Whole-body Norepinephrine Spillover Research Articles

Differential sympathetic response to lesion-induced chronic kidney disease in rabbits

Chronic kidney disease (CKD) is associated with greater sympathetic nerve activity but it is unclear if this is a kidney-specific response or due to generalized stimulation of sympathetic nervous system activity. To determine this, we used a rabbit model of CKD in which quantitative comparisons with control rabbits could be made of kidney sympathetic nerve activity and whole-body norepinephrine spillover. Rabbits either had surgery to lesion 5/6th of the cortex of one kidney by electro-lesioning and two weeks later removal of the contralateral kidney, or sham lesioning and sham nephrectomy. After three weeks, the blood pressure was statistically significantly 20% higher in conscious rabbits with CKD compared to rabbits with a sham operation, but their heart rate was similar. Strikingly, kidney nerve activity was 37% greater than in controls, with greater burst height and frequency. Total norepinephrine spillover was statistically significantly lower by 34%, and kidney baroreflex curves were shifted to the right in rabbits with CKD. Plasma creatinine and urine output were elevated by 38% and 131%, respectively, and the glomerular filtration rate was 37% lower than in sham-operated animals (all statistically significant). Kidney gene expression of fibronectin, transforming growth factor-β, monocyte chemotactic protein1, Nox4 and Nox5 was two- to eight-fold greater in rabbits with CKD than in control rabbits. Overall, the glomerular layer lesioning model in conscious rabbits produced a moderate, stable degree of CKD characterized by elevated blood pressure and increased kidney sympathetic nerve activity. Thus, our findings, together with that of a reduction in total norepinephrine spillover, suggest that kidney denervation, rather than generalized sympatholytic treatments, may represent a preferable management for CKD associated hypertension.

Comparable Attenuation of Sympathetic Nervous System Activity in Obese Subjects with Normal Glucose Tolerance, Impaired Glucose Tolerance, and Treatment Naïve Type 2 Diabetes following Equivalent Weight Loss.

Background and Purpose: Elevated sympathetic nervous system (SNS) activity is a characteristic of obesity and type 2 diabetes (T2D) that contributes to target organ damage and cardiovascular risk. In this study we examined whether baseline metabolic status influences the degree of sympathoinhibition attained following equivalent dietary weight loss.Methods: Un-medicated obese individuals categorized as normal glucose tolerant (NGT, n = 15), impaired glucose tolerant (IGT, n = 24), and newly-diagnosed T2D (n = 15) consumed a hypocaloric diet (29% fat, 23% protein, 45% carbohydrate) for 4-months. The three groups were matched for baseline age (56 ± 1 years), body mass index (BMI, 32.9 ± 0.7 kg/m2), and gender. Clinical measurements included whole-body norepinephrine kinetics, muscle sympathetic nerve activity (MSNA, by microneurography), spontaneous cardiac baroreflex sensitivity (BRS), and oral glucose tolerance test.Results: Weight loss averaged −7.5 ± 0.8, −8.1 ± 0.5, and −8.0 ± 0.9% of body weight in NGT, IGT, and T2D groups, respectively. T2D subjects had significantly greater reductions in fasting glucose, 2-h glucose and glucose area under the curve (AUC0−120) compared to NGT and IGT (group effect, P <0.001). Insulinogenic index decreased in IGT and NGT groups and increased in T2D (group × time, P = 0.04). The magnitude of reduction in MSNA (−7 ± 3, −8 ± 4, −15 ± 4 burst/100 hb, respectively) and whole-body norepinephrine spillover rate (−28 ± 8, −18 ± 6, and −25 ± 7%, respectively), time effect both P <0.001, did not differ between groups. After adjustment for age and change in body weight, Δ insulin AUC0−120 was independently associated with reduction in arterial norepinephrine concentration, whilst Δ LDL-cholesterol and improvement in BRS were independently associated with decrease in MSNA.Conclusions: Equivalent weight loss through hypocaloric diet is accompanied by similar sympathoinhibition in matched obese subjects with different baseline glucose tolerance. Attenuation of hyperinsulinemia and hyperlipidemia, rather than glycemic indices, is associated with reduction in SNS activity following weight loss intervention.

Renal sympathetic denervation for treatment of ventricular arrhythmias: a review on current experimental and clinical findings.

Ventricular arrhythmias (VAs) remain the major cause of mortality and sudden cardiac death (SCD) in almost all forms of heart disease. Despite so many therapeutic advances, such as pharmacological therapies, catheter ablation, and arrhythmia surgery, management of VAs remains a great challenge for cardiologists. Evidence from histological studies and from direct nerve activity recordings have suggested that increased sympathetic nerve density and activity contribute to the generation of VAs and SCD. It is well known that renal sympathetic nerve (RSN), either afferent component or efferent component, plays an important role in modulation of central sympathetic activity. We have recently shown that RSN activation by electrical stimulation significantly increases cardiac and systemic sympathetic activity and promotes the incidence of acute ischemia-induced VAs, suggesting RSN has a role in the development of VAs. Initial experience of RSN denervation (RDN) in patients with resistant hypertension showed that this novel and minimally invasive device-based approach significantly reduced not only kidney but also whole-body norepinephrine spillover. In addition, experimental studies find that left stellate ganglion nerve activity is significantly decreased after RDN. Based on these observations, it is reasonable to conclude that RDN may be an effective therapy for the management of VAs. Indeed, RDN has provided a protection against VAs in both animal models and patients. In this article, we review the role of the RSN in the generation of VAs and SCD and the role of RDN as a potential treatment strategy for VAs and SCD.

Renal denervation using catheter-based radiofrequency ablation with temperature control: renovascular safety profile and underlying mechanisms in a hypertensive canine model

Objective: Renal denervation is a novel method for hypertension treatment. In this study, we aimed to investigate the safety and efficacy of radiofrequency ablation (RFA) at ablation temperatures of 45 °C or 50 °C and its possible mechanisms. Methods: A hypertensive canine model was established by abdominal aortic constriction in 20 healthy hybrid dogs. These dogs were then randomly assigned to the treatment and the control groups, with dogs in the treatment group further randomly assigned to receive RFA at ablation temperatures of 45 °C or 50 °C. In the treatment group, RFA was performed at 1 month after modeling; renal angiography was performed at 2 months after ablation. The arterial vessels of the dogs were examined histologically with hematoxylin and eosin staining. Changes in blood pressure in the foreleg and whole-body norepinephrine spillover rate were also assessed. Results: No arterial stenosis, dissection, thrombosis or other abnormalities were detected in the treated vessels by renal angiography, yet histology results showed minimal to mild renal arterial injury. Renal denervation resulted in a marked decrease in the whole-body norepinephrine spillover rate (p < 0.05) in addition to significantly reducing blood pressure (p < 0.05), with no significant differences detected between the 45 °C and 50 °C subgroups for both (p > 0.05). Conclusion: Renal denervation can be performed without acute major adverse events, using catheter-based RFA with temperature control. The procedure was feasible in reducing blood pressure by at least partially inhibiting sympathetic drive and systemic sympathetic outflow.

Comment on: Straznicky et al. Neuroadrenergic Dysfunction Along the Diabetes Continuum: A Comparative Study in Obese Metabolic Syndrome Subjects. Diabetes 2012;61:2506–2516

In the recent article by Straznicky et al. (1), the authors demonstrate that the onset of diabetes is associated with increased central sympathetic outflow, altered norepinephrine disposition, and blunted sympathetic responsiveness to carbohydrates. In fact, insulin resistance highly correlated with neuroadrenergic function, as shown by the independent correlation of insulin-stimulated glucose uptake (M/I) with whole-body norepinephrine spillover. Muscle sympathetic nerve activity (MSNA), on the contrary, failed to correlate with insulin resistance. This apparently surprising result can, however, find a logical explanation (2), which actually reinforces the data of Straznicky et al. Sympathetic overactivity, similarly …

Response to Comment on: Straznicky et al. neuroadrenergic dysfunction along the diabetes continuum: a comparative study in obese metabolic syndrome subjects. Diabetes 2012;61:2506-2516.

We wish to thank Dr. Frontoni (1) for her insightful comments regarding the disparate relationship of glucose utilization to two indices of sympathetic nervous system activity—whole-body norepinephrine spillover rate and muscle sympathetic nerve activity (MSNA), within our cohort of obese metabolic syndrome subjects (2). Both arterial norepinephrine concentration and norepinephrine spillover rate showed a strong inverse relationship with clamp-derived glucose utilization (M/I value, r = −0.47, P = 0.008), whereas MSNA was not significantly associated with glucose utilization. Rather, total MSNA was influenced by the prevailing insulin concentration as indicated by positive associations with fasting C-peptide levels ( r = 0.37, P = 0.04) and insulin area under the curve …

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.

The Effects of Weight LossVersusWeight Loss Maintenance on Sympathetic Nervous System Activity and Metabolic Syndrome Components

Sympathetic nervous system (SNS) overactivity participates in both the pathogenesis and adverse clinical complications of metabolic syndrome (MetS) obesity. We conducted a prospective lifestyle intervention trial to compare the effects of active weight loss and extended weight loss maintenance on SNS function and MetS components. Untreated subjects (14 males, four females; mean age, 53 ± 1 yr; body mass index, 30.9 ± 0.9 kg/m(2)) who fulfilled Adult Treatment Panel III criteria were randomized to 12-wk hypocaloric diet alone (n = 8) or together with aerobic exercise training (n = 10). This was followed by a 4-month weight maintenance period. Measurements of muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine kinetics, substrate oxidation by indirect calorimetry, baroreflex sensitivity, plasma renin activity (PRA), and MetS components were performed. Body weight decreased by 9.3 ± 0.8% at wk 12 (P < 0.001), and this was maintained. During active weight loss, norepinephrine spillover rate decreased by 23 ± 16% (P = 0.004), MSNA by 25 ± 3 bursts per 100 heartbeats (P < 0.001), and PRA by 0.25 ± 0.09 ng/ml · h (P = 0.007), whereas baroreflex sensitivity increased by 5.2 ± 2.2 msec/mm Hg (P = 0.005). After weight maintenance, beneficial effects of weight loss on norepinephrine spillover rate were preserved, whereas PRA and MSNA rebounded (by 0.24 ± 0.11 ng/ml · h, P = 0.02; and 20 ± 5 bursts/100 heartbeats, P = 0.0003), and baroreflex sensitivity was attenuated. Divergent effects of successful weight loss maintenance on whole-body norepinephrine spillover rate and MSNA suggest organ-specific differentiation in SNS adaptation to weight loss under conditions of negative vs. stable energy balance.

Interventionelle renale Sympathikusdenervation

The pathophysiology of resistant hypertension is complex. Activation of the sympathetic nervous system has been suggested to be one of the main contributors for maintenance of blood pressure elevation and the development of comorbidities. Catheter-based renal denervation - by ablation of the efferent and afferent renal sympathetic nerves - is a new approach to selectively denervate the kidneys from their sympathetic control. Renal denervation is associated with substantial and sustained blood pressure reduction (24 months), lowers central sympathetic outflow, and reduces whole-body norepinephrine spillover. The procedure is feasible and safe. The randomised controlled Symplicity-HTN-2 trial (results reported at AHA 2010, Nov 13-17) provides important information to determine the role of this new method for the treatment of drug resistant hypertension.

Interventionelle Behandlung der malignen Hypertonie – Pathophysiologie und klinische Daten

Overactivity of the sympathetic nervous system has been identified as one of the main contributors to the complex pathophysiology of resistant hypertension and the development of comorbidities. There is evidence that catheter-based renal sympathetic denervation can lower central sympathetic outflow, reduce whole-body norepinephrine spillover and is associated with substantial and sustained reduction in blood pressure. Interventional sympathetic renal denervation is easy achievable, safe and effective and might be helpful in the management of patients with therapy resistant hypertension. The results of the ongoing randomised controlled Symplicity HTN-2 trial are required to definitively determine the role of this new method.

Neuroadrenergic dysfunction in obesity: an overview of the effects of weight loss

The prevalence of obesity is rising to epidemic proportions worldwide, and in tandem so is that of type 2 diabetes. Neuroadrenergic abnormalities, comprising increased resting sympathetic nervous system activity and blunted sympathetic neural responsiveness are recognized features of metabolic syndrome obesity, which contribute importantly to both the pathophysiology and adverse clinical prognosis of this high-risk population. Weight loss is recommended as first-line treatment for obesity. This review examines the effects of nonpharmacological weight loss on sympathetic nervous system function under basal and stimulated conditions. Human weight loss trials show that even moderate weight reduction is accompanied by significant attenuation in resting whole-body norepinephrine spillover rate and muscle sympathetic nerve activity, an improvement in cardiac autonomic modulation, and a reversal of blunted sympathetic responsiveness at both peripheral and central nervous system levels. Recent findings underscore the relevance of insulin resistance in mediating blunted sympathetic responsiveness to endogenous hyperinsulinemia induced by glucose ingestion. Impaired insulin transport across the blood-brain barrier may be one mechanism mediating these effects. Weight loss reverses blunted sympathetic responsiveness to glucose, which has implications for postprandial energy expenditure and body weight homeostasis. The autonomic dysfunction of obesity is reversible with weight loss, highlighting the importance of lifestyle intervention as a key therapeutic modality.

Weight Loss May Reverse Blunted Sympathetic Neural Responsiveness to Glucose Ingestion in Obese Subjects With Metabolic Syndrome

OBJECTIVEThe purpose of this study was to examine the effects of weight loss on sympathetic nervous system responsiveness to glucose ingestion in obese subjects with metabolic syndrome, in whom such responses are reportedly blunted.RESEARCH DESIGN AND METHODSThirty four subjects, 19 insulin resistant and 15 insulin sensitive and aged 55 ± 1 years (mean ± SE) with BMI 31.6 ± 0.6 kg/m2, who fulfilled the Adult Treatment Panel III criteria for metabolic syndrome participated. Simultaneous measurements of whole-body norepinephrine spillover rate, calf blood flow, and intra-arterial blood pressure were made at times 0, 30, 60, 90, and 120 min postglucose (75 g). The experiment was repeated after a 3-month hypocaloric diet with or without an exercise program.RESULTSBody weight decreased by 8.1 ± 0.9 and 8.4 ± 1.1 kg and resting norepinephrine spillover by 94 ± 31 and 166 ± 58 ng/min (all P ≤ 0.01) in insulin-resistant and insulin-sensitive subjects, respectively. Weight loss was accompanied by a marked increase in sympathetic responsiveness after glucose but only in insulin-resistant subjects. In this subgroup, comparative increases in norepinephrine spillover rates at baseline and after weight loss averaged −3 ± 25 versus 73 ± 24 ng/min at 30 min (P = 0.039), 36 ± 21 versus 115 ± 28 ng/min at 60 min (P = 0.045), 9 ± 21 versus 179 ± 50 ng/min at 90 min (P < 0.001), and 40 ± 48 versus 106 ± 39 ng/min at 120 min (P = 0.24).CONCLUSIONSWeight loss reverses blunted sympathetic responsiveness to glucose ingestion in insulin-resistant subjects with metabolic syndrome, which is relevant to postprandial energy utilization and body weight homeostasis.

Blunted sympathetic neural response to oral glucose in obese subjects with the insulin-resistant metabolic syndrome

BackgroundGlucose ingestion stimulates sympathetic nervous system (SNS) activity in lean subjects, whereas blunted responses have been reported in the obese. ObjectiveThe objective was to investigate the impact of insulin resistance on the SNS response to oral glucose. DesignNineteen insulin-resistant (IR) and 12 insulin-sensitive (IS) obese subjects with the metabolic syndrome and matched for age, sex, and blood pressure participated. Simultaneous measurements of muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine spillover rate, cardiac baroreflex sensitivity (BRS), calf blood flow, and arterial blood pressure were made at baseline and 30, 60, 90, and 120 min after a 75-g glucose load. ResultsIR subjects had a higher insulin area under the curve from 0 to 120 min (AUC0–120: 13,468 ± 677 compared with 6399 ± 612 mU/L · min; P < 0.001), glucose AUC0–120 (P < 0.05), and resting MSNA (41 ± 3 compared with 31 ± 3 bursts/min; P = 0.03) than did IS subjects. MSNA and the norepinephrine spillover rate increased from baseline (by 29 ± 7% and 40 ± 13%, respectively; P ≤ 0.001 for both) in IS subjects after the glucose load. In contrast, there was a blunted and delayed sympathetic response in IR subjects. Cardiac BRS and diastolic blood pressure decreased, whereas calf blood flow increased after the glucose load and by a similar magnitude in both groups (P < 0.01). Body mass index, abdominal fat, and insulin AUC0–120 were independent (inverse) predictors of the SNS response. ConclusionsIR subjects with the metabolic syndrome have a blunted SNS response to oral glucose compared with IS subjects with the metabolic syndrome, which is related to central adiposity and the insulin response but not to differences in skeletal muscle vasodilation or BRS.

Altered Sympathetic Nervous Reactivity and Norepinephrine Transporter Expression in Patients With Postural Tachycardia Syndrome

Clinical observations in patients with postural tachycardia syndrome (POTS) suggest abnormal sympathetic nervous system activity and a dysfunction of the norepinephrine (NE) transporter (NET). We examined sympathetic nervous system responses to head-up tilt by combining NE plasma kinetics measurements and muscle sympathetic nerve activity recordings and by quantifying NET protein content in peripheral sympathetic nerves in patients with POTS compared with that in controls. POTS patients had an elevated heart rate during supine rest (81+/-2 bpm versus 66+/-2 bpm in healthy subjects [HS], P<0.01). Head-up tilt to 40 degrees induced a greater rise in heart rate in patients with POTS (+24+/-4 bpm versus +13+/-2 bpm in HS, P<0.001). During rest in the supine position, muscle sympathetic nerve activity, arterial NE concentration, and whole-body NE spillover to plasma were similar in both groups. Muscle sympathetic nerve activity response to head-up tilt was greater in the POTS group (+29+/-3 bursts/min in patients with POTS and +13+/-2 bursts/min in HS, P<0.001), but the NE spillover rise was similar in both groups (51% in the POTS subjects and 50% in the HS). Western blot analysis of NET protein extracted from forearm vein biopsies in patients with POTS and HS demonstrated a decrease in the expression of NET protein in patients with POTS. Patients with POTS exhibit a decrease in NET protein in their peripheral sympathetic nerves. Paradoxically, whole-body NE spillover to plasma during rest in the supine position and in response to head-up tilt is not altered despite excessive nerve firing rate in response to the head-up tilt.

Leptin-Receptor Polymorphisms Relate to Obesity through Blunted Leptin-Mediated Sympathetic Nerve Activation in a Caucasian Male Population

Leptin plays a key role in the regulation of body weight through the sympathetic nervous system; however, the contributions of leptin-receptor polymorphisms to obesity and sympathetic nerve activity have not been fully clarified. In the present study, we examined the relationships between leptin-receptor polymorphisms, plasma leptin and whole-body norepinephrine (NE) spillover as an index of sympathetic nerve activity in a Caucasian male cohort. In 129 young healthy normotensive men with a wide range of body mass index (BMI) (19.4-39.5 kg/m(2)), we measured leptin-receptor polymorphisms (Gln223Arg, Lys656Asn, and Lys109Arg), plasma leptin levels, whole-body NE spillover, whole-body NE clearance, BMI and blood pressure (BP) levels in the supine position after overnight fasting. Overweight-obese (BMI>or=25 kg/m(2)) subjects had significantly greater BMI, BP levels, plasma leptin and whole-body NE spillover compared to lean (BMI<25 kg/m(2)) subjects, but the NE clearance was similar. Overweight-obese subjects had significantly higher frequencies of the Arg223 allele and the Arg223 homozygous allele of Gln223Arg and the Asn656 allele of Lys656Asn compared to lean subjects. Subjects carrying the Arg223 homozygous or the Asn656 allele had higher levels of plasma leptin, BMI, waist circumference, and waist-to-hip ratio, but significantly less whole-body NE spillover, especially when they were also overweight-obese. BP levels and whole-body NE clearance were similar between subjects with and without the Arg223 homozygous or Asn656 allele. No differences were found in the distributions of the Arg109 allele of Lys109Arg polymorphism between nonobese and overweight-obese subjects. In addition, BMI, BP, plasma leptin levels, whole-body NE spillover and whole-body NE clearance were similar between those with and without the Arg109 allele. Together, these findings demonstrate that leptin-receptor polymorphisms were related to the incidence of obesity in a Caucasian male population. These polymorphisms were accompanied by high plasma leptin levels (leptin resistance) and lower whole-body plasma NE spillover (blunted sympathetic nerve activity). We therefore hypothesize that leptin-receptor play a role in the development of obesity through leptin resistance and blunted leptin-mediated sympathetic nerve activity.

Abstract 3559: β2-adrenoceptor Protein Expression Is Different Between Buffy Coat And Adipose Tissue

Background: Obesity and hypertension are associated with β2-adrenoceptor polymorphisms accompanying with heightened sympathetic nerve activity. In the present study we compared β2-adrenoceptor protein expression between buffy coats (white blood cells as a representive for whole-body) and abdominal subcutaneous fat to further evaluate the contributions of sympathetic nerve activity and β2-adrenoceptor to obesity and hypertension. Methods: In 17 obese normotensive Caucasian men (BMI≥30.0 kg/m2) and 8 age-matched lean Caucasian men (BMI&lt;25 kg/m2), we measured BMI, blood pressure (BP), whole-body plasma norepinephrine (NE) spillover, NE clearance, plasma leptin, and β2-adrenoceptor protein concentration and leptin receptor protein concentration in buffy coats and in abdominal subcutaneous adipose tissue. The β2-adrenoceptor protein expression and leptin receptor protein expression were analysed by Western blotting. Results: Obese subjects had significantly higher whole-body NE spillover (673±245 ng/mL vs. 431±156, P&lt;0.05), plasma leptin (15.2±4.3 ng/mL vs. 4.8±2.4, P&lt;0.01), and BP levels (P&lt;0.05) compared to lean subjects, but the whole-body NE clearance rate was similar. Obese subjects had significantly greater expression of β2-adrenoceptor protein in buffy coats (P&lt;0.05) compared to lean subjects, while they had significantly less β2-adrenoceptor protein expression in abdominal fat (P&lt;0.05). Leptin receptor protein expression in both buffy coats and abdominal fat were greater in obese subjects compared to lean subjects. Conclusions: Obese subjects had greater β2-adrenoceptor protein expression in buffy coats, but less β2-adrenoceptor protein expression in fat. This may suggest that blunted sympathetic nerve activity in adipose tissue (observed by less β2-adrenoceptor protein expression in fat) might relate to obesity and heightened sympathetic nerve activity in whole-body (observed by greater β2-adrenoceptor protein expression in buffy coats and higher NE spillover) may be linked to hypertension. The findings support the concept of selective leptin resistance. Sympathetic nerve activity and β2-adrenoceptor, not leptin, plays an important role is mechanisms of obesity and obesity-related hypertension.

Effects of intravenous brain natriuretic peptide on regional sympathetic activity in patients with chronic heart failure as compared with healthy control subjects

OBJECTIVESWe sought to assess the effects of brain natriuretic peptide (BNP) on systemic and regional sympathetic nervous activity (SNA) in both patients with congestive heart failure (CHF) and healthy control subjects.BACKGROUNDAlthough the response of SNA to atrial natriuretic peptide (ANP) has been well documented, the response of SNA to BNP is largely unknown.METHODSWe assessed cardiac and whole-body SNA using the norepinephrine (NE) tracer dilution method before and after infusion of two doses of BNP (3 and 15 ng/kg body weight per min) in 11 patients with stable CHF (ejection fraction 24 ± 2%) and 12 age-matched healthy control subjects. In addition, renal SNA and hemodynamic variables were assessed at baseline and after the higher BNP dose.RESULTSLow dose BNP did not change blood pressure or whole-body NE spillover, but reduced cardiac NE spillover in both groups by 32 ± 13 pmol/min (p < 0.05). In both groups, high dose BNP reduced pulmonary capillary pressure by 5 ± 1 mm Hg (p < 0.001) and mean arterial pressure by 6 ± 3 mm Hg (p < 0.05), without a concomitant increase in whole-body NE spillover; however, cardiac NE spillover returned to baseline levels. Renal NE spillover remained virtually unchanged in healthy control subjects (501 ± 120 to 564 ± 115 pmol/min), but was reduced in patients with CHF (976 ± 133 to 656 ± 127 pmol/min, p < 0.01).CONCLUSIONSOur results demonstrate a sympathoinhibitory effect of BNP. Cardiac sympathetic inhibition was observed at BNP concentrations within the physiologic range, whereas high dose BNP, when arterial and filling pressures fell and reflex sympathetic stimulation was expected, systemic and cardiac SNA equated to baseline values. There was inhibition of renal SNA in patients with CHF, but not in healthy control subjects. Whether this effect is specific to BNP or related to reduced filling pressure remains to be determined.

Attenuated cardiac sympathetic responsiveness during dynamic exercise in patients with heart failure.

Cardiac norepinephrine (NE) spillover is increased in patients with chronic heart failure. This elevation is partly due to augmented NE release but also to reduced capacity for cardiac NE removal processes. In patients with mild to moderate heart failure, it is not known whether the described alteration in cardiac sympathetic function also affects cardiac NE spillover during intense sympathetic activation and whether other organs respond in proportion to the heart. Twenty-two patients with heart failure and 15 age-matched healthy subjects were studied. Whole-body and regional (NE) spillovers from the heart and kidneys were assessed at baseline and during supine cycling exercise (10 minutes) with the use of steady-state infusions of tritiated NE (isotope dilution). Cardiac performance was evaluated by means of catheterization of the right side of the heart. Cardiac NE spillover was higher (P < .05) at baseline in the patient group than in healthy subjects, whereas renal and whole-body NE spillovers were similar between the study groups. During exercise, cardiac NE spillover increased 13-fold (P < .05) in healthy subjects but only 5-fold (P < .05) in the cardiac failure group, the latter reaching a lower peak value (P < .05). In contrast, there was no difference between the study groups in either renal or whole-body NE spillover responsiveness to exercise. Patients with mild to moderate heart failure demonstrated a selective attenuation of cardiac sympathetic responsiveness during dynamic exercise. This attenuation may convey reduced inotropic and chronotropic support to the failing heart.