ablation is associated with a substantial reduction in efferent renal sympathetic nerve activity and accompanied by favorable changes in systemic and renal hemodynamic and neurohormonal parameters. Reductions in central sympathetic outflow and whole body noradrenaline spillover are likely due to alterations in afferent signaling from the treated kidneys.

393 NEUROADRENERGIC DYSFUNCTION ALONG THE DIABETIC CONTINUUM

Background: Neuroadrenergic function in type 2 diabetic (T2D) patients is poorly characterized, particularly in the early stages of disease, before the onset of peripheral neuropathy. We therefore compared sympathetic nervous system (SNS) activity at rest and during a standard oral glucose tolerance test (OGTT) in obese metabolic syndrome (MetS) subjects classified using WHO criteria as glucose intolerant (IGT) or treatment naïve T2D. Design and methods: Untreated subjects (17 IGT, 17 T2D) matched for age (mean 59 ± 1 yr), gender, body mass index (32.4 ± 0.6 kg/m2) and family history of diabetes were studied. We measured muscle sympathetic nerve activity (MSNA) by microneurography, whole-body noradrenaline kinetics by isotope dilution, neuronal noradrenaline re-uptake as the steady state tritiated 3,4-dihydroxyphenylglycol to tritiated noradrenaline ratio (3H-DHPG: 3H-NA), insulin sensitivity by euglycaemic hyperinsulinemic clamp (M/I) and MetS components. Results: T2D subjects had higher resting MSNA burst incidence (67 ± 4 versus 55 ± 3 bursts per 100 heartbeats, P = 0.05) and arterial noradrenaline levels (264 ± 33 versus 167 ± 16 pg/ml, P = 0.02), lower plasma noadrenaline clearance (by 17%, P = 0.03) and reduced neuronal re-uptake compared with IGT subjects (by 46%, P = 0.04). Moreover, noradrenaline spillover responses to glucose ingestion were significantly blunted in T2D subjects. The M/I value independently predicted whole-body noadrenaline spillover (r = −0.47, P = 0.008), whilst fasting insulin level related to neuronal noradrenaline re-uptake (r = −0.35, P = 0.047). Conclusions: These findings demonstrate that progression to T2D is associated with increased central sympathetic drive, blunted sympathetic responsiveness and altered noradrenaline disposition.

Long-acting dihydropyridine calcium-channel blockers and sympathetic nervous system activity in hypertension: A literature review comparing amlodipine and nifedipine GITS

Calcium-channel blockers (CCBs) constitute a diverse group of compounds but are often referred to as a single homogeneous class of drug and the clinical responses indiscriminately summarized. Even within the dihydropyridine subgroup, there are significant differences in formulations, pharmacokinetics, durations of action and their effects on blood pressure, heart rate, end organs and the sympathetic nervous system. Amlodipine and nifedipine in the gastrointestinal therapeutic system (GITS) formulation are the most studied of the once-daily CCBs. Amlodipine has an inherently long pharmacokinetic half-life, whereas, in contrast, nifedipine has an inherently short half-life but in the GITS formulation the sophisticated delivery system allows for once-daily dosing. This article is derived from a systematic review of the published literature in hypertensive patients. The following search terms in three main databases (MEDLINE, Embase, Science Citation Index) from 1990 to 2011 were utilized: amlodipine, nifedipine, sympathetic nervous system, sympathetic response, sympathetic nerve activity, noradrenaline, norepinephrine and heart rate. More than 1500 articles were then screened to derive the relevant analysis. As markers of sympathetic nervous system activation, studies of plasma norepinephrine concentrations, power spectral analysis, muscle sympathetic nerve activity and norepinephrine spillover were reviewed. Overall, each drug lowered blood pressure in hypertensive patients in association with only small changes in heart rate (i.e. <1 beat/min). Plasma norepinephrine concentrations, as the most widely reported marker of sympathetic nervous system activity, showed greater increases in patients treated with amlodipine than with nifedipine GITS. The evidence indicates that both these once-daily dihydropyridine CCBs lower blood pressure effectively with minimal effects on heart rate. There are small differences between the drugs in the extent to which each activates the sympathetic nervous system with an overall non-significant trend in favour of nifedipine GITS.

Central Sympathetic Inhibition by Mineralocorticoid Receptor But Not Angiotensin II Type 1 Receptor Blockade

See related article, pp 319–325 Chronic sympathetic hyperactivity, characteristic of the majority of patients with hypertension or heart failure, can contribute to cardiovascular morbidity and mortality via a number of actions. Pharmacological strategies to prevent these adverse effects have had variable success. β-Blockers clearly benefit patients with heart failure but have less definitive effects in patients with hypertension, whereas α1-blockers or centrally acting agents have shown mixed results, and all of these classes can cause bothersome adverse effects. Device-based approaches, such as baroreflex activation therapy and renal denervation, have been shown to lower sympathetic activity in patients with hypertension, but beneficial actions on cardiovascular outcomes have yet to be demonstrated. So, where do the central nervous system (CNS) actions of angiotensin II (Ang II), aldosterone, and, hence, Ang II type 1 (AT1) receptor and mineralocorticoid receptor (MR) blockers fit in? Experimental studies have demonstrated that both circulating Ang II and aldosterone act within the CNS to cause sympatho-excitation and raise blood pressure.1,2 Ang II stimulates AT1 receptors in nuclei of the lamina terminalis and thereby activates mainly angiotensinergic pathways to the paraventricular nucleus (PVN) and rostral ventrolateral medulla. Circulating Ang II, in addition, activates an MR-endogenous ouabain pathway. This slowly acting, neuromodulatory pathway appears responsible for most of the persistent neuronal activation in, for example, the PVN, and the progressive hypertension induced by circulating Ang II. Studies using central infusions of an aldosterone synthase inhibitor suggest that the CNS MR activation by Ang II largely depends on locally produced aldosterone rather than circulation-derived aldosterone.1 However, the progressive hypertension caused by a chronic increase in circulating aldosterone can also be prevented by specific CNS blockade of either MR or AT1 receptors,2 suggesting that both circulating aldosterone and Ang II may activate …

Catheter-based renal denervation for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 Trial.

Hypertension represents a significant global public health concern, contributing to vascular and renal morbidity, cardiovascular mortality, and economic burden. The opportunity to influence clinical outcomes through hypertension management is therefore paramount. Despite adherence to multiple available medical therapies, a significant proportion of patients have persistent blood pressure elevation, a condition termed resistant hypertension. Recent recognition of the importance of the renal sympathetic and somatic nerves in modulating blood pressure and the development of a novel procedure that selectively removes these contributors to resistant hypertension represents an opportunity to provide clinically meaningful benefit across wide and varied patient populations. Early clinical evaluation with catheter-based, selective renal sympathetic denervation in patients with resistant hypertension has mechanistically correlated sympathetic efferent denervation with decreased renal norepinephrine spillover and renin activity, increased renal plasma flow, and has demonstrated clinically significant, sustained reductions in blood pressure. The SYMPLICITY HTN-3 Trial is a pivotal study designed as a prospective, randomized, masked procedure, single-blind trial evaluating the safety and effectiveness of catheter-based bilateral renal denervation for the treatment of uncontrolled hypertension despite compliance with at least 3 antihypertensive medications of different classes (at least one of which is a diuretic) at maximal tolerable doses. The primary effectiveness endpoint is measured as the change in office-based systolic blood pressure from baseline to 6 months. This manuscript describes the design and methodology of a regulatory trial of selective renal denervation for the treatment of hypertension among patients who have failed pharmacologic therapy.

Mechanisms regulating norepinephrine‐mediated α2‐IPSCs in the rat locus coeruleus

Dopamine (DA) in the ventral tegmental area (VTA) and norepinephrine (NE) in the locus coeruleus (LC) provide feedback inhibition that allows these cells to auto‐regulate their excitability. Previously, we characterized DA D2‐receptor‐mediated inhibitory postsynaptic currents (D2‐IPSCs) in the VTA. Here, we characterized NE α2‐receptor‐mediated IPSCs (α2‐IPSCs) in the LC. Both D2 and α2 receptors activate potassium channels. Despite analogous signaling, the duration of the D2‐IPSC was about one‐fourth that of the α2‐IPSC (D2‐IPSC tau: 347 ms, n=8; α2‐IPSC tau: 1346 ms, n=17). To characterize transmission, we evoked IPSCs with varying‐intensity stimulations. In the VTA, increased stimulus intensity increased the amplitude, but not the time course, of the D2‐IPSCs (tau = 92 + 4%, n =12). In contrast, in the LC, increased stimulation intensity increased the amplitude and duration of the α2‐IPSCs (tau = 142 + 13%, n = 13). Increased stimulus intensity may evoke spillover of NE. To examine glutamate input, we applied the AMPA receptor antagonist DNQX. DNQX had no effect on the amplitude or duration of the D2‐IPSCs, but reduced the amplitude and duration of the α2‐IPSC (control tau: 1282 ms, DNQX tau: 660 ms, n=9). Thus, stimulation of the LC may drive glutamate release that potentiates NE release. These data indicate that different mechanisms may regulate catecholamine transmission. Support: DA026417.

The Role of Renal Denervation in the Treatment of Heart Failure

The heart and kidney interact in terms of hemodynamics and neurohumoral regulatory mechanisms, and this helps to maintain circulatory homeostasis under normal conditions. However, the normal regulatory mechanisms become inappropriate in the setting of congestive heart failure (CHF), and significant renal dysfunction often develops in CHF patients. Activation of renal sympathetic efferent nerves causes renin release, sodium and water retention, and reduced renal blood flow, all hallmarks of the renal manifestations of CHF. An increase in plasma levels of angiotensin II that is mediated in part by renal sympathetic activation has an effect on the central nervous system to further increase global sympathetic tone. Renal sympathetic activity can be assessed clinically by renal norepinephrine spillover, and an increase in renal norepinephrine spillover in CHF predicts reduced survival. In addition to efferent sympathetic activation, activation of renal sensory nerves in CHF may cause a reflex increase in sympathetic tone that contributes to elevated peripheral vascular resistance and vascular remodeling as well as left ventricular remodeling and dysfunction. In animal models of heart failure, surgical renal denervation has been shown to improve both renal and ventricular function. Although surgical renal denervation has long been known to lower blood pressure and improve survival in patients with hypertension, the invasive nature of this approach and its associated complications has limited its appeal. However, a novel catheter-based device has recently been introduced that specifically interrupts both efferent and afferent renal nerves, and there is significant interest in the use of this device to treat both hypertension and CHF. Several ongoing clinical trials are investigating the safety and efficacy of renal denervation in patients with CHF.

Renal nerve ablation reduces blood pressure in a patient with renovascular hypertension resistant to drug and revascularisation therapies

Amongst specific causes of secondary hypertension renovascular hypertension remains the second most common form which frequently presents with resistance to pharmacologic treatment. Activation of both the renin–angiotensin system and the sympathetic nervous system are well recognized mechanisms involved in renovascular hypertension as evidenced by increased plasma renin activity and angiotensin II levels, as well as increased rates of efferent sympathetic-nerve firing and total body noradrenaline spillover [1,2].

Endogenous adenosine contributes to renal sympathetic neurotransmission via postjunctional A1receptor-mediated coincident signaling

Adenosine A(1) receptor antagonists have diuretic/natriuretic activity and may be useful for treating sodium-retaining diseases, many of which are associated with increased renal sympathetic tone. Therefore, it is important to determine whether A(1) receptor antagonists alter renal sympathetic neurotransmission. In isolated, perfused rat kidneys, renal vasoconstriction induced by renal sympathetic nerve simulation was attenuated by 1) 1,3-dipropyl-8-p-sulfophenylxanthine (xanthine analog that is a nonselective adenosine receptor antagonist, but is cell membrane impermeable and thus does not block intracellular phosphodiesterases), 2) xanthine amine congener (xanthine analog that is a selective A(1) receptor antagonist), 3) 1,3-dipropyl-8-cyclopentylxanthine (xanthine analog that is a highly selective A(1) receptor antagonist), and 4) FK453 (nonxanthine analog that is a highly selective A(1) receptor antagonist). In contrast, FR113452 (enantiomer of FK453 that does not block A(1) receptors), MRS-1754 (selective A(2B) receptor antagonist), and VUF-5574 (selective A(3) receptor antagonist) did not alter responses to renal sympathetic nerve stimulation, and ZM-241385 (selective A(2A) receptor antagonist) enhanced responses. Antagonism of A(1) receptors did not alter renal spillover of norepinephrine. 2-Chloro-N(6)-cyclopentyladenosine (highly selective A(1) receptor agonist) increased renal vasoconstriction induced by exogenous norepinephrine, an effect that was blocked by 1,3-dipropyl-8-cyclopentylxanthine, U73122 (phospholipase C inhibitor), GF109203X (protein kinase C inhibitor), PP1 (c-src inhibitor), wortmannin (phosphatidylinositol 3-kinase inhibitor), and OSU-03012 (3-phosphoinositide-dependent protein kinase-1 inhibitor). These results indicate that adenosine formed during renal sympathetic nerve stimulation enhances the postjunctional effects of released norepinephrine via coincident signaling and contributes to renal sympathetic neurotransmission. Likely, the coincident signaling pathway is: phospholipase C → protein kinase C → c-src → phosphatidylinositol 3-kinase → 3-phosphoinositide-dependent protein kinase-1.

Caveat utilitor: take measure of your marker

Caveat utilitor: take measure of your marker

C-001 EFFECTS OF LONG ACTING DIHYDROPYRIDINE CALCIUM CHANNEL BLOCKERS ON SYMPATHETIC ACTIVITY IN HYPERTENSION

Background Calcium channel blockers (CCBs) constitute a diverse group of compounds, with three principal subgroups and multiple variations in formulation. CCBs are often referred to as a single homogeneous class of drug and the clinical responses indiscriminately summarized. Even within the main subgroup, the dihydropyridine subgroup, there are significant differences in formulations, pharmacokinetics, durations of action and their effects on blood pressure, heart rate, end organs and the sympathetic nervous system. Amlodipine and Nifedipine in the GITS formulation are the most studied of the once daily CCBs and are registered in most major countries worldwide. Amlodipine has an inherently long pharmacokinetic half life whereas, in contrast, nifedipine has an inherently short half life but in the GITS formulation the sophisticated delivery system allows for once daily dosing. Methods This presentation is derived from a systematic review of the published literature in hypertensive patients to date. The following search terms in three main databases (MEDLINE, Embase, Science Citation Index) from 1990 to 2011 were utilized: amlodipine, nifedipine, sympathetic nervous system, sympathetic response, sympathetic nerve activity, noradrenaline, norepinephrine and heart rate. More than 1,500 articles were then screened to derive the relevant analysis. Results As markers of sympathetic nervous system activation, plasma norepinephrine, power spectral analysis, muscle sympathetic nerve activity and norepinephrine spillover studies were reviewed. Although direct comparisons of the two drugs in one study would present the ideal this was rarely reported. Durations of treatment with either drug ranged from 1 week to 52 weeks. Doses of amlodipine ranged from 2.5 to 10 mg once a day and 20 to 150 mg once a day for nifedipine GITS. Each drug lowered blood pressure in patients with small changes in heart rate (i.e. < 1 b/min). Plasma norepinephrine measurements were the most reported marker of sympathetic nervous system activity and showed a greater increase in patients treated with amlodipine than nifedipine GITS. Conclusions The evidence indicates that both these once daily dihydropyridine CCBs lower blood pressure effectively with minimal effects on heart rate. However, there are small differences between the drugs in the extent to which each activates the sympathetic nervous system: overall, the available evidence favours nifedipine GITS.

Recurrent Postural Vasovagal Syncope

Background— The pathophysiology of vasovagal syncope is poorly understood, and the treatment usually ineffective. Our clinical experience is that patients with vasovagal syncope fall into 2 groups, based on their supine systolic blood pressure, which is either normal (&gt;100 mm Hg) or low (70–100 mm Hg). We investigated neural circulatory control in these 2 phenotypes. Methods and Results— Sympathetic nervous testing was at 3 levels: electric, measuring sympathetic nerve firing (microneurography); neurochemical, quantifying norepinephrine spillover to plasma; and cellular, with Western blot analysis of sympathetic nerve proteins. Testing was done during head-up tilt (HUT), simulating the gravitational stress of standing, in 18 healthy control subjects and 36 patients with vasovagal syncope, 15 with the low blood pressure phenotype and 21 with normal blood pressure. Microneurography and norepinephrine spillover increased significantly during HUT in healthy subjects. The microneurography response during HUT was normal in normal blood pressure and accentuated in low blood pressure phenotype ( P =0.05). Norepinephrine spillover response was paradoxically subnormal during HUT in both patient groups ( P =0.001), who thus exhibited disjunction between nerve firing and neurotransmitter release; this lowered norepinephrine availability, impairing the neural circulatory response. Subnormal norepinephrine spillover in low blood pressure phenotype was linked to low tyrosine hydroxylase (43.7% normal, P =0.001), rate-limiting in norepinephrine synthesis, and in normal blood pressure to increased levels of the norepinephrine transporter (135% normal, P =0.019), augmenting transmitter reuptake. Conclusions— Patients with recurrent vasovagal syncope, when phenotyped into 2 clinical groups based on their supine blood pressure, show unique sympathetic nervous system abnormalities. It is predicted that future therapy targeting the specific mechanisms identified in the present report should translate into more effective treatment.

Splanchnic sympathetic nerves in the development of mild DOCA-salt hypertension

We previously reported that mild deoxycorticosterone acetate (DOCA)-salt hypertension develops in the absence of generalized sympathoexcitation. However, sympathetic nervous system activity (SNA) is regionally heterogeneous, so we began to investigate the role of sympathetic nerves to specific regions. Our first study on that possibility revealed no contribution of renal nerves to hypertension development. The splanchnic sympathetic nerves are implicated in blood pressure (BP) regulation because splanchnic denervation effectively lowers BP in human hypertension. Here we tested the hypothesis that splanchnic SNA contributes to the development of mild DOCA-salt hypertension. Splanchnic denervation was achieved by celiac ganglionectomy (CGX) in one group of rats while another group underwent sham surgery (SHAM-GX). After DOCA treatment (50 mg/kg) in rats with both kidneys intact, CGX rats exhibited a significantly attenuated increase in BP compared with SHAM-GX rats (15.6 ± 2.2 vs. 25.6 ± 2.2 mmHg, day 28 after DOCA treatment). In other rats, whole body norepinephrine (NE) spillover, measured to determine if CGX attenuated hypertension development by reducing global SNA, was not found to be different between SHAM-GX and CGX rats. In a third group, nonhepatic splanchnic NE spillover was measured as an index of splanchnic SNA, but this was not different between SHAM (non-DOCA-treated) and DOCA rats during hypertension development. In a final group, CGX effectively abolished nonhepatic splanchnic NE spillover. These data suggest that an intact splanchnic innervation is necessary for mild DOCA-salt hypertension development but not increased splanchnic SNA or NE release. Increased splanchnic vascular reactivity to NE during DOCA-salt treatment is one possible explanation.

On the contribution of group III and IV muscle afferents to the circulatory response to rhythmic exercise in humans

We investigated the role of skeletal muscle afferent feedback in circulatory control during rhythmic exercise in humans. Nine healthy males performed single leg knee-extensor exercise (15/30/45 watts, 3 min each) under both control conditions (Ctrl) and with lumbar intrathecal fentanyl impairing μ-opioid receptor-sensitive muscle afferents. Cardiac output and femoral blood flow were determined, and femoral arterial/venous blood samples were collected during the final minute of each workload. To rule out cephalad migration of fentanyl to the brainstem,we documented unchanged resting ventilatory responses to different levels of hypercapnia. There were no haemodynamic differences between conditions at rest. However, during exercise cardiac output was -2 % lower with fentanyl blockade compared to control (P < 0.05), secondary to a 6% and 13% reduction in heart rate and stroke volume, respectively. Throughout exercise mean arterial pressure (MAP) was reduced by 7% (P < 0.01) which is likely to have contributed to the 15% fall in femoral blood flow. However, MAP was not completely responsible for this peripheral haemodynamic change as vascular conductance was also attenuated (-9%). Evidence of increasing noradrenaline spillover (P = 0.09) implicated an elevation in sympathetic outflow in this response. The attenuated femoral blood flow during exercise with fentanyl was associated with a 17%reduction in leg O2 delivery (P < 0.01) and a concomitant rise in the arteriovenous O2 difference (4–9%), but leg O2 consumption remained 7–13% lower than control (P < 0.05). Our findings reveal an essential contribution of continuous muscle afferent feedback to ensure the appropriate haemodynamic and ultimately metabolic response to rhythmic exercise in humans