Muscle Sympathetic Nerve Activity Activity Research Articles

The interactive effects of age and sex on the neuro-cardiovascular responses during fatiguing rhythmic handgrip exercise.

The impact of age on exercise pressor responses is equivocal, likely because of sex-specific neuro-cardiovascular changes with age. However, assessments of the interactive effects of age and sex on muscle sympathetic nerve activity (MSNA) responses to exercise are lacking. We tested the hypothesis that older females would exhibit exaggerated increases in blood pressure (BP) and MSNA discharge patterns during handgrip exercise compared with similarly aged males and young adults. Twenty-five young (25 (2) years; mean (SD)) males (YM; n=12) and females (YF; n=13) and 23 older (71 (5) years) males (OM; n=11) and females (OF; n=12) underwent assessments of BP, total peripheral resistance (TPR; Modelflow) and MSNA action potential (AP) discharge patterns (microneurography) during incremental rhythmic handgrip exercise and post-exercise circulatory occlusion (PECO). OM demonstrated larger ∆BP and ∆TPR from baseline than YM (both P < 0.001) despite smaller increases in ∆APs/burst (OM: 0.4 (3) vs. YM: 5 (3) spikes/burst, P < 0.001) and ∆AP clusters/burst (OM: 0.1 (1) vs. YM: 1.8 (1) clusters/burst, P < 0.001) during exercise. Testosterone was lower in OM than YM (P < 0.001) and was inversely related to ∆BP but positively related to ∆AP clusters/burst in males (both P=0.03). Conversely, YF and OF demonstrated similar ∆BP and ∆AP discharge during exercise (range: P=0.75-0.96). Age and sex did not impact haemodynamics or AP discharge during PECO (range: P=0.08-0.94). Altogether, age-related changes in neuro-cardiovascular reactivity exist in males but not females during fatiguing exercise and seem to be related to testosterone. This sex-specific impact of age underscores the importance of considering biological sex when assessing age-related changes in neuro-cardiovascular control during exercise. KEY POINTS: Older males have the largest increase in blood pressure despite having the smallest increases in sympathetic vasomotor outflow during rhythmic handgrip exercise. Young males demonstrate greater increases in sympathetic action potential (AP) discharge compared with young females during rhythmic handgrip exercise. Older adults (regardless of sex) demonstrate smaller increases in muscle sympathetic nerve activity (MSNA) burst amplitude and total AP clusters compared with young adults during exercise, as well as smaller increases in integrated MSNA burst frequency, incidence and total MSNA activity during post-exercise circulatory occlusion (i.e. independent effect of age). Males, but not females (regardless of age), reflexively modify AP conduction velocity during exercise. Our results indicate that age and sex independently and interactively impact the neural and cardiovascular homeostatic adjustments to fatiguing small muscle mass exercise.

Different Relationship Between Glycemic Status and Autonomic Function in Patients with Type 2 Diabetes Mellitus and in Healthy Controls

Autonomic neuropathy is a common complication in diabetes mellitus (DM). Decreased vagal nerve activity and augmented sympathetic nerve activity have been reported in patients with DM. However, the relationship between autonomic function and glycemic status in DM and in individuals without DM remains unclear. We hypothesized that indices of sympathetic and vagal nerve activity are related to glycemic status. Eleven patients who were clinically diagnosed with type‐2 DM (HbA1c, 6.8 ± 0.3%; age, 54 ± 3 yrs), and 20 healthy non‐DM individuals (including 10 pre‐DM; HbA1c &lt; 6.5%; range 5.1‐6.1%; age, 59 ± 2 yrs) were studied (19 male, 12 female). Five DM patients had hypertension. Patients with DM and hypertensives were treated with standard medications. Beat‐by‐beat blood pressure (BP), heart rate (HR) and muscle sympathetic nerve activity (MSNA) were recorded under resting conditions. HR variability (HRV) was calculated and spontaneous cardiovagal baroreflex sensitivity (CBRS) was evaluated with the sequence method. CBRS in DM was lower than in non‐DM subjects (P &lt; 0.05). MSNA in DM was also lower than in non‐DM subjects (P &lt; 0.05). In linear regression analyses with data from all subjects, CBRS was negatively correlated with fasting blood glucose (FBG) (R = ‐0.47), insulin (R = ‐0.42), and homeostasis model assessment of insulin resistance (HOMA‐IR) (R = ‐0.43) (P &lt; 0.05 for all). MSNA was negatively correlated with HbA1c and HOMA‐IR (R = ‐0.41, ‐0.42, respectively; both, P &lt; 0.05). The high frequency (HF) component of HRV (i.e., an index of vagal tone) was negatively correlated with insulin (R = ‐0.46) and HOMA‐IR (R = ‐0.42) in all subjects (P &lt; 0.05 for both). In non‐DM subjects, CBRS was negatively correlated with FBG (R = ‐0.53, P &lt;0.05). HF was negatively correlated with FBG (R = ‐0.51), insulin (R = ‐0.66), and HOMA‐IR (R = ‐0.66) (P &lt; 0.05 for all), but MSNA was not correlated with glycemic/insulin status in non‐DM subjects. Whereas in DM patients, MSNA tended to be negatively correlated with HOMA‐IR (R = ‐0.77, P = 0.07). In the present study, both MSNA and vagal activity (CBRS and HF) were decreased in relation to the glycemic/insulin status. Vagal nerve activity was associated with the glycemic/insulin status even in non‐DM subjects (i.e., healthy and pre‐DM). Based on these results, we speculate that both vagal and sympathetic nerves were injured by DM progression, and that vagal neuropathy preceded the sympathetic neuropathy. Our results differ from prior reports that showed that MSNA in DM was higher than in non‐DM. However, in our study subjects, the severity of DM was mild, and except for hypertension in 5 subjects, none had manifestations of diabetic end‐organ damage. Differences in the duration and severity of DM as well as the effects of the treatments could contribute to the differences in the results. Further studies on the autonomic function during the DM progression are warranted.

Does COVID‐19 influence the sympathetic regulation of blood pressure?

Does COVID‐19 influence the sympathetic regulation of blood pressure?

Sympathetic Effect of Auricular Transcutaneous Vagus Nerve Stimulation on Healthy Subjects: A Crossover Controlled Clinical Trial Comparing Vagally Mediated and Active Control Stimulation Using Microneurography.

Introduction: Auricular low-level transcutaneous vagus nerve stimulation (aLL-tVNS) has emerged as a promising technology for cardiac arrhythmia management but is still experimental. In this physiological study, we hypothesized that aLL-tVNS modulated the autonomic nervous balance through a reduction of sympathetic tone and an increase in heart rate variability (HRV). We investigated the muscle sympathetic nerve activity (MSNA) recorded by microneurography during vagally mediated aLL-tVNS and active control on healthy volunteers. Methods: In this crossover, double-blind controlled study, healthy men (N = 28; 27 ± 4 years old) were assigned to aLL-tVNS applied to cymba and lobe (active control) of the right ear. Each participant was randomly allocated to the three sequences (5 Hz, 20 Hz, and active control-5 Hz) during one session. MSNA signal was recorded at rest, during voluntarily apnea and aLL-tVNS. Sympathetic activity was expressed as: 1) number of bursts per minute (burst frequency, BF) and 2) MSNA activity calculated as BF x mean burst amplitude and expressed as changes from baseline (%). RR intervals, HRV parameters and sympathetic activity were analyzed during 5 min-baseline, 10 min-stimulation, and 10 min-recovery periods. Mixed regression models were performed to evaluate cymba-(5—20 Hz) effects on the parameters with stimulation. Results: During apnea and compared to baseline, BF and MSNA activity increased (p = 0.002, p = 0.001, respectively). No stimulation effect on RR intervals and HRV parameters were showed excepted a slightly increase of the LF/HF ratio with stimulation in the cymba-5Hz sequence (coef. ± SE: 0.76 ± 0.32%; p = 0.02). During stimulation, reductions from baseline in BF (Coef. ± SE: −4.8 ± 1.1, p < 0.001) was observed but was not statistically different from that one in the active control. Reduction of MSNA activity was not significantly different between sequences. Conclusion: Acute right cymba aLL-tVNS did not induce any overall effects neither on heart rate, HRV nor MSNA variables on healthy subjects when compared to active control. Interestingly, these findings questioned the role of active controls in medical device clinical trials that implied subjective endpoints.

PERSONALIZED EXERCISE TRAINING PROGRAM AS A COUNTERMEASURE TO ORTHOSTATIC INTOLERANCE AFTER SPACE FLIGHTS.

PERSONALIZED EXERCISE TRAINING PROGRAM AS A COUNTERMEASURE TO ORTHOSTATIC INTOLERANCE AFTER SPACE FLIGHTS.

Vestibular Modulation of Sympathetic Nerve Activity to Muscle and Skin in Humans.

We review the existence of vestibulosympathetic reflexes in humans. While several methods to activate the human vestibular apparatus have been used, galvanic vestibular stimulation (GVS) is a means of selectively modulating vestibular afferent activity via electrodes over the mastoid processes, causing robust vestibular illusions of side-to-side movement. Sinusoidal GVS (sGVS) causes partial entrainment of sympathetic outflow to muscle and skin. Modulation of muscle sympathetic nerve activity (MSNA) from vestibular inputs competes with baroreceptor inputs, with stronger temporal coupling to the vestibular stimulus being observed at frequencies remote from the cardiac frequency; “super entrainment” was observed in some individuals. Low-frequency (<0.2 Hz) sGVS revealed two peaks of modulation per cycle, with bilateral recordings of MSNA or skin sympathetic nerve activity, providing evidence of lateralization of sympathetic outflow during vestibular stimulation. However, it should be noted that GVS influences the firing of afferents from the entire vestibular apparatus, including the semicircular canals. To identify the specific source of vestibular input responsible for the generation of vestibulosympathetic reflexes, we used low-frequency (<0.2 Hz) sinusoidal linear acceleration of seated or supine subjects to, respectively, target the utricular or saccular components of the otoliths. While others had discounted the semicircular canals, we showed that the contributions of the utricle and saccule to the vestibular modulation of MSNA are very similar. Moreover, that modulation of MSNA occurs at accelerations well below levels at which subjects are able to perceive any motion indicates that, like vestibulospinal control of posture, the vestibular system contributes to the control of blood pressure through potent reflexes in humans.

The impact of baroreflex function on endogenous pain control: a microneurography study.

The interaction between sympathetic vasoconstrictor activity to muscles [muscle sympathetic nerve activity (MSNA), burst frequency (BF) and burst incidence (BI)] and different stress and somatosensory stimuli is still unclear. Eighteen healthy men (median age 28 years) underwent microneurography recordings from the peroneal nerve. MSNA was recorded during heat pain (HP) and cold pain (CP) alone as well as combined with different stress tasks (mental arithmetic, singing, giving a speech). An additional nine healthy men (median age 26 years) underwent the stimulation protocol with an additional control task (thermal pain combined with listening to music) to evaluate possible attentional confounders. MSNA was significantly increased by CP and HP. CP-evoked responses were smaller. The diastolic blood pressure followed the time course of MSNA while heart rate remained unchanged. The mental stress tasks further increased MSNA and were sufficient to reduce pain while the control task had no effect. MSNA activity correlated negatively with pain intensity and positively with analgesia. High blood pressure values were associated with lower pain intensity. Our study indicates an impact of central sympathetic drive on pain and pain control.

Identification of Sites of Sympathetic Outflow During Concurrent Recordings of Sympathetic Nerve Activity and fMRI

The sympathetic division of the nervous system is critical for maintaining both resting arterial pressure and for producing changes in regional perfusion required by behavioral state changes. A primary determinant of arterial pressure is the level of vasoconstriction within skeletal muscle. It is well established that there is a tight relationship between dynamic changes in arterial pressure and muscle sympathetic nerve activity (MSNA) through the workings of the baroreflex. While the central circuitry underlying the baroreflex has been extensively investigated in anesthetized experimental animals, few studies have investigated the central circuitry responsible for the baroreflex in awake human subjects. Recently we were the first to record concurrently MSNA (using microneurography) and brain activity (using functional magnetic resonance imaging) in awake humans in a series of experiments designed to determine the central circuitry underlying the baroreflex in humans. We confirmed that the baroreflex involves activity changes within the nucleus tractus solitarius, caudal ventrolateral, and rostral ventrolateral medulla. Because conditions such as essential hypertension, obesity, and obstructive sleep apnea are all characterized by significant increases in resting MSNA, it is important to understand both brainstem and cortical sites involved in regulating resting levels of MSNA. Future investigations which define cortical sites involved in generating and modulating MSNA are important if we are to understand the underlying mechanisms of many conditions characterized by hypertension.

Postural change alters autonomic responses to breath-holding

We used breath-holding during inspiration as a model to study the effect of pulmonary stretch on sympathetic nerve activity. Twelve healthy subjects (7 females, 5 males; 19-27 years) were tested while they performed an inspiratory breath-hold, both supine and during a 60 degrees head-up tilt (HUT 60). Heart rate (HR), mean arterial blood pressure (MAP), respiration, muscle sympathetic nerve activity (MSNA), oxygen saturation (SaO(2)) and end tidal carbon dioxide (ETCO(2)) were recorded. Cardiac output (CO) and total peripheral resistance (TPR) were calculated. While breath-holding, ETCO(2) increased significantly from 41 +/- 2 to 60 +/- 2 Torr during supine (p < 0.05) and 38 +/- 2 Torr to 58 +/- 2 during HUT60 (p < 0.05); SaO(2) decreased from 98 +/- 1.5% to 95 +/- 1.4% supine, and from 97 +/- 1.5% to 94 +/- 1.7% during HUT60 (p = NS). MSNA showed three distinctive phases, a quiescent phase due to pulmonary stretch associated with decreased MAP, HR, CO, and TPR; a second phase of baroreflex-mediated elevated MSNA which was associated with recovery of MAP and HR only during HUT60; CO and peripheral resistance returned to baseline while supine and HUT60; a third phase of further increased MSNA activity related to hypercapnia and associated with increased TPR. Breath-holding results in initial reductions of MSNA, MAP, and HR by the pulmonary stretch reflex followed by increased sympathetic activity related to the arterial baroreflex and chemoreflex.

Role of SNA in the pathophysiology of cardiovascular collapse during syncope: muscle vs. brain

Role of SNA in the pathophysiology of cardiovascular collapse during syncope: muscle <i>vs.</i> brain

Levosimedan improves hemodynamics functions without sympathetic activation in severe heart failure patients: Direct evidence from sympathetic neural recording

Levosimendan is a new inodilatory agent with calcium sensitizing activity. A major concern regarding the use of inotropic agent in heart failure is their effect on the sympathetic tone. This effect could explain increase in short term mortality with other inotropes. We aimed to assess the effect of levosimendan on sympathetic tone measured directly by microneurogra-phy. In a group of acute decompensated heart failure patients, we assessed cardiac performance by digital plethysmography measurement. Sympathetic tone was assessed through recording of muscle sympathetic nerve activity (MSNA) by micro-neurography. Recording were done blindly, for each patient after dobutamine perfusion was stopped (baseline) and 48 h after levosimendan infusion. Clinical, biological and morphological data were collected. We compared cardiac parameters and MSNA before and after administration of levosimendan. 13 patients were recruited (48 +/- 3.6 years). Systolic blood pressure and rate pressure product (mmHg x Beat/min) decreased significantly after levosimendan infusion (P< 0.05). Cardiac output and stroke volume were significantly increased after levosimendan infusion (P< 0.05). A significant decrease of MSNA activity is observed after levosimendan infusion (P< 0.01). Levosimendan induced improvement of cardiac performance, associated with a decreased in MSNA. This study show for the first time that levosimendan has no direct detrimental effect on the sympathetic nervous system.

Slow head-up tilt causes lower activation of muscle sympathetic nerve activity: loading speed dependence of orthostatic sympathetic activation in humans

Many earlier human studies have reported that increasing the tilt angle of head-up tilt (HUT) results in greater muscle sympathetic nerve activity (MSNA) response, indicating the amplitude dependence of sympathetic activation in response to orthostatic stress. However, little is known about whether and how the inclining speed of HUT influences the MSNA response to HUT, independent of the magnitude of HUT. Twelve healthy subjects participated in passive 30 degrees HUT tests at inclining speeds of 1 degrees (control), 0.1 degrees (slow), and 0.0167 degrees (very slow) per second. We recorded MSNA (tibial nerve) by microneurography and assessed nonstationary time-dependent changes of R-R interval variability using a complex demodulation technique. MSNA averaged over every 10 degrees tilt angle increased during inclination from 0 degrees to 30 degrees , with smaller increases in the slow and very slow tests than in the control test. Although a 3-min MSNA overshoot after reaching 30 degrees HUT was observed in the control test, no overshoot was detected in the slow and very slow tests. In contrast with MSNA, increases in heart rate during the inclination and after reaching 30 degrees were similar in these tests, probably because when compared with the control test, greater increases in plasma epinephrine counteracted smaller autonomic responses in the very slow test. These results indicate that slower HUT results in lower activation of MSNA, suggesting that HUT-induced sympathetic activation depends partially on the speed of inclination during HUT in humans.

Lateralization of expression of neural sympathetic activity to the vessels and effects of carotid baroreceptor stimulation

Human studies suggest that cardiovascular neural sympathetic control is predominantly modulated by the right cerebral hemisphere. It is unknown whether post-ganglionic sympathetic activity [muscle sympathetic nerve activity (MSNA)] shows any functional asymmetry. Eight right-handed volunteers (3 women and 5 men, 32 +/- 2 yr of age) underwent ECG, beat-by-beat blood pressure, respiratory activity, and simultaneous right and left MSNA recordings during spontaneous and controlled breathing (CB, 15 breaths/min, 0.25 Hz). Dynamic carotid baroreceptor stimulation was obtained by 0.1-Hz sinusoidal suction, from 0 to -50 mmHg, randomly applied to the right, left, and combined right and left sides of the neck during CB. Laterality was assessed by changes in the MSNA burst rate (in bursts/min, and bursts/100 beats), strength [amplitude (A) and area (AA)], and the oscillatory component at 0.1 Hz during baroreceptor stimulation. Amplitude parameters were normalized by CB burst mean amplitude and area of the same side. At rest, the right and left MSNA burst rate and total MSNA activity were similar. Conversely, the right MSNA normalized burst A(N) (1.36 +/- 0.18) and AA(N) (1.31 +/- 0.16) were larger than the left MSNA A(N) (1.04 +/- 0.09) and AA(N) (1.02 +/- 0.08). Unilateral and bilateral carotid baroreflex stimulation abolished the right prevalence of A(N) and AA(N). In conclusion, the right lateralization of sympathetic activity to the vessels is indicated by normalized burst strength parameters of bilateral MSNA recordings at rest during spontaneous breathing. Carotid baroreceptor stimulation disrupted such expression of MSNA lateralization possibly by disturbing the synchronizing action of right cerebral hemisphere.

Resistance exercise training enhances sympathetic nerve activity during fatigue-inducing isometric handgrip trials

Muscle sympathetic nerve activity (MSNA) was investigated 1 week before (pre-training), 1 week after, and 4-6 weeks after strength training using fatigue-inducing handgrip exercises and post-exercise forearm occlusion. Eighteen volunteers underwent forearm training, which consisted of 30 maximal effort, 10-s-duration static handgrips, 4 days per week for 4 weeks. A second group of 18 volunteers served as a control. MSNA was recorded from the tibial nerve by microneurography. Maximal handgrip force increased at 1 week post-training. The MSNA response during fatigued handgrip also increased at 1 week post-training, as compared to pre-training (52.6 +/- 5.8 vs. 40.6 +/- 4.4 bursts min(-1) (mean +/- SEM), respectively). However, at 4 weeks post-training, MSNA activity returned to the pre-training level (44.0 +/- 5.2 bursts min(-1); p < 0.0001 by ANOVA), while the control group showed no changes throughout this period. The MSNA response during post-exercise forearm occlusion was constant throughout the experiment in both groups. Our results indicate that an increased MSNA response after strength training is likely to be the result of central neural factors rather than the muscle metaboreflex.

Altered Interaction Between Plasminogen Activator Inhibitor Type 1 Activity and Sympathetic Nerve Activity With Aging

It has been reported that sympathetic nerve activity (SNA) is associated with fibrinolysis, but the interaction between SNA and the fibrinolytic system with aging has not been elucidated in humans. The purpose of this study was to examine the effect of age-related SNA on the activity of plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (tPA) using muscle SNA (MSNA). This study included 16 young subjects (mean age 26.1 years) and 10 aged subjects (mean age 56.9 years). Lower body negative pressure (LBNP) was performed at -40 mmHg for 30 min. LBNP significantly increased both tPA and PAI-1 activity (from 5.2+/-0.5 to 7.3+/-1.2 IU/ml and from 2.85+/-0.68 to 4.06+/-0.73 U/ml, p<0.01, respectively) in the aged group. In the young group, tPA activity tended to increase, whereas PAI-1 activity was unchanged. There was a correlation between MSNA and PAI-1 activity in the aged group (r=0.47, p<0.01). SNA in an aging subject leads to an increase in the activity of PAI-1, which indicates that an altered interaction between SNA and PAI-1 activity contributes to increased cardiovascular events in the elderly population.

Central chemoreflex sensitivity and sympathetic neural outflow in elite breath-hold divers

Repeated hypoxemia in obstructive sleep apnea patients increases sympathetic activity, thereby promoting arterial hypertension. Elite breath-holding divers are exposed to similar apneic episodes and hypoxemia. We hypothesized that trained divers would have increased resting sympathetic activity and blood pressure, as well as an excessive sympathetic nervous system response to hypercapnia. We recruited 11 experienced divers and 9 control subjects. During the diving season preceding the study, divers participated in 7.3 +/- 1.2 diving fish-catching competitions and 76.4 +/- 14.6 apnea training sessions with the last apnea 3-5 days before testing. We monitored beat-by-beat blood pressure, heart rate, femoral artery blood flow, respiration, end-tidal CO(2), and muscle sympathetic nerve activity (MSNA). After a baseline period, subjects began to rebreathe a hyperoxic gas mixture to raise end-tidal CO(2) to 60 Torr. Baseline MSNA frequency was 31 +/- 11 bursts/min in divers and 33 +/- 13 bursts/min in control subjects. Total MSNA activity was 1.8 +/- 1.5 AU/min in divers and 1.8 +/- 1.3 AU/min in control subjects. Arterial oxygen saturation did not change during rebreathing, whereas end-tidal CO(2) increased continuously. The slope of the hypercapnic ventilatory and MSNA response was similar in both groups. We conclude that repeated bouts of hypoxemia in elite, healthy breath-holding divers do not lead to sustained sympathetic activation or arterial hypertension. Repeated episodes of hypoxemia may not be sufficient to drive an increase in resting sympathetic activity in the absence of additional comorbidities.

Sympathetic nerve activity is inappropriately increased in chronic renal disease.

The hypothesis that in hypertensive patients with renal parenchymal disease sympathetic activity is "inappropriately" elevated and that this overactivity is a feature of renal disease and not of a reduced number of nephrons per se is addressed. Fifty seven patients with renal disease (various causes, no diabetes, all on antihypertensive medication) were studied, age range 18 to 62, creatinine clearance 10 to 114 ml/min per 1.73 m(2). Antihypertensives were stopped, but diuretics were allowed, to prevent overhydration. Matched control subjects were also studied. The effect of changes in fluid status was examined in seven patients while on and after stopping diuretics and in eight control subjects while on low- and high-sodium diet. Seven kidney donors were studied before and after unilateral nephrectomy. Sympathetic activity was quantified as muscle sympathetic nerve activity (MSNA) in the peroneal nerve. Mean arterial pressure, MSNA, and plasma renin activity were higher in patients than in control subjects, respectively (115 +/- 12 and 88 +/- 11 mmHg, 31 +/- 15 and 18 +/- 10 bursts/min, and 500 [20 to 6940] and 220 [40 to 980] fmol/L per s; P < 0.01 for all items). Extracellular fluid volume (bromide distribution) did not differ. Seven patients were studied again after stopping diuretics. MSNA decreased from 34 +/- 18 to 19 +/- 18 bursts/min (P < 0.01). Eight healthy subjects were studied during low- and high-sodium diet. MSNA was 26 +/- 12 and 13 +/- 7 bursts/min (P < 0.01). The curves relating extracellular fluid volume to MSNA were parallel in the two groups but shifted to a higher level of MSNA in the patients. In the kidney donors, creatinine clearance reduced by 25%, but MSNA was identical before and after donation. It is concluded that in hypertensive patients with renal parenchymal disease, sympathetic activity is inappropriately high for the volume status and that reduction of nephron number in itself does not influence sympathetic activity.

Pathophysiology of orthostatic hypotension after bed rest: paradoxical sympathetic withdrawal.

Although orthostatic hypotension is a common clinical syndrome after spaceflight and its ground-based simulation model, 6 degrees head-down bed rest (HDBR), the pathophysiology remains unclear. The authors' hypothesis that a decrease in sympathetic nerve activity is the major pathophysiology underlying orthostatic hypotension after HDBR was tested in a study involving 14-day HDBR in 22 healthy subjects who showed no orthostatic hypotension during 15-min 60 degrees head-up tilt test (HUT) at baseline. After HDBR, 10 of 22 subjects demonstrated orthostatic hypotension during 60 degrees HUT. In subjects with orthostatic hypotension, total activity of muscle sympathetic nerve activity (MSNA) increased less during the first minute of 60 degrees HUT after HDBR (314% of resting supine activity) than before HDBR (523% of resting supine activity, P < 0.05) despite HDBR-induced reduction in plasma volume (13% of plasma volume before HDBR). The postural increase in total MSNA continued during several more minutes of 60 degrees HUT while arterial pressure was maintained. Thereafter, however, total MSNA was paradoxically suppressed by 104% of the resting supine level at the last minute of HUT (P < 0.05 vs. earlier 60 degrees HUT periods). The suppression of total MSNA was accompanied by a 22 +/- 4-mmHg decrease in mean blood pressure (systolic blood pressure <80 mmHg). In contrast, orthostatic activation of total MSNA was preserved throughout 60 degrees HUT in subjects who did not develop orthostatic hypotension. These data support the hypothesis that a decrease in sympathetic nerve activity is the major pathophysiological factor underlying orthostatic hypotension after HDBR. It appears that the diminished sympathetic activity, in combination with other factors associated with HDBR (e.g., hypovolemia), may predispose some individuals to postural hypotension.

Sympathetic activation in exercise is not dependent on muscle acidosis. Direct evidence from studies in metabolic myopathies.

Muscle acidosis has been implicated as a major determinant of reflex sympathetic activation during exercise. To test this hypothesis we studied sympathetic exercise responses in metabolic myopathies in which muscle acidosis is impaired or augmented during exercise. As an index of reflex sympathetic activation to muscle, microneurographic measurements of muscle sympathetic nerve activity (MSNA) were obtained from the peroneal nerve. MSNA was measured during static handgrip exercise at 30% of maximal voluntary contraction force to exhaustion in patients in whom exercise-induced muscle acidosis is absent (seven myophosphorylase deficient patients; MD [McArdle's disease], and one patient with muscle phosphofructokinase deficiency [PFKD]), augmented (one patient with mitochondrial myopathy [MM]), or normal (five healthy controls). Muscle pH was monitored by 31P-magnetic resonance spectroscopy during handgrip exercise in the five control subjects, four MD patients, and the MM and PFKD patients. With handgrip to exhaustion, the increase in MSNA over baseline (bursts per minute [bpm] and total activity [%]) was not impaired in patients with MD (17+/-2 bpm, 124+/-42%) or PFKD (65 bpm, 307%), and was not enhanced in the MM patient (24 bpm, 131%) compared with controls (17+/-4 bpm, 115+/-17%). Post-handgrip ischemia studied in one McArdle patient, caused sustained elevation of MSNA above basal suggesting a chemoreflex activation of MSNA. Handgrip exercise elicited an enhanced drop in muscle pH of 0.51 U in the MM patient compared with the decrease in controls of 0.13+/-0.02 U. In contrast, muscle pH increased with exercise in MD by 0.12+/-0.05 U and in PFKD by 0.01 U. In conclusion, patients with glycogenolytic, glycolytic, and oxidative phosphorylation defects show normal muscle sympathetic nerve responses to static exercise. These findings indicate that muscle acidosis is not a prerequisite for sympathetic activation in exercise.

Total norepinephrine spillover, muscle sympathetic nerve activity and heart-rate spectra analysis in a patient with dopamine β-hydroxylase deficiency

Dopamine-β-hydroxylase (DβH) is the enzyme responsible for intraneural conversion of dopamine to norepinephrine. Its deficiency results in failure of norepinephrine synthesis, excessive dopamine release and orthostatic hypotension. We studied a young patient with this deficiency using the currently available methods to assess sympathetic function namely measurement of norepinephrine kinetics, microneurography to assess muscle sympathetic nerve activity (MSNA), and heart-rate spectral analysis. We compared these findings with those in 24 young healthy controls, and 4 patients with peripheral autonomic failure (PAF). Recordings were made in our subject before and after 5 months of treatment with l-threo-3,4-dihydroxyphenylserine (DOPS) (which is converted directly into l-norepinephrine bypassing the DβH enzymatic step); measurements were made at rest in the supine position and after 15 min of 30° head-up tilt. Our subject with DβH deficiency had a high resting nerve firing rate (40.3 bursts/min) compared with the mean value in normal controls (19.3 burst/min), and an appropriate increase in nerve firing rate during tilt. Total body norepinephrine spillover at rest was very low, 38 ng/min, compared with age-matched normals (519 ± 43.3 ng/min, mean ± SEM), and epinephrine secretion was undetectable. Conversely, the plasma concentrations of dopamine, DOPAC, HVA and DOPA were raised. At rest, low-frequency heart-rate variability (0.1 Hz) was absent with preservation of the respiratory-related high-frequency peak. In contrast, the PAF subjects had no detectable muscle sympathetic nerve activity, very low levels of norepinephrine spillover and epinephrine secretion and a reduction in heart rate variability at all frequencies. After 5 months treatment with l-threo-3,4-dihydroxyphenylserine (DOPS) in the DβH deficiency patient there was a dramatic clinical improvement with resolution of the orthostatic symptoms, dramatic reduction in MSNA activity at rest, and return of plasma norepinephrine, norepinephrine spillover, DHPG and MHPG to within the normal range, indicating intraneuronal production of norepinephrine.