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.     

Sympathetic nerve discharge is coupled to muscle cell pH during exercise in humans.

We used phosphorus nuclear magnetic resonance spectroscopy (31P-NMR) to probe the cellular events in contracting muscle that initiate the reflex stimulation of sympathetic outflow during exercise. In conscious humans, we performed 31P-NMR on exercising forearm muscle and simultaneously recorded muscle sympathetic nerve activity (MSNA) with microelectrodes in the peroneal nerve to determine if the activation of MSNA is coupled to muscle pH, an index of glycolysis, or to the concentrations (II) of inorganic phosphate (Pi) and adenosine diphosphate (ADP) which are modulators of mitochondrial respiration. During both static and rhythmic handgrip, the onset of sympathetic activation in resting muscle coincided with the development of cellular acidification in active muscle. Furthermore, increases in MSNA were correlated closely with decreases in intracellular pH but dissociated from changes in phosphocreatine [( PCr]), [Pi], and [ADP]. The principal new conclusion is that activation of muscle sympathetic outflow during exercise in humans is coupled to the cellular accumulation of protons in contracting muscle.     

Arterial baroreflex buffering of sympathetic activation during exercise-induced elevations in arterial pressure.

Static muscle contraction activates metabolically sensitive muscle afferents that reflexively increase sympathetic nerve activity and arterial pressure. To determine if this contraction-induced reflex is modulated by the sinoaortic baroreflex, we performed microelectrode recordings of sympathetic nerve activity to resting leg muscle during static handgrip in humans while attempting to clamp the level of baroreflex stimulation by controlling the exercise-induced rise in blood pressure with pharmacologic agents. The principal new finding is that partial pharmacologic suppression of the rise in blood pressure during static handgrip (nitroprusside infusion) augmented the exercise-induced increases in heart rate and sympathetic activity by greater than 300%. Pharmacologic accentuation of the exercise-induced rise in blood pressure (phenylephrine infusion) attenuated these reflex increases by greater than 50%. In contrast, these pharmacologic manipulations in arterial pressure had little or no effect on: (a) forearm muscle cell pH, an index of the metabolic stimulus to skeletal muscle afferents; or (b) central venous pressure, an index of the mechanical stimulus to cardiopulmonary afferents. We conclude that in humans the sinoaortic baroreflex is much more effective than previously thought in buffering the reflex sympathetic activation caused by static muscle contraction.     

Forearm elevation augments sympathetic activation during handgrip exercise in humans

Although angina pectoris in patients with coronary heart disease often occurs when their forearms are in an elevated position for a prolonged period, and sympathetic activation is a major cause of this condition, little is known about the physiological effects of forearm elevation on sympathetic activity during forearm exercise. We hypothesized that forearm elevation augments sympathetic activation during the static handgrip exercise in humans. A total of 10 healthy male volunteers performed 2 min of static handgrip exercise at 30% of maximal voluntary contraction followed by 2 min of post-exercise muscle ischaemia (PEMI; specific activation of the muscle metaboreflex) with two forearm positions: the exercising forearm was elevated 50 cm above the heart (forearm-elevated trial) or fixed at the level of the heart (heart-level trial). Muscle sympathetic nerve activity (MSNA), blood pressure and heart rate were monitored. MSNA increased during handgrip exercise in both forearm positions (P<0.001); the increase was 51% greater in the forearm-elevated trial (516+/-99 arbitrary units) than in the heart-level trial (346+/-44 units; P<0.05). The increase in mean blood pressure was 8.4 mmHg greater during exercise in the forearm-elevated trial (P<0.05), while changes in heart rate were similar in both forearm positions. The increase in MSNA during PEMI was 71% greater in the forearm-elevated trial (393+/-71 arbitrary units/min) than in the heart-level trial (229+/-29 units/min; P<0.05). These results support the hypothesis that forearm elevation augments sympathetic activation during handgrip exercise. The excitatory effect of forearm elevation on exercising MSNA may be mediated primarily by increased activation of the muscle metaboreflex.     

Differential control of heart rate and sympathetic nerve activity during dynamic exercise. Insight from intraneural recordings in humans.

We used microelectrode recordings of muscle sympathetic nerve activity (MSNA) from the peroneal nerve in the leg during arm exercise in conscious humans to test the concept that central command and muscle afferent reflexes produce mass sympathetic discharge at the onset of exercise. Nonischemic rhythmic handgrip and mild arm cycling produced graded increases in heart rate and arterial pressure but did not increase MSNA, whereas ischemic handgrip and moderate arm cycling dramatically increased MSNA. There was a slow onset and offset of the MSNA responses, which suggested metaboreceptor mediation. When forearm ischemia was continued after ischemic handgrip, MSNA remained elevated (muscle chemoreflex stimulation) but heart rate returned to control (elimination of central command). The major new conclusions are that: the onset of dynamic exercise does not produce mass, uniform sympathetic discharge in humans, and muscle chemoreflexes and central command appear to produce differential effects on sympathetic and parasympathetic responses.     

Role of adenosine in the sympathetic activation produced by isometric exercise in humans.

Isometric exercise increases sympathetic nerve activity and blood pressure. This exercise pressor reflex is partly mediated by metabolic products activating muscle afferents (metaboreceptors). Whereas adenosine is a known inhibitory neuromodulator, there is increasing evidence that it activates afferent nerves. We, therefore, examined the hypothesis that adenosine stimulates muscle afferents and participates in the exercise pressor reflex in healthy volunteers. Intraarterial administration of adenosine into the forearm, during venous occlusion to prevent systemic effects, mimicked the response to exercise, increasing muscle sympathetic nerve activity (MSNA, lower limb microneurography) and mean arterial blood pressure (MABP) at all doses studied (2, 3, and 4 mg). Heart rate increased only with the highest dose. Intrabrachial adenosine (4 mg) increased MSNA by 96 +/- 25% (n = 6, P < 0.01) and MABP by 12 +/- 3 mmHg (P < 0.01). Adenosine produced forearm discomfort, but equivalent painful stimuli (forearm ischemia and cold exposure) increased MSNA significantly less than adenosine. Furthermore, adenosine receptor antagonism with intrabrachial theophylline (1 microgram/ml forearm per min) blocked the increase in MSNA (92 +/- 15% vs. 28 +/- 6%, n = 7, P < 0.01) and MABP (38 +/- 6 vs. 27 +/- 4 mmHg, P = 0.01) produced by isometric handgrip (30% of maximal voluntary contraction) in the infused arm, but not the contralateral arm. Theophylline did not prevent the increase in heart rate produced by handgrip, a response mediated more by central command than muscle afferent activation. We propose that endogenous adenosine contributes to the activation of muscle afferents involved in the exercise pressor reflex in humans.     

Hydrogen ion concentration is not the sole determinant of muscle metaboreceptor responses in humans.

We examined the effects of exercise conditioning on muscle sympathetic nerve activity (MSNA) during handgrip and posthandgrip circulatory arrest (PHG-CA). Two conditioning stimuli were studied: forearm dominance and bodybuilding. Static handgrip at 30% maximal voluntary contraction followed by PHG-CA led to a rise in MSNA smaller in dominant than in nondominant forearms (99% vs. 222%; P less than 0.02) and in body builders than in normal volunteers (28% vs. 244%; P less than 0.01). Separate 31P NMR experiments showed no effect of dominance on forearm pH but a pH in bodybuilders higher (6.88) than in normal volunteers (6.79; P less than 0.02) during PHG-CA. Our second goal was to determine if factors besides attenuated [H+] contribute to this conditioning effect. If differences in MSNA during exercise were noted at the same pH, then other mechanisms must contribute to the training effect. We measured MSNA during ischemic fatiguing handgrip. No dominance or bodybuilding effect on pH was noted. However, we noted increases in MSNA smaller in dominant than nondominant forearms (212% vs. 322%; P less than 0.02) and in bodybuilders than in normal volunteers (161% vs. 334%; P less than 0.01). In summary, MSNA responses were less during exercise of conditioned limbs. Factors aside from a lessening of muscle acidosis contribute to this effect.     

Limb congestion and sympathoexcitation during exercise. Implications for congestive heart failure.

During static exercise, heart failure (HF) subjects activate the sympathetic nervous system differently than normal controls. HF causes metaboreceptor desensitization with either enhanced mechanoreceptor activity or central command. In this report, we examined whether increased muscle interstitial pressure, as seen in HF, augments other neural systems. We measured muscle sympathetic nerve activity (MSNA; peroneal nerve) in 10 normals during static exercise (40% maximal voluntary grip) and posthandgrip circulatory arrest (PHG-CA). This was repeated after venous congestion (VC; cuff inflation to 90 mmHg). VC increased forearm volume (plethysmography) by 4.7%. MSNA responses to exercise were greater after VC (150.5 +/- 41.8 vs. 317.3 +/- 69.9 arbitrary units; P < 0.01). However, MSNA responses during PHG-CA were not affected by VC, and 31P nuclear magnetic resonance (n = 5) demonstrated no effect of VC on pH or H2PO4-. Similar effects of VC on MSNA were noted after ischemic exercise (n = 7), excluding flow alterations as the explantation. VC probably sensitized mechanically sensitive afferents since MSNA during involuntary biceps contractions increased after VC (n = 6), and skin sympathetic nerve responses during handgrip, an index of central command, were not increased by VC (n = 6).     

Differential sympathetic neural control of oxygenation in resting and exercising human skeletal muscle.

Metabolic products of skeletal muscle contraction activate metaboreceptor muscle afferents that reflexively increase sympathetic nerve activity (SNA) targeted to both resting and exercising skeletal muscle. To determine effects of the increased sympathetic vasoconstrictor drive on muscle oxygenation, we measured changes in tissue oxygen stores and mitochondrial cytochrome a,a3 redox state in rhythmically contracting human forearm muscles with near infrared spectroscopy while simultaneously measuring muscle SNA with microelectrodes. The major new finding is that the ability of reflex-sympathetic activation to decrease muscle oxygenation is abolished when the muscle is exercised at an intensity > 10% of maximal voluntary contraction (MVC). During high intensity handgrip, (45% MVC), contraction-induced decreases in muscle oxygenation remained stable despite progressive metaboreceptor-mediated reflex increases in SNA. During mild to moderate handgrips (20-33% MVC) that do not evoke reflex-sympathetic activation, experimentally induced increases in muscle SNA had no effect on oxygenation in exercising muscles but produced robust decreases in oxygenation in resting muscles. The latter decreases were evident even during maximal metabolic vasodilation accompanying reactive hyperemia. We conclude that in humans sympathetic neural control of skeletal muscle oxygenation is sensitive to modulation by metabolic events in the contracting muscles. These events are different from those involved in either metaboreceptor muscle afferent activation or reactive hyperemia.     

Gender-related differences in the sympathetic vasoconstrictor drive of normal subjects

The risk of cardiovascular disease has been linked to sympathetic activation and its incidence is known to be lower in women than in men. However, the effect of gender on the sympathetic vasoconstrictor drive has not yet been established. In the present study, we investigated whether there is a gender difference in MSNA (muscle sympathetic nerve activity) and blood flow, and to determine the mechanisms involved. We examined 68 normal subjects, 34 women and 34 men, matched for age, BMI (body mass index) and waist circumference. MSNA was measured as the mean frequency of single units (s-MSNA) and as multi-unit bursts (m-MSNA) from the peroneal nerve simultaneously with its supplied muscle CBF (calf blood flow). Women had lower (P=0.0007) s-MSNA (24+/-2.0 impulses/100 cardiac beats) than men (34+/-2.3 impulses/100 cardiac beats), and a greater baroreceptor reflex sensitivity controlling efferent sympathetic nerve activity than men. The sympathetic activity was inversely and directly correlated respectively, with CBF (P=0.03) and CVR (calf vascular resistance; P=0.01) in men only. The responses of an increase in CVR to cold pressor and isometric handgrip tests were significantly smaller in women (P=0.002) than in men, despite similar increases in efferent sympathetic nerve activity. Women had a lower central sympathetic neural output to the periphery, the mechanism of which involved differences in central and reflex control, as well as a lower vasoconstrictor response to this neural output. It is suggested that this may partly explain the observed lower incidence of cardiovascular events in women compared with men.     

Expression of muscle-type phosphorylase in innervated and aneural cultured muscle of patients with myophosphorylase deficiency.

Patients with McArdle's myopathy lack muscle glycogen phosphorylase (M-GP) activity. Regenerating and cultured muscle of patients with McArdle's myopathy presents a glycogen phosphorylase (GP) activity, but it is not firmly established whether M-GP or non-M-GP isoforms are expressed. We have cultured myoblasts from biopsy specimen of five patients with McArdle's myopathy. Skeletal muscle was cultured aneurally or was innervated by coculture with fetal rat spinal cord explants. In the patients' muscle biopsies and in their cultured innervated and aneural muscle we studied total GP activity, isoenzymatic pattern, reactivity with anti-M-GP antiserum, and presence of M-GP mRNA. There was no detectable enzymatic activity, no immunoreactivity with anti-M-GP antiserum, and no M-GP mRNA in the muscle biopsy of all patients. GP activity, M-GP isozyme, and anti-M-GP antiserum reactivity were present in patients' aneural cultures, increased after innervation, and were undistinguishable from control. M-GP mRNA was demonstrated in both aneural and innervated cultures of patients and control by primer extension and PCR amplification of total RNA. Our studies indicate that the M-GP gene is normally transcribed and translated in cultured muscle of patients with myophosphorylase deficiency.     

Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle in obese humans.

The sympathetic nervous system is an important regulatory mechanism of both metabolic and cardiovascular function, and altered sympathetic activity may play a role in the etiology and/or complications of obesity. In lean subjects, insulin evokes sympathetic activation and vasodilation in skeletal muscle. In obese subjects such vasodilation is impaired and, in turn, may contribute to insulin resistance. To examine the relationship between sympathetic and vasodilatory responses in skeletal muscle to hyperinsulinemia, we simultaneously measured muscle sympathetic nerve activity (MSNA) and calf blood flow at basal and during a 2-h hyperinsulinemic (6 pmol/kg per min) euglycemic clamp in eight lean and eight obese subjects. The major findings of this study are twofold: obese subjects had a 2.2 times higher fasting rate of MSNA, and euglycemic hyperinsulinemia, which more than doubled MSNA and increased calf blood flow by roughly 30% in lean subjects, had only a minor vasodilatory and sympathoexcitatory effect in obese subjects. In contrast, two non-insulin-sympathetic stimuli evoked comparably large increases in MSNA in lean and obese subjects. We conclude that insulin resistance in obese subjects is associated with increased fasting MSNA and a specific impairment of sympathetic neural responsiveness to physiological hyperinsulinemia in skeletal muscle tissue.     

Muscle metaboreflex contribution to resting limb haemodynamic control is preserved in older subjects

Ageing is associated with tonic elevations in basal sympathetic vasoconstrictor outflow to skeletal muscle and a parallel decline in vascular function. The purpose of this study was to test the hypothesis that older individuals exhibit attenuated calf vascular resistance (CVR) responses to muscle metaboreflex activation in comparison with young subjects. Fourteen young (mean +/- SD age 23 +/- 3 years) and 13 older (62 +/- 7 years) sedentary subjects participated in the study. To evaluate muscle metaboreflex, we measured heart rate, mean blood pressure (MBP), calf blood flow (CBF) (venous occlusion plethysmography) and CVR responses to static handgrip exercise at 30% of maximal voluntary contraction, followed by recovery with [postexercise circulatory occlusion, (PECO+)] or without (PECO-) circulatory occlusion. Mean BP and CVR increased significantly (ANOVA P<0.05) throughout exercise and remained elevated during PECO+ when compared with PECO- in both groups. There were no significant differences between the two groups in BP and CVR relative changes from baseline during the entire protocol in both trials. CBF responses were also similar in the young and older subjects, except for the first minute of exercise, where young subjects had higher CBF responses. Our results demonstrate that older subjects have similar BP and calf haemodynamic responses to static handgrip exercise and selective action of the muscle metaboreflex when compared with young subjects, compatible with preserved muscle metaboreflex contribution to resting limb haemodynamic control with ageing in humans.     

Ventral medial prefrontal cortex and cardiovagal control in conscious humans

The autonomic nervous system plays a critical role in regulating the cardiovascular responses to mental and physical stress. Recent neuroimaging studies have demonstrated that sympathetic outflow to the heart is modulated by the activity of the anterior cingulate cortex (ACC). However, the cortical modulation of cardiovagal activity is still unclear in humans. The present study used functional MRI to investigate the cortical network involved in cardiovagal control. Seventeen healthy individuals performed graded handgrip exercise while heart rate (HR) and cortical activity were recorded. Muscle sympathetic nerve activity (MSNA), mean arterial pressure (MAP) and HR were measured while participants repeated the same protocol in a parallel experiment session. The handgrip exercise elevated HR and MAP without concurrent elevations in MSNA supporting earlier conclusions that the cardiovascular responses are mainly modulated by vagal withdrawal. The imaging data showed activation in the insular cortex, thalamus, parietal cortices and cerebellum during the exercise period. Consistently across all the participants, the HR response correlated with the deactivation in the ventral medial prefrontal cortex (vMPFC), which has substantial anatomical connection with the subcortical autonomic structures. The deactivation of the vMPFC was independent of the motor control and was observed commonly in both left and right hand exercise. Stronger vMPFC deactivation was observed when participants completed a higher intensity exercise that elicited a larger HR response. Our findings support the hypothesis that the vMPFC is involved in modulating the vagal efferent outflow to the heart and the suppression of its activity elevates cardiovascular arousal in conscious humans.     

Skeletal muscle metaboreflex in patients with chronic renal failure

The sympathetic nervous system is affected in patients with chronic renal failure (CRF). This study tested the hypothesis that patients with CRF have an altered skeletal muscle metaboreflex. Twenty patients with CRF and 18 healthy subjects of similar age participated in the study. The muscle metaboreflex was determined based on heart rate (HR), mean arterial pressure, calf blood flow and calf vascular resistance (CVR) in response to handgrip exercise. The control of vascular resistance in the calf muscle mediated by the metaboreflex was estimated by subtracting the area under the curve with circulatory occlusion from that without occlusion. Arterial pressure and HR responses during exercise and recovery were similar in two groups of subjects. In the control group, CVR increased during exercise and remained elevated during circulatory occlusion, whereas no significant change was seen in the patients. Thus, the index of the metaboreflex was 7·82 ± 9·57 in the patients versus16·52 ± 14 units in the controls. The findings demonstrate that patients with CRF have a decreased vascular resistance response in the calf during the handgrip exercise, which suggests that CRF condition attenuates this reflex.     

Muscle sympathetic nerve activity during isometric exercise in patients with cerebrovascular accidents

OBJECTIVES: To define isometric exercise-induced pressor responses in patients with cerebrovascular accidents (CVAs) and to assess potential cardiovascular and sympathetic nervous system abnormalities during isometric exercise in CVA. DESIGN: Nonrandomized study. SETTING: University laboratory setting. PARTICIPANTS: Eight men with CVA who had documented damage of subcortical structures and 8 sex-matched controls. INTERVENTIONS: A 2-minute sustained contraction of elbow flexor muscles in the unaffected side at 35% of maximal voluntary contraction (MVC; isometric exercise). MAIN OUTCOME MEASURES: Heart rate, arterial blood pressure, and muscle sympathetic nerve activity (MSNA), recorded from the peroneal nerve on the affected side. RESULTS: The percent changes in total MSNA, heart rate, and mean blood pressure in patients with CVA increased during isometric exercise but were attenuated compared with the controls. Total MSNA (mean burst amplitude per minute times burst rate) increased significantly in CVA and control subjects during isometric exercise by 18.7%+/-6.3% and 95.8%+/-25.2%, respectively. CONCLUSIONS: The attenuated pressor responses during isometric exercise in subjects with CVA relative to the controls indicated damage to subcortical structures; such damage lowered sympathetic nervous response to isometric exercise. Our findings suggest that isometric exercise at 35% of MVC does not put patients with CVA at risk for serious tachycardia or hypertension.     

McArdle''s disease heterozygotes. Metabolic adaptation assessed using 31P-nuclear magnetic resonance.

Two daughters of a propositus with documented McArdle's disease were shown by enzyme assay, gel electrophoresis, and immunoblotting to be partially deficient in skeletal muscle phosphorylase and, presumably, heterozygous for the trait. Both exhibited only the adult form of the skeletal muscle isozyme. By 31P-nuclear magnetic resonance, both heterozygotes showed a greater production of acid during fully aerobic exercise than when blood flow was occluded in ischemic exercise. This pattern is in contrast to that of control subjects, where there is significantly greater acid production in ischemic versus aerobic exercise, and distinct from that of phosphorylase-negative patients in which no acid is produced in either circumstance. We suggest that these heterozygotes may have adapted to their diminished phosphorylase by enhancing utilization of plasma glucose. If so, this mechanism could account for the observation that most of the symptoms of McArdle's disease are often manifest only in adulthood. These studies also show that although there are very high concentrations of phosphorylase in skeletal muscle (approximately 2% of the soluble protein), such a high level is essential for normal muscle glycogenolysis.     

McArdle disease presenting as acute renal failure

In 1951, McArdle described a glycogen storage disorder which presents primarily as a myopathy. It is characterized by muscle pain, weakness and exercise intolerance with elevated creatine kinase from rhabdomyolysis. The pathophysiology involves a deficiency of myophosphorylase enzyme resulting in an inability to degrade glycogen stores. We present a novel case of McArdle disease (glycogen storage disease V [GSDV]) in a patient who had sickle cell trait and bulimia. The disease went unrecognized despite several admissions to the hospital with increased creatine kinase and muscle myopathy until the patient's initial presentation with acute renal failure.     

Acute renal failure in McArdle's disease.

A case of reversible acute renal failure in an adult with myophosphorylase deficiency (McArdle's disease) is described. Myoglobinuria, possibly abetted by intravenous urography, was incriminated as the cause of impairment of renal function.A muscle biopsy specimen contained necrotic fibers and no histochemically demonstrable phosphorylase activity. Ultrastructurally, nonspecific degenerative changes were observed.     

Attenuated cardiac baroreflex in men with presyncope evoked by lower body negative pressure

Mechanisms responsible for presyncope during lower body negative pressure (LBNP) in otherwise healthy subjects are poorly understood. Muscle sympathetic nerve activity (MSNA), blood pressure, heart rate (HR), HR power spectra, central venous pressure (CVP) and stroke volume were determined in 14 healthy men subjected to incremental LBNP. Of these, seven experienced presyncope at LBNP >-15 mmHg. Subjects who tolerated LBNP >-15 mmHg had significantly lower CVP (2.6+/-1.0 versus 7.2+/-1.2 mmHg; means+/-S.E.M., P<0.02), HR (59+/-2 versus 66+/-3 beats/min, P<0.05) and MSNA burst frequency (29.0+/-2.4 versus 39.0+/-3.5 bursts/min, P<0.05) during supine rest. LBNP at -15 mmHg had no effect on blood pressure, but caused similar and significant reductions in stroke volume and cardiac output in both groups. Subjects who tolerated LBNP had significant reflex increases in HR, MSNA burst frequency and burst amplitude with LBNP of -15 mmHg. These responses were absent in those who experienced presyncope. The gain of the cardiac baroreflex regulation of MSNA was markedly attenuated in pre-syncopal subjects (1.2+/-0.6 versus 8.8+/-1.4 bursts/100 heart beats per mmHg; P<0.001). Healthy subjects who experience presyncope in response to LBNP appear more dependent, when supine, upon MSNA to maintain preload, and less able to increase sympathetic vasoconstrictor discharge to skeletal muscle reflexively in response to orthostatic stimuli.