Decreases Muscle Sympathetic Nerve Activity Research Articles

Acute effects of electronic cigarettes on arterial pressure and peripheral sympathetic activity in young nonsmokers.

Electronic cigarettes (e-cigarettes) are marketed as an alternative to smoking for those who want to decrease the health risks of tobacco. Tobacco cigarettes increase heart rate (HR) and arterial pressure, while reducing muscle sympathetic nerve activity (MSNA) through sympathetic baroreflex inhibition. The acute effects of e-cigarettes on arterial pressure and MSNA have not been reported: our purpose was to clarify this issue. Using a randomized crossover design, participants inhaled on a JUUL e-cigarette containing nicotine (59 mg/mL) and a similar placebo e-cigarette (0 mg/mL). Experiments were separated by ∼1 mo. We recorded baseline ECG, finger arterial pressure (n = 15), and MSNA (n = 10). Subjects rested for 10 min (BASE) and then inhaled once every 30 s on an e-cigarette that contained nicotine or placebo (VAPE) for 10 min followed by a 10-min recovery (REC). Data were expressed as Δ means ± SE from BASE. Heart rate increased in the nicotine condition during VAPE and returned to BASE values in REC (5.0 ± 1.3 beats/min nicotine vs. 0.1 ± 0.8 beats/min placebo, during VAPE; P < 0.01). Mean arterial pressure increased in the nicotine condition during VAPE and remained elevated during REC (6.5 ± 1.6 mmHg nicotine vs. 2.6 ± 1 mmHg placebo, during VAPE and 4.6.0 ± 1.7 mmHg nicotine vs. 1.4 ± 1.4 mmHg placebo, during REC; P < 0.05). MSNA decreased from BASE to VAPE and did not restore during REC (-7.1 ± 1.6 bursts/min nicotine vs. 2.6 ± 2 bursts/min placebo, during VAPE and -5.8 ± 1.7 bursts/min nicotine vs. 0.5 ± 1.4 bursts/min placebo, during REC; P < 0.05). Our results show that acute e-cigarette usage increases mean arterial pressure leading to a baroreflex-mediated inhibition of MSNA.NEW & NOTEWORTHY The JUUL e-cigarette is the most popular e-cigarette in the market. In the present study, inhaling on a JUUL e-cigarette increased mean arterial pressure and heart rate, and decreased muscle sympathetic nerve activity (MSNA). In contrast, inhaling on a placebo e-cigarette without nicotine elicited no sympathomimetic effects. Although previous tobacco cigarette studies have demonstrated increased mean arterial pressure and MSNA inhibition, ours is the first study to report similar responses while inhaling on an e-cigarette. Listen to this article's corresponding podcast at @ https://ajpheart.podbean.com/e/aerosolized-nicotine-and-cardiovascular-control/.

High-Intensity Interval Training Decreases Muscle Sympathetic Nerve Activity in Men With Essential Hypertension and in Normotensive Controls.

Exercise training is a cornerstone in reducing blood pressure (BP) and muscle sympathetic nerve activity (MSNA) in individuals with essential hypertension. High-intensity interval training (HIIT) has been shown to be a time efficient alternative to classical continuous training in lowering BP in essential hypertension, but the effect of HIIT on MSNA levels has never been investigated. Leg MSNA responsiveness to 6 weeks of HIIT was examined in 14 hypertensive men (HYP; age: 62 ± 7 years, night time BP: 136 ± 12/83 ± 8 mmHg, BMI: 28 ± 3 kg/m2), and 10 age-matched normotensive controls (NORM; age: 60 ± 8 years, night time BP: 116 ± 2/68 ± 4 mmHg and BMI: 27 ± 3 kg/m2). Before training, MSNA levels were not different between HYP and NORM (burst frequency (BF): 41.0 ± 10.3 vs. 33.6 ± 10.6 bursts/min and burst incidence (BI): 67.5 ± 19.7 vs. 64.2 ± 17.0 bursts/100 heart beats, respectively). BF decreased (P < 0.05) with training by 13 and 5% in HYP and NORM, respectively, whereas BI decreased by 7% in NORM only, with no difference between groups. Training lowered (P < 0.05) night-time mean arterial- and diastolic BP in HYP only (100 ± 8 vs. 97 ± 5, and 82 ± 6 vs. 79 ± 5 mmHg, respectively). The change in HYP was greater (P < 0.05) compared to NORM. Training reduced (P < 0.05) body mass, visceral fat mass, and fat percentage similarly within- and between groups, with no change in fat free mass. Training increased (P < 0.05) V̇O2-max in NORM only. Six weeks of HIIT lowered resting MSNA levels in age-matched hyper- and normotensive men, which was paralleled by a significant reduction in BP in the hypertensive men.

High‐intensity interval training decreases muscle sympathetic nerve activity and improves peripheral vascular function in patients with heart failure with reduced ejection fraction

BackgroundModerate intensity continuous exercise (MICT) has been shown to reduce muscle sympathetic nerve activity (MSNA) in heart failure patients with reduced ejection fraction (HFrEF). However, the effects of high‐intensity interval training (HIIT) on MSNA in HFrEF patients are unknown. We hypothesized that reductions in MSNA would be greater following HIIT than MICT and correspond with improvements in peripheral vascular function.MethodsHFrEF patients (30 ‐ 65 years), left ventricular ejection fraction ≤ 40%, Functional Classes II–III, were randomized into HIIT, MICT or no training (NT) three times/week for 12 weeks. MSNA was assessed by microneurography. Brachial artery flow‐mediated dilation (FMD), blood flow and vascular conductance were assessed by ultrasonography, blood pressure (BP) and heart rate (HR) by plethysmography and peak oxygen uptake (V̇O2peak) by a cardiopulmonary exercise test.ResultsBoth, HIIT and MICT, led to reductions in MSNA (frequency and incidence burst) relative to NT (p&lt;0.05). However, the reduction in MSNA was more pronounced following HIIT than MICT (p&lt;0.05). Increases in brachial artery FMD, resting blood flow and conductance were also greater following HIIT than MICT (p&lt;0.05), while V̇O2peak increased similarly following HIIT and MICT relative to NT. No changes in BP or HR were observed in either exercise condition. Further analysis showed a negative correlation between changes in MSNA and FMD following the interventions (r=−0.60, p=0.005).ConclusionOur findings indicate that 12 weeks of HIIT is superior to MICT in reducing sympathetic overactivity and improving vascular function in patients with HFrEF, despite similar increases in exercise capacity.Support or Funding InformationFAPESP Grants (2014/11671‐6 and 2017/25613‐6)

Countdown before voluntary exercise induces muscle vasodilation with decreased muscle sympathetic nerve activity in humans

We examined whether countdown (CD) before voluntary bicycle ergometer exercise induced cerebro‐cardiovascular responses and, if so, whether these responses to CD were altered by postural change from the semi‐recumbent to supine position. Young men (n=14) performed voluntary cycle exercise in the semi‐recumbent position while middle cerebral artery blood flow velocity (CBF; Doppler ultrasonography), heart rate (HR), blood pressure (finger photoplethysmography), oxygen consumption rate (VO2), oxygen saturation in the right thigh muscle (StO2; near‐infrared spectrometry), cardiac output (CO; cZ method) and total peripheral resistance (TPR) were measured. The subjects repeated 8 trials, intermitted by more than 5‐min rest. In 4 trials randomly selected from 8 trials, the onset of exercise was signaled by a 30‐sec CD, whereas in the remaining 4 trials, exercise was started without CD. We found that CD increased CBF, HR, CO, mean blood pressure, and VO2 sequentially, decreasing TPR with increased StO2. To assess efferent signals causing vasodilation and the effects of posture change from the semi‐recumbent to supine position, other groups of subjects underwent the same exercise protocol but using only right leg in the semi‐recumbent (n=10) or supine (n=8) positions while muscle sympathetic nerve activity (MSNA; microneurography) and StO2 were measured in the left and right leg, respectively. We found that CD decreased MSNA burst frequency and total MSNA (both, P&lt;0.05), which were significantly correlated with the increase in StO2 (both, P&lt;0.001). However, these responses to CD were nearly abolished by the postural change. Thus, CD before starting voluntary exercise induced cerebro‐cardiovascular responses from central system to effector organs in a sequential manner in the semi‐recumbent position, but these responses were minimized while in the supine position.Support or Funding InformationThis study was supported by grants from the Japan Society for the Promotion of Science (24689014 and 15H04680).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Mild Whole Body Heating Decreases Muscle Sympathetic Nerve Activity in Middle Aged and Older Individuals

A number of reports suggest that whole body heat stress (i.e. increase in core temperature (Tcore) &gt; 0.5 °C) induces a significant increase in muscle sympathetic nerve activity (MSNA) in young and older individuals. However, the effects of mild whole body heating (MWBH) on MSNA have not been specifically examined. A prior report from this laboratory suggests that MSNA is lower in the summer than it is in the winter. In this study, we hypothesized that MWBH would decrease the resting MSNA in middle aged and older individuals. MSNA from a peroneal nerve, ECG and heart rate (HR), blood pressure (BP), Tcore with telemetry temperature pill, mean skin temperature (Tsk), forearm skin blood flow (SkBF) and sweat rate (SR) were measured throughout the study in 8 male healthy subjects (59.6 ± 2.4 years, 177 ± 3 cm, 88 ± 6 kg). After the normothermic (Tsk at ~34 °C) data collection, passive whole body heating was applied via water‐perfused suits with ~46 °C water. After Tsk reached ~36 °C, the water temperature was slightly decreased. The MWBH data were collected during a period (1522 ± 61 sec) with Tsk &gt; 36 °C and the peak increase in Tcore &lt; 0.35 °C. Cardiac output was measured with echocardiography during baseline and MWBH. During a separate visit, a time control trial (non‐heating trial) was performed when the Tsk was controlled at ~34 °C throughout the study. The data were collected during the same time windows as those in the heating trial. Over the MWBH period, the averaged Tsk was 36.8 ± 0.3 °C, and the averaged increase in Tcore was 0.09 ± 0.05 °C. From normothermic baseline, SkBF (100 to 174 ± 31%) and cutaneous vascular conductance (CVC, 100 to 190 ± 43%) increased. Systolic BP (117.5 ± 1.3 to 113.5 ± 2.2 mmHg) did not significantly change, while diastolic BP (75.3 ± 1.9 to 70.7 ± 2.5 mmHg) and mean BP (89.4 ± 1.3 to 85.0 ± 2.3 mmHg, both P &lt; 0.05) fell. MSNA burst rate (38.9 ± 3.0 to 28.9 ± 3.4 bursts/min), burst incidence (60.4 ± 4.5 to 42.4 ± 5.2 bursts/100 beats) and total activity (847 ± 47 to 583 ± 66 units/min, all P &lt; 0.05) decreased, while HR (64.7 ± 2.9 to 69.1 ± 3.0 beats/min) increased. Cardiac output increased (P &lt; 0.05). In the non‐heating time control trial, none of these variables changed. These data suggest that the MWBH may decrease resting MSNA and BP in middle aged and older individuals. Further studies are necessary to examine the mechanisms.Support or Funding InformationSupported by American Heart Association Grant 15GRNT24480051 (Cui), National Institutes of Health Grants P01 HL096570 (Sinoway) and UL1 TR000127 (Sinoway).

Muscle electrical stimulation improves neurovascular control and exercise tolerance in hospitalised advanced heart failure patients.

We investigated the effects of muscle functional electrical stimulation on muscle sympathetic nerve activity and muscle blood flow, and, in addition, exercise tolerance in hospitalised patients for stabilisation of heart failure. Thirty patients hospitalised for treatment of decompensated heart failure, class IV New York Heart Association and ejection fraction ≤ 30% were consecutively randomly assigned into two groups: functional electrical stimulation (n = 15; 54 ± 2 years) and control (n = 15; 49 ± 2 years). Muscle sympathetic nerve activity was directly recorded via microneurography and blood flow by venous occlusion plethysmography. Heart rate and blood pressure were evaluated on a beat-to-beat basis (Finometer), exercise tolerance by 6-minute walk test, quadriceps muscle strength by a dynamometer and quality of life by Minnesota questionnaire. Functional electrical stimulation consisted of stimulating the lower limbs at 10 Hz frequency, 150 ms pulse width and 70 mA intensity for 60 minutes/day for 8-10 consecutive days. The control group underwent electrical stimulation at an intensity of < 20 mA. Baseline characteristics were similar between groups, except age that was higher and C-reactive protein and forearm blood flow that were smaller in the functional electrical stimulation group. Functional electrical stimulation significantly decreased muscle sympathetic nerve activity and increased muscle blood flow and muscle strength. No changes were found in the control group. Walking distance and quality of life increased in both groups. However, these changes were greater in the functional electrical stimulation group. Functional electrical stimulation improves muscle sympathetic nerve activity and vasoconstriction and increases exercise tolerance, muscle strength and quality of life in hospitalised heart failure patients. These findings suggest that functional electrical stimulation may be useful to hospitalised patients with decompensated chronic heart failure.

Exercise Training Increases Baroreflex Control of Heart Rate and Decreases Muscle Sympathetic Nerve Activity in Chronic Chagasic Cardiomyopathy Patients

Asymptomatic or mild symptomatic chronic chagasic cardiomyopathy (CCC) patients even with preserved ventricular function already have autonomic dysfunction. It is well known that decreased baroreflex control of heart rate (HR) and increased muscle sympathetic nerve activity (MSNA) increases mortality of patients with ventricular dysfunction to mortality, and that exercise training (ET) improves cardiovascular autonomic function of these patients. However, the effects of ET on baroreflex control of HR and MSNA in CCC patients with preserved ventricular function are unknown. We hypothesized that ET would increase baroreflex control of HR and decrease MSNA of these patients. Twenty CCC patients with electrocardiographic alterations and ejection fraction (EF)&gt;55% were randomly divided into 2 groups: exercise‐trained (n=8; 47.8±2.5 yrs) and untrained (n=12, 51.7±2.4 yrs). Baroreflex control of HR (ECG) was assessed by stepwise intravenous infusions of phenylephrine and sodium nitroprusside and analyzed by linear regression. MSNA was measured using microneurography. BP was monitored on a beat‐to‐beat basis. Peak VO2 was determined by cardiopulmonary exercise test and cardiac function by echocardiography. ET consisted of three 60‐minute exercise sessions per week on a cycle ergometer for four months. There were no significant differences in gender, age and body mass index among groups. Under baseline conditions (before training), HR, BP, Peak VO2, MSNA and baroreflex control of HR were similar among groups. ET decreased resting HR (67.8±3.6 vs 59.7±3.7 bpm, P=0.009) and increased peak VO2 (25.5±2.6 vs 29.6±1.5 ml/kg/min, P=0.04) whereas there was no change in BP. ET increased baroreflex control of HR in response to phenylephrine infusion (0.24±0.1 vs 0.46±0.1, P=0.01). Furthermore, ET also reduced MSNA (31.8±3.3 vs 22.4±2.8 bursts/min, P=0.04). In conclusion, ET enhanced cardiovascular autonomic function in CCC patients with electrocardiographic alterations and preserved ventricular function. These findings highlight importance of including ET in the treatment of these patients which may lead to a better prognosis of them.Support or Funding InformationThis study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP ‐ #2011/17533‐6d) and, in part, by Fundação Zerbini. Adriana O Sarmento was supported by Conselho Nacional de Pesquisa (CNPq, #142179/2013‐2). Ligia M Antunes‐Correa was supported by FAPESP (#2013/15651‐7). Denise ML Lobo was supported by Conselho Nacional de Pesquisa (CNPq #140265/2013‐9). Carlos E Negrao and Maria UPB Rondon were supported by CNPq (#301867/2010‐0 and #308068/2011‐4, respectively).

N-Acetylcysteine reduces hyperacute intermittent hypoxia-induced sympathoexcitation in human subjects.

What is the central question of this study? This study evaluated the following central question: does N-acetylcysteine (N-AC), an antioxidant that readily penetrates the blood-brain barrier, have the capability to reduce the increase in sympathetic nerve activity observed during hyperacute intermittent hypoxia? What is the main finding and its importance? We demonstrate that N-AC decreases muscle sympathetic nerve activity in response to hyperacute intermittent hypoxia versus placebo control. This finding suggests that antioxidants, such as N-AC, have therapeutic potential in obstructive sleep apnoea. This investigation tested the following hypotheses: that (i) N-acetylcysteine (N-AC) attenuates hyperacute intermittent hypoxia-induced sympathoexcitation, (ii) without elevating superoxide measured in peripheral venous blood. Twenty-eight healthy human subjects were recruited to the study. One hour before experimentation, each subject randomly ingested either 70 mg kg(-1) of N-AC (n = 16) or vehicle placebo (n = 12). Three-lead ECG and arterial blood pressure, muscle sympathetic nerve activity (n = 17) and whole-blood superoxide concentration (using electron paramagnetic resonance spectroscopy; n = 12) were measured. Subjects underwent a 20 min hyperacute intermittent hypoxia training (hAIHT) protocol that consisted of cyclical end-expiratory apnoeas with 100% nitrogen. N-AC decreased muscle sympathetic nerve activity after hAIHT compared with placebo (P < 0.02). However, N-AC did not alter superoxide concentrations in venous blood compared with placebo (P > 0.05). Moreover, hAIHT did not increase superoxide concentrations in the peripheral circulation as measured by electron paramagnetic resonance (P > 0.05). Based on these findings, we contend that (i) hAIHT and (ii) the actions of N-AC in hAIHT are primarily mediated centrally rather than peripherally, although central measurements of reactive oxygen species are difficult to obtain in human subjects, thus making this assertion difficult to verify. This investigation suggests the possibility of developing a pharmaceutical therapy to inhibit the sympathoexcitation associated with obstructive sleep apnoea.

Increase in paced heart rate reduces muscle sympathetic nerve activity in heart failure patients treated with cardiac resynchronization therapy.

To test the hypothesis that acute increased biventricularly (BiV) paced heart rate (pHR) results in decreased muscle sympathetic nerve activity (MSNA), and that dyssynchronous pacing (AAI) attenuates this effect, in heart failure patients receiving cardiac resynchronization therapy (CRT). Fourteen CRT patients (NYHA II-III, 12 males, mean EF 28 ± 14%) were recruited. Three different pHRs (50-90 b.p.m.) were randomly programmed in BiV- and AAI-pacing modes. Muscle sympathetic nerve activity (total sympathetic nerve activity/min (units) and number of bursts/100 RR) were recorded from the peroneal nerve using a microelectrode. In addition, cardiac output (CO) and mean blood pressure (mBP) were measured. With BiV pacing, the total MSNA/min was lower at 70 b.p.m. (-7 ± 21%, P = 0.18) and 90 b.p.m. (-29 ± 18%, P = 0.01) compared with at 50 b.p.m. (280 ± 180 U). Similarly, bursts/100RR decreased with increased BiV pHR. Cardiac output (3.7 L/min at 50 b.p.m., +12 ± 12% at 70 b.p.m., and +18 ± 19% at 90 b.p.m.) and mBP (78 ± 11 mmHg at 50 b.p.m., +6 ± 6% at 70 b.p.m. and +11 ± 8% at 90 b.p.m.) increased significantly at elevated pHRs in BiV-pacing mode. The effect on MSNA, CO, and mBP was less pronounced in AAImode but we found no significant differences between the pacing modes. Increased pHR acutely reduces MSNA and improves haemodynamics in HF patients treated with CRT with no evident differences between BiV- and AAI-pacing modes. Further studies are warranted to guide the programming of basic pHR in CRT patients.

Abstract 18671: Exercise Training Associated With Testosterone Replacement Decreases Muscle Sympathetic Nerve Activity in Heart Failure Patients With Hypogonadism

Purpose: Heart failure (HF) is characterized by increase in muscle sympathetic nerve activity (MSNA). Advanced HF can be associated to testosterone deficiency. Study with HF patients and testosterone therapy showed improvement in VO2 and baroreflex sensitivity. The role of exercise with or without testosterone is unknown. Therefore, the aim of the study was to investigate if aerobic exercise with or without testosterone replacement decreases MSNA. Methods: 24 HF patients (52±2 yr) with low testosterone, FC III (NYHA) and LVEF 26±2%, were divided: Exercise Training (ET,n=9) Testosterone (Testo,n=8) and Exercise Training+Testosterone (ET+Testo,n=7). Total (TT) and free (FT) testosterone and SHBG were measured. Testosterone deficiency was characterized as TT &lt;350 ng/dL and FT &lt;131 pmol/L. Cardiopulmonary exercise was performed on bike. MSNA was measured by microneurography. Both groups Testo and ET+Testo were treated with undecilate of testosterone (intramuscular) at the beginning of the protocol and were monitored monthly. The exercise consisted in three 40-minutes sessions per week on an ergometer bike. Exercise intensity was between anaerobic threshold and respiratory compensation point. Results: After 4 months, TT and FT were restored in ET (307±40 to 429±93 ng/dL; p&lt;.001 and 160±26 to 246±50 pmol/L; p&lt;.001), Testo (279±33 to 575±66 ng/dL; p&lt;.001 and 137±18 to 381±55 pmol/L; p&lt;.001) and ET+Testo (223±18 to 497±82 ng/dL; p&lt;.001 and 135±22 to 353±49 pmol/L; p&lt;.001) groups. Peak VO2 increased in ET (14.76±1.60 to 18.06±2.26 ml/kg/min; p=.01), Testo (19.33±1.87 to 20.34±2.08 ml/kg/min; p=.01) and ET+Testo (17.61±1.37 to 20.63±2.72 ml/kg/min; p=.01). Maximal power (watts) was increased only within ET+Testo (75±8 to 129±21 watts; p&lt;.001). MSNA decreased in ET (49±4 to 34±1 bursts/min; p=.02) and ET+Testo (61±4 to 32±2 bursts/min; p&lt;.001) but was not different within Testo (39±4 to 34±3 bursts/min; p=.89). Conclusion: Functional capacity increased in all groups, but only ET+Testo improved muscle strength. Interestingly, exercise alone was able to restore testosterone. In addition, ET and ET+Testo reduced MSNA. These findings emphasize that ET and testosterone together should be included in the treatment of HF patients with hypogonadism.

Acute electromyostimulation Decreases Muscle Sympathetic Nerve Activity in Patients with Advanced Chronic Heart Failure (EMSICA Study)

BackgroundMuscle passive contraction of lower limb by neuromuscular electrostimulation (NMES) is frequently used in chronic heart failure (CHF) patients but no data are available concerning its action on sympathetic activity. However, Transcutaneous Electrical Nerve Stimulation (TENS) is able to improve baroreflex in CHF. The primary aim of the present study was to investigate the acute effect of TENS and NMES compared to Sham stimulation on sympathetic overactivity as assessed by Muscle Sympathetic Nerve Activity (MSNA).MethodsWe performed a serie of two parallel, randomized, double blinded and sham controlled protocols in twenty-two CHF patients in New York Heart Association (NYHA) Class III. Half of them performed stimulation by TENS, and the others tested NMES.ResultsCompare to Sham stimulation, both TENS and NMES are able to reduce MSNA (63.5 ± 3.5 vs 69.7 ± 3.1 bursts / min, p < 0.01 after TENS and 51.6 ± 3.3 vs 56.7 ± 3.3 bursts / min, p < 0, 01 after NMES). No variation of blood pressure, heart rate or respiratory parameters was observed after stimulation.ConclusionThe results suggest that sensory stimulation of lower limbs by electrical device, either TENS or NMES, could inhibit sympathetic outflow directed to legs in CHF patients. These properties could benefits CHF patients and pave the way for a new non-pharmacological approach of CHF.

Roles of Sex Steroid Hormones and Nitric Oxide in the Regulation of Sympathetic Nerve Activity in Women

HomeHypertensionVol. 61, No. 4Roles of Sex Steroid Hormones and Nitric Oxide in the Regulation of Sympathetic Nerve Activity in Women Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBRoles of Sex Steroid Hormones and Nitric Oxide in the Regulation of Sympathetic Nerve Activity in Women Kazushi Tsuda Kazushi TsudaKazushi Tsuda Cardiovascular and Metabolic Research CenterKansai University of Health SciencesOsaka, Japan Search for more papers by this author Originally published4 Mar 2013https://doi.org/10.1161/HYPERTENSIONAHA.111.01075Hypertension. 2013;61:e36Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2013: Previous Version 1 To the Editor:We read with great interest the article by Dr Carter et al1 dealing with the relationship between ovarian cycle and sympathoexcitation in premenopausal women. The results of their study demonstrated that the mid luteal phase of the ovarian cycle was characterized by sympathoexcitation, and that the degree of sympathoexcitation might be partially dependent on the degree of sex steroid surges. The authors indicated that increases in estradiol were associated with decreases in muscle sympathetic nerve activity during the the mid luteal phase, suggesting that estradiol might be sympathoinhibitory. In addition, the strong inverse association between muscle sympathetic nerve activity and changes in estradiol/progesterone ratio was observed. The authors proposed that a dynamic interaction among estradiol, progesterone, and muscle sympathetic nerve activity may be related to the cardiovascular risk in postmenopausal women.Evidence indicates that one of the mechanisms underlying the cardiovascular protective effects of estrogen may be the enhancement of NO production. In an in vitro study presented earlier, we demonstrated that 17β-estradiol significantly improved membrane microviscosity of red blood cells through the NO-dependent mechanism in postmenopausal women.2 It was also shown that hormone replacement therapy ameliorated membrane microviscosity of red blood cells with a concomitant increase in plasma NO-metabolite levels in postmenopausal women.3 In this context, it is strongly suggested that estrogen-induced NO might have a beneficial effect on the rheological behavior and the microcirculation in postmenopausal women. Vongpatanasin et al4 have reported that transdermal estrogen replacement therapy decreased muscle sympathetic nerve activity at rest in postmenopausal women. On the contrary, it was demonstrated that acute intravenous administration of NO synthase inhibitors might increase blood pressure and activate sympathetic nerve activity,5 suggesting that NO might act as a sympathoinhibitory substance. Therefore, we would like to know whether the degree of estradiol and estradiol/progesterone ratio during the ovarian cycle might be correlated with the endothelial function, such as plasma and urinary NO-metabolite levels or flow-mediated dilatation of the brachial artery, in the study of Dr Carter et al. It would be important to assess more precisely the relationships among estrogen, progesterone, and NO, and their role in the regulation of sympathetic nerve activity during sex steroid surges.Kazushi TsudaCardiovascular and Metabolic Research CenterKansai University of Health SciencesOsaka, JapanDisclosuresNone.FootnotesLetters to the Editor will be published, if suitable, as space permits. They should not exceed 500 words (typed double-spaced) plus 5 references in length and may be subject to editing or abridgment.

Simvastatin reduces sympathetic activity in men with hypertension and hypercholesterolemia

Beyond their hypolipidemic effect, statins reduce cardiovascular risk in hypertensive subjects via various mechanisms; one suggested mechanism is that they reduce sympathetic activity. We investigated the hypothesis that simvastatin decreased muscle sympathetic nerve activity (MSNA) in 31 hypertensive subjects with hypercholesterolemia (aged 38.7 ± 10 years). In this randomized, placebo-controlled, double-blinded study, patients were treated with simvastatin (40 mg day(-1); n=15) or placebo (n=16) for 8 weeks. Before and after treatment, we measured MSNA, blood pressure and heart rate. Baroreceptor control of the heart rate, or baroreceptor sensitivity (BRS), was computed by the sequence method, a cross-analysis of systolic blood pressure and the electrocardiogram R-R interval. Blood samples were tested for plasma levels of catecholamines, neuropeptide Y, aldosterone, endothelin and renin activity. Simvastatin significantly reduced MSNA (from 36.5 ± 5 to 27.8 ± 6 bursts per min, P=0.001), heart rate (from 77 ± 6.7 to 71 ± 6.1 beats per min, P=0.01) and both total and low-density lipoprotein cholesterol (from 249 ± 30.6 to 184 ± 28.3 mg dl(-1), P=0.001 and from 169 ± 30.6 to 117 ± 31.2 mg dl(-1), P=0.01, respectively). Simvastatin also improved BRS (from 10.3 ± 4.1 to 17.1 ± 4.3 ms per mm Hg, P=0.04). No changes were observed in systolic or diastolic blood pressures, or in plasma levels of catecholamines, neuropeptide Y, endothelin, aldosterone and renin activity. After simvastatin therapy, MSNA and BRS were inversely related (r=-0.94, P<0.05). In conclusion, we found that, in patients with hypertension and hypercholesterolemia, simvastatin reduced MSNA, and this was related to increased baroreceptor sensitivity.

Differential Effects of Oral β Blockade on Cardiovascular and Sympathetic Regulation

In patients with hypertension, beta blockade decreases muscle sympathetic nerve activity (MSNA; micrographic technique) expressed in burst frequency (burst/min) but does not affect MSNA expressed in burst incidence (burst/100 heart beats), because reductions in blood pressure (BP) upon each diastole continue to deactivate the arterial baroreceptors, but at a slower heart rate (HR). We studied the effects of oral beta blockade on MSNA and baroreflex sensitivity (BRS) in normal participants. Bisoprolol (5 mg, 1 week) was administered in 10 healthy young adults, using a double-blind, placebo-controlled, randomized cross-over study design. The beat-to-beat mean RR interval (RR) and systolic blood pressure (SBP) series were analyzed by power spectral analysis and power computation over the very low frequency (VLF), low frequency, and high frequency (HF) bands. Baroreflex sensitivity was computed from SBP and RR cross-analysis, using time and frequency domain methods. Bisoprolol increased RR (P < .0005), decreased mean SBP and diastolic blood pressure values (P < .01), did not change the SBP and RR powers, except for RR power in VLF (P < .02) and SBP power in HF (P < .03). The MSNA variability (P > .13) and respiratory pattern (P = .84) did not change from placebo to bisoprolol condition. The bisoprolol-induced bradycardia was associated with higher burst/100 heart beats (P < .05) and bisoprolol did not affect burst/min (P = .80). Time domain BRS estimates were increased after bisoprolol (P < .05), while frequency domain ones did not change (P > .1). Oral bisoprolol induces differential effects on sympathetic burst frequency and incidence in normal participants. Peripheral sympathetic outflow over time is preserved as a result of an increased burst incidence, in the presence of a slower HR. Unchanged BP and HR and MSNA variability suggests that the larger burst incidence is not due to sympathetic activation.

Antecedent Hypoglycemia Impairs Autonomic Cardiovascular Function

OBJECTIVE— Glycemic control decreases the incidence and progression of diabetic complications but increases the incidence of hypoglycemia. Hypoglycemia can impair hormonal and autonomic responses to subsequent hypoglycemia. Intensive glycemic control may increase mortality in individuals with type 2 diabetes at high risk for cardiovascular complications. We tested the hypothesis that prior exposure to hypoglycemia leads to impaired cardiovascular autonomic function.RESEARCH DESIGN AND METHODS— Twenty healthy subjects (age 28 ± 2 years; 10 men) participated in two 3-day inpatient visits, separated by 1–3 months. Autonomic testing was performed on days 1 and 3 to measure sympathetic, parasympathetic, and baroreflex function. A 2-h hyperinsulinemic [hypoglycemic (2.8 mmol/l) or euglycemic (5.0 mmol/l)] clamp was performed in the morning and in the afternoon of day 2.RESULTS— Comparison of the day 3 autonomic measurements demonstrated that antecedent hypoglycemia leads to 1) reduced baroreflex sensitivity (16.7 ± 1.8 vs. 13.8 ± 1.4 ms/mmHg, P = 0.03); 2) decreased muscle sympathetic nerve activity response to transient nitroprusside-induced hypotension (53.3 ± 3.7 vs. 40.1 ± 2.7 bursts/min, P < 0.01); and 3) reduced (P < 0.001) plasma norepinephrine response to lower body negative pressure (3.0 ± 0.3 vs. 2.0 ± 0.2 nmol/l at −40 mmHg).CONCLUSIONS— Baroreflex sensitivity and the sympathetic response to hypotensive stress are attenuated after antecedent hypoglycemia. Because impaired autonomic function, including decreased cardiac vagal baroreflex sensitivity, may contribute directly to mortality in diabetes and cardiovascular disease, our findings raise new concerns regarding the consequences of hypoglycemia.

Cigarette Smoking Augments Sympathetic Nerve Activity in Patients With Coronary Heart Disease

It has been shown that cigarette smoking increases blood pressure (BP) and heart rate (HR), and decreases muscle sympathetic nerve activity (MSNA) in healthy young smokers. The decrease in MSNA might be secondary to baroreflex responses to the pressor effect. We tested the hypothesis that cigarette smoking increases MSNA in smokers with impaired baroreflex function. The effects of cigarette smoking on BP, HR, forearm blood flow (FBF), forearm vascular resistance (FVR), and MSNA were examined in 14 patients with stable effort angina (59+/-3 years, group CAD) and 10 healthy smokers (23+/-1 years, group C). In group CAD, the arterial baroreflex sensitivity (BRS) was significantly lower than in group C (4.7+/-0.8 versus 15.1+/-2.2 msec/mmHg, P<0.01). In both groups, cigarette smoking increased the plasma concentration of nicotine, systolic and diastolic BP, HR, and FVR significantly (P<0.01), but decreased FBF significantly (P<0.01). After smoking, MSNA was decreased significantly in group C (from 35.2+/-3.5 to 23.5+/-3.2 bursts/100 beats, P<0.01), but increased significantly in group CAD (from 48.8+/-5.4 to 57.3+/-5.5 bursts/100 beats, P<0.01). There was significant correlation between BRS and changes in MSNA (r= -0.62, P<0.01). Cigarette smoking increased MSNA in smokers with impaired baroreflex function. This demonstrates that cigarette smoking stimulates sympathetic nerve activity by both a direct peripheral effect and a centrally mediated effect.

Exercise training reduces sympathetic nerve activity in heart failure patients treated with carvedilol

Evidence suggests that carvedilol decreases muscle sympathetic nerve activity (MSNA) in patients with heart failure (HF) but carvedilol fails to improve forearm vascular resistance and overall functional capacity. Exercise training in HF reduces MSNA and improves forearm vascular resistance and functional capacity. To investigate whether the beneficial effects exercise training on MSNA are maintained in the presence of carvedilol. Twenty seven HF patients, NYHA Class II-III, EF <35%, peak VO(2) <20 ml/kg/min, treated with carvedilol were randomly divided into two groups: exercise training (n=15) and untrained (n=12). MSNA was recorded by microneurography. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. The four-month training program consisted of three 60-min exercise/week on a cycloergometer. Baseline parameters were similar between groups. Exercise training reduced MSNA (-14+/-3.3 bursts/100 HB, p=0.001) and increased forearm blood flow (0.6+/-0.1 mL/min/100 g, p<0.001) in HF patients on carvedilol. In addition, exercise training improved peak VO(2) in HF patients (20+/-6%, p=0.002). MSNA, FBF and peak VO(2) were unchanged in untrained HF patients on carvedilol. Exercise training reduces MSNA in heart failure patients treated with carvedilol. In addition, the beneficial effects of exercise training on muscle blood flow and functional capacity are still realized in patients on carvedilol.

Sympathetic control after cardiac resynchronization therapy: responders versus nonresponders

Cardiac resynchronization therapy (CRT) decreases muscle sympathetic nerve activity (MSNA) in patients with severe congestive heart failure (CHF) and cardiac asynchrony. Whether this affects equally patients who clinically respond or not to CRT is unknown. We tested the hypothesis that the favorable effects of CRT on MSNA disappear on CRT interruption only in those who respond to CRT. Twenty-three consecutive CHF patients participated in the study, among whom 16 presented a symptomatic improvement by one or more New York Heart Association (NYHA) functional classes 15 +/- 5 mo after CRT (responders), and seven had not improved after 12 +/- 4 mo of CRT (nonresponders). MSNA and echocardiographic recordings were obtained in random order during atrio-right ventricular pacing (ARV), without stimulation in patients who were not pacemaker dependent (OFF, n = 17), and during atrio-biventricular pacing (BIV). Responders had a longer 6-min walking distance, a lower NYHA class and brain natriuretic peptide levels, and a better quality of life than did nonresponders (all P < 0.05). MSNA increased by 25 +/- 7% in the responders, whereas it remained unchanged in the nonresponders, when shifting from the BIV mode to a nonsynchronous condition (ARV and OFF modes) (P < 0.01). Cardiac output decreased by 0.7 +/- 0.2 l/min in the responders but did not change when shifting from the BIV mode to the nonsynchronous pacing mode in the nonresponders (P < 0.01). In conclusion, reversible sympathoinhibition is a marker of the clinical response to CRT.

Decreased muscle sympathetic nerve activity does not explain increased vascular conductance during contralateral isometric exercise in humans

At the onset of both electrically evoked (STIM) and voluntary (VOL) isometric calf exercise there is an increase in vascular conductance of the contralateral lower limb, suggesting withdrawal of muscle sympathetic nerve activity (MSNA). Seven subjects performed STIM or VOL ischaemic calf exercise at 30% maximum voluntary contraction in a seated position. Blood pressure, heart rate and peroneal MSNA in the resting contralateral lower limb were recorded. During both STIM and VOL exercise blood pressure increased (P < 0.05). Blood flow increased by 40 +/- 3 and 35 +/- 3% and conductance increased by 37 +/- 3 and 31 +/- 4% (P < 0.05) after 10 s of STIM and VOL, respectively, and thereafter declined. The time course and direction of these changes persisted with subjects in a semisupine position, confirming that the transient conductance changes were not an artefact of the dependent leg position. Thigh cuff inflation for 1 min without exercise caused a 47 +/- 7.5% (P < 0.05) reduction in MSNA, which recovered when the circulation was restored. However, when cuff inflation was followed by STIM or VOL exercise, MSNA did not fall further. These data suggest that the transient increase in vascular conductance at the onset of contralateral electrically evoked or voluntary lower limb exercise is unrelated to MSNA.

Sympathetic nerve activity in obstructive sleep apnoea.

The mechanisms underlying the link between obstructive sleep apnoea (OSA) and cardiovascular disease are not completely established. However, there is increasing evidence that autonomic mechanisms are implicated. A number of studies have consistently shown that patients with OSA have high levels of sympathetic nerve traffic. During sleep, repetitive episodes of hypoxia, hypercapnia and obstructive apnoea act through chemoreceptor reflexes and other mechanisms to increase sympathetic drive. Remarkably, the high sympathetic drive is present even during daytime wakefulness when subjects are breathing normally and no evidence of hypoxia or chemoreflex activation is apparent. Several neural and humoral mechanisms may contribute to maintenance of higher sympathetic activity and blood pressure. These mechanisms include chemoreflex and baroreflex dysfunction, altered cardiovascular variability, vasoconstrictor effects of nocturnal endothelin release and endothelial dysfunction. Long-term continuous positive airway pressure treatment decreases muscle sympathetic nerve activity in OSA patients. The vast majority of OSA patients remain undiagnosed. Unrecognized OSA may contribute, in part, to the metabolic and cardiovascular derangements that are thought to be linked to obesity, and to the association between obesity and cardiovascular risk. Furthermore, acting through sympathetic neural mechanisms, OSA may contribute to or augment elevated levels of blood pressure in a large proportion of the hypertensive patient population.