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ABSTRACT: BACKGROUND Dyslipidemia is one the most well-established risk factors for cardiovascular disease development. Moreover, hypercholesterolemia and plasma cholesterol level in the high to normal range are established triggers for impairment in endothelial function. Evidence indicates that endothelial function is closely linked with sympathetic nervous activity in healthy individuals. We therefore investigated whether both endothelial and sympathetic functions may be impaired in young females with abnormal plasma cholesterol levels. METHODS Baseline endothelial function (digital pulse amplitude) and muscle sympathetic nervous activity (microneurography) were retrospectively analyzed in 14 young healthy females with dyslipidemia as indicated by total cholesterol ≥197mg/dL, high-density lipoprotein ≤39mg/dL, or low-density lipoprotein >116mg/dL, and in 13 females with lipids in the healthy range. RESULTS Subjects with dyslipidemia had significantly impaired endothelial function compared to those with a normal cholesterol profile (reactive hyperemia index; 1.61±0.10 vs. 2.32±0.14, P < 0.001), increased muscle sympathetic nervous activity (after adjusting for body mass and age, 36±3 vs. 27±3 bursts per 100 heartbeats, P = 0.049) and elevated high-sensitivity C-reactive protein (4.13±0.77 vs. 1.92±0.61mg/L, P = 0.03). DISCUSSION Our results indicate that young healthy females with dyslipidemia present with a strong impairment of endothelial function and increased sympathetic drive. The sympathetic activation observed in the subjects with an elevated cholesterol profile may play a role in the development of cardiovascular disease development.
American Journal of Hypertension 02/2013; 26(2):250-6. · 3.18 Impact Factor
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ABSTRACT: BACKGROUND: Children with transposition of the great arteries, in whom an arterial switch operation (ASO) is performed, have been shown to have an increased incidence of sudden death, which may be due to cardiac autonomic imbalance and repolarisation instability. We hypothesised that i) cardiac norepinephrine (NE) kinetics and ii) arterial baroreflex sensitivity (BRS), reflecting sympathetic activity and vagal function respectively, are altered in this group. METHODS AND RESULTS: 17 children (15.8±1.5years of age) with ASO-surgery in the neonatal period were studied. 17 had cardiac BRS assessed by spontaneous fluctuations of systolic blood pressure and RR-interval, and repolarisation was measured as QT variability index. Matched healthy subjects were controls. Cardiac vagal function and repolarisation pattern were unchanged following ASO-surgery. At cardiac catheterisation, we infused tritiated NE in 8 of these children to examine total body and cardiac sympathetic function at baseline and following 5min of adenosine infusion to induce reflex sympathetic activation. Blood was sampled simultaneously from the aorta and coronary sinus. Cardiac fractional extraction of ([3H])NE was substantially lower in operated children, being 56±10 vs. 82±9% (p=0.0001). Following i.v. adenosine in the operated group, NE total body spillover doubled vs. baseline (p<0.002) and the coronary venous-arterial concentration gradient of ([3H])dihydroxyphenylglycol increased 4-fold (p=0.04). CONCLUSIONS: Arterial switch operation performed neonatally appears to leave cardiac vagal function intact and, although cardiac sympathetic activation in response to adenosine occurs, cardiac neuronal NE reuptake is impaired. This may be pro-arrhythmic by reducing removal capacity of NE from the cardiac synaptic cleft.
International journal of cardiology 01/2013; · 7.08 Impact Factor
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Hypertension 12/2012; · 6.21 Impact Factor
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Helen Kiriazis,
Nicole L Jennings,
Pamela Davern, Gavin Lambert,
Yidan Su,
Terence Pang,
Xin Du,
Luisa La Greca,
Geoffrey A Head,
Anthony J Hannan,
Xiao-Jun Du
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ABSTRACT: Huntington's disease (HD) is a heritable neurodegenerative disorder with heart disease implicated as one major cause of death. While the responsible mechanism remains unknown, autonomic nervous system (ANS) dysfunction may play a role. We studied the cardiac phenotype in R6/1 transgenic mice at early (3-month-old) and advanced (7-month-old) stages of HD. While exhibiting a modest reduction in cardiomyocyte diameter, R6/1 mice had preserved baseline cardiac function. Conscious ECG telemetry revealed absence of 24-hour variation of heart rate (HR) and higher HR levels than wild-type littermates in young but not older R6/1 mice. Older R6/1 mice had increased plasma level of noradrenaline which was associated with reduced cardiac noradrenaline content. R6/1 mice also had unstable R-R intervals that were reversed following atropine treatment, suggesting parasympathetic nervous activation, and developed brady- and tachy-arrhythmias, including paroxysmal atrial fibrillation and sudden death. c-Fos immunohistochemistry revealed greater numbers of active neurons in ANS-regulatory regions of R6/1 brains. Collectively, R6/1 mice exhibit profound ANS-cardiac dysfunction involving both sympathetic and parasympathetic limbs that may be related to altered central autonomic pathways and lead to cardiac arrhythmias and sudden death.
The Journal of Physiology 08/2012; · 4.72 Impact Factor
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ABSTRACT: The postural tachycardia syndrome (POTS) has multiple symptoms, chief among which are tachycardia, weakness, and recurrent blackouts while standing. Previous research has implicated dysfunction of the norepinephrine transporter. A coding mutation in the norepinephrine transporter gene (SLC6A2) sequence has been reported in 1 family kindred only. The goal of the present study was to further characterize the role and regulation of the SLC6A2 gene in POTS.
Sympathetic nervous system responses to head-up tilt were examined by combining norepinephrine plasma kinetics measurements and muscle sympathetic nerve activity recordings in patients with POTS compared with that in controls. The SLC6A2 gene sequence was investigated in leukocytes from POTS patients and healthy controls using single nucleotide polymorphisms genotyping, bisulphite sequencing, and chromatin immunoprecipitation assays for histone modifications and binding of the transcriptional regulatory complex, methyl-CpG binding protein 2. The expression of norepinephrine transporter was lower in POTS patients compared with healthy volunteers. In the absence of altered SLC6A2 gene sequence or promoter methylation, this reduced expression was directly correlated with chromatin modifications.
We propose that chromatin-modifying events associated with SLC6A2 gene suppression may constitute a mechanism of POTS.
Arteriosclerosis Thrombosis and Vascular Biology 06/2012; 32(8):1910-6. · 6.37 Impact Factor
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Elisabeth Lambert,
Yves d'Udekem,
Michael Cheung,
Carolina Ika Sari,
Julia Inman,
Anna Ahimastos,
Nina Eikelis,
Atul Pathak,
Ingrid King,
Leanne Grigg,
Markus Schlaich, Gavin Lambert
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ABSTRACT: BACKGROUND: Patients with Fontan circulation are known to have increased systemic vascular resistance (SVR) however the underlying mechanisms are uncertain. We therefore further investigated the haemodynamic and vascular profile of Fontan patients. METHODS: Eighteen adult subjects aged 25±1years who had undergone the Fontan procedure in their childhood (at age 6±1years) and not in clinical failure at the time of study were assessed for: 1) autonomic function, including direct muscle sympathetic nerve activity (MSNA) recording and sympathetic and cardiac baroreflex function, 2) endothelial function by means of reactive hyperaemia using the Endopat peripheral arterial tonometry (PAT) technique and plasma endothelin concentration and gene expression, 3) pulse wave reflections (digital and central augmentation index (AI)) and 4) haemodynamic changes to head-up tilt. Data were compared to that obtained in a group of 23 age- and weight-matched healthy subjects. RESULTS: Fontan participants presented with elevated MSNA compared with controls (40±5 vs 27±3 bursts per 100 heartbeats), decreased cardiac baroreflex function (16.0±3.3 versus 30.9±3.7ms·mm Hg(-1)), normal sympathetic baroreflex function, decreased endothelial function (PAT ratio=0.35±0.09 vs 0.77±0.11), and increased digital (5.9±3.0% vs -9.7±2.3%) and central (1.4±2.7% vs -10.2±3.9%) AI. Ten minute head-up tilt (60°) induced greater reductions in cardiac output (CO) and stroke volume (SV) in Fontan patients (CO: -28% vs -11%, SV: -40% vs -25%). CONCLUSION: Adult Fontan patients have increased MSNA and altered endothelial function that are likely to contribute to their known increased SVR. Therapies aiming at reducing the peripheral resistances should target endothelial function and sympathetic activity.
International journal of cardiology 04/2012; · 7.08 Impact Factor
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ABSTRACT: In humans, sympathetic activity is commonly assessed by measuring the efferent traffic in the peroneal nerve. The firing activity is the sum of several active neurons, which have the tendency to fire together in a bursting manner. While the estimation of overall sympathetic nervous activity using this multiunit recording approach has advanced our understanding of sympathetic regulation in health and disease no information is gained regarding the underling mechanisms generating the bursts of sympathetic activity. The introduction of single-unit recording has been a major step forward, enabling the examination of specific sympathetic firing patterns in diverse clinical conditions. Disturbances in sympathetic nerve firing, including high firing probabilities, high firing rates or high incidence of multiple firing, or a combination of both may impact on noradrenaline release and effector response, and therefore have clinical implications with regards to the development and progression of target organ damage. Understanding the mechanisms and consequences of specific firing patterns would permit the development of therapeutic strategies targeting these nuances of sympathetic overdrive.
Frontiers in physiology. 01/2012; 3:11.
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ABSTRACT: 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 (>100 mm Hg) or low (70-100 mm Hg). We investigated neural circulatory control in these 2 phenotypes.
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.
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.
Circulation Arrhythmia and Electrophysiology 08/2011; 4(5):711-8. · 6.46 Impact Factor
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Elisabeth Lambert, Gavin Lambert,
Carolina Ika-Sari,
Tye Dawood,
Katie Lee,
Reena Chopra,
Nora Straznicky,
Nina Eikelis,
Sara Drew,
Alan Tilbrook,
John Dixon,
Murray Esler,
Markus P Schlaich
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ABSTRACT: Ghrelin is a growth hormone-releasing peptide secreted by the stomach with potent effects on appetite. Experimental and clinical studies indicate that ghrelin also influences cardiovascular regulation and metabolic function and mediates behavioral responses to stress. We investigated the effects of ghrelin on blood pressure (BP), sympathetic nervous system activity, and mental stress responses in lean (n=13) and overweight or obese (n=13) individuals. Subjects received an intravenous infusion of human ghrelin (5 pmol/kg per minute for 1 hour) and saline in a randomized fashion. Ghrelin decreased systolic (-6 and -11 mm Hg) and diastolic BP (-8 mm Hg for both), increased muscle sympathetic nervous system activity (18±2 to 28±3 bursts per min, P<0.05 and from 21±2 to 32±3 bursts per min, P<0.001) in lean and overweight or obese subjects, respectively, without a significant change in heart rate, calf blood flow, or vascular resistance. Ghrelin induced a rise in plasma glucose concentration in lean individuals (P<0.05) and increased cortisol levels in both groups (P<0.05). Stress induced a significant change in mean BP (+22 and +27 mm Hg), heart rate (+36 and +29 bpm), and muscle sympathetic nervous system activity (+6.1±1.6 and +6.8±2.7 bursts per min) during saline infusion in lean and overweight or obese subjects, respectively. During ghrelin infusion, the changes in BP and muscle sympathetic nerve activity in response to stress were significantly reduced in both groups (P<0.05). In conclusion, ghrelin exerts unique effects in that it reduces BP and increases muscle sympathetic nervous system activity and blunts cardiovascular responses to mental stress. These responses may represent a combination of peripheral (baroreflex-mediated) and central effects of ghrelin.
Hypertension 07/2011; 58(1):43-50. · 6.21 Impact Factor
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ABSTRACT: The aim of this study was to assess cardiac ventricular repolarization in patients with postural tachycardia syndrome (POTS) and further the possible link between ventricular repolarization and sympathetic nervous system activity.
We recorded body surface ECGs together with plasma noradrenaline (NE) spillover, and muscle sympathetic nerve activity (MSNA) in twelve healthy control subjects (CON; 5 males; age: 23±2 yrs) and 13 subjects with postural tachycardia syndrome (POTS; 4 males; 32±13 yrs) during graded head-up tilt (0°-20°-30°-40°). Ventricular repolarization was assessed by computing various measures of beat-to-beat QT interval variability and T wave amplitude.
In patients with POTS, baseline heart rates were higher and MSNA increases during tilt were more pronounced than in CON. None of the QT variability measures was significantly affected by tilt or different between CON and POTS when corrected for heart rate. Contrary, the T wave amplitude flattened due to tilt (p<0.001) and this effect was significantly more pronounced in POTS (32% at 40°) than in CON (21% at 40°; p=0.03).
Beat-to-beat variability of the QT interval is normal in patients with POTS. However, significantly more attenuated T waves during head-up tilt together with elevated MSNA levels suggest increased sympathetic outflow to the ventricular myocardium in patients with POTS.
Monitoring of the T wave during tilt test may provide a non-invasive tool for assessing excessive sympathetic outflow to the ventricular myocardium.
Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 02/2011; 122(2):405-9. · 3.12 Impact Factor
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Journal of hypertension 02/2011; 29(2):189-93. · 4.02 Impact Factor
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Markus P Schlaich,
Nora Straznicky,
Mariee Grima,
Carolina Ika-Sari,
Tye Dawood,
Felix Mahfoud,
Elisabeth Lambert,
Reena Chopra,
Flora Socratous,
Sarah Hennebry,
Nina Eikelis,
Michael Böhm,
Henry Krum, Gavin Lambert,
Murray D Esler,
Paul A Sobotka
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ABSTRACT: Polycystic ovary syndrome (PCOS) is associated with sympathetic nervous system activation, insulin resistance, and blood pressure elevation. Renal nerve ablation has been demonstrated to reduce sympathetic outflow and improve blood pressure control. Here we report on the effects of renal denervation on hemodynamic, metabolic, and renal parameters in two obese PCOS patients with hypertension.
Sympathetic nerve activity was assessed at baseline using microneurography and norepinephrine spillover measurements. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. Measurements of cystatin-C, creatinine clearance, and urinary albumin-creatinine ratio were also obtained. All measurements were repeated 3 months after bilateral renal denervation achieved via percutaneous endovascular radiofrequency ablation.
Muscle sympathetic nerve activity and whole body norepinephrine spillover were substantially elevated at baseline in both patients by approximately 2.5-3-fold. Bilateral renal nerve ablation reduced both indices of sympathetic nerve activity. This was associated with moderate reductions in blood pressure and a substantial improvement in insulin sensitivity by approximately 17.5% in the absence of weight changes at 3-month follow-up. Glomerular hyperfiltration and urinary albumin excretion were also reduced.
These findings corroborate the relevance of sympathetic activation in PCOS and suggest that renal denervation exerts beneficial effects not only on blood pressure control but also on insulin sensitivity, renal, and endocrine abnormalities characteristic of PCOS.
Journal of hypertension 02/2011; 29(5):991-6. · 4.02 Impact Factor
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ABSTRACT: Elevated QT interval variability is a predictor of malignant ventricular arrhythmia, but the underlying mechanisms are incompletely understood. A recent study in dogs with pacing-induced heart failure suggests that QT variability is linked to cardiac sympathetic nerve activity. The aim of this study was to determine whether increased cardiac sympathetic activity is associated with increased beat-to-beat QT interval variability in patients with essential hypertension. We recorded resting norepinephrine (NE) spillover into the coronary sinus and single-lead, short-term, high-resolution, body-surface ECG in 23 patients with essential hypertension and 9 normotensive control subjects. To assess beat-to-beat QT interval variability, we calculated the overall QT variability (QTVN) as well as the QT variability index (QTVi). Cardiac NE spillover (12.2 ± 6.5 vs. 20.7 ± 14.7, P = 0.03) and QTVi (-1.75 ± 0.36 vs. -1.42 ± 0.50, P = 0.05) were significantly increased in hypertensive patients compared with normotensive subjects. QTVN was significantly correlated with cardiac NE spillover (r(2) = 0.31, P = 0.001), with RR variability (r(2) = 0.20, P = 0.008), and with systolic blood pressure (r(2) = 0.16, P = 0.02). Linear regression analysis identified the former two as independent predictors of QTVN. In conclusion, elevated repolarization lability is directly associated with sympathetic cardiac activation in patients with essential hypertension.
AJP Heart and Circulatory Physiology 01/2011; 300(4):H1412-7. · 3.71 Impact Factor
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Cell cycle (Georgetown, Tex.) 11/2010; 9(22):4600-1. · 5.36 Impact Factor
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Hypertension 06/2010; 55(6):e20; author reply e21. · 6.21 Impact Factor
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Journal of hypertension 04/2010; 28(4):637-43. · 4.02 Impact Factor
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Journal of hypertension 04/2010; 28(4):676-8. · 4.02 Impact Factor
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ABSTRACT: Recent evidence indicates that stress is associated with obesity, hypertension and metabolic abnormalities. Stress pathways, including both the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, are activated in individuals with the metabolic syndrome. In order to gain some insight into the relation between sympathetic nervous system activation, metabolic profile and stress, we examined the pattern of sympathetic nervous firing in eight women and 17 men with the metabolic syndrome and elevated blood pressure (BP) in relation to their underlying psychological stress.
Both multiunit and single-unit muscle sympathetic nerve activity (MSNA) were recorded by using the technique of microneurography and psychological stress was assessed by Spielberger's State and Trait Anxiety scores and the Beck Depression Inventory II (BDI-II). Women had higher cholesterol levels, higher depressive symptom scores and similar multiunit MSNA compared with the men but displayed a disturbed firing pattern of sympathetic activity as indicated by a higher incidence of multiple spikes per burst (P < 0.05). In all individuals, regression analysis after adjustment for sex indicated that the single-unit sympathetic nerve-firing pattern did not correlate with any aspect of the metabolic profile; however it was significantly associated with anxiety state and trait and the affective component of the BDI scores. In particular, higher incidence of multiple firing (more than two spikes) during a sympathetic neural burst was associated with higher trait anxiety score (R = 0.557, P = 0.004) and higher affective depressive symptoms (R = 0.517, P = 0.008). Somatic symptoms bore no association with the sympathetic firing pattern.
These results suggest that chronic mental stress modulates the pattern of sympathetic activity, which, in turn, may confer greater cardiovascular risk on individuals with the metabolic syndrome and elevated BP.
Journal of hypertension 02/2010; 28(3):543-50. · 4.02 Impact Factor
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ABSTRACT: 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.
Current opinion in lipidology 10/2009; 21(1):21-30. · 6.13 Impact Factor
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ABSTRACT: We examined whether a specific increase in sympathetic nervous system (SNS) activity accounts for the enhanced depressor response to ganglion blockade in angiotensin II (AngII)-induced hypertension in rabbits or whether it reflects a general increased sensitivity of arterial pressure to vasodilatation.
Rabbits were renal denervated or sham-operated and 2 weeks later AngII (50 ng/kg per min) infusion commenced. Mean arterial pressure (MAP) responses to ganglion blockade (pentolinium) and vasodilators nitroprusside and adenosine were measured 2-4 weeks later.
Basal MAP was 74 +/- 2 mmHg and maximum hypotensive responses to pentolinium, nitroprusside and adenosine were -17 +/- 2, -17 +/- 1 and -21 +/- 2 mmHg. AngII increased MAP similarly in intact and renal denervated rabbits (+25 +/- 4 mmHg and +31 +/- 4 mmHg, respectively). In intact rabbits, depressor responses to pentolinium were augmented by 75% during AngII infusion but responses to vasodilators also increased by 73-106% suggesting general augmentation of vascular reactivity rather than a specific increase in SNS neural activity. Consistent with this notion, total noradrenaline spillover was similar in normal and AngII-treated rabbits. In renal denervated rabbits, AngII enhanced depressor responses to vasodilators but not pentolinium, suggesting that sympathetic activity may be reduced by AngII hypertension when renal nerves are absent. In anaesthetized rabbits, methoxamine-induced decreases in hindlimb vascular conductance were greater in hypertensive than normotensive rabbits suggesting the presence of vascular hypertrophy of sufficient magnitude to explain increased responses to ganglion blockade and vasodilators.
Enhanced depressor responses to ganglion blockade in AngII hypertension do not reflect augmented SNS activity, but rather, augmented sympathetic vasoconstriction mediated by a vascular amplifier effect.
Journal of hypertension 07/2009; 27(9):1838-48. · 4.02 Impact Factor
