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Sympathetic Nerve Activity Efferent Drive and Beta-Blocker Treatment - Effect of Interaction in Systolic Heart Failure.
Joho, S, Akabane, T, Ushijima, R, Hirai, T, Kinugawa, K
Circulation journal : official journal of the Japanese Circulation Society. 2016;(10):2149-54
Abstract
BACKGROUND Although both β-blocker dose (BBD) and sympathetic activity efferent drive are associated with prognosis in chronic heart failure (HF), little is known about the prognostic value of the interaction between them. METHODS AND RESULTS Potential prognostic variables including resting muscle sympathetic nerve activity (MSNA) were investigated in 133 patients with HF (ejection fraction [EF] <0.45). BBD was normalized to therapeutically equivalent doses of carvedilol. Primary cardiovascular endpoints included cardiovascular death and HF hospitalization. Predictors for outcomes were assessed on univariate, multivariate, and Kaplan-Meier analysis. EF was followed for 9 months after MSNA measurement in 102 patients. During the 1,419±824-day follow-up period, 24 patients died (sudden death, n=10; progressive HF, n=14). On multivariate Cox proportional hazard analysis, higher MSNA (P=0.037; HR, 2.01) and lower BBD (<5.0 mg/day; P=0.041; HR, 1.94) were independent predictors of cardiovascular events. Patients were divided into higher MSNA (≥64 bursts/100 beats) and lower MSNA groups. Although lower BBD remained an independent predictor in patients with higher MSNA, BBD was not statistically significant in patients with lower MSNA on univariate analysis. Additionally, there was a lower EF change in patients with lower BBD and higher MSNA. CONCLUSIONS Higher BBD might be necessary to avoid cardiovascular events in HF patients with central sympathetic overactivation. (Circ J 2016; 80: 2149-2154).
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The effects of the L/N-type calcium channel blocker (cilnidipine) on sympathetic hyperactive morning hypertension: results from ACHIEVE-ONE.
Kario, K, Ando, S, Kido, H, Nariyama, J, Takiuchi, S, Yagi, T, Shimizu, T, Eguchi, K, Ohno, M, Kinoshita, O, et al
Journal of clinical hypertension (Greenwich, Conn.). 2013;(2):133-42
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Abstract
The Ambulatory Blood Pressure Control and Home Blood Pressure (Morning and Evening) Lowering By N-Channel Blocker Cilnidipine (ACHIEVE-ONE) trial is a large-scale clinical study on blood pressure (BP) and pulse rate (PR) in the real world with use of cilnidipine, a unique L/N-type Ca channel blocker, possessing a suppressive action on increased sympathetic activity in patients with essential hypertension. The effects of cilnidipine on morning hypertension were examined. The authors examined 2319 patients treated with cilnidipine for 12 weeks. Clinic systolic BP (SBP) decreased by 19.6 mm Hg from 155.0 mm Hg, whereas morning SBP decreased by 17.0 mm Hg from 152.9 mm Hg after 12-week cilnidipine treatment. Cilnidipine reduced both morning SBP and PR more markedly in patients with higher baseline morning SBP (-3.2 mm Hg and -1.3 beats per minute in the first quartile of morning SBP, -30.9 mm Hg and -3.2 beats per minute in the fourth quartile), and also reduced both morning PR and SBP more markedly in patients with higher baseline morning PR (0.6 beats per minute and -15.6 mm Hg in <70 beats per minute, and -9.7 beats per minute and -20.2 mm Hg in ≥85 beats per minute). Cilnidipine significantly reduced BP and PR in hypertensive patients at the clinic and at home, especially with higher BP and PR in the morning.
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Differential effects of metaboreceptor and chemoreceptor activation on sympathetic and cardiac baroreflex control following exercise in hypoxia in human.
Gujic, M, Laude, D, Houssière, A, Beloka, S, Argacha, JF, Adamopoulos, D, Xhaët, O, Elghozi, JL, van de Borne, P
The Journal of physiology. 2007;(Pt 1):165-74
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Abstract
Muscle metaboreceptors and peripheral chemoreceptors exert differential effects on the cardiorespiratory and autonomic responses following hypoxic exercise. Whether these effects are accompanied by specific changes in sympathetic and cardiac baroreflex control is not known. Sympathetic and cardiac baroreflex functions were assessed by intravenous nitroprusside and phenylephrine boluses in 15 young male subjects. Recordings were performed in random order, under locally circulatory arrested conditions, during: (1) rest and normoxia (no metaboreflex and no chemoreflex activation); (2) normoxic post-handgrip exercise at 30% of maximum voluntary contraction (metaboreflex activation without chemoreflex activation); (3) hypoxia without handgrip (10% O2 in N2, chemoreflex activation without metaboreflex activation); and (4) post-handgrip exercise in hypoxia (chemoreflex and metaboreflex activation). When compared with normoxic rest (-42 +/- 7% muscle sympathetic nerve activity (MSNA) mmHg(-1)), sympathetic baroreflex sensitivity did not change during normoxic post-exercise ischaemia (PEI; -53 +/- 9% MSNA mmHg(-1), P = 0.5) and increased during resting hypoxia (-68 +/- 5% MSNA mmHg(-1), P < 0.01). Sympathetic baroreflex sensitivity decreased during PEI in hypoxia (-35 +/- 6% MSNA mmHg(-1), P < 0.001 versus hypoxia without exercise; P = 0.16 versus normoxic PEI). Conversely, when compared with normoxic rest (11.1 +/- 1.7 ms mmHg(-1)), cardiac baroreflex sensitivity did not change during normoxic PEI (8.3 +/- 1.3 ms mmHg(-1), P = 0.09), but decreased during resting hypoxia (7.3 +/- 0.8 ms mmHg(-1), P < 0.05). Cardiac baroreflex sensitivity was lowest during PEI in hypoxia (4.3 +/- 1 ms mmHg(-1), P < 0.01 versus hypoxia without exercise; P < 0.001 versus normoxic exercise). The metaboreceptors and chemoreceptors exert differential effects on sympathetic and cardiac baroreflex function. Metaboreceptor activation is the major determinant of sympathetic baroreflex sensitivity, when these receptors are stimulated in the presence of hypoxia.
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Relationship between muscle sympathetic nerve activity and systemic hemodynamics during nitric oxide synthase inhibition in humans.
Charkoudian, N, Joyner, MJ, Barnes, SA, Johnson, CP, Eisenach, JH, Dietz, NM, Wallin, BG
American journal of physiology. Heart and circulatory physiology. 2006;(3):H1378-83
Abstract
Large interindividual differences exist in resting sympathetic nerve activity (SNA) among normotensive humans with similar arterial pressure (AP). We recently showed inverse relationships of resting SNA with cardiac output (CO) and vascular adrenergic responsiveness that appear to balance the influence of differences in SNA on blood pressure. In the present study, we tested whether nitric oxide (NO)-mediated vasodilation has a role in this balance by evaluating hemodynamic responses to systemic NO synthase (NOS) inhibition in individuals with low and high resting muscle SNA (MSNA). We measured MSNA via peroneal microneurography, CO via acetylene uptake and AP directly, at baseline and during increasing systemic doses of the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA). Baseline MSNA ranged from 9 to 38 bursts/min (13 to 68 bursts/100 heartbeats). L-NMMA caused dose-dependent increases in AP and total peripheral resistance and reflex decreases in CO and MSNA. Increases in AP with L-NMMA were greater in individuals with high baseline MSNA (PANOVA<0.05). For example, after 8.5 mg/kg of L-NMMA, in the low MSNA subgroup (n=6, 28+/-4 bursts/100 heartbeats), AP increased 9+/-1 mmHg, whereas in the high-MSNA subgroup (n=6, 58+/-3 bursts/100 heartbeats), AP increased 15+/-2 mmHg (P<0.01). The high-MSNA subgroup had lower baseline CO and smaller decreases in CO with L-NMMA, but changes in total peripheral resistance were not different between groups. We conclude that differences in CO among individuals with varying sympathetic traffic have important hemodynamic implications during disruption of NO-mediated vasodilation.
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Sympathetic neural regulation in endurance-trained humans: fitness vs. fatness.
Alvarez, GE, Halliwill, JR, Ballard, TP, Beske, SD, Davy, KP
Journal of applied physiology (Bethesda, Md. : 1985). 2005;(2):498-502
Abstract
We tested the hypothesis that muscle sympathetic nerve activity (MSNA) would be higher in endurance-trained (ET) compared with sedentary (Sed) men with similar levels of total body and abdominal adiposity. We further hypothesized that sympathetic baroreflex gain would be augmented in ET compared with Sed men independent of the level of adiposity. To address this, we measured MSNA (via microneurography), sympathetic and vagal baroreflex responses (the modified Oxford technique), body composition (dual-energy X-ray absorptiometry), and waist circumference (Gulick tape) in Sed (n = 22) and ET men (n = 8). The ET men were also compared with a subgroup of Sed men (n = 6) with similar levels of total body and abdominal adiposity. Basal MSNA was greater in the ET compared with Sed men with similar levels of total body and abdominal adiposity (28 +/- 2.0 vs. 21 +/- 2.0 bursts/min; P < 0.05) but similar to the larger group of Sed men (n = 22) with higher total body and abdominal adiposity (vs. 26 +/- 3 bursts/min; P > 0.05). In contrast to our hypothesis, sympathetic baroreflex gain was lower in the ET compared with Sed men (-6.4 +/- 0.8 vs. -8.4 +/- 0.4 arbitrary integrative units x beat(-1) x mmHg(-1); P < 0.05) regardless of the level of adiposity. Taken together, the results of the present study suggest that MSNA is higher in ET compared with Sed men with similar levels of total body and abdominal adiposity. In addition, sympathetic baroreflex gain is lower in ET compared with Sed men. That sympathetic baroreflex gain was lower in ET compared with Sed men regardless of the level of adiposity suggests an influence of the ET state per se.
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Exogenous nitric oxide inhibits sympathetically mediated vasoconstriction in human skin.
Durand, S, Davis, SL, Cui, J, Crandall, CG
The Journal of physiology. 2005;(Pt 2):629-34
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Abstract
Two experiments were performed to identify whether nitric oxide (NO) inhibits sympathetically mediated vasoconstriction in human skin. In eight subjects increasing doses of sodium nitroprusside (SNP; 8.4 x 10(-6)-8.4 x 10(-3)m) were administered via intradermal microdialysis. At each dose of SNP, cutaneous vasoconstrictor responsiveness was assessed during a 3 min whole-body cold stress. The relative reduction in forearm cutaneous vascular conductance (CVC) during the cold stress was significantly attenuated for SNP doses greater than 8.4 x 10(-4)m (control: 63.0 +/- 4.1%, SNP 8.4 x 10(-6)m: 57.1 +/- 4.7%, SNP 8.4 x 10(-5)m: 57.0 +/- 3.6%, SNP 8.4 x 10(-4)m: 44.5 +/- 5.4% and SNP 8.4 x 10(-3)m: 28.8 +/- 7.9%). The second experiment was performed to identify whether this response was due to NO attenuating sympathetically mediated vasoconstriction or due to a non-specific effect of an elevated CVC secondary to SNP administration. In seven subjects forearm CVC during a whole-body cold stress was assessed at two sites: at a site dilated via microdialysis administration of SNP and at a site dilated with isoproterenol (ISO). CVC was not different between sites prior to (SNP: 0.42 +/- 0.11; ISO: 0.46 +/- 0.11 AU mmHg(-1) (AU, arbitrary units), P > 0.05) or following drug infusion (SNP: 1.36 +/- 0.21; ISO: 1.27 +/- 0.23 AU mmHg(-1), P > 0.05). The reduction in CVC during the subsequent cold stress was significantly less at the SNP site (38.1 +/- 6.2%) relative to the ISO site (65.0 +/- 5.5%; P= 0.007). These data suggest NO is capable of inhibiting sympathetically mediated vasoconstriction in the cutaneous vasculature.
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Influence of increased central venous pressure on baroreflex control of sympathetic activity in humans.
Charkoudian, N, Martin, EA, Dinenno, FA, Eisenach, JH, Dietz, NM, Joyner, MJ
American journal of physiology. Heart and circulatory physiology. 2004;(4):H1658-62
Abstract
Volume expansion often ameliorates symptoms of orthostatic intolerance; however, the influence of this increased volume on integrated baroreflex control of vascular sympathetic activity is unknown. We tested whether acute increases in central venous pressure (CVP) diminished subsequent responsiveness of muscle sympathetic nerve activity (MSNA) to rapid changes in arterial pressure. We studied healthy humans under three separate conditions: control, acute 10 degrees head-down tilt (HDT), and saline infusion (SAL). In each condition, heart rate, arterial pressure, CVP, and peroneal MSNA were measured during 5 min of rest and then during rapid changes in arterial pressure induced by sequential boluses of nitroprusside and phenylephrine (modified Oxford technique). Sensitivities of integrated baroreflex control of MSNA and heart rate were assessed as the slopes of the linear portions of the MSNA-diastolic blood pressure and R-R interval-systolic pressure relations, respectively. CVP increased approximately 2 mmHg in both SAL and HDT conditions. Resting heart rate and mean arterial pressure were not different among trials. Sensitivity of baroreflex control of MSNA was decreased in both SAL and HDT condition, respectively: -3.1 +/- 0.6 and -3.3 +/- 1.0 versus -5.0 +/- 0.6 units.beat(-1).mmHg(-1) (P < 0.05 for SAL and HDT vs. control). Sensitivity of baroreflex control of the heart was not different among conditions. Our results indicate that small increases in CVP decrease the sensitivity of integrated baroreflex control of sympathetic nerve activity in healthy humans.
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Spironolactone improves cardiac sympathetic nerve activity and symptoms in patients with congestive heart failure.
Kasama, S, Toyama, T, Kumakura, H, Takayama, Y, Ichikawa, S, Suzuki, T, Kurabayashi, M
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2002;(10):1279-85
Abstract
UNLABELLED We evaluated whether spironolactone would improve cardiac sympathetic nerve activity and symptoms in patients with congestive heart failure (CHF). METHODS Thirty patients with CHF (left ventricular ejection fraction [LVEF] < 40%; mean, 30% +/- 9%) were treated with an angiotensin-converting enzyme inhibitor, a loop diuretic, and, in most cases, digoxin. Fifteen patients (group A) were assigned to additionally receive spironolactone (12.5-50 mg/day), and the remaining 15 patients (group B) continued their current regimen. Patients were studied before and 6 mo after treatment. The delayed heart-to-mediastinum count ratio (H/M ratio), delayed total defect score (TDS), and washout rate (WR) were determined from (123)I-meta-iodobenzylguanidine (MIBG) images. LVEF was determined by echocardiography, and New York Heart Association (NYHA) functional class was estimated. RESULTS Before treatment, LVEF, TDS, H/M ratio, WR, and NYHA functional class were similar in both groups. With treatment, LVEF did not significantly improve in either group. However, after treatment in group A, TDS decreased from 37 +/- 9 to 25 +/- 13 (P = 0.0001), H/M ratio increased from 1.62 +/- 0.20 to 1.83 +/- 0.27 (P < 0.0001), and WR decreased from 51 +/- 9 to 40 +/- 15 (P < 0.001). In group B, these parameters did not significantly change. NYHA functional class improved in both groups (in group A, from 3.3 +/- 0.5 to 1.7 +/- 0.5 [P < 0.0001]; in group B, from 3.3 +/- 0.5 to 2.4 +/- 0.6 [P = 0.01]); this was a significantly greater improvement in group A than in group B (P < 0.01). CONCLUSION Spironolactone improves cardiac sympathetic nerve activity and symptoms in patients with CHF.
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Is sympathetic neural vasoconstriction blunted in the vascular bed of exercising human muscle?
Tschakovsky, ME, Sujirattanawimol, K, Ruble, SB, Valic, Z, Joyner, MJ
The Journal of physiology. 2002;(Pt 2):623-35
Abstract
Sympathetic vasoconstriction of muscle vascular beds is important in the regulation of systemic blood pressure. However, vasoconstriction during exercise can also compromise blood flow support of muscle metabolism. This study tested the hypothesis that local factors in exercising muscle blunt vessel responsiveness to sympathetic vasoconstriction. We performed selective infusions of three doses of tyramine into the brachial artery (n = 8) to evoke endogenous release of noradrenaline (norepinephrine) at rest and during moderate and heavy rhythmic handgrip exercise. In separate experiments, tyramine was administered during two doses of adenosine infusion (n = 7) and two doses of sodium nitroprusside (SNP) infusion (n = 8). Vasoconstrictor effectiveness across conditions was assessed as the percentage reduction in forearm vascular conductance (FVC), calculated from invasive blood pressure and non-invasive Doppler ultrasound blood flow measurements at the brachial artery. Tyramine evoked a similar dose-dependent vasoconstriction at rest in all three groups, with the highest dose resulting in a 42-46 % reduction in FVC. This vasoconstriction was blunted with increasing exercise intensity (e.g. tyramine high dose percentage reduction in FVC; rest -43.4 +/- 3.7 %, moderate exercise -27.5 +/- 2.3 %, heavy exercise -16.7 +/- 3.6 %; P < 0.05). In contrast, tyramine infusion resulted in a greater percentage reduction in FVC during both doses of adenosine vs. rest (P < 0.05). Finally, percentage change in FVC was greater during low dose SNP infusion vs. rest (P < 0.05), but not different from rest at the high dose of SNP infusion (P = 0.507). A blunted percentage reduction in FVC during endogenous noradrenaline release in exercise but not vasodilator infusion indicates that sympathetic vasoconstriction is blunted in exercising muscle. This blunting appears to be exercise intensity-dependent.
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Muscle sympathetic nerve responses to physiological changes in prostaglandin production in humans.
Doerzbacher, KJ, Ray, CA
Journal of applied physiology (Bethesda, Md. : 1985). 2001;(2):624-9
Abstract
Previous studies suggest that prostaglandins may contribute to exercise-induced increases in muscle sympathetic nerve activity (MSNA). To test this hypothesis, MSNA was measured at rest and during exercise before and after oral administration of ketoprofen, a cyclooxygenase inhibitor, or placebo. Twenty-one subjects completed two bouts of graded dynamic and isometric handgrip to fatigue. Each exercise bout was followed by 2 min of postexercise muscle ischemia. The second exercise bouts were performed after 60 min of rest in which 11 subjects were given ketoprofen (300 mg) and 10 subjects received a placebo. Ketoprofen significantly lowered plasma thromboxane B(2) in the drug group (from 36 +/- 6 to 22 +/- 3 pg/ml, P < 0.04), whereas thromboxane B(2) in the placebo group increased from 40 +/- 5 to 61 +/- 9 pg/ml from trial 1 to trial 2 (P < 0.008). Ketoprofen and placebo did not change sympathetic and cardiovascular responses to dynamic handgrip, isometric handgrip, and postexercise muscle ischemia. There was no relationship between thromboxane B(2) concentrations and MSNA or arterial pressure responses during both exercise modes. The data indicate that physiological increases or decreases in prostaglandins do not alter exercise-induced increases in MSNA and arterial pressure in humans. These findings suggest that contraction-induced metabolites other than prostaglandins mediate MSNA responses to exercise in humans.