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. 2013 May 31;305(3):H378–H385. doi: 10.1152/ajpheart.00019.2013

Distension of central great vein decreases sympathetic outflow in humans

Jian Cui 1, Zhaohui Gao 1, Cheryl Blaha 1, Michael D Herr 1, Jessica Mast 1, Lawrence I Sinoway 1,✉
PMCID: PMC3742879  PMID: 23729210

Abstract

Classic canine studies suggest that central great vein distension evokes an autonomic reflex tachycardia (Bainbridge reflex). It is unclear whether central venous distension in humans is a necessary and sufficient stimulus to evoke a reflex increase in heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA). Prior work from our laboratory suggests that limb venous distension evokes a reflex increase in BP and MSNA in humans. We hypothesized that in humans, compared with the limb venous distension, inferior vena cava (IVC) distension would evoke a less prominent increase in HR and MSNA. IVC distension (monitored with ultrasonography) was induced by two methods: 1) head-down tilt (HDT, N = 13); and 2) lower-body positive pressure (LBPP, N = 10). Two minutes of HDT induced IVC distension (Δ2.6 ± 0.2 mm, P < 0.001, ∼27% in cross-sectional area), slightly increased mean BP (Δ2.3 ± 0.7 mmHg, P = 0.005), decreased MSNA (Δ5.2 ± 0.8 bursts/min, P < 0.001, N = 10), and did not alter HR (P = 0.37). LBPP induced similar IVC distension, increased BP (Δ2.0 ± 0.7 mmHg, P < 0.01), and did not alter HR (P = 0.34). Thus central venous distension leads to a rapid increase in BP and a subsequent fall in MSNA. Central venous distension does not evoke either bradycardia or tachycardia in humans. The absence of a baroreflex-mediated bradycardia suggests that the Bainbridge reflex is engaged. Clearly, this reflex differs from the powerful sympathoexcitation peripheral venous distension reflex described in humans.

Keywords: Bainbridge reflex, venous distention, blood pressure control, sympathoexcitation, autonomic

postural changes induce changes in central venous volume and cardiac output without significant alterations of arterial pressure (28, 36). It is widely accepted that cardiopulmonary (36) and arterial (27, 42) baroreceptor disengagement occurs with the decrease in central blood volume/pressure during standing and leads to tachycardia and peripheral vasoconstriction in humans. Moreover, cardiopulmonary baroreceptor disengagement may alter carotid baroreflex sensitivity (45). However, head-down tilt (HDT) and lower-body positive pressure (LBPP) maneuvers that increase central venous return (37, 39, 41) do not evoke a bradycardia (20, 23, 24, 34, 37–39, 41). Thus other mechanisms must be acting to raise heart rate (HR) during central volume loading. Classic studies have suggested that central volume loading stimulates afferents at the junctions of the right atrium and caval veins or at the junctions of the pulmonary veins and the left atrium (30, 31) and evoke a reflex tachycardia in dogs (4, 9, 30, 31) and cats (29). This response has been termed the “Bainbridge reflex” (25).

In humans, although prior studies (5, 6, 11, 22) have examined interventions suggested to evoke central venous enlargement (the presumed necessary and sufficient stimulus), there are no prior reports that have examined measures of central venous distension and the resulting systemic autonomic response (11, 20, 23–25, 34, 37–39, 41). Since animal data suggest that the central great veins distension may play an important role in evoking the “Bainbridge reflex” (30, 31), we felt that it is important to examine central venous distension in human subjects.

HDT and LBPP both increase the central venous pressure (8, 37). Previous studies using these interventions (8, 20, 23, 24, 34, 37–39, 41) have examined their effect on cardiopulmonary baroreceptor; and the possible role of the Bainbridge reflex was not specifically examined. Additionally, central venous pressure was examined in these prior reports, and large vein distension was not directly examined in these prior studies. However, the relationship between central venous pressure and great vein distension may be nonlinear and influenced by interstitial pressure as well as the relative position of inner organs (e.g., liver) while HDT or LBPP is employed. Moreover, vessel mechanoreceptors sense wall tension, while the vessel radius contributes to the wall tension by the law of Laplace. Thus, although previous studies showed that HDT (8, 41) decreased muscle sympathetic nerve activity (MSNA), from those observations it cannot be directly concluded whether the central venous distension would lead to a tachycardia or a decrease in sympathetic outflow in humans. Thus one purpose of the present study was to examine whether central venous distension would evoke a systemic sympathetic activation.

Finally, recent reports from our laboratory have shown that distension of forearm veins evokes a large increase in MSNA and raises arterial blood pressure in humans (14–16). It has been suggested that this peripheral venous distension reflex in these prior reports was in fact the Bainbridge reflex. Since the peripheral venous distension reflex evokes large increases in MSNA and blood pressure that are not buffered by the baroreflexes, we felt it is unlikely that limb venous distension experiments could be explained by the mechanism during central venous distension. It was our contention that in humans the Bainbridge reflex's primary role would be in preventing a baroreflex-mediated bradycardic response as central volume is increased. Thus another purpose of this study was to compare the autonomic responses to the central venous distension with those seen during limb venous distension.

Therefore, we performed these studies using both HDT and LBPP to induce inferior vena cava (IVC) distension to examine the relationship between central large vein distension (i.e., the stimulus for the Bainbridge reflex) and autonomic response in humans. We hypothesized that in humans, compared with the limb venous distension, IVC distension would evoke a less prominent increase in HR and MSNA.

METHODS

Subjects

Thirteen subjects (7 men, 6 women) participated in the study. The average age was 25 ± 1 (SE) yr, and all were of normal height (172 ± 3 cm) and weight (72 ± 4 kg). All subjects were normotensive (supine blood pressures <140/90 mmHg) and in good health, and none were taking medication. Subjects refrained from caffeine, alcohol, and exercise 24 h prior to the study. The experimental protocol was approved by the Institutional Review Board of the Milton S. Hershey Medical Center and conformed with the Declaration of Helsinki. Each subject had the purposes and risks of the protocol explained to them before written informed consent was obtained.

Measurements

Beat-by-beat HR was monitored from the electrocardiogram (Cardicap 5, Datex-Ohmeda, GE Healthcare). Beat-by-beat blood pressure was recorded from a finger (Finometer, Finapres Medical Systems, Amsterdam, The Netherlands) with resting values verified by the cuff pressure from the brachial artery (SureSigns VS3, Philips, Philip Medical System). The hand was put at the heart level during the HDT protocol. Respiratory excursion was monitored using piezoelectric pneumography, as subjects were instructed to avoid breath holding during the protocols. Multifiber recordings of MSNA were obtained with a tungsten microelectrode inserted in the peroneal nerve of a leg. A reference electrode was placed subcutaneously 2–3 cm from the recording electrode. The recording electrode was adjusted until a site was found in which muscle sympathetic bursts were clearly identified using previously established criteria (44). The nerve signal was amplified, band-pass filtered with a bandwidth of 500–5,000 Hz, and integrated with a time constant of 0.1 s (Iowa Bioengineering, Iowa City, IA). The nerve signal was also routed to a loudspeaker and a computer for monitoring throughout the study. The diameter of the IVC was measured with echocardiography (iE33, Philips Medical, Bothell, WA). A series of images of the IVC were recorded during the protocols.

Protocols

HDT protocol.

After the instrumentation (without microneurography), while the IVC was imaged, the table was finely adjusted to head town until the IVC was clearly distended (angle ∼12–16°). HDT was maintained for 2 min. This trial was employed to ensure that IVC was distended by the HDT in each subject. This practice trial also offered the opportunity to slightly adjust body position to obtain the best quality images. Tilt table was then returned to the horizontal position, and microneurography was performed (∼30 min).

After a 5-min baseline data collection, HDT was again performed for 2 min as the IVC image was monitored. The HDT angle of the practice trial was reproduced without fine adjustment of the table, since these adjustments with our apparatus increase the risk for losing the nerve recording. We reported the HDT angle, IVC diameter, MSNA, and hemodynamic variables from this trial.

LBPP protocol.

During a separate visit, subjects laid supine with the lower half of their body in the LBPP tank (N = 10). A neoprene skirt was secured around their waist. After the instrumentation (without microneurography), two or three LBPP trials (40 mmHg) were applied to adjust the seals and the body position. Our pilot experiments demonstrated ∼35–40 mmHg of pressure are needed to induce IVC distension. Moreover it was noted that a relative small change in body position (e.g., shifting the lower body ∼3–5 cm in or out of the tank) could significantly affect the extent of the IVC distension. Thus during the ensuing data collection periods, care was taken to reproduce the position of the subjects relative to the tank as positive pressure was employed. After over 20 min of rest from the practice trials, 40 mmHg positive pressure was employed for 2 min as IVC size was monitored. MSNA was not measured.

Limb venous distension protocol.

This protocol was employed to determine whether limb venous distension evoked a prominent MSNA activation in the same subjects in whom central venous distension was induced in the study. The limb venous distension was induced via infusion of saline into an arterially occluded arm in five subjects during a separate visit. The details of this protocol have been described in our previous reports (13–15). In brief, a forearm was fitted with three occlusion cuffs from the wrist to the elbow. A fourth cuff was placed on the upper arm. From the wrist to the upper arm, the cuffs were inflated to 250 mmHg in sequence. Then the three cuffs on the forearm were deflated and removed, while the upper arm cuff remained inflated. After 4-min preinfusion data were collected, normal saline (0.9% concentration) equal to 5% arm volume (∼40–70 ml) was infused into the occluded forearm via an intravenous catheter in the antecubital fossa at a rate of 30 ml/min. After 5 min from the end of infusion, the upper arm cuff was deflated. Because we have shown the limb venous distension induced with the same protocol evoked significant MSNA and blood pressure increases in previous reports (13–15), this protocol in this study was only performed in five subjects.

Data Analysis

Data were sampled at 200 Hz via a data-acquisition system (MacLab, AD Instruments, Castle Hill, Australia). Mean arterial blood pressure (MAP) was calculated from the Finometer waveform during each trial, while the baseline MAP was verified by an automated sphygmomanometer from an upper arm. MSNA bursts were first identified in real time by visual inspection of the data, coupled with the burst sound from the audio amplifier. These bursts were further evaluated by a computer program that identified bursts based upon fixed criteria, including an appropriate latency following the R-wave of the electrocardiogram (12, 17, 18 ). Integrated MSNA was normalized by assigning a value of 100 to the mean amplitude of the top 10% largest bursts during the 5-min baseline period. Normalization of the MSNA signal was performed to reduce variability between subjects attributed to factors including needle placement and signal amplification. Total MSNA was identified from burst area of the integrated neurogram on a beat-by-beat basis. If no MSNA burst was detected for a particular cardiac cycle, a zero value was assigned for this cardiac cycle. Beat-by-beat HR and MAP were obtained simultaneously.

HDT trial.

The average values of MSNA, HR, and MAP over the 5-min baseline and 2-min HDT were used in statistical analyses. To observe the transient changes in HR and MAP, the beat-by-beat HR and MAP were interpolated (cubic spline) and resampled at 1 Hz. The mean HR and MAP over each second were analyzed from the last 2 min of baseline and the 2 min of HDT. Because MSNA does not occur in each cardiac cycle, the mean MSNA over each 10 s were analyzed.

LBPP trial.

Similarly, the average and transient HR and MAP data in LBPP trials were analyzed.

Limb venous distension trial.

Because the peak MSNA and MAP responses occurred toward the end of the infusion period (14–16), the mean values obtained during the last 30 s of infusion and the first 30 s of the postinfusion period (i.e., the entire 60 s) were defined as the “maximal responses.” The average values for MSNA, MAP, and HR were analyzed over the 6-min freely perfused baseline, forearm occlusion, the last 3-min of the preinfusion, the maximal responses, the 30–60 s of postinfusion, and the second and the third minute of postinfusion.

Statistics

Statistical analyses were performed with the use of SigmaStat software (SPSS Science). Differences in the diameter of IVC, the average values of HR and MAP between the 5-min baselines, and the 2-min HDT were evaluated via paired t-test. Differences in the transient HR and MAP over each second and MSNA over each 10 s were evaluated via repeated-measures one-way ANOVA. When appropriate, Tukey post hoc analyses were employed. In a similar manner, the HR and MAP responses in the LBPP protocol were evaluated. The absolute values of MAP, HR, and MSNA over the stages during the limb venous distension trial were used to examine the effects of the interventions in the protocol (e.g., infusion, etc.) via repeated-measures one-way ANOVA. When appropriate, Tukey post hoc analyses were employed. All values are reported as means ± SE. P values of <0.05 were considered statistically significant.

RESULTS

Distension of IVC

The diameter of IVC was increased during HDT (13.4 ± 0.4°) in each subject (20.6 ± 1.3 to 23.1 ± 1.4 mm, P < 0.001). IVC distension represented a ∼12% increase in diameter and ∼27% increase in cross-sectional area. One example of changes in IVC during supine and HDT is shown in Fig. 1. LBPP also induced significant increase in IVC diameter (18.6 ± 0.8 to 21.0 ± 0.8 mm, P < 0.001, ∼13% increase in diameter and ∼28% increase in cross-sectional area).

Fig. 1.

Fig. 1.

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Representative images of the inferior vena cava (IVC) during supine baseline and head-down tilt (HDT). Left panels: supine. Right panels: head-down tilt. Top panels: 2-D mode. Bottom panels: M-mode. The diameter of IVC during HDT was clearly larger than supine baseline.

Average HR, MAP, and MSNA Changes During HDT

The representative recordings of beat-by-beat HR, integrated MSNA, blood pressure, and respiratory excursion during HDT are shown in Fig. 2. Compared with the baseline, the HR changed little in the 13 subjects (61.6 ± 3.4 vs. 61.1 ± 3.3 beats/min, P = 0.373, Fig. 3). Of note, average MAP increased slightly during HDT (82.4 ± 2.4 84.7 ± 2.7 mmHg, P = 0.005). The increase in MAP was seen early after HDT and was not associated with a fall in HR (Fig. 4). MSNA was successfully recorded during HDT in 10 subjects. MSNA expressed in both burst rate (14.5 ± 2.0 vs. 9.3 ± 2.0 bursts/min, P < 0.001) and total activity (303 ± 42 vs. 185 ± 44 units/min, P < 0.001) decreased during HDT in each subject (Fig. 3).

Fig. 2.

Fig. 2.

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Representative tracing of beat-by-beat heart rate (HR), muscle sympathetic nerve activity (MSNA), arterial blood pressure (BP), and respiratory excursion (Resp) during supine baseline and HDT. MSNA clearly decreased during HDT in all subjects.

Fig. 3.

Fig. 3.

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HR, MAP, MSNA burst rate, and total activity during supine baseline and HDT. Small symbols represent individual data. Bars represent the average values of the group. Values were calculated as means over the 5-min baseline and the 2-min HDT, respectively. N = 13 for HR and MAP; N = 10 for MSNA.

Fig. 4.

Fig. 4.

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Transient HR, MAP, and MSNA change during HDT. There was no significant change in HR (1-way ANOVA, P = 0.991). There was significant change in MAP (1-way ANOVA, P < 0.001). MAP significantly increased at the onset of HDT (*P < 0.05 vs. the −14th s). There was significant change in MSNA burst rate (top right panel, 1-way ANOVA, P = 0.006) and total activity (bottom right panel, 1-way ANOVA, P = 0.027). There was no transient MSNA increase at the onset of HDT. MSNA significantly decreased during HDT (*P < 0.05 vs. the −50th s).

Transient HR and MAP and MSNA Changes During HDT

There was no significant change in mean HR over each second during the HDT (Fig. 4, 1-way ANOVA, P = 0.991). One-way ANOVA showed that MAP and MSNA significantly changed during HDT (all P < 0.001). There was a transient MAP increase at the onset of HDT (Fig. 4). There was no transient MSNA increase at the onset of HDT (Fig. 4).

HR and MAP Changes During LBPP

Compared with the baseline, the HR changed little over the 2 min of LBPP in the 10 subjects studied (63.0 ± 4.1 vs. 62.3 ± 3.8 beats/min, P = 0.342, Fig. 5). The average MAP increased slightly during LBPP (84.1 ± 2.2 vs. 86.1 ± 2.5 mmHg, P = 0.007). There was no transient HR change during LBPP (1-way ANOVA P = 0.468, Fig. 5), while the transient MAP significantly changed during LBPP (1-way ANOVA, P < 0.001, Fig. 5). A transient MAP increase was noted at the onset of LBPP.

Fig. 5.

Fig. 5.

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Left panels: HR and MAP during baseline and lower-body positive pressure (LBPP). Small symbols represent individual data. Bars represent the average values of the group. Values were calculated as means over the 5-min baseline and the 2-min LBPP, respectively. Right panels: transient HR and MAP change at the onset of LBPP. There was no significant change in HR (1-way ANOVA, P = 0.468). There was significant change in MAP (1-way ANOVA, *P < 0.001).

MSNA, MAP, and HR Responses During Arm Venous Distension Trial

One-way ANOVA shows that infusion of saline into veins of the occluded forearm evoked significant increases in MSNA (P < 0.001, for both burst rate and total activity, N = 5) and MAP (P < 0.001), and did not significantly alter HR (P = 0.653) in the five subjects in this study. The MSNA during the “maximal response” period (29.3 ± 5.4 bursts/min, 794 ± 195 units/min) was significantly greater than baseline (14.7 ± 2.4 bursts/min, P < 0.01; 273 ± 44 units/min, P < 0.01) or the preinfusion (14.0 ± 2.4 bursts/min, P < 0.01; 287 ± 64 units/min, P < 0.01). The MAP during the maximal response period (94.1 ± 6.7 mmHg) was also significantly greater than baseline (78.0 ± 2.9 mmHg, P < 0.01) or the preinfusion (82.7 ± 3.6 mmHg, P < 0.05). The recordings of HR, MSNA, and blood pressure during HDT and during the arm venous distension trial in a representative subject are shown in Fig. 6. Figure 6 clearly shows that the two interventions had different time courses and totally different MSNA and blood pressure responses.

Fig. 6.

Fig. 6.

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HR, MSNA, and BP during HDT (top panels) and during the saline infusion into an occluded arm (bottom panels) in 1 subject. MSNA clearly decreased during HDT whereas it increased during the limb venous distension. bpm, beats/min.

DISCUSSION

The main findings of this study are that 1) HDT and LBPP induced central venous distension; 2) no mean or transient increases in HR occurred during HDT or LBPP; 3) no transient increase in MSNA was noted; and 4) mean MSNA decreased during HDT. The results suggest that central venous distension does not lead to tachycardia or to sympathetic activation. These responses to the central venous distension are distinctly different from those seen during limb venous distension, which evokes large increases in MSNA and blood pressure.

Both HDT and LBPP induce a cephalad fluid shift, thus increasing central volume, evoking a rise in central venous pressure and perhaps a central venous distension. It has been suggested that the necessary and sufficient stimulus to evoke the Bainbridge reflex is central venous distension. Thus, in these studies, we employed direct measurement of venous size to obviate any concerns raised by using pressure as an index for venous volume. This could be particularly important as the relationship between venous pressure and volume may be nonlinear during LBPP and HDT. On the other hand, IVC distension can be considered as an index of the increases in central volume and pressure.

Both HDT (41) and LBPP (37, 39) will load cardiopulmonary baroreceptors. MAP clearly increased at the onset of HDT or LBPP (see Figs. 4 and 5). This blood pressure increase (due to an increase in venous return) should have loaded the baroreceptors and should have evoked at least a transient decrease in HR. However, although in some individuals the HR transiently and slightly decreased at the onset of HDT (e.g., the individual in Fig. 2) or LBPP, in some other individuals, both HR and blood pressure transiently and slightly increased at the onset of HDT (e.g., the individual in Fig. 6) or LBPP. Thus, mean HR did not significantly decrease during HDT or LBPP. We think lack of a bradycardia may have been due to the combined Bainbridge and baroreflex inputs, which offset one another.

Previous reports using LBPP suggested that an unchanged or slightly increased HR was due to the stimulation of intramuscular mechanoreceptors (20, 34, 37–39). However, our study employed both HDT and LBPP to induce IVC distension. HDT does not engage low-extremity muscle mechanoreceptors. Since both the interventions evoked similar levels of central venous distension, it is likely that central great vein distension itself (and not muscle mechanoreceptor stimulation) contributes to HR control and prevents a baroreflex-mediated bradycardia. In sum, we suspect that the lack of a fall in HR in these studies was due to engagement of the Bainbridge reflex (5, 6, 22). However, no significant tachycardia was observed in our human experiment as those seen in dogs. We cannot exclude that the relative changes in central volume evoked by HDT or LBPP may be smaller than those seen in the prior animal experiments with volume loading. This could contribute to the lack of a tachycardia in our human experiment. On the other hand, HDT and LBPP likely evoke vena cava diameter changes encountered by people during normal daily activity, and thus the observed responses should reflect the property of the reflex in normal humans. Thus we suspect that although the Bainbridge reflex contributes to the HR control, it may not be able to override the other inputs (e.g., baroreceptors) in humans and evoke the tachycardia as seen in dogs, and thus its role is limited in humans (6, 11, 21, 32, 48).

In contrast to HR control, mean MSNA clearly decreased during the IVC distension, and no transient MSNA increase was observed at the onset of HDT. The MSNA suppression observed reflects the net result of the stimulation of multiple different receptor types located in the heart and the central great vessels. These receptors would include sympathetic and vagal afferents. Loading of both cardiopulmonary and arterial baroreceptors likely contributes to the MSNA suppression. The roles of the stimulation of vagal afferents cannot be excluded. Moreover, a previous study showed that increases in central venous pressure by ∼2 mmHgby HDT or by volume infusion decreased the sensitivity of integrated baroreflex control of MSNA (8). The decreased baroreflex sensitivity observed in the previous study (8) may also contribute to the decrease in MSNA during HDT. Clearly, the decrease in MSNA suggests that the net effect of stimulation of these varied receptors in the heart and central great vessels does not evoke a sympathoexcitatory reflex in humans. In any case, the decrease in MSNA seen during IVC distension suggests that the Bainbridge reflex is distinctly different from the limb venous distension reflex recently characterized by our laboratory (14–16). The data from the arm venous distension trial in the present study also clearly show that the limb venous distension evoked large increases in MSNA and blood pressure in the same subjects in whom the MSNA was suppressed during IVC distension (see Fig. 6). Moreover, the blood pressure gradually and steadily increased during the limb venous distension trial, while the blood pressure rose slightly but abruptly at the onset of HDT (Fig. 6).

It has been proposed that the “Bainbridge reflex” is evoked via stimulating afferents located at the junctions of the veins and both the right and left atria (30, 31). Although all of central great veins (30, 31), large abdominal veins (3), large limb veins (43, 47) and small veins in muscles (1, 26, 40, 46) are similarly innervated with myelinated and unmyelinated afferents, it is not surprising that different pools of afferents when engaged evoke distinct autonomic response patterns.

In contrast to the central venous distension pattern described in this report, prior studies suggest that peripheral venous distension evokes a predominant engagement of systemic sympathetic nerves. For example, the abdominal venous distension increases sympathetic efferent activity in rabbits (2) and dogs (19). Limb venous ligation evokes vasoconstriction in both the occluded and contralateral extremities in dogs (10). In humans, our recent reports (14–16) and the data in the present study have shown that distension of veins via volume infusion (saline or albumin solution) into the veins of an occluded forearm evokes a large increase in MSNA and arterial blood pressure. The magnitude of the MSNA and blood pressure responses depends on the volume and the rate of the infusate during arm vein distension (monitored with ultrasonography) (14). Infusions of albumin, a potent intravascular oncotic agent, evoked larger and more sustained increases in MSNA and blood pressure than did equal volume infusions of saline. Moreover, when lidocaine was added to the forearm infusate, the MSNA response to venous distension was abolished (15). These observations clearly suggest that limb venous distension and/or the increased pressure gradient across the vessel evokes a sympathoexcitatory reflex and thus increases blood pressure in humans. Although MSNA and blood pressure are impressively activated with this limb venous distension reflex, HR is not altered (14, 15).

In sum, although the limb venous distension reflex and the Bainbridge reflex share similarities (e.g., venous distension), their role in blood pressure and MSNA regulation appears distinctly different. We postulate that the differences in sensory innervation of the heart and central vessels from limb vessels cause the differences in the autonomic and blood pressure responses. The heart and the central great vessels are innervated with both sympathetic and vagal afferents. In the central circulation a stimulus may be either excitatory or inhibitory according to the time-specific chemical and mechanical milieu (35). In humans, it is likely that the central venous afferents are predominately influenced by cardiopulmonary receptors that adapt to postural adjustment seen with normal daily life. It is unlikely that the Bainbridge reflex plays a predominate role (6). In contrast, limb vessels are not innervated with vagal nerves. The group III and IV fibers in limb vessels (1, 26, 40, 46) respond to the peripheral venous volume changes (43, 47). We believe these afferents play a large role in controlling sympathetic outflow.

Clinical Implications

Passive leg raising is often employed as a bedside method to determine a given patient's “fluid responsiveness” (7, 33). Based on our work, this intervention will elicit vena cava distension, a short-lived blood pressure response, as well as sympathetic withdrawal. We suspect that passive leg raising technique probably stimulates both inhibitory and excitatory systems in the heart and central vessels, and that the autonomic responses to this stimulus vary among individuals. Moreover, the autonomic adjustments are likely to be transient and reflective of multiple inputs from large veins and cardiac vagal and sympathetic afferents.

In conclusion, the autonomic adjustments seen with central and peripheral venous distension are distinctly different. Central venous distension inhibits the systemic sympathetic outflow and does not evoke either bradycardia or tachycardia in normal humans. Limb venous distension evokes a large increase in MSNA and arterial blood pressure in humans.

GRANTS

This work was supported by National Institutes of Health Grants P01-HL-096570 and UL1-TR-000127.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

AUTHOR CONTRIBUTIONS

Author contributions: J.C. and L.I.S. conception and design of research; J.C., Z.G., C.A.B., M.D.H., and J.L.M. performed experiments; J.C. and Z.G. analyzed data; J.C. and L.I.S. interpreted results of experiments; J.C. prepared figures; J.C. and L.I.S. drafted manuscript; J.C. and L.I.S. edited and revised manuscript; J.C., Z.G., C.A.B., M.D.H., J.L.M., and L.I.S. approved final version of manuscript.

ACKNOWLEDGMENTS

We are grateful to Marc Kaufman for suggestions in the study design. We are grateful to Jennifer L. Stoner for secretarial help in preparing this manuscript.

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