Decreased Plasma Norepinephrine Research Articles

Oxidative Products of Catecholamines During Heightened Sympathetic Activity Due to Congestive Heart Failure: Possible Role of Antioxidants.

The past several decades have shown the functional status of sympathetic activity in congestive heart failure. The results, particularly through clinical and basic studies in heart failure, indicate an increased sympathetic neural activity. The definitive and compelling evidence of the involvement of catecholamines is the demonstration that many drugs that are therapeutically useful in the treatment of heart failure also affect the sympathetic nervous system at various sites, including its synthesis, release and uptake of catecholamines and a decreased plasma norepinephrine level. Although it is not surprising that the sympathetic system is altered as cardiac function is compromised in heart failure, it now appears that this system may overreact in chronic situations. The detrimental cardiovascular problems result in the production of aminochrome and free radicals. Antioxidant therapy to target the production of aminochrome from autooxidation of catecholamines should provide an insight into the future therapeutic goal in situations like congestive heart failure.

Optimal Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea Reduces Daytime Resting Heart Rate in Prediabetes: A Randomized Controlled Study.

BackgroundIt has been widely recognized that obstructive sleep apnea (OSA) is linked to cardiovascular disease. Yet, randomized controlled studies failed to demonstrate a clear cardiovascular benefit from OSA treatment, mainly because of poor adherence to continuous positive airway pressure (CPAP). To date, no prior study has assessed the effect of CPAP treatment on daytime resting heart rate, a strong predictor of adverse cardiovascular outcomes and mortality.Methods and ResultsWe conducted a randomized controlled study in 39 participants with OSA and prediabetes, who received either in‐laboratory all‐night (ie, optimal) CPAP or an oral placebo for 2 weeks. During daytime, participants continued daily activities outside the laboratory. Resting heart rate was continuously assessed over 19 consecutive days and nights using an ambulatory device consisting of a single‐lead ECG and triaxis accelerometer. Compared with placebo, CPAP reduced daytime resting heart rate (treatment difference, −4.1 beats/min; 95% CI, −6.5 to −1.7 beats/min; P=0.002). The magnitude of reduction in daytime resting heart rate after treatment significantly correlated with the magnitude of decrease in plasma norepinephrine, a marker of sympathetic activity (r=0.44; P=0.02), and the magnitude of decrease in OSA severity (ie, apnea‐hypopnea index [r=0.48; P=0.005], oxygen desaturation index [r=0.50; P=0.003], and microarousal index [r=0.57; P<0.001]).ConclusionsThis proof‐of‐concept randomized controlled study demonstrates, for the first time, that CPAP treatment, when optimally used at night, reduces resting heart rate during the day, and therefore has positive cardiovascular carry over effects. These findings suggest that better identification and treatment of OSA may have important clinical implications for cardiovascular disease prevention.RegistrationURL: https:/// www.clini​caltr​ials.gov; Unique identifier: NCT01156116.

Cardiovascular Benefits of Extended-Time Nocturnal Hemodialysis.

Hemodialysis (HD) remains the most utilized treatment for End-Stage Kidney Disease (ESKD) globally, mainly as conventional HD administered in 4 h sessions thrice weekly. Despite advances in HD delivery, patients with ESKD carry a heavy cardiovascular morbidity and mortality burden. This is associated with cardiac remodeling, left ventricular hypertrophy (LVH), myocardial stunning, hypertension, decreased heart rate variability, sleep apnea, coronary calcification and endothelial dysfunction. Therefore, intensive HD regimens closer to renal physiology were developed. They include longer, more frequent dialysis or both. Among them, Nocturnal Hemodialysis (NHD), carried out at night while asleep, provides efficient dialysis without excessive interference with daily activities. This regimen is closer to the physiology of the native kidneys. By providing increased clearance of small and middle molecular weight molecules, NHD can ameliorate uremic symptoms, control hyperphosphatemia and improve quality of life by allowing a liberal diet and free time during the day. Lastly, it improves reproductive biology leading to successful pregnancies. Conversion from conventional to NHD is followed by improved blood pressure control with fewer medications, regression of LVH, improved LV function, improved sleep apnea, and stabilization of coronary calcifications. These beneficial effects have been associated, among others, with better extracellular fluid volume control, improved endothelial- dependent vasodilation, decreased total peripheral resistance, decreased plasma norepinephrine levels and restoration of heart rate variability. Some of these effects represent improvements in outcomes used as surrogates of hard outcomes related to cardiovascular morbidity and mortality. In this review, we consider the cardiovascular effects of NHD.

Are the cardiovascular side effects of bevacizumab caused by autonomic nervous system toxicity?

429 Background: Bevacizumab, a monoclonal antibody that inhibits the activity of vascular endothelial growth factor, has demonstrated activity against several malignancies. Reported adverse effects include hypertension, endothelial dysfunction, and heart failure. Animal models have suggested ANS toxicity as the mechanism. This pilot study investigates the effects of bevacizumab on short and long-term ANS function using a pre-post intervention design protocol. We report on the acute effects herein. Methods: Patients were recruited among those starting bevacizumab for colon cancer. A 10-minute ECG was recorded prior to, during, and following a first dose and analysed for heart rate variability (HRV), a marker of ANS dysfunction. The HRV values were compared using paired t-tests and repeated measures ANOVA. Plasma hormones were drawn before and after infusion and compared using paired t-tests. Results: Nine patients without a cardiac history were tested. Mean age was 63 years and 5 were male. All were in sinus rhythm with normal systolic function by echo. The Table reports changes in HRV indices and plasma hormones. Conclusions: Acute administration of bevacizumab produced a statistically significant decrease in plasma aldosterone and was associated with a trend towards decreases in plasma norepinephrine and the low/high frequency domain ratio of HRV. These changes may be signs of an early ANS imbalance. Both a larger patient series and longer follow-up are planned to characterize the effects of bevacizumab on the ANS. [Table: see text]

Blood pressure and neurohormonal responses to renal nerve ablation in treatment-resistant hypertension

Catheter-based renal nerve ablation is a novel therapy for treatment-resistant hypertension. Although the precise mechanism is unknown, a reduction in global sympathetic tone and renal sympathetic tone, potentially resulting in a decrease in renin, may account for the antihypertensive effect. In 17 patients (mean age 51.2 ± 9.4 years) with treatment-resistant hypertension (antihypertensive drugs 4.7 ± 1.3), office and ambulatory blood pressure (BP) measurements and circulating concentrations of catecholamines, renin, aldosterone and endothelin-1 were measured at baseline and 6 and 12 months after ablation. Office BP was measured for 1 h at 5-min intervals using an automatic device. Office BP (164.7 ± 27.7/102.3 ± 19.3 mmHg) decreased by 5.7 ± 18.8 mmHg (P = 0.11) systolic and by 2.6 ± 10.7 (P = 0.33) mmHg diastolic after 6 months, whereas after 12 months decreases were 12.7 ± 16.0 mmHg (P = 0.007) and 7.3 ± 11.9 mmHg (P = 0.02). Heart rate, 24-h (151.8 ± 12.6/94.2 ± 10.3 mmHg) and day and night ambulatory BP did not change, after either 6 or 12 months. Of the neurohormones, only plasma noradrenaline (397 pg/ml, interquartile range 268-461 pg/ml) decreased by 128 ± 167 pg/ml (P = 0.008) after 6 months, whereas other neurohormones remained unchanged. Forty-seven percent of patients had at least 10 mmHg decrease in 24-h ambulatory SBP. In these responders, office and ambulatory BP tended to be higher than in nonresponders, but neurohormones or changes after ablation between responders and nonresponders did not differ. Renal nerve ablation in treatment-resistant hypertensive patients had a moderate effect on office BP and is associated with a decrease in plasma noradrenaline but not in renin. The absent decrease in renin may imply that the intensity of efferent renal denervation achieved with the number of ablations applied was insufficient.

Chronic Therapy With a Partial Adenosine A1-Receptor Agonist Improves Left Ventricular Function and Remodeling in Dogs With Advanced Heart Failure

Adenosine elicits cardioprotection through A1-receptor activation. Therapy with adenosine A1-receptor agonists, however, is limited by undesirable actions of full agonism, such as bradycardia. This study examined the effects of capadenoson (CAP), a partial adenosine A1-receptor agonist, on left ventricular (LV) function and remodeling in dogs with heart failure. Twelve dogs with microembolization-induced heart failure were randomized to 12 weeks oral therapy with CAP (7.5 mg BID; n=6) or to no therapy (control; n=6). LV end-diastolic and end-systolic volumes, ejection fraction, plasma norepinephrine, and n-terminal pro-brain natriuretic peptide were measured before (pre) and 1 and 12 weeks after therapy (post). LV tissue obtained at post was used to assess volume fraction of interstitial fibrosis, sarcoplasmic reticulum calcium ATPase-2a activity, expression of mitochondria uncoupling proteins (UCP) and glucose transporters (GLUT). In controls, end-diastolic and end-systolic volumes increased and ejection fraction decreased significantly from pre to post (ejection fraction, 30±2 versus 27±1%; P<0.05). In CAP-treated dogs, end-diastolic volume was unchanged; ejection fraction increased significantly after 1 week (36±2 versus 27±2%; P<0.05) with a further increase at post (39±2%; P<0.05), whereas end-systolic volume decreased. CAP significantly decreased volume fraction of interstitial fibrosis, normalized sarcoplasmic reticulum calcium ATPase-2a activity and expression of UCP-2 and UCP-3, and GLUT-1 and GLUT-2 and significantly decreased plasma norepinephrine and n-terminal pro-brain natriuretic peptide. In heart failure dogs, CAP improves LV function and prevents progressive remodeling. Improvement of LV systolic function occurs early after initiating therapy. The results support development of partial adenosine A1-receptor agonists for the treatment of chronic heart failure.

Epicardial Fat Thickness in Heart Failure and Other Clinical Conditions

In this issue of Angiology, Karayannis et al report that epicardial fat thickness (EFT) is related to anthropometric characteristics (body mass index [BMI], waist, or thigh perimeter) in both non-cachectic congestive heart failure (CHF) patients and controls. In addition, they found that in healthy individuals, decreased plasma ghrelin and increased high-sensitivity C-reactive protein (hsCRP) levels significantly predicted increased EFT, even after adjustment for BMI. On the other hand, the positive association of increased leptin with increased EFT in non-cachetic CHF was blunted after adjustment for BMI. Leptin is an adipocyte-derived protein hormone that is elevated in obesity and results in inhibition of food intake. Leptin causes energy consumption through central stimulation of sympathetic activation. Leptin appears to play multiple roles that include: functioning as a growth factor for various cell types, as a mediator of energy expenditure, as a permissive factor for puberty, and as a signal for modulation of fetal–maternal metabolism. Perhaps most importantly, leptin interacts with other hormonal mediators/regulators of energy metabolism such as insulin, glucagon, insulin-like growth factors, growth hormone (GH) and glucocorticoids. The complexity of the leptin axis suggests the unlikely development of simple obesity treatments. On the other hand, ghrelin is an appetite-stimulating peptide that is secreted by the stomach with regulation by food intake and it causes the release of GH. Ghrelin is released and circulates in the bloodstream under fasting conditions with transmission of a hunger signal to the central nervous system. As a peptide predominantly produced by the stomach and with strong GH-releasing activity, ghrelin contributes significantly to the regulation of diverse functions of the gut–brain axis. Therefore, ghrelin plays an important role in maintaining GH release and energy homeostasis in vertebrates. In patients with CHF, ghrelin has been shown to decrease plasma norepinephrine, increase left ventricular (LV) ejection fraction, increase LV mass, decrease LV endsystolic volume, decrease skeletal muscle wasting, and, during exercise, to increase peak workload plus peak oxygen consumption.

Angiotensin II receptor blockers improve endothelial dysfunction associated with sympathetic hyperactivity in metabolic syndrome

Renin-angiotensin system inhibitors are preferred for the treatment of hypertension with metabolic syndrome (MetS). Underlying endothelial dysfunction and sympathetic nervous system (SNS) activation are critically involved in the pathogenesis of hypertension in MetS. We investigated whether treatment with angiotensin II type 1 receptor blockers (ARBs) improves endothelial and autonomic function in patients with MetS. We conducted a prospective, randomized, open-label, blinded endpoint trial. Sixty patients with MetS were randomized into three treatment groups: telmisartan, candesartan, or diet therapy (control; n = 20 each), and treated for 6 months. To evaluate the endothelial function of forearm resistance arteries, blood flow and vascular resistance were measured using a strain-gauge plethysmograph during intra-arterial infusion of acetylcholine (ACh) or sodium nitroprusside (SNP). At 6 months, both telmisartan and candesartan comparably decreased blood pressure. Furthermore, ARB treatment ameliorated impaired forearm vasodilation in response to ACh. Telmisartan had a greater effect than candesartan on ACh-induced forearm vasodilation. In contrast, forearm vasodilation in response to SNP was comparable between the telmisartan and candesartan-treated groups. ARB treatment increased high-molecular-weight (HMW) adiponectin levels and baroreflex sensitivity, but telmisartan had a stronger effect than candesartan. In addition, only telmisartan treatment significantly decreased plasma norepinephrine concentrations, blood pressure variability, and heart rate variability based on spectral analysis. These findings indicate that ARBs improve impaired endothelial and baroreflex function, and increase HMW adiponectin levels in patients with MetS. Telmisartan exhibited more beneficial effects than candesartan, and only telmisartan reduced sympathetic hyperactivity, despite similar depressor effects.

Abstract P131: The Effects of Weight Loss on Liver Function in Obese Hypertensive Patients

Objective: Insulin resistance and visceral adiposity are predisposing factors for fatty liver disease. This study was undertaken to evaluate the weight loss effects on liver function (ALT, AST, GGT). Methods: 90 overweight/obese, mild hypertensive men without medications or liver dysfunction were randomized into the 3 weight loss (WL) regimens over 24 weeks. WL was achieved with i) a mild calorie restricted diet alone (D alone; 1800kcal/day, 55% carbohydrate, 30% protein, 15% fat), ii) mild exercise alone (EX alone; 1-hr walking), or iii) a combination with a mild calorie restricted diet + exercise (D+EX) over 24 weeks. BMI, waist/hip ratio (W/H), total body fat-mass, blood pressure (BP), plasma norepinephrine (NE), fasting insulin, glucose, HOMA-IR, total cholesterol (Tch), triglyceride (TG), and liver function (ALT, AST, GGT) were measured every 4 weeks over 24 weeks with WL. Results: At entry period, BMI, fat-mass, W/H, BP levels, plasma NE, HOMA-IR, Tch, TG, ALT, AST, and GGT were similar between the 3 groups. At 24 weeks, the D+EX group had significantly higher prevalence of normalizations of BMI and BP levels (53.3%, 56.7%, respectively) compared to the D alone (13.3%, 23.3%, 30.0%) or EX alone (26.6%, 23.3%). In the D alone group, significant decreases in plasma NE and TG was observed at 2 weeks followed by significant reductions in Tch, body weight, fat mass, and HOMA at 8 weeks. Significant reductions in W/H, BP and GGT were also observed at 8 weeks, and ALT and AST decreased gradually but significantly at 12 weeks. On the other hand, in the EX alone group, significant fat loss and significant reduction in W/H, HOMA-IR and GGT were observed at 4 weeks. Body weight and plasma NE decreased significantly at 8 weeks, and significant BP reduction and decreases in TG and Tch were occurred at 12 weeks followed by decreases in ALT and AST at 16 weeks. Reductions in GGT were similar between the D alone and D+EX groups, but the groups including D had greater reduction in GGT, ALT and AST compared to the EX alone group. In the combination group (D+EX group), every improvement was observed earlier and stronger. Significant suppression on plasma NE and TG was at 2 weeks, decreases in HOMA, Tch, weight, fat-mass, W/H, systolic BP and GGT were at 4 weeks, and diastolic BP, ALT, and AST were at 8 weeks. In all subjects, reductions in HOMA-IR preceded to decreases in liver function parameters (GGT, ALT, and AST), and reductions in GGT was followed by decreases in ALT or AST. In multiple regression analyses, at both period of entry and 24-week, HOMA-IR was a significant determinant for GGT, TG and Tch. At entry and 24-week periods, Tch, but not TG, was a significant determinant for GGT, ALT, and AST. Conclusions: Improvement of insulin resistance associated with WL may play an important role of improvement of liver function during lifestyle modifications. WL is an effective treatment for fatty liver disease associated with obesity.

Effects of Diclofenac, Piroxicam and α-Tocopherol on Monoamine-lymphopoietic Interfacing in Mice

The non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac (CAS 15307-79-6) and piroxicam (CAS 36322-90-4) were shown in previous works to induce bone marrow lymphopoiesis. The present work aimed at evaluating the extent to which lymphopoietic effects of the above mentioned drugs as well as their interactions with alpha-tocopherol (CAS 10191-41-0) may be reflected in changes in the tissue levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT). The study was performed in male adult mice. The doses were given once daily for 7 days. The evaluations were performed in 2 phases. First, dose-response relationships of each of diclofenac, piroxicam and alpha-tocopherol were evaluated using bone marrow lymphocytes counts and monoamines levels in plasma, brain and spleen. Then, interactions of alpha-tocopherol (10 mg/kg) with diclofenac (20 mg/kg) and piroxicam (3 mg/kg), respectively, were evaluated. The interaction evaluations included effects on bone marrow lymphocytes count, monoamines levels in plasma, brain, spleen and thymus, as well as spleen weight. The obtained findings revealed that diclofenac, piroxicam and alpha-tocopherol decreased NE and DA levels in plasma, brain and spleen. There was some correlation between the decrease in plasma NE and the bone marrow lymphopoiesis. Pre-administration of alpha-tocopherol failed to maintain monoamines levels at the range of normal values in plasma, brain and spleen of NSAIDs-treated mice except splenic DA levels. In addition, the decrease in NE level induced by administration of piroxicam or diclofenac, either alone or together with a-tocopherol, corresponded to the increase in bone marrow lymphopoiesis. The present work suggests that the diclofenac- and piroxicam-induced bone marrow lymphopolesis as well as their respective interactions with alpha-tocopherol are associated with parallel changes in monoamines levels, especially those of NE and 5-HT.

Catecholamine metabolism in children with Asperger’s and Kanner’s syndromes

In a stable state children with Asperger’s and Kanner’s syndromes demonstrate a similar decrease in plasma norepinephrine. In the aggravated state, these changes become more expressed and are characterized by a decrease in plasma tyrosine, norepinephrine, normetanephrine, and by an increase in dopamine and homovanillic acid and a decrease in excretion of norepinephrine and an increase in excretion of homovanillic acid, epinephrine and 3-methoxy-4-hydroxyphenylglycol (MHPG). In the aggravated state children with Kanner’s syndrome were characterized by increased plasma MHPG, decreased excretion of tyrosine and increased expression of normetanephrine. The observed imbalance in dopamine and epinephrine/norepinephrine systems suggests importance of combined analysis of changes in catecholamines and their metabolites as the most informative approach in the study of the effect of autistic disorders.

Catecholamines and their metabolites in children with asperger and kanner syndromes

Children with Asperger and Kanner syndromes in the stable state demonstrate similar decrease in plasma norepinephrine. In the aggravated state, these changes become more expressed and are characterized by a decrease in plasma tyrosine, norepinephrine, normetanephrine and by an increase in dopamine and homovanylic acid and a decrease in excretion of norepinephrine and an increase in excretion of homovanylic acid, epinephrine and MHPG. Only in children with Kanner syndrome in the aggravated state plasma MHPG increases, excretion of tyrosine decreases and excretion of normetanephrine increases. The observed imbalance in dopamine and epinephrine/norepinephrine systems justifies combined analysis of changes in catecholamines and their metabolites levels as the most informative approach in the study of the effect of autistic disorders.

The effects of clonidine on arterial baroreflex sensitivity and cardiopulmonary barorefex control of sympathetic nerve activity in patients with left ventricular dysfunction

Clonidine is a potent sympatholytic drug with central neural effects. The aim of this study was to evaluate the effects of clonidine on arterial baroreflex sensitivity (BRS) and cardiopulmonary (CP) baroreflex control of muscle sympathetic nerve activity (MSNA) in patients with left ventricular (LV) dysfunction. Twenty patients were randomly assigned to either clonidine or placebo groups (10 in each group). BRS (by phenylephrine method) and CP baroreflex (by lower body negative pressure) effects on sympathetic nerve activity (circulating norepinephrine and MSNA recordings) were measured before and after a 4-week treatment period. Clonidine lowered blood pressure and heart rate. Clonidine was accompanied not only by a decrease in plasma noradrenaline (from 444±196 to 260±144 pg ml(-1) ) but also by a reduction in directly measured MSNA (from 47±16 to 36±16 bursts min(-1) ). BRS increased significantly from 3·01±1·19 to 6·86±2·84 ms mmHg(-1) after clonidine. When expressed as per cent change in MSNA during CP baroreceptor stimulation, CP baroreflex control of MSNA was significantly increased from 9·26±8·93% to 28·83±11·96% after clonidine. However, there were no significant changes in the measured variables in the control group. Clonidine enhanced BRS and CP baroreflex control of MSNA while reducing baseline sympathetic activity in patients with LV dysfunction.

Short-term sympathoadrenal inhibition augments the thermogenic response to β-adrenergic receptor stimulation

Sedentary behavior is associated with an attenuated thermogenic response to beta-adrenergic receptor (beta-AR) stimulation, an important regulator of energy expenditure (EE) in humans. Chronic stimulation of beta-ARs, via heightened activity of the sympathoadrenal system, leads to diminished beta-AR function. We have investigated the hypothesis that the thermogenic response of sedentary adults to beta-AR stimulation will be increased during short-term sympathoadrenal inhibition. Using a randomly ordered, repeated measures study design, resting EE (REE; indirect calorimetry, ventilated hood technique) and the % increase in EE above REE (%DeltaEE) during acute i.v. isoproterenol administration (nonselective beta-AR agonist; 6, 12, and 24 ng/kg fat-free mass per min) were determined in 16 sedentary adults (nine females and seven males, 25+/-1 years, body mass index: 26.1+/-0.9 kg/m(2), maximal oxygen uptake: 40+/-2 ml/kg per min (mean+/-s.e.m.)) in the basal state and on the 6th day of transdermal clonidine administration (centrally acting alpha2-AR agonist; 0.2 mg/day). Relative to baseline, clonidine inhibited sympathoadrenal activity, as evidenced by decreased plasma norepinephrine concentration (1.04+/-0.13 vs 0.34+/-0.03 nmol/l; P<0.001), skeletal muscle sympathetic nerve activity (22.5+/-3.8 vs 8.5+/-1.9 bursts/min; P=0.003), and resting heart rate (63+/-2 vs 49+/-1 beats/min; P<0.001). Sympathoadrenal inhibition decreased REE (6510+/-243 vs 5857+/-218 kJ/day; P<0.001), increased respiratory exchange ratio (0.84+/-0.01 vs 0.86+/-0.01; P=0.03), and augmented the thermogenic response to beta-AR stimulation (%DeltaEE: 11+/-2, 16+/-2, and 24+/-2 vs 14+/-1, 20+/-2, and 31+/-2; P=0.04). These data demonstrate that in sedentary humans, short-term inhibition of sympathoadrenal activity increases the thermogenic response to beta-AR stimulation, an important determinant of EE and hence energy balance.

Systemic nitric oxide clamping in normal humans guided by total peripheral resistance

We wanted to stabilize the availability of nitric oxide (NO) at levels compatible with normal systemic haemodynamics to provide a model for studies of complex regulations in the absence of changes in NO levels. Normal volunteers (23-28 years) were infused i.v. with the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) at 0.5 mg kg(-1) h(-1). One hour later, the NO donor sodium nitroprusside (SNP) was co-infused in doses eliminating the haemodynamic effects of l-NAME. Haemodynamic measurements included blood pressure (MABP) and cardiac output (CO) by impedance cardiography. l-NAME increased MABP and total peripheral resistance (TPR, 1.02 + or - 0.05 to 1.36 + or - 0.07 mmHg s mL(-1), mean + or - SEM, P < 0.001). With SNP, TPR fell to a stable value slightly below control (0.92 + or - 0.05 mmHg s mL(-1), P < 0.05). CO decreased with l-NAME (5.8 + or - 0.3 to 4.7 + or - 0.3 L min(-1), P < 0.01) and returned to control when SNP was added (6.0 + or - 0.3 L min(-1)). A decrease in plasma noradrenaline (42%, P < 0.01) during l-NAME administration was completely reversed by SNP. Plasma renin activity decreased during l-NAME administration and returned towards normal after addition of SNP. In contrast, plasma aldosterone was increased by l-NAME and remained elevated. Concomitant NOS inhibition and NO donor administration can be adjusted to maintain TPR at control level for hours. This approach may be useful in protocols in which stabilization of the peripheral supply of NO is required. However, the dissociation between renin and aldosterone secretion needs further investigation.

Neuroprotective effects of testosterone upon cardiac sympathetic function in rats with induced heart failure

The current study was designed to determine whether castration with or without testosterone replacement resulted in changes in cardiac sympathetic nerve activity in rats with heart failure induced by isoproterenol. At eight weeks post-castration, dysfunction of the cardiac sympathetic nerve system was aggravated as indicated by elevated plasma norepinephrine, reduced myocardial norepinephrine content and tyrosine hydroxylase (TH) protein. These effects of castration were reversed by testosterone replacement, as indicated by decreased plasma norepinephrine, increased myocardial norepinephrine and density of TH-labeled nerve fibers, as well as by an upregulated expression of myocardial TH protein. We also explored whether the neuroprotective effect of testosterone was influenced by the antiandrogen, flutamide. Interestingly, flutamide failed to block these testosterone-induced neuroprotective effects on the cardiac sympathetic nervous system in castrated rats with heart failure. These results provide the first evidence that endogenous testosterone deprivation in rats significantly worsened cardiac sympathetic function during pathophysiological changes associated with heart failure, and testosterone replacement reversed these adverse effects. These neuroprotective effects of testosterone, may, in part, be mediated through an upregulation in TH protein, but do not appear to involve the androgen receptor. Therefore, androgens may play an important role in modulating pathophysiological changes in the cardiac sympathetic nervous system that result from heart failure and our findings suggest the potential for beneficial effects of testosterone in the treatment of this condition.

Cytokine blockade attenuates sympathoexcitation in heart failure: Cross‐talk between nNOS, AT‐1R and cytokines in the hypothalamic paraventricular nucleus

To investigate evidence for the interplay between cytokines, angiotensin II and nNOS in the paraventricular nucleus (PVN), for regulating sympathetic outflow in a rat model of CHF. Heart failure was induced in Sprague-Dawley rats by coronary artery ligation. One group of rats was treated with pentoxifylline (PTX, 30 mg/kg IP), a cytokine blocker, or vehicle, for 5 weeks. Another group of rats was pre-treated with PTX before coronary ligation to study prior cytokine blocking effect on survival. Both groups were combined in the analysis. Echocardiography demonstrated an increase in LV end-diastolic pressure and Tei index after 5 weeks in CHF rats. ELISA revealed a significant increase in plasma TNF-alpha and IL-1beta in CHF rats. Inducible NOS (iNOS) and angiotensin receptor-type 1 (AT-1R) mRNA expressions were increased, while neuronal NOS (nNOS) was decreased in the PVN of CHF rats; these changes were reversed by PTX. PTX treatment also decreased plasma norepinephrine and epinephrine levels and improved baroreflex control of renal sympathoexcitation in CHF rats. Immunohistochemistry revealed elevated 3-nitrotyrosine formation in the heart and the PVN of CHF rats, but not in PTX treated rats. PTX decreased both peripheral and central cytokine expression, alleviated nitric oxide dysregulation, and inhibited the formation of peroxynitrite in the PVN resulting in decreased sympathoexcitation in CHF rats.

Exercise training delays cardiac dysfunction and prevents calcium handling abnormalities in sympathetic hyperactivity-induced heart failure mice

Exercise training (ET) is a coadjuvant therapy in preventive cardiology. It delays cardiac dysfunction and exercise intolerance in heart failure (HF); however, the molecular mechanisms underlying its cardioprotection are poorly understood. We tested the hypothesis that ET would prevent Ca(2+) handling abnormalities and ventricular dysfunction in sympathetic hyperactivity-induced HF mice. A cohort of male wild-type (WT) and congenic alpha(2A)/alpha(2C)-adrenoceptor knockout (alpha(2A)/alpha(2C)ARKO) mice with C57BL6/J genetic background (3-5 mo of age) were randomly assigned into untrained and exercise-trained groups. ET consisted of 8-wk swimming session, 60 min, 5 days/wk. Fractional shortening (FS) was assessed by two-dimensional guided M-mode echocardiography. The protein expression of ryanodine receptor (RyR), phospho-Ser(2809)-RyR, sarcoplasmic reticulum Ca(2+) ATPase (SERCA2), Na(+)/Ca(2+) exchanger (NCX), phospholamban (PLN), phospho-Ser(16)-PLN, and phospho-Thr(17)-PLN were analyzed by Western blotting. At 3 mo of age, no significant difference in FS and exercise tolerance was observed between WT and alpha(2A)/alpha(2C)ARKO mice. At 5 mo, when cardiac dysfunction is associated with lung edema and increased plasma norepinephrine levels, alpha(2A)/alpha(2C)ARKO mice presented reduced FS paralleled by decreased SERCA2 (26%) and NCX (34%). Conversely, alpha(2A)/alpha(2C)ARKO mice displayed increased phospho-Ser(16)-PLN (76%) and phospho-Ser(2809)-RyR (49%). ET in alpha(2A)/alpha(2C)ARKO mice prevented exercise intolerance, ventricular dysfunction, and decreased plasma norepinephrine. ET significantly increased the expression of SERCA2 (58%) and phospho-Ser(16)-PLN (30%) while it restored the expression of phospho-Ser(2809)-RyR to WT levels. Collectively, we provide evidence that improved net balance of Ca(2+) handling proteins paralleled by a decreased sympathetic activity on ET are, at least in part, compensatory mechanisms against deteriorating ventricular function in HF.

Direct and reflexive effects of nitric oxide synthase inhibition on blood pressure

Direct effects of vasoactive substances on blood pressure can be examined in individuals with tetraplegia due to disruption of descending spinal pathways to sympathetic preganglionic neurons, as cervical lesions interfere with baroreceptor reflex buffering of sympathetic outflow. In this study, we assessed effects of the nitric oxide synthase inhibitor nitro-L-arginine methyl ester (L-NAME) on mean arterial pressure, heart rate, and plasma norepinephrine concentrations in individuals with tetraplegia vs. effects shown in a neurologically intact control group. Seven individuals with tetraplegia and seven age-matched controls received, on separate visits and in the following order, placebo (30 ml normal saline) and 0.5, 1, 2, and 4 mg/kg L-NAME intravenously over 60 min. Supine hemodynamic data were collected, and blood was sampled at the end of each infusion and at 120, 180, and 240 min thereafter. L-NAME increased mean arterial pressure, and the relative increase was greater in the tetraplegia group than in the control group. Heart rate was reduced after L-NAME administration in both groups. L-NAME decreased plasma norepinephrine in the control group but not in the group with tetraplegia. These findings suggest that reflexive sympathoinhibition normally buffers the pressor response to nitric oxide synthase inhibition, an effect that is not evident in individuals with tetraplegia as a result of decentralized sympathetic vasomotor control.

ANG II-induced attenuation of salt gland function in Pekin ducks is not catecholamine-dependent

Pekin ducks (Anas platyrhynchos) were bilaterally adrenalectomized (biADX), injected with 1 mg of triamcinolone (TRIAM) kg bw(-1) im and given 0.9% saline drinking water during a 24 h recovery period followed by chemical sympathectomy with 6OH DOPA 3 h before the start of experimental observations. Baseline plasma dopamine (DA) concentrations decreased from 283 +/- 88.5 pmol ml(-1) to 42.4 +/- 11.1 pmol ml(-1); epinephrine (E) from 142 +/- 46 pmol ml(-1) to 18.4 +/- 9.2 pmol ml(-1) and norepinephrine (NE) from 742 +/- 84 pmol ml(-1) to 406 +/- 38 pmol ml(-1) 1 day after biADX + TRIAM but before chemical sympathectomy. Baseline MABP increased from 132 +/- 3.2 mmHg to 209 +/- 14.3 mmHg (P < 0.05) in response to TRIAM. After chemical sympathectomy with 6OH DOPA there was an additional 90% decrease in plasma NE to 42 +/- 9.4 pmol ml(-1) and a concurrent 60% decrease in MABP to 83.4 +/- 6.9 mmHg (P < 0.05). Nasal fluid secretion was maintained by the continuous infusion of hypertonic saline (1,000 mosmol kg H(2)O(-1) at a rate of 0.3 ml kg(-1) min(-1)). Rates of nasal fluid secretion and fluid electrolyte concentrations were unchanged following biADX + TRIAM + 6OH DOPA. Angiotensin II (ANG II; dose 1 microg kg bw(-1) i.v.), attenuated nasal fluid secretion showing that the response to ANG II was not NE- dependent. Plasma NE concentrations decreased following Tyramine i.v. (33 +/- 8.5 pmol ml(-1)) there being no vasopressor response. This is the first report of the ANG II induced attenuation of duck salt gland secretion in the absence of measurable E and NE.