Interaction of the vestibular system and baroreflexes on sympathetic nerve activity in humans

Muscle sympathetic nerve activity (MSNA) is altered by vestibular otolith stimulation. This study examined interactive effects of the vestibular system and baroreflexes on MSNA in humans. In study 1, MSNA was measured during 4 min of lower body negative pressure (LBNP) at either -10 or -30 mmHg with subjects in prone posture. During the 3rd min of LBNP, subjects lowered their head over the end of a table (head-down rotation, HDR) to engage the otolith organs. The head was returned to baseline upright position during the 4th min. LBNP increased MSNA above baseline during both trials with greater increases during the -30-mmHg trial. HDR increased MSNA further during the 3rd min of LBNP at -10 and -30 mmHg (Delta32% and Delta34%, respectively; P < 0.01). MSNA returned to pre-HDR levels during the 4th min of LBNP when the head was returned upright. In study 2, MSNA was measured during HDR, LBNP, and simultaneously performed HDR and LBNP. The sum of MSNA responses during individual HDR and LBNP trials was not significantly different from that observed during HDR and LBNP performed together (Delta131 +/- 28 vs. Delta118 +/- 47 units and Delta340 +/- 77 vs. Delta380 +/- 90 units for the -10 and -30 trials, respectively). These results demonstrate that vestibular otolith stimulation can increase MSNA during unloading of the cardiopulmonary and arterial baroreflexes. Also, the interaction between the vestibulosympathetic reflex and baroreflexes is additive in humans. These studies indicate that the vestibulosympathetic reflex may help defend against orthostatic challenges in humans by increasing sympathetic outflow.     

Regulation of muscle sympathetic nerve activity after bed rest deconditioning

Cardiovascular deconditioning reduces orthostatic tolerance. To determine whether changes in autonomic function might produce this effect, we developed stimulus-response curves relating limb vascular resistance, muscle sympathetic nerve activity (MSNA), and pulmonary capillary wedge pressure (PCWP) with seven subjects before and after 18 days of -6 degrees head-down bed rest. Both lower body negative pressure (LBNP; -15 and -30 mmHg) and rapid saline infusion (15 and 30 ml/kg body wt) were used to produce a wide variation in PCWP. Orthostatic tolerance was assessed with graded LBNP to presyncope. Bed rest reduced LBNP tolerance from 23.9 +/- 2.1 to 21.2 +/- 1.5 min, respectively (means +/- SE, P = 0.02). The MSNA-PCWP relationship was unchanged after bed rest, though at any stage of the LBNP protocol PCWP was lower, and MSNA was greater. Thus bed rest deconditioning produced hypovolemia, causing a shift in operating point on the stimulus-response curve. The relationship between limb vascular resistance and MSNA was not significantly altered after bed rest. We conclude that bed rest deconditioning does not alter reflex control of MSNA, but may produce orthostatic intolerance through a combination of hypovolemia and cardiac atrophy.     

Effects of lower body negative pressure on sympathetic discharge to leg muscles in humans

Recent studies indicate that nonhypotensive orthostatic stress in humans causes reflex vasoconstriction in the forearm but not in the calf. We used microelectrode recordings of muscle sympathetic nerve activity (MSNA) from the peroneal nerve in conscious humans to determine if unloading of cardiac baroreceptors during nonhypotensive lower body negative pressure (LBNP) increases sympathetic discharge to the leg muscles. LBNP from -5 to -15 mmHg had no effect on arterial pressure or heart rate but caused graded decreases in central venous pressure and corresponding large increases in peroneal MSNA. Total MSNA (burst frequency X mean burst amplitude) increased by 61 +/- 22% (P less than 0.05 vs. control) during LBNP at only -5 mmHg and rose progressively to a value that was 149 +/- 29% greater than control during LBNP at -15 mmHg (P less than 0.05). The major new conclusion is that nonhypotensive LBNP is a potent stimulus to muscle sympathetic outflow in the leg as well as the arm. During orthostatic stress in humans, the cardiac baroreflex appears to trigger a mass sympathetic discharge to the skeletal muscles in all of the extremities.     

Attenuated sympathetic nerve responses after 24 hours of bed rest

Bed rest reduces orthostatic tolerance. Despite decades of study, the cause of this phenomenon remains unclear. In this report we examined hemodynamic and sympathetic nerve responses to graded lower body negative pressure (LBNP) before and after 24 h of bed rest. LBNP allows for baroreceptor disengagement in a graded fashion. We measured heart rate (HR), cardiac output (HR x stroke volume obtained by echo Doppler), and muscle sympathetic nerve activity (MSNA) during a progressive and graded LBNP paradigm. Negative pressure was increased by 10 mmHg every 3 min until presyncope or completion of -60 mmHg. After bed rest, LBNP tolerance was reduced in 11 of 13 subjects (P <.023), HR was greater (P <.002), cardiac output was unchanged, and the ability to augment MSNA at high levels of LBNP was reduced (rate of rise for 30- to 60-mmHg LBNP before bed rest 0.073 bursts x min(-1) x mmHg(-1); after bed rest 0.035 bursts x min(-1) x mmHg(-1); P < 0.016). These findings suggest that 24 h of bed rest reduces sympathetic nerve responses to LBNP.     

Sympathetic vascular transduction is augmented in young normotensive blacks.

The purpose of the present study was to determine sympathetic vascular transduction in young normotensive black and white adults. We hypothesized that blacks would demonstrate augmented transduction of muscle sympathetic nerve activity (MSNA) into vascular resistance. To test this hypothesis, MSNA, forearm blood flow, heart rate, and arterial blood pressure were measured during lower body negative pressure (LBNP). At rest, no differences existed in arterial blood pressure, heart rate, forearm blood flow, and forearm vascular resistance (FVR). Likewise, LBNP elicited comparable responses of these variables for blacks and whites. Baseline MSNA did not differ between blacks and whites, but whites demonstrated greater increases during LBNP (28 +/- 7 vs. 55 +/- 18%, 81 +/- 21 vs. 137 +/- 42%, 174 +/- 81 vs. 556 +/- 98% for -5, -15, and -40 mmHg LBNP, respectively; P < 0.001). Consistent with smaller increases in MSNA but similar FVR responses during LBNP, blacks demonstrated greater sympathetic vascular transduction (%FVR/%MSNA) than whites (0.95 +/- 0.07 vs. 0.82 +/- 0.07 U; 0.82 +/- 0.11 vs. 0.64 +/- 0.09 U; 0.95 +/- 0.37 vs. 0.35 +/- 0.09 U; P < 0.01). In summary, young whites demonstrate greater increases in MSNA during baroreceptor unloading than age-matched normotensive blacks. However, more importantly, for a given increase in MSNA, blacks demonstrate greater forearm vasoconstriction than whites. This finding may contribute to augmented blood pressure reactivity in blacks.     

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 affects calf venous compliance at rest and during baroreceptor unloading in humans

Leg venous compliance is a determinant of peripheral venous pooling during orthostatic stress such that high venous compliance could contribute to reduced orthostatic tolerance. We tested the hypotheses that 1) calf venous compliance is reduced during baroreceptor unloading, and 2) calf venous compliance is greater in women than men. Twelve men (27 +/- 2 yr) and 12 women (25 +/- 2 yr) were studied in the supine posture. Calf venous compliance was determined by inflating a thigh venous collecting cuff to 60 mmHg for 8 min and then decreasing cuff pressure at a rate of 1 mmHg/s to 0 mmHg. The slope of the pressure-compliance relation (compliance = beta(1) + 2.beta(2).cuff pressure), which is the first derivative of the quadratic pressure-volume relation [(Deltalimb volume) = beta(0) + beta(1).(cuff pressure) + beta(2).(cuff pressure)(2)] during the reduction in collecting cuff pressure, was used to assess venous compliance at baseline and during one-legged lower body negative pressure (LBNP; -50 mmHg). At baseline, calf venous compliance was 48% lower (P < 0.001) in women than men and decreased in men (Delta-25 +/- 8%; P < 0.05) but not women (Delta1 +/- 11%) during LBNP. Rhythmic ischemic handgrip (Delta6 +/- 9%) and cold pressor testing (Delta-9 +/- 7%) did not alter calf venous compliance in a subgroup of men (n = 6). These data indicate gender-dependent effects on calf venous compliance under conditions associated with low sympathetic outflow (i.e., rest) and high sympathetic outflow (i.e., LBNP). However, they cannot explain gender-associated differences in orthostatic tolerance.     

Cardiopulmonary baroreflexes do not modulate exercise-induced sympathoexcitation

The purpose of this study was to test the general hypothesis that sympathoinhibitory cardiopulmonary baroreflexes modulate sympathetic outflow during voluntary exercise in humans. Direct (microneurographic) measurements of postganglionic sympathetic nerve activity to noncontracting muscle (MSNA) were made from the right peroneal nerve in the leg, and arterial pressure (AP) and heart rate (HR) were recorded in 10 healthy subjects before (control) and for 2.5 min during each of five interventions: 1) lower-body negative pressure at -10 mmHg (LBNP) alone, 2 and 3) isometric handgrip exercise at 15 and 30% of maximal voluntary contraction (MVC) alone, and 4 and 5) handgrip at 15 and 30% MVC performed during LBNP. During LBNP alone, which should have reduced cardiopulmonary baroreflex sympathoinhibition, AP and HR did not change from control, but MSNA increased 93 +/- 24% (P less than 0.05). Handgrip elicited contraction intensity-dependent increases in AP and HR (P less than 0.05), but MSNA increased above control only at the 30% MVC level (165 +/- 30%, P less than 0.05). The HR, AP, and MSNA responses to either level of handgrip performed during LBNP were not different from the algebraic sums of the corresponding responses to handgrip and LBNP performed separately (P greater than 0.05). Since there was no facilitation of the MSNA response to handgrip when performed during LBNP compared with algebraic sums of the separate responses, our results do not support the hypothesis that cardiopulmonary baroreflexes modulate (inhibit) sympathetic outflow during exercise in humans.     

Influence of acute alcohol ingestion on sympathetic neural responses to orthostatic stress in humans

Acute alcohol consumption is reported to decrease mean arterial pressure (MAP) during orthostatic challenge, a response that may contribute to alcohol-mediated syncope. Muscle sympathetic nerve activity (MSNA) increases during orthostatic stress to help maintain MAP, yet the effects of alcohol on MSNA responses during orthostatic stress have not been determined. We hypothesized that alcohol ingestion would blunt arterial blood pressure and MSNA responses to lower body negative pressure (LBNP). MAP, MSNA, and heart rate (HR) were recorded during progressive LBNP (-5, -10, -15, -20, -30, and -40 mmHg; 3 min/stage) in 30 subjects (age 24 ± 1 yr). After an initial progressive LBNP (pretreatment), subjects consumed either alcohol (0.8 g ethanol/kg body mass; n = 15) or placebo (n = 15), and progressive LBNP was repeated (posttreatment). Alcohol increased resting HR (59 ± 2 to 65 ± 2 beats/min, P < 0.05), MSNA (13 ± 3 to 19 ± 4 bursts/min, P < 0.05), and MSNA burst latency (1,313 ± 16 to 1,350 ± 17 ms, P < 0.05) compared with placebo (group × treatment interactions, P < 0.05). During progressive LBNP, a pronounced decrease in MAP was observed after alcohol but not placebo (group × time × treatment, P < 0.05). In contrast, MSNA and HR increased during all LBNP protocols, but there were no differences between trials or groups. However, alcohol altered MSNA burst latency response to progressive LBNP. In conclusion, the lack of MSNA adjustment to a larger drop in arterial blood pressure during progressive LBNP, coupled with altered sympathetic burst latency responses, suggests that alcohol blunts MSNA responses to orthostatic stress.     

Vestibulosympathetic reflex during orthostatic challenge in aging humans

Aging attenuates the increase in muscle sympathetic nerve activity (MSNA) and elicits hypotension during otolith organ engagement in humans. The purpose of the present study was to determine the neural and cardiovascular responses to otolithic engagement during orthostatic stress in older adults. We hypothesized that age-related impairments in the vestibulosympathetic reflex would persist during orthostatic challenge in older subjects and might compromise arterial blood pressure regulation. MSNA, arterial blood pressure, and heart rate responses to head-down rotation (HDR) performed with and without lower body negative pressure (LBNP) in prone subjects were measured. Ten young (27 +/- 1 yr) and 11 older subjects (64 +/- 1 yr) were studied prospectively. HDR performed alone elicited an attenuated increase in MSNA in older subjects (Delta106 +/- 28 vs. Delta20 +/- 7% for young and older subjects). HDR performed during simultaneous orthostatic stress increased total MSNA further in young (Delta53 +/- 15%; P < 0.05) but not older subjects (Delta-5 +/- 4%). Older subjects demonstrated consistent significant hypotension during HDR performed both alone (Delta-6 +/- 2 mmHg) and during LBNP (Delta-7 +/- 2 mmHg). These data provide experimental support for the concept that age-related impairments in the vestibulosympathetic reflex persist during orthostatic challenge in older adults. Furthermore, these findings are consistent with the concept that age-related alterations in vestibular function might contribute to altered orthostatic blood pressure regulation with age in humans.     

Neural and cardiovascular responses to emotional stress in humans

Sympathetic neural responses to mental stress are well documented but controversial, whereas sympathetic neural responses to emotional stress are unknown. The purpose of this study was to investigate neural and cardiovascular responses to emotional stress evoked by negative pictures and reexamine the relationship between muscle sympathetic nerve activity (MSNA) and perceived stress. Mean arterial pressure (MAP), heart rate (HR), MSNA, and perceived stress levels were recorded in 18 men during three randomized trials: 1) neutral pictures, 2) negative pictures, and 3) mental stress. MAP and HR increased during mental stress (Delta14 +/- 2 mmHg and Delta15 +/- 2 beats/min, P < 0.001) but did not change during viewing of negative or neutral pictures. MSNA did not change during viewing of neutral (Delta1 +/- 1 burst/min, n = 16) or negative (Delta0 +/- 1 burst/min, n = 16) pictures or during mental stress (Delta1 +/- 2 burst/min, n = 13). Perceived stress levels were higher during mental stress (3 +/- 0 arbitrary units) than during viewing negative pictures (2 +/- 0 arbitrary units, P < 0.001). Perceived stress levels were not correlated to changes in MSNA during negative pictures (r = 0.10, P = 0.84) or mental stress (r = 0.36, P = 0.23). In conclusion, our results demonstrate robust increases in MAP and HR during mental stress, but not during emotional stress evoked by negative pictures. Although the influence of mental stress on MSNA remains unresolved, our findings challenge the concept that perceived stress levels modulate MSNA during mental stress.     

Strength training reduces arterial blood pressure but not sympathetic neural activity in young normotensive subjects.

The effects of resistance training on arterial blood pressure and muscle sympathetic nerve activity (MSNA) at rest have not been established. Although endurance training is commonly recommended to lower arterial blood pressure, it is not known whether similar adaptations occur with resistance training. Therefore, we tested the hypothesis that whole body resistance training reduces arterial blood pressure at rest, with concomitant reductions in MSNA. Twelve young [21 +/- 0.3 (SE) yr] subjects underwent a program of whole body resistance training 3 days/wk for 8 wk. Resting arterial blood pressure (n = 12; automated sphygmomanometer) and MSNA (n = 8; peroneal nerve microneurography) were measured during a 5-min period of supine rest before and after exercise training. Thirteen additional young (21 +/- 0.8 yr) subjects served as controls. Resistance training significantly increased one-repetition maximum values in all trained muscle groups (P < 0.001), and it significantly decreased systolic (130 +/- 3 to 121 +/- 2 mmHg; P = 0.01), diastolic (69 +/- 3 to 61 +/- 2 mmHg; P = 0.04), and mean (89 +/- 2 to 81 +/- 2 mmHg; P = 0.01) arterial blood pressures at rest. Resistance training did not affect MSNA or heart rate. Arterial blood pressures and MSNA were unchanged, but heart rate increased after 8 wk of relative inactivity for subjects in the control group (61 +/- 2 to 67 +/- 3 beats/min; P = 0.01). These results indicate that whole body resistance exercise training might decrease the risk for development of cardiovascular disease by lowering arterial blood pressure but that reductions of pressure are not coupled to resistance exercise-induced decreases of sympathetic tone.     

Muscle sympathetic nerve activity during lower body negative pressure is accentuated in heat-stressed humans.

The purpose of this project was to test the hypothesis that increases in muscle sympathetic nerve activity (MSNA) during an orthostatic challenge is attenuated in heat-stressed individuals. To accomplish this objective, MSNA was measured during graded lower body negative pressure (LBNP) in nine subjects under normothermic and heat-stressed conditions. Progressive LBNP was applied at -3, -6, -9, -12, -15, -18, -21, and -40 mmHg for 2 min per stage. Whole body heating caused significant increases in sublingual temperature, skin blood flow, sweat rate, heart rate, and MSNA (all P < 0.05) but not in mean arterial blood pressure (P > 0.05). Progressive LBNP induced significant increases in MSNA in both thermal conditions. However, during the heat stress trial, increases in MSNA at LBNP levels higher than -9 mmHg were greater compared with during the same LBNP levels in normothermia (all P < 0.05). These data suggest that the increase in MSNA to orthostatic stress is not attenuated but rather accentuated in heat-stressed humans.     

Vagosympathetic interactions in ischemia-induced myocardial norepinephrine and acetylcholine release

To elucidate the pathophysiological roles of vagosympathetic interactions in ischemia-induced myocardial norepinephrine (NE) and acetylcholine (ACh) release, we measured myocardial interstitial NE and ACh levels in response to a left anterior descending coronary occlusion in the following groups of anesthetized cats: intact autonomic innervation (INT, n = 7); vagotomy (VX, n = 6); local administration of atropine (Atro, n = 6); transection of the stellate ganglia (TSG, n = 5); local administration of phentolamine (Phen, n = 6); and combined vagotomy and transection of the stellate ganglia (VX+TSG, n = 5). The maximum NE release was enhanced in the VX group (141 +/- 30 nmol/l, means +/- SE, P < 0.05) compared with the INT group (61 +/- 12 nmol/l). Neither the Atro (50 +/- 24 nmol/l) nor VX+TSG groups (84 +/- 25 nmol/l) showed enhanced NE release. The maximum ACh release was unaltered in the TSG and Phen groups compared with the INT group (19 +/- 4, 18 +/- 4, and 13 +/- 3 nmol/l, respectively). These findings indicate that the cardiac vagal afferent but not efferent activity reduced the ischemia-induced myocardial NE release. In contrast, the cardiac sympathetic afferent and efferent activities played little role in the ischemia-induced myocardial ACh release.     

Hypoxia potentiates exercise-induced sympathetic neural activation in humans.

Our purpose was to test the hypothesis that hypoxia potentiates exercise-induced sympathetic neural activation in humans. In 15 young (20-30 yr) healthy subjects, lower leg muscle sympathetic nerve activity (MSNA, peroneal nerve; microneurography), venous plasma norepinephrine (PNE) concentrations, heart rate, and arterial blood pressure were measured at rest and in response to rhythmic handgrip exercise performed during normoxia or isocapnic hypoxia (inspired O2 concn of 10%). Study I (n = 7): Brief (3-4 min) hypoxia at rest did not alter MSNA, PNE, or arterial pressure but did induce tachycardia [17 +/- 3 (SE) beats/min; P less than 0.05]. During exercise at 50% of maximum, the increases in MSNA (346 +/- 81 vs. 207 +/- 14% of control), PNE (175 +/- 25 vs. 120 +/- 11% of control), and heart rate (36 +/- 2 vs. 20 +/- 2 beats/min) were greater during hypoxia than during normoxia (P less than 0.05), whereas the arterial pressure response was not different (26 +/- 4 vs. 25 +/- 4 mmHg). The increase in MSNA during hypoxic exercise also was greater than the simple sum of the separate responses to hypoxia and normoxic exercise (P less than 0.05). Study II (n = 8): In contrast to study I, during 2 min of exercise (30% max) performed under conditions of circulatory arrest and 2 min of postexercise circulatory arrest (local ischemia), the MSNA and PNE responses were similar during systemic hypoxia and normoxia. Arm ischemia without exercise had no influence on any variable during hypoxia or normoxia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Forebrain regions associated with postexercise differences in autonomic and cardiovascular function during baroreceptor unloading

The cortical regions representing peripheral autonomic reactions in humans are poorly understood. This study examined whether changes in forebrain activity were associated with the altered physiological responses to lower body negative pressure (LBNP) following a single bout of dynamic exercise (POST-EX). We hypothesized that, compared with the nonexercised condition (NO-EX), POST-EX would elicit greater reductions in stroke volume (SV) and larger increases in heart rate (HR) and muscle sympathetic nerve activity (MSNA) during LBNP (5, 15, and 35 mmHg). Forebrain neural activity (n = 11) was measured using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. HR, SV, arterial blood pressure (ABP), and MSNA were collected separately. Compared with NO-EX, baseline ABP was reduced, whereas HR and total vascular conductance (TVC) were elevated in POST-EX (P < 0.05). In both conditions, 5 mmHg LBNP did not elicit a change (from baseline) in any physiological parameter. Compared with NO-EX, 35 mmHg LBNP-mediated decreases in SV and TVC produced greater increases in HR and MSNA during POST-EX (P < 0.05). The right posterior insula and dorsal anterior cingulate cortex demonstrated a larger decrease in BOLD at 5 mmHg LBNP but greater BOLD increase at 15 and 35 mmHg LBNP POST-EX vs. NO-EX (P < 0.005). Conversely, the thalamus and ventral medial prefrontal cortex displayed the opposite BOLD activity pattern (i.e., larger increase at 5 mmHg LBNP but greater decrease at 15 and 35 mmHg LBNP POST-EX vs. NO-EX). Our findings suggest that discrete forebrain regions may be involved with the generation of baroreflex-mediated sympathetic and cardiovascular responses elicited by moderate LBNP.     

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.     

Sympathetic activity and the heterogenous blood pressure response to exercise training in hypertensives.

To test whether changes in sympathetic nervous system (SNS) activity or insulin sensitivity contribute to the heterogeneous blood pressure response to aerobic exercise training, we used compartmental analysis of [3H]norepinephrine kinetics to determine the extravascular norepinephrine release rate (NE2) as an index of systemic SNS activity and determined the insulin sensitivity index (S(I)) by an intravenous glucose tolerance test, before and after 6 mo of aerobic exercise training, in 30 (63 +/- 7 yr) hypertensive subjects. Maximal O2 consumption increased from 18.4 +/- 0.7 to 20.8 +/- 0.7 ml x kg(-1) x min(-1) (P = 0.02). The average mean arterial blood pressure (MABP) did not change (114 +/- 2 vs. 114 +/- 2 mmHg); however, there was a wide range of responses (-19 to +17 mmHg). The average NE2 did not change significantly (2.11 +/- 0.15 vs. 1.99 +/- 0.13 microg x min(-1) x m(-2)), but there was a significant positive linear relationship between the change in NE2 and the change in MABP (r = 0.38, P = 0.04). S(I) increased from 2.81 +/- 0.37 to 3.71 +/- 0.42 microU x 10(-4) x min(-1) x ml(-1) (P = 0.004). The relationship between the change in S(I) and the change in MABP was not statistically significant (r = -0.03, P = 0.89). When the changes in maximal O2 consumption, percent body fat, NE2, and S(I) were considered as predictors of the change in MABP, only NE2 was a significant independent predictor. Thus suppression of SNS activity may play a role in the reduction in MABP and account for a portion of the heterogeneity of the MABP response to aerobic exercise training in older hypertensive subjects.     

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.     

Prostaglandin modulation of venoconstriction to physiological stress in normals and heart failure patients

Prostaglandins released from blood vessels modulate vascular tone, and inhibition of their production during exogenous infusions of catecholamines causes increased venoconstriction. To determine the influence of prostaglandin production on venoconstriction during physiological stimuli known to cause sympathetic activation, and to assess its importance in chronic heart failure (CHF), we studied 11 normal subjects (62 +/- 4 yr) and 14 patients with CHF (64 +/- 2 yr, left ventricular ejection fraction 23 +/- 1%, New York Heart Association classes II and III) (means +/- SE). Dorsal hand vein distension was measured during mental arithmetic (MA), cold pressor test (CPT), and lower body negative pressure (LBNP; -10 and -40 mmHg), with saline infusion in one hand and local indomethacin (cyclooxygenase inhibitor) infusion (3 microg/min) in the other. Acetylcholine (0.01-1 nmol/min) dilated veins preconstricted with PGF(2alpha) in normals but, consistent with endothelial dysfunction, barely did so in CHF patients (P = 0.001). Nonendothelial venodilation to sodium nitroprusside (0.3-10 nmol/min) was not different between normals and CHF patients. Resting venous norepinephrine levels were higher in CHF patients (2,812 +/- 420 pmol/l) than normals (1,418 +/- 145 pmol/l, P = 0.007). In normals, indomethacin caused increased venoconstriction to MA (from 4.9 +/- 1.5 to 19.2 +/- 4.5%, P = 0.022) and CPT (from 2.9 +/- 3.8 to 17.6 +/- 4.2%, P = 0.007). In CHF, indomethacin caused increased venoconstriction to MA (from 6.6 +/- 3.9% to 19.0 +/- 4.5%, P = 0.014), CPT (from 9.6 +/- 2.1% to 20.1 +/- 3.7%, P = 0.001), and -40 mmHg LBNP (from 10.7 +/- 3.0% to 23.2 +/- 3.8%, P = 0.041). Control responses for all tests were not different between normals and CHF patients. The effects of indomethacin on venoconstriction to MA and CPT were not different between normals and CHF patients, but venoconstriction to -40 mmHg LBNP was accentuated in CHF patients (P = 0.036). Inhibition of prostaglandins by indomethacin significantly enhances hand vein constriction to physiological stimuli in both normals and CHF patients, although a differential effect exists for LBNP.