Biomedical subjects

Gavin W Lambert

Publications and source records attributed to Gavin W Lambert.

9 recordsLinked to original sources

PubMed2006

Evidence for increased atrial sympathetic innervation in persistent human atrial fibrillation.

OBJECTIVE: In this study, we aimed to compare the level of atrial sympathetic innervation in human atrial fibrillation (AF) to that in sinus rhythm (SR). BACKGROUND: Histological studies of atrial tissue obtained from animals with experimentally induced AF indicate that sympathetic hyperinnervation could play a role in the pathogenesis of AF. METHODS: In 24 patients (12 in SR and 12 in AF) undergoing bypass surgery, we collected right atrial appendage tissue. In AF patients, left atrial appendage tissue was also acquired. The degree of sympathetic innervation was quantified by measuring the amount of staining for tyrosine hydroxylase (TH) and tissue norepinephrine (NE). In conjunction, nerve growth factor (NGF) mRNA expression was assessed by real-time polymerase chain reaction (PCR). Growth-associated protein 43 (GAP43) immunostaining was used to assess degree of new neural growth. RESULTS: When corrected for differences in tissue fibrosis, the expression of both TH (AF 0.45 +/- 0.1%, SR 0.09 +/- 0.03%, P = 0.02) and tissue NE (AF 358 +/- 49 pg/mg, SR 225 +/- 39 pg/mg, P = 0.04) was greater in atrial tissue of the AF cohort. The degree of atrial TH staining (P = 0.01) and NE content (P < 0.001) was also significantly greater in the right compared with left atrial samples in the AF cohort. There were no differences in NGF mRNA expression or GAP43 staining. CONCLUSION: This study provides evidence for the presence of heightened atrial sympathetic innervation in patients with persistent AF, suggesting autonomic remodeling may be part of atrial substrate for AF.

Adaptation, Physiological↗

PubMed2005

Effects of dietary weight loss on sympathetic activity and cardiac risk factors associated with the metabolic syndrome.

CONTEXT: Weight reduction, the first line treatment for the metabolic syndrome, improves insulin sensitivity and associated metabolic and cardiovascular abnormalities, but there is a paucity of data regarding its effect on sympathetic nervous system (SNS) activity in this clinical setting. OBJECTIVES: The objectives of this study were to test the hypothesis that dietary weight loss attenuates both insulin resistance and SNS activity and to examine the relationships between SNS activity and metabolic syndrome (MetS) components. DESIGN: This was a single-sample, repeated measures design study. SETTING: This study was performed at a tertiary referral center. PARTICIPANTS: Twenty-three MetS subjects (age, 58 +/- 2 yr; body mass index, 33.3 +/- 0.8 kg/m2; mean +/- sem) were studied. INTERVENTION: A hypocaloric modified Dietary Approaches to Stop Hypertension diet (26% fat, 22% protein, and 51% carbohydrate; 100 mmol/d sodium) was consumed for 3 months. MAIN OUTCOME MEASURES: The main outcome measures were postganglionic muscle sympathetic nerve activity (microneurography at a peroneal nerve), whole-body plasma norepinephrine spillover rate, spontaneous cardiac baroreflex function, and insulin sensitivity. RESULTS: The hypocaloric diet significantly reduced body weight by 7% and improved all MetS components. Norepinephrine spillover decreased from 877 +/- 180 to 503 +/- 39 ng/min (P = 0.005), and muscle sympathetic nerve activity decreased from 40.6 +/- 2.1 to 34.6 +/- 2.4 bursts/min (P = 0.01), whereas cardiac baroreflex sensitivity increased by 23.0 +/- 8.0% (P = 0.02). The change in the norepinephrine spillover rate correlated positively and independently with the change in plasma leptin concentration (r = 0.49; P = 0.03). CONCLUSION: Weight loss by a hypocaloric diet with moderate sodium restriction diminishes SNS activity in MetS subjects. This may be due to the consequences of decreased leptin concentration, enhanced insulin sensitivity, or improvements in cardiac baroreflex function.

Aged↗

PubMed2005

Paradoxical structural effects in the unilaterally denervated spontaneously hypertensive rat kidney.

OBJECTIVE: To determine the effects of chronic denervation on renal vascular structure and function in young adult spontaneously hypertensive rats (SHRs). DESIGN: Unilateral renal denervation (SHRUDx) or sham-operation (SHRS) was performed in SHRs at 6 weeks of age. At 10 weeks, rats were allocated to one of three procedures designed to examine renal vascular structure and function. A further group underwent bilateral renal denervation. METHODS: In SHRUDx or SHRS groups, either the kidneys were perfusion-fixed for stereological estimates of artery wall and lumen dimensions or for vascular casting to determine arteriole lumen diameters, or the rats were anaesthetized for estimation of glomerular capillary pressure. RESULTS: Chronic unilateral renal denervation had no significant effect on the development of hypertension between 6 and 10 weeks of age, as previously reported, but resulted in luminal narrowing of the interlobular artery (denervated group 52 +/- 2 mum, sham-operated group 64 +/- 1 mum; P < 0.01 for interaction between strain and treatment), without alterations in interlobular or arcuate artery wall dimensions. There were no significant effects on either afferent or efferent arteriole lumen diameters. Estimated glomerular capillary pressure was significantly lower in the denervated kidneys of SHRUDx (47 +/- 1 mmHg) compared with kidneys of the SHRS (50 +/- 1 mmHg; P < 0.04). Mean arterial pressure was approximately 12 mmHg lower in the bilaterally denervated SHRs than in the sham-operated SHRs. CONCLUSIONS: Although bilateral denervation attenuated the development of hypertension in SHRs, unilateral denervation did not, indicating that one neurally intact kidney was sufficient to drive the normal development of SHR hypertension, but only with apparent prohypertensive compensatory changes in the denervated kidney.

Animals↗

PubMed2004

Pre-weaning carvedilol treatment in spontaneously hypertensive rats.

Hypertension in spontaneously hypertensive rats (SHR) has been permanently abolished by aggressive treatment regimens targeted against the sympathetic nervous system and adrenal medulla, initiated during the pre-weaning period (guanethidine and nerve growth factor antiserum combined with either adrenal demedullation or prazosin treatment). To investigate the components of the sympatho-adrenal system involved, we treated pre-weaning SHR with the combined alpha(1)- and beta-adrenoceptor antagonist carvedilol (60 mg/kg/day s.c.; postnatal days 1-21). Carvedilol treatment significantly blocked adrenoceptors during the treatment period, delayed development (eye opening), reduced growth, and reduced arterial pressure and heart rate. However, there was only modest attenuation of the subsequent development of hypertension at 10 weeks of age (mean arterial pressure 129.5+/-1.8 versus 136.1+/-1.6 mm Hg in vehicle-treated littermates; P<0.05). Thus pre-weaning carvedilol treatment slightly but significantly attenuated the development of SHR hypertension at 10 weeks, suggesting that the profound antihypertensive effects of pre-weaning sympatho-adrenal ablation are attributable to factors other than alpha(1)- and beta-adrenoceptor-mediated effects of catecholamines during this period.

Adrenergic alpha-Antagonists↗

PubMed2003

Urotensin II acts centrally to increase epinephrine and ACTH release and cause potent inotropic and chronotropic actions.

Urotensin II is a small peptide whose receptor was recently identified in mammals as the orphan G protein-coupled receptor-14. The reported cardiovascular responses to systemic urotensin II administration are variable, and there is little detailed information on its central cardiovascular actions. We examined the cardiovascular and humoral actions of intracerebroventricular urotensin II (0.02 and 0.2 nmol/kg and vehicle) and intravenous urotensin II (2, 20, and 40 nmol/kg and vehicle) in conscious ewes previously surgically implanted with flow probes and intracerebroventricular guide tubes. Two hours after intracerebroventricular infusion of urotensin II (0.2 nmol/kg over 1 hour; n=5), heart rate (+56+/-13 beats per minute [bpm]), dF/dt (an index of cardiac contractility; +533+/-128 L x min(-1) x s(-1)), and cardiac output (+3.4+/-0.4 L/min) increased significantly compared with vehicle, as did renal, mesenteric, and iliac blood flows and conductances. Plasma epinephrine, adrenocorticotropic hormone, and glucose levels also increased dramatically (+753+/-166 pg/mL, +14.3+/-3.5 pmol/L, and +7.0+/-1.4 mmol/L, respectively). All of these variables remained elevated for up to 4 hours after infusion. In contrast, 1 hour after intravenous urotensin II (40 nmol/kg bolus; n=6), a sustained tachycardia (+25+/-8 bpm) ensued, but cardiac output, cardiac contractility, total peripheral conductance, and plasma glucose levels did not change significantly. In summary, this is the first study to show that urotensin II acts centrally to stimulate sympathoadrenal and pituitary-adrenal pathways, resulting in increased adrenocorticotropic hormone and epinephrine release and potent chronotropic and inotropic actions. In contrast, tachycardia was the only major response to intravenous urotensin II. These findings suggest that urotensin II is a novel stimulator of central pathways that mediate responses to alerting stimuli or stress.

Adrenocorticotropic Hormone↗

PubMed2002

Norepinephrine turnover is increased in suprabulbar subcortical brain regions and is related to whole-body sympathetic activity in human heart failure.

BACKGROUND: Although it is established that heightened sympathetic drive exists in congestive heart failure (CHF), the reflex processes by which this may occur and the sites in the central nervous system that may be responsible for mediating this process are not yet fully elucidated. METHODS AND RESULTS: Eight patients with moderate to severe CHF and 8 healthy control subjects underwent simultaneous arterial and bilateral internal jugular venous blood sampling and cerebral venous blood pool scanning for anatomical determination of the origin of internal jugular venous blood flow. We estimated sympathetic nervous activity by measuring total body norepinephrine (NE) spillover using radiotracer methodology and determined brain NE turnover by measuring the internal jugular overflow of NE and its lipophilic metabolites, 3-methoxy-4-hydroxyphenylglycol and 3,4-dihydroxyphenylglycol. Suprabulbar subcortical turnover of NE was significantly greater in CHF patients than in the healthy group (2.77 +/- 0.75 versus 0.66 +/- 0.40 nmol/min, P<0.05). There was a significant positive correlation between suprabulbar subcortical turnover of NE and total body NE spillover (r=0.62, P=0.01). CONCLUSIONS: This study, for the first time, demonstrates elevated suprabulbar subcortical noradrenergic activity in human CHF and identifies a positive correlation between this and the level of whole-body NE spillover. The findings suggest that the activation of noradrenergic neurons projecting rostrally from the brain stem mediates sympathetic nervous stimulation in CHF.

Blood Flow Velocity↗

PubMed2002

Sympathetic and cardiac baroreflex function in panic disorder.

BACKGROUND: Recent reports have demonstrated increased cardiac risk, and an association with essential hypertension in patients with panic disorder. The cause is not known, but possibly involves sympathetic nervous activation. In this study, we evaluated the arterial baroreflex control of vascular sympathetic nervous outflow and cardiac baroreflex function in panic disorder patients. METHODS AND RESULTS: We studied nine patients suffering from panic disorder and ten healthy subjects. Microneurographic recording of muscle sympathetic nerve activity (MSNA) was made with simultaneous recording of blood pressure (BP) and electrocardiogram (ECG). The relationship between MSNA and spontaneous diastolic BP (DBP) changes was assessed at rest and was defined as the arterial baroreflex control of MSNA. Cardiac baroreflex function was assessed using the sequence method. Anxiety was assessed using Spielberger's anxiety state and trait inventory. The slopes of the relationship between MSNA and DBP were more negative (steeper) in the panic disorder group compared with the control subjects (-5.97 +/- 0.45 versus -3.06 +/- 0.43 bursts/100 heart beats per mmHg, P < 0.001). Panic disorder patients had significantly higher state and trait anxiety scores. The slope of the relationship between MSNA and diastolic BP was significantly related to the trait anxiety of the subjects. There was no difference between the cardiac baroreflex sensitivity between the two groups. CONCLUSION: Patients with panic disorder exhibit enhanced reflex gain of the arterial baroreflex control of MSNA but no change in the cardiac baroreflex. While any clinical significance this observation might have in relation to increased cardiac risk in panic disorder, or to concordance with essential hypertension, remains to be elucidated, increased reactivity of vasoconstricting sympathetic nerves may be a trait characteristic in this cohort.

Adult↗

PubMed2002

Essential role for the lymphostromal plasma membrane Ly-6 superfamily molecule thymic shared antigen 1 in development of the embryonic adrenal gland.

Thymic shared antigen 1 (TSA-1) is a plasma membrane protein of the Ly-6 superfamily expressed on thymocytes, thymic stromal cells, and other cells of the hematopoietic system. TSA-1 is also expressed in other nonhematopoietic tissues, in particular, embryonic and adult adrenal glands. To address the function of TSA-1, we generated mutant mice in which TSA-1 expression was inactivated by gene targeting. Here we show that deletion of both TSA-1 alleles results in abnormal adrenal gland development and midgestational lethality due to cardiac abnormalities. We also report that TSA-1-deficient adrenal glands have significantly reduced levels of the catecholamines noradrenaline and adrenaline. We conclude that TSA-1 is required for normal embryonic development but that deletion of its expression does not obviously impair lymphoid development.

Adrenal Glands↗

PubMed2002

Noradrenaline, but not neuropeptide Y, is elevated in cerebrospinal fluid from the third cerebral ventricle following audiovisual stress in gonadectomised rams and ewes.

There are sex differences in the activation of the hypothalamo-pituitary-adrenal axis in response to stress, but the source of these differences is unknown. The hypothalamo-pituitary-adrenal axis is regulated by corticotropin-releasing hormone and arginine-vasopressin neurones located in the paraventricular nucleus and these, in turn, are regulated by neural systems that include afferent noradrenergic and neuropeptide Y (NPY)-producing neural pathways. We tested the hypothesis that concentrations of noradrenaline and NPY will be elevated in cerebrospinal fluid (CSF) sampled from the third cerebral ventricle in response to stress, and these responses will differ in males and females. We collected concurrent samples of CSF (1 ml) from the third ventricle and blood (5 ml) from the jugular vein from gonadectomised rams (n = 7) and ewes (n = 5) at 10-min intervals for 3 h. This procedure was conducted on a day when no stress was imposed and on a day when audiovisual stress was imposed for 5 min after 1 h of sampling. Following the audiovisual stress, plasma concentrations of cortisol and CSF concentrations of noradrenaline were elevated (p < 0.05), but CSF concentrations of NPY did not change. Adrenaline was not detected in samples of CSF. The rise in plasma cortisol following the stress was greater (p < 0.05) in ewes than in rams, but there were no sex differences in the rise in noradrenaline. Basal concentrations of NPY in the CSF were higher (p < 0.05) in rams than in ewes. We conclude that the sex differences in the stress-induced activity of the hypothalamo-pituitary-adrenal axis in sheep are not likely to be due to differences in the level of noradrenergic and/or NPY input to the hypothalamus.

Acoustic Stimulation↗