Subcutaneous obesity is not associated with sympathetic neural activation

We tested the hypothesis that muscle sympathetic nerve activity (MSNA) would not differ in subcutaneously obese (SUBOB) and nonobese (NO) men with similar levels of abdominal visceral fat despite higher plasma leptin concentrations in the former. We further hypothesized that abdominal visceral fat would be the strongest body composition- or regional fat distribution-related correlate of MSNA among these individuals. To accomplish this, we measured MSNA (via microneurography), body composition (via dual-energy X-ray absorptiometry), and abdominal fat distribution (via computed tomography) in 15 NO (body mass index 0.05, respectively) despite approximately 2.6-fold higher (P < 0.05) plasma leptin concentration in the SUBOB men. Furthermore, abdominal visceral fat was the only body composition- or regional fat distribution-related correlate (r = 0.45; P < 0.05) of MSNA in the pooled sample. In addition, abdominal visceral fat was related to MSNA in NO (r = 0.58; P = 0.0239) but not SUBOB (r = 0.39; P = 0.3027) men. Taken together with our previous observations, our findings suggest that the relation between obesity and MSNA is phenotype dependent. The relation between abdominal visceral fat and MSNA was evident in NO but not in SUBOB men and at levels of abdominal visceral fat below the level typically associated with elevated cardiovascular and metabolic disease risk. Our observations do not support an obvious role for leptin in contributing to sympathetic neural activation in human obesity and, in turn, are inconsistent with the concept of selective leptin resistance.     

Effect of baroreflex loading on the responsiveness of the vestibulosympathetic reflex in humans.

Activation of the vestibular otolith organs with head-down rotation (HDR) increases muscle sympathetic nerve activity (MSNA) in humans. Previously, we demonstrated this vestibulosympathetic reflex (VSR) elicits increases in MSNA during baroreflex unloading (i.e., lower body negative pressure) in humans. Whether such an effect persists during baroreflex loading is unknown. We tested the hypothesis that the ability of the VSR to increase MSNA is preserved during baroreflex unloading and inhibited during baroreflex loading. Ten subjects (26 +/- 1 yr) performed three trials of HDR to activate the VSR. These trials were performed after a period of sustained saline (control), nitroprusside (baroreflex unloading: 0.8-1.0 microg.kg(-1).min(-1)), and phenylephrine (baroreflex loading: 0.6-0.8 microg.kg(-1).min(-1)) infusion. Nitroprusside infusion decreased (Delta7 +/- 1 mmHg, where Delta is change; P < 0.001) and phenylephrine infusion increased mean arterial pressure (Delta8 +/- 1 mmHg; P < 0.001) at rest. HDR performed during the control [Delta3 +/- 2 bursts/min, Delta314 +/- 154 arbitrary units (au) total activity, Delta41 +/- 18% total activity; P < 0.05] and nitroprusside trials [Delta5 +/- 2 bursts/min, Delta713 +/- 241 au total activity, Delta49 +/- 20% total activity; P < 0.05] increased MSNA similarly despite significantly elevated levels at rest (13 +/- 2 to 26 +/- 3 bursts/min) in the latter. In contrast, HDR performed during the phenylephrine trial failed to increase MSNA (Delta0 +/- 1 bursts/min, Delta-15 +/- 33 au total activity, Delta-8 +/- 21% total activity). These results confirm previous findings that the ability of the VSR to increase MSNA is preserved during baroreflex unloading. In contrast, the ability of the VSR to increase MSNA is abolished during baroreflex loading. These results provide further support for the concept that the VSR may act primarily to defend against hypotension in humans.     

Differential distribution of muscle and skin sympathetic nerve activity in patients with end-stage renal disease

End-stage renal disease (ESRD) is characterized by resting sympathetic overactivity. Baseline muscle sympathetic nerve activity (MSNA), which is governed by baroreflexes and chemoreflexes, is elevated in ESRD. Whether resting skin sympathetic nerve activity (SSNA), which is independent from baroreflex and chemoreflex control, is also elevated has never been reported in renal failure. The purpose of this study was to determine whether sympathetic overactivity of ESRD is generalized to include the skin distribution. We measured sympathetic nerve activity to both muscle and skin using microneurography in eight ESRD patients and eight controls. MSNA was significantly (P = 0.025) greater in ESRD (37.3 +/- 3.6 bursts/min) when compared with controls (23.1 +/- 4.4 bursts/min). However, SSNA was not elevated in ESRD (ESRD vs. controls, 17.6 +/- 2.2 vs. 16.1 +/- 1.7 bustst/min, P = 0.61). Similar results were obtained when MSNA was quantified as bursts per 100 heartbeats. We report the novel finding that although sympathetic activity directed to muscle is significantly elevated, activity directed to skin is not elevated in ESRD. The differential distribution of sympathetic outflow to the muscle vs. skin in ESRD is similar to the pattern seen in other disease states characterized by sympathetic overactivity such as heart failure and obesity.     

Effects of gender and hypovolemia on sympathetic neural responses to orthostatic stress

We tested the hypothesis that women have blunted sympathetic neural responses to orthostatic stress compared with men, which may be elicited under hypovolemic conditions. Muscle sympathetic nerve activity (MSNA) and hemodynamics were measured in eight healthy young women and seven men in supine position and during 6 min of 60 degrees head-up tilt (HUT) under normovolemic and hypovolemic conditions (randomly), with approximately 4-wk interval. Acute hypovolemia was produced by diuretic (furosemide) administration approximately 2 h before testing. Orthostatic tolerance was determined by progressive lower body negative pressure to presyncope. We found that furosemide produced an approximately 13% reduction in plasma volume, causing a similar increase in supine MSNA in men and women (mean +/- SD of 5 +/- 7 vs. 6 +/- 5 bursts/min; P = 0.895). MSNA increased during HUT and was greater in the hypovolemic than in the normovolemic condition (32 +/- 6 bursts/min in normovolemia vs. 44 +/- 15 bursts/min in hypovolemia in men, P = 0.055; 35 +/- 9 vs. 45 +/- 8 bursts/min in women, P < 0.001); these responses were not different between the genders (gender effect: P = 0.832 and 0.814 in normovolemia and hypovolemia, respectively). Total peripheral resistance increased proportionately with increases in MSNA during HUT; these responses were similar between the genders. However, systolic blood pressure was lower, whereas diastolic blood pressure was similar in women compared with men during HUT, which was associated with a smaller stroke volume or stroke index. Orthostatic tolerance was lower in women, especially under hypovolemic conditions. These results indicate that men and women have comparable sympathetic neural responses during orthostatic stress under normovolemic and hypovolemic conditions. The lower orthostatic tolerance in women is predominantly because of a smaller stroke volume, presumably due to less cardiac filling during orthostasis, especially under hypovolemic conditions, which may overwhelm the vasomotor reserve available for vasoconstriction or precipitate neurally mediated sympathetic withdrawal and syncope.     

Effect of acute hyperlipidemia on autonomic and cardiovascular control in humans.

Blood lipids may detrimentally affect autonomic and circulatory control. We tested the hypotheses that acute elevations in free fatty acids and triglycerides (acute hyperlipidemia) impair baroreflex control of cardiac period [cardiovagal baroreflex sensitivity (BRS)] and muscle sympathetic nerve activity (MSNA: sympathetic BRS), increase MSNA at rest, and augment physiological responses to exercise. Eighteen young adults were examined in this randomized, double-blinded, and placebo-controlled study. BRS was determined using the modified Oxford technique before (pre) and 60 min (post) after initiating infusion of Intralipid (0.8 ml x m(-2) x min(-1)) and heparin (1,000 U/h) (experimental; n = 12) to induce acute hyperlipidemia, or saline (0.8 ml x m(-2) x min(-1)) and heparin (1,000 U/h) (control; n = 6). Responses to isometric handgrip to fatigue (IHG) were also determined. Blood pressure increased more (P < 0.05) in experimental than control subjects during the infusion. MSNA at rest (14 +/- 2 vs. 11 +/- 1 bursts/min), cardiovagal (19.8 +/- 1.8 vs. 19.1 +/- 2.4 ms/mmHg pre and post, respectively) and sympathetic BRS (-5.5 +/- 0.6 vs. -5.2 +/- 0.4 au x beat(-1) x mmHg(-1)), and the neural and cardiovascular responses to IHG were unchanged by acute hyperlipidemia (pre vs. post) in experimental subjects. Similarly, MSNA at rest (10 +/- 2 vs. 12 +/- 2 bursts/min), cardiovagal (22.1 +/- 4.0 vs. 21.0 +/- 4.6 ms/mmHg) and sympathetic BRS (-5.8 +/- 0.5 vs. -5.5 +/- 0.5 au x beat(-1) x mmHg(-1)), and the neural and cardiovascular responses to IHG were unchanged by the infusion in control subjects. These data do not provide experimental support for the concept that acute hyperlipidemia impairs reflex cardiovagal or sympathetic regulation in humans.     

Baroreflex control of muscle sympathetic nerve activity in postural orthostatic tachycardia syndrome

Postural orthostatic tachycardia syndrome (POTS) is characterized by excessive tachycardia during orthostasis. To test the hypothesis that patients with POTS have decreased sympathetic neural responses to baroreflex stimuli, we measured heart rate (HR) and muscle sympathetic nerve activity (MSNA) responses to three baroreflex stimuli including vasoactive drug boluses (modified Oxford technique), Valsalva maneuver, and head-up tilt (HUT) in POTS patients and healthy control subjects. The MSNA response to the Valsalva maneuver was significantly greater in the POTS group (controls, 26 +/- 7 vs. POTS, 48 +/- 6% of baseline MSNA/mmHg; P = 0.03). POTS patients also had an exaggerated MSNA response to 30 degrees HUT (controls, 123 +/- 24 vs. POTS, 208 +/- 30% of baseline MSNA; P = 0.03) and tended to have an exaggerated response to 45 degrees HUT (controls, 137 +/- 27 vs. POTS, 248 +/- 58% of baseline MSNA; P = 0.10). Sympathetic baroreflex sensitivity calculated during administration of the vasoactive drug boluses also tended to be greater in the POTS patients; however, this did not reach statistical significance (P = 0.15). Baseline MSNA values during supine rest were not different between the groups (controls, 23 +/- 4 vs. POTS, 16 +/- 5 bursts/100 heartbeats; P = 0.30); however, resting HR was significantly higher in the POTS group (controls, 58 +/- 3 vs. POTS, 82 +/- 4 beats/min; P = 0.0001). Our results suggest that POTS patients have exaggerated MSNA responses to baroreflex challenges compared with healthy control subjects, although resting supine MSNA values did not differ between the groups.     

Previous exercise attenuates muscle sympathetic activity and increases blood flow during acute euglycemic hyperinsulinemia.

Insulin infusion causes muscle vasodilation, despite the increase in sympathetic nerve activity. In contrast, a single bout of exercise decreases sympathetic activity and increases muscle blood flow during the postexercise period. We tested the hypothesis that muscle sympathetic activity would be lower and muscle vasodilation would be higher during hyperinsulinemia performed after a single bout of dynamic exercise. Twenty-one healthy young men randomly underwent two hyperinsulinemic euglycemic clamps performed after 45 min of seated rest (control) or bicycle exercise (50% of peak oxygen uptake). Muscle sympathetic nerve activity (MSNA, microneurography), forearm blood flow (FBF, plethysmography), blood pressure (BP, oscillometric method), and heart rate (HR, ECG) were measured at baseline (90 min after exercise or seated rest) and during hyperinsulinemic euglycemic clamps. Baseline glucose and insulin concentrations were similar in the exercise and control sessions. Insulin sensitivity was unchanged by previous exercise. During the clamp, insulin levels increased similarly in both sessions. As expected, insulin infusion increased MSNA, FBF, BP, and HR in both sessions (23 +/- 1 vs. 36 +/- 2 bursts/min, 1.8 +/- 0.1 vs. 2.2 +/- 0.2 ml.min(-1).100 ml(-1), 89 +/- 2 vs. 92 +/- 2 mmHg, and 58 +/- 1 vs. 62 +/- 1 beats/min, respectively, P < 0.05). BP and HR were similar between sessions. However, MSNA was significantly lower (27 +/- 2 vs. 31 +/- 2 bursts/min), and FBF was significantly higher (2.2 +/- 0.2 vs. 1.8 +/- 0.1 ml.min(-1).100 ml(-1), P < 0.05) in the exercise session compared with the control session. In conclusion, in healthy men, a prolonged bout of dynamic exercise decreases MSNA and increases FBF. These effects persist during acute hyperinsulinemia performed after exercise.     

Modest weight gain is associated with sympathetic neural activation in nonobese humans

We tested the hypothesis that modest, overfeeding-induced weight gain would increase sympathetic neural activity in nonobese humans. Twelve healthy males (23 +/- 2 years; body mass index, 23.8 +/- 0.7) were overfed approximately 1,000 kcal/day until a 5-kg weight gain was achieved. Muscle sympathetic nerve activity (MSNA, microneurography), blood pressure, body composition (dual energy X-ray absorptiometry), and abdominal fat distribution (computed tomography) were measured at baseline and following 4 wk of weight stability at each individual's elevated body weight. Overfeeding increased body weight (73.5 +/- 3.1 vs. 78.4 +/- 3.2 kg, P < 0.001) and body fat (14.9 +/- 1.2 vs. 18 +/- 1.1 kg, P < 0.001) in 42 +/- 8 days. Total abdominal fat increased (220 +/- 22 vs. 266 +/- 22 cm(2), P < 0.001) with weight gain, due to increases in both subcutaneous (158 +/- 15 vs. 187 +/- 12 cm(2), P < 0.001) and visceral fat (63 +/- 8 vs. 79 +/- 12 cm(2), P = 0.004). As hypothesized, weight gain elicited increases in MSNA burst frequency (32 +/- 2 vs. 38 +/- 2 burst/min, P = 0.002) and burst incidence (52 +/- 4 vs. 59 +/- 3 bursts/100 heart beats, P = 0.026). Systolic, but not diastolic blood pressure increased significantly with weight gain. The change in MSNA burst frequency was correlated with the percent increase in body weight (r = 0.59, P = 0.022), change in body fat (r = 0.52, P = 0.043) and percent change in body fat (r = 0.51, P = 0.045). The results of the current study indicate that modest diet-induced weight gain elicits sympathetic neural activation in nonobese males. These findings may have important implications for understanding the link between obesity and hypertension.     

Forebrain neural patterns associated with sex differences in autonomic and cardiovascular function during baroreceptor unloading

Generally, women demonstrate smaller autonomic and cardiovascular reactions to stress, compared with men. The mechanism of this sex-dependent difference is unknown, although reduced baroreflex sensitivity may be involved. Recently, we identified a cortical network associated with autonomic cardiovascular responses to baroreceptor unloading in men. The current investigation examined whether differences in the neural activity patterns within this network were related to sex-related physiological responses to lower body negative pressure (LBNP, 5, 15, and 35 mmHg). Forebrain activity in healthy men and women (n = 8 each) was measured using functional magnetic resonance imaging with blood oxygen level-dependent (BOLD) contrast. Stroke volume (SV), heart rate (HR), and muscle sympathetic nerve activity (MSNA) were collected on a separate day. Men had larger decreases in SV than women (P < 0.01) during 35 mmHg LBNP only. At 35 mmHg LBNP, HR increased more in males then females (9 +/- 1 beats/min vs. 4 +/- 1 beats/min, P < 0.05). Compared with women, increases in total MSNA were similar at 15 mmHg LBNP but greater during 35 mmHg LBNP in men [1,067 +/- 123 vs. 658 +/- 103 arbitrary units (au), P < 0.05]. BOLD signal changes (P < 0.005, uncorrected) were identified within discrete forebrain regions associated with these sex-specific HR and MSNA responses. Men had larger increases in BOLD signal within the right insula and dorsal anterior cingulate cortex than women. Furthermore, men demonstrated greater BOLD signal reductions in the right amygdala, left insula, ventral anterior cingulate, and ventral medial prefrontal cortex vs. women. The greater changes in forebrain activity in men vs. women may have contributed to the elevated HR and sympathetic responses observed in men during 35 mmHg LBNP.     

Gender difference in cardiovagal baroreflex gain in humans.

We tested the hypothesis that women would demonstrate lower cardiovagal baroreflex gain compared with men. If so, we further hypothesized that the lower cardiovagal baroreflex gain in women would be associated with their lower aerobic fitness and higher body fat percentage compared with men. To accomplish this, we measured cardiovagal baroreflex gain (modified Oxford technique) in sedentary, nonobese (body mass index < 25 kg/m2) men (age = 26.0 +/- 2.1 yr, n = 11) and women (age = 26.9 +/- 1.6 yr, n = 14). Resting R-R interval and diastolic blood pressure were similar in the two groups, but systolic blood pressure was lower (P < 0.05) in the women. Cardiovagal baroreflex gain was significantly lower in the women compared with the men (13.3 +/- 1.5 vs. 20.0 +/- 2.8 ms/mmHg, P < 0.05). The lower cardiovagal baroreflex gain in the women was not related (P > 0.05) to their lower aerobic fitness and was only marginally related to their higher body fat percentage (r = -0.34, P < 0.05). There were no gender differences in the threshold and saturation, operating range, or operating point (all P > 0.05), although the operating point fell significantly to left (i.e., at a lower systolic blood pressure) compared with men. Therefore, the findings of this study suggest that the gain of the cardiovagal baroreflex is reduced whereas other parameters were similar in women compared with men. The mechanisms responsible for the reduced cardiovagal baroreflex gain remain unclear.     

Relationship between blood pressure,sleep K-complexes,and muscle sympathetic nerve activity in humans

Stage 2 sleep is characterized by the EEG appearance of "K-complexes" and blood pressure oscillations. K-complexes may be directly related to blood pressure changes or they may reflect central sympathetic activation. We analyzed the temporal relationship among K-complexes, heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) during sleep in eight healthy volunteers (3 men and 5 women, age 22-41 yr). Most K-complexes presented as single large complexes (56 +/- 20%), followed by single small complexes (15 +/- 14%) and as couplets or triplets (13 +/- 6%). Single large K-complexes were preceded by a baroreflex-mediated increase of MSNA in approximately one-half (55%) of the cases. Detailed analysis of HR, BP, and MSNA was possible in 63 (45%) large single K-complexes not disturbed by preceding baroreflex-related changes. Systolic and diastolic BP and MSNA increased significantly after single events (22.5 +/- 13, 5.2 +/- 2.1, and 6.5 +/- 3.0%). Mean sympathetic baroreflex latency was similar after the single large K-complexes compared with the mean value during stage 2 sleep (1,290 +/- 126 vs. 1,279 +/- 61 ms). The area under the burst was significantly increased after single large K-complexes (median 3.9 vs. 9.0 arbitrary units, P < 0.03). The results support the hypothesis that K-complexes express cortical activation leading to temporary facilitation of sympathetic outflow in a graded fashion. Their functional effects appear to be independent of baroreflex modulation of MSNA in approximately 50% of the cases.     

Sympathetic neural responses to 24-hour sleep deprivation in humans: sex differences

Sleep deprivation has been linked to hypertension, and recent evidence suggests that associations between short sleep duration and hypertension are stronger in women. In the present study we hypothesized that 24 h of total sleep deprivation (TSD) would elicit an augmented pressor and sympathetic neural response in women compared with men. Resting heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were measured in 30 healthy subjects (age, 22 ± 1; 15 men and 15 women). Relations between spontaneous fluctuations of diastolic arterial pressure and MSNA were used to assess sympathetic baroreflex function. Subjects were studied twice, once after normal sleep and once after TSD (randomized, crossover design). TSD elicited similar increases in systolic, diastolic, and mean BP in men and women (time, P < 0.05; time × sex, P > 0.05). TSD reduced MSNA in men (25 ± 2 to 16 ± 3 bursts/100 heart beats; P = 0.02), but not women. TSD did not alter spontaneous sympathetic or cardiovagal baroreflex sensitivities in either sex. However, TSD shifted the spontaneous sympathetic baroreflex operating point downward and rightward in men only. TSD reduced testosterone in men, and these changes were correlated to changes in resting MSNA (r = 0.59; P = 0.04). Resting HR, respiratory rate, and estradiol were not altered by TSD in either sex. In conclusion, TSD-induced hypertension occurs in both sexes, but only men demonstrate altered resting MSNA. The sex differences in MSNA are associated with sex differences in sympathetic baroreflex function (i.e., operating point) and testosterone. These findings may help explain why associations between sleep deprivation and hypertension appear to be sex dependent.     

Feedback effects of circulating norepinephrine on sympathetic outflow in healthy subjects

The amplitude of low-frequency (LF) oscillations of heart rate (HR) usually reflects the magnitude of sympathetic activity, but during some conditions, e.g., physical exercise, high sympathetic activity results in a paradoxical decrease of LF oscillations of HR. We tested the hypothesis that this phenomenon may result from a feedback inhibition of sympathetic outflow caused by circulating norepinephrine (NE). A physiological dose of NE (100 ng.kg(-1).min(-1)) was infused into eight healthy subjects, and infusion was continued after alpha-adrenergic blockade [with phentolamine (Phe)]. Muscle sympathetic nervous activity (MSNA) from the peroneal nerve, LF (0.04-0.15 Hz) and high frequency (HF; 0.15-0.40 Hz) spectral components of HR variability, and systolic blood pressure variability were analyzed at baseline, during NE infusion, and during NE infusion after Phe administration. The NE infusion increased the mean blood pressure and decreased the average HR (P < 0.01 for both). MSNA (10 +/- 2 vs. 2 +/- 1 bursts/min, P < 0.01), LF oscillations of HR (43 +/- 13 vs. 35 +/- 13 normalized units, P < 0.05), and systolic blood pressure (3.1 +/- 2.3 vs. 2.0 +/- 1.1 mmHg2, P < 0.05) decreased significantly during the NE infusion. During the NE infusion after PHE, average HR and mean blood pressure returned to baseline levels. However, MSNA (4 +/- 2 bursts/min), LF power of HR (33 +/- 9 normalized units), and systolic blood pressure variability (1.7 +/- 1.1 mmHg2) remained significantly (P < 0.05 for all) below baseline values. Baroreflex gain did not change significantly during the interventions. Elevated levels of circulating NE cause a feedback inhibition on sympathetic outflow in healthy subjects. These inhibitory effects do not seem to be mediated by pressor effects on the baroreflex loop but perhaps by a presynaptic autoregulatory feedback mechanism or some other mechanism that is not prevented by a nonselective alpha-adrenergic blockade.     

Aldosterone impairs baroreflex sensitivity in healthy adults

Animal studies suggest that acute and chronic aldosterone administration impairs baroreceptor/baroreflex responses. We tested the hypothesis that aldosterone impairs baroreflex control of cardiac period [cardiovagal baroreflex sensitivity (BRS)] and muscle sympathetic nerve activity (MSNA, sympathetic BRS) in humans. Twenty-six young (25 +/- 1 yr old, mean +/- SE) adults were examined in this study. BRS was determined by using the modified Oxford technique (bolus infusion of nitroprusside, followed 60 s later by bolus infusion of phenylephrine) in triplicate before (Pre) and 30-min after (Post) beginning aldosterone (experimental, 12 pmol.kg(-1).min(-1); n = 10 subjects) or saline infusion (control; n = 10). BRS was quantified from the R-R interval-systolic blood pressure (BP) (cardiovagal BRS) and MSNA-diastolic BP (sympathetic BRS) relations. Aldosterone infusion increased serum aldosterone levels approximately fourfold (P < 0.05) and decreased (P < 0.05) cardiovagal (19.0 +/- 2.3 vs. 15.6 +/- 1.7 ms/mmHg Pre and Post, respectively) and sympathetic BRS [-4.4 +/- 0.4 vs. -3.0 +/- 0.4 arbitrary units (AU).beat(-1).mmHg(-1)]. In contrast, neither cardiovagal (19.3 +/- 3.3 vs. 20.2 +/- 3.3 ms/mmHg) nor sympathetic BRS (-3.8 +/- 0.5 vs. -3.6 +/- 0.5 AU.beat(-1).mmHg(-1)) were altered (Pre vs. Post) in the control group. BP, heart rate, and MSNA at rest were similar in experimental and control subjects before and after the intervention. Additionally, neural and cardiovascular responses to a cold pressor test and isometric handgrip to fatigue were unaffected by aldosterone infusion (n = 6 subjects). These data provide direct experimental support for the concept that aldosterone impairs baroreflex function (cardiovagal and sympathetic BRS) in humans. Therefore, aldosterone may be an important determinant/modulator of baroreflex function in humans.     

Vestibulosympathetic reflex during the early follicular and midluteal phases of the menstrual cycle

Evidence suggests that both the arterial baroreflex and vestibulosympathetic reflex contribute to blood pressure regulation, and both autonomic reflexes integrate centrally in the medulla cardiovascular center. A previous report indicated increased sympathetic baroreflex sensitivity during the midluteal (ML) phase of the menstrual cycle compared with the early follicular (EF) phase. On the basis of this finding, we hypothesize an augmented vestibulosympathetic reflex during the ML phase of the menstrual cycle. Muscle sympathetic nerve activity (MSNA), mean arterial pressure (MAP), and heart rate responses to head-down rotation (HDR) were measured in 10 healthy females during the EF and ML phases of the menstrual cycle. Plasma estradiol (Delta72 +/- 13 pg/ml, P < 0.01) and progesterone (Delta8 +/- 2 ng/ml, P < 0.01) were significantly greater during the ML phase compared with the EF phase. The menstrual cycle did not alter resting MSNA, MAP, and heart rate (EF: 13 +/- 3 bursts/min, 80 +/- 2 mmHg, 65 +/- 2 beats/min vs. ML: 14 +/- 3 bursts/min, 81 +/- 3 mmHg, 64 +/- 3 beats/min). During the EF phase, HDR increased MSNA (Delta3 +/- 1 bursts/min, P < 0.02) but did not change MAP or heart rate (Delta0 +/- 1 mmHg and Delta1 +/- 1 beats/min). During the ML phase, HDR increased both MSNA and MAP (Delta4 +/- 1 bursts/min and Delta3 +/- 1 mmHg, P < 0.04) with no change in heart rate (Delta0 +/- 1 beats/min). MSNA and heart rate responses to HDR were not different between the EF and ML phases, but MAP responses to HDR were augmented during the ML phase (P < 0.03). Our results demonstrate that the menstrual cycle does not influence the vestibulosympathetic reflex but appears to alter MAP responses to HDR during the ML phase.     

Endotoxemia causes central downregulation of sympathetic vasomotor tone in healthy humans

Experimental endotoxemia as a model of the initial septic response affects the autonomic nervous system with profound cardiovascular sequelae. Whether the postsynaptic sympathoneural activity to the muscle vascular bed is altered in the early septic phase remains to be determined. The present study aimed to elucidate the early effects of LPS on muscle sympathetic nerve activity (MSNA) and cardiovascular regulation in healthy humans. Young, healthy volunteers randomly received either an LPS bolus (4 ng/kg body wt, n = 11) or placebo (saline; n = 7). Experimental baroreflex assessment (baseline measurements followed by infusion of vasoactive drugs nitroprusside/phenylephrine) was done prior to and 90 min following LPS or placebo challenge. MSNA, heart rate, blood pressure, and blood levels of catecholamines, TNF-alpha and IL-6 were measured sequentially. Endotoxin but not placebo-induced flu-like symptoms and elevated cytokine levels. In contrast to placebo, LPS significantly suppressed MSNA burst frequency 90 min after injection [mean +/- SE: 12.1 +/- 2.9 vs. 27.5 +/- 3.3 burst/min (post- vs. pre-LPS); P < 0.005] but increased heart rate [78.4 +/- 3.1 vs. 60.6 +/- 2.0 beats/min (post- vs. pre-LPS); P < 0.001]. Baseline blood pressure was not altered, but baroreflex testing demonstrated a blunted MSNA response and uncoupling of heart rate modulation to blood pressure changes in the endotoxin group. We conclude that endotoxin challenge in healthy humans has rapid suppressive effects on postsynaptic sympathetic nerve activity to the muscle vascular bed and alters baroreflex function which may contribute to the untoward cardiovascular effects of sepsis.     

Low-dose estrogen therapy does not change postexercise hypotension, sympathetic nerve activity reduction, and vasodilation in healthy postmenopausal women

The aim of this study was to determine whether estrogen therapy enhances postexercise muscle sympathetic nerve activity (MSNA) decrease and vasodilation, resulting in a greater postexercise hypotension. Eighteen postmenopausal women received oral estrogen therapy (ET; n=9, 1 mg/day) or placebo (n=9) for 6 mo. They then participated in one 45-min exercise session (cycle ergometer at 50% of oxygen uptake peak) and one 45-min control session (seated rest) in random order. Blood pressure (BP, oscillometry), heart rate (HR), MSNA (microneurography), forearm blood flow (FBF, plethysmography), and forearm vascular resistance (FVR) were measured 60 min later. FVR was calculated. Data were analyzed using a two-way ANOVA. Although postexercise physiological responses were unaltered, HR was significantly lower in the ET group than in the placebo group (59+/-2 vs. 71+/-2 beats/min, P<0.01). In both groups, exercise produced significant decreases in systolic BP (145+/-3 vs. 154+/-3 mmHg, P=0.01), diastolic BP (71+/-3 vs. 75+/-2 mmHg, P=0.04), mean BP (89+/-2 vs. 93+/-2 mmHg, P=0.02), MSNA (29+/-2 vs. 35+/-1 bursts/min, P<0.01), and FVR (33+/-4 vs. 55+/-10 units, P=0.01), whereas it increased FBF (2.7+/-0.4 vs. 1.6+/-0.2 ml x min(-1) x 100 ml(-1), P=0.02) and did not change HR (64+/-2 vs. 65+/-2 beats/min, P=0.3). Although ET did not change postexercise BP, HR, MSNA, FBF, or FVR responses, it reduced absolute HR values at baseline and after exercise.     

Effects of lower body positive pressure on muscle sympathetic nerve activity response to head-up tilt

The present study was performed to test the hypothesis that application of lower body positive pressure (LBPP) during orthostasis would reduce the baroreflex-mediated enhancement in sympathetic activity in humans. Eight healthy young men were exposed to a 70 degrees head-up tilt (HUT) on application of 30 mmHg LBPP. Muscle sympathetic nerve activity (MSNA) was microneurographically recorded from the tibial nerve, along with hemodynamic variables. We found that in the supine position with LBPP, MSNA remained unchanged (13.4 +/- 3.3 vs. 11.8 +/- 2.3 bursts/min, without vs. with LBPP; P > 0.05), mean arterial pressure was elevated, but arterial pulse pressure and heart rate did not alter. At 70 degrees HUT with LBPP, the enhanced MSNA response was reduced (33.8 +/- 5.0 vs. 22.5 +/- 2.2 bursts/min, without vs. with LBPP; P < 0.05), mean arterial pressure was higher, the decreased pulse pressure was restored, and the increased heart rate was attenuated. We conclude that the baroreflex-mediated enhancement in sympathetic activity during HUT was reduced by LBPP. Application of LBPP in HUT induced an obvious cephalad fluid shift as well as a restoration of arterial pulse pressure, which reduced the inhibition of the baroreceptors. However, the activation of the intramuscular mechanoreflexes produced by 30 mmHg LBPP might counteract the effects of baroreflexes.     

Relationship between muscle sympathetic nerve activity and systemic hemodynamics during nitric oxide synthase inhibition in humans

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.     

Vestibulosympathetic reflex during mental stress.

Increases in sympathetic neural activity occur independently with either vestibular or mental stimulation, but it is unknown whether sympathetic activation is additive or inhibitive when both stressors are combined. The purpose of the present study was to investigate the combined effects of vestibular and mental stimulation on sympathetic neural activation and arterial pressure in humans. Muscle sympathetic nerve activity (MSNA), arterial pressure, and heart rate were recorded in 10 healthy volunteers in the prone position during 1) head-down rotation (HDR), 2) mental stress (MS; using arithmetic), and 3) combined HDR and MS. HDR significantly (P < 0.05) increased MSNA (9 +/- 2 to 13 +/- 2 bursts/min). MS significantly increased MSNA (8 +/- 2 to 13 +/- 2 bursts/min) and mean arterial pressure (87 +/- 2 to 101 +/- 2 mmHg). Combined HDR and MS significantly increased MSNA (9 +/- 1 to 16 +/- 2 bursts/min) and mean arterial pressure (89 +/- 2 to 100 +/- 3 mmHg). Increases in MSNA (7 +/- 1 bursts/min) during the combination trial were not different from the algebraic sum of each trial performed alone (8 +/- 2 bursts/min). We conclude that the interaction for MSNA and arterial pressure is additive during combined vestibular and mental stimulation. Therefore, vestibular- and stress-mediated increases of MSNA appear to occur independently in humans.